Modified peptide nucleic acid compositions

Abstract

The present disclosure relates to compounds that are useful for detecting or modulating target nucleic acids, including DNA and RNA.The present disclosure also relates to the method for treating trinucleotide repeat disorders, which can comprise administering the oligonucleotide analogue that can bind to the pathogenic nucleotide repeat in DNA or RNA.In some embodiments, the present disclosure provides a method for treating a condition in a subject, comprising administering to the subject a therapeutically effective amount of any compound of the present disclosure.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 002,326, filed March 30, 2020, which is hereby incorporated by reference in its entirety. [Background technology]

[0002] background Huntington's disease (HD) is a neurodegenerative genetic disorder caused by mutations in the huntingtin (HTT) gene, which is thought to be important for many essential cellular activities. People with HD lose neurons in their brains over time, often due to the toxic buildup of defective HTT protein in their cells. While current treatment options act to attenuate an individual's motor and psychiatric symptoms, no treatment for HD can slow or halt disease progression.

[0003] INCORPORATION BY REFERENCE All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. Summary of the Invention [Means for solving the problem]

[0004] Summary of the Invention In some embodiments, the disclosure provides compounds comprising a chain, the chain comprising a series of atoms connected to form the chain, wherein the atoms connected to form the chain are each independently substituted with a substituent having a guanidino group, the chain having a pattern of one atom independently substituted with a substituent having a guanidino group, followed by five consecutive atoms that are not substituted with a substituent having a guanidino group, followed by a second atom independently substituted with a substituent having a guanidino group, followed by another five consecutive atoms that are not substituted with a substituent having a guanidino group, followed by a third atom independently substituted with a substituent having a guanidino group, and wherein the first end of the chain or the second end of the chain is substituted with a peptide.

[0005] In some embodiments, the present disclosure provides a compound comprising a peptide nucleic acid sequence and a cell permeabilizing group attached to the peptide nucleic acid sequence, wherein when a radiolabeled analog of the compound is subjected to an assay, the assay: (a) a first component comprising: (i) administering a 5 mg / kg intravenous bolus dose of the radiolabeled analogue into the tail vein of a male cynomolgus monkey; (ii) euthanizing the monkey 4 hours after the administering step; (iii) after (ii), freezing the monkey in a mixture of hexane and solid carbon dioxide for at least 2 hours to provide a frozen carcass; (iv) embedding the frozen cadaver left side up in 2% w / v aqueous carboxymethylcellulose sodium solution to provide an embedded cadaver; (v) cutting the embedded carcasses into 40 μm sagittal whole-body sections by cryomacrotome; (vi) mounting 40 μm sagittal whole-body sections onto pressure-sensitive tape; (vii) after (vi), dehydrating the whole-body sections in a cryomacrotome at about −20° C. for about 60 hours; (viii) after (vii), placing the whole-body section on a carbon-14 sensitive imaging plate for a period not exceeding four days; (ix) after (viii), scanning the image plate with a phosphor imager system; and (x) after (ix), determining the concentration of the radiolabeled analog in brain tissue of the whole-body section; and a first component containing (b) a second component similar to the first component, except that a second monkey was used that was euthanized 168 hours after the administering step; Including, The radiolabeled analogue 14 the compound comprises an N-terminus substituted by a C-enriched glycine residue, and the radiolabeled analog is 14 which differs structurally from the compound only in that it lacks a C-enriched glycine residue, In this case, a compound is provided in which the concentration of the radiolabeled analog in brain tissue determined in the second component of the assay is equivalent to at least about 80% of the concentration of the radiolabeled analog in brain tissue determined in the first component.

[0006] In some embodiments, the disclosure provides a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence comprises: (i) a series of peptide nucleic acid residues having triplet repeats of nucleobase side chains; and (ii) a cell-permeabilizing group attached to the series of peptide nucleic acid residues, wherein when the compound is subjected to an assay, the assay: (a) administering to a mouse a compound at a dose of about 0.1 mg / kg to about 2 mg / kg by intracerebroventricular administration; (b) euthanizing the mice at a time point between approximately 1 hour and 28 days after intracerebroventricular administration; (c) collecting brain tissue from the mouse after euthanasia; and (d) Determining the concentration of ATP in mouse brain tissue using liquid chromatography-tandem mass spectrometry. wherein in the assay, a mean peak brain concentration is observed in mice from about 1 hour to about 50 hours after administration, and the mean peak brain concentration in the mice is observed to be between about 3000 ng / mL and about 22000 ng / mL. A compound is provided.

[0007] In some embodiments, the disclosure provides a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence comprises: (i) a series of peptide nucleic acid residues having triplet repeats of nucleobase side chains; and (ii) a cell-permeabilizing group attached to the series of peptide nucleic acid residues, wherein when the compound is subjected to an assay, the assay provides: (a) administering to a mouse a compound at a dose of about 0.1 mg / kg to about 1.5 mg / kg by intracerebroventricular administration; (b) collecting blood samples from the vena cava of the mice at time points between about 1 hour and 28 days after intracerebroventricular administration; (c) collecting the blood sample, followed by euthanizing the mouse at a time point between about 1 hour and 28 days after intracerebroventricular administration; (d) collecting brain, intestine, liver, lung, kidney, or muscle tissue from the mouse after euthanasia; and (e) determining the concentration of the compound in the collected brain, intestine, liver, lung, kidney, or muscle tissue using liquid chromatography-tandem mass spectrometry; and (f) determining the concentration of the compound in plasma from blood samples collected from the mice using liquid chromatography-tandem mass spectrometry; wherein in an assay, the compound is observed to accumulate in the brain of the mouse for up to about one month after the administering step, and the compound is not detected at detectable levels in the plasma, intestine, liver, lung, kidney, or muscle tissue of the mouse during that one month period. A compound is provided.

[0008] In some embodiments, the disclosure provides a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence comprises: (i) a series of peptide nucleic acid residues having triplet repeats of nucleobase side chains; and (ii) a cell-permeabilizing group attached to the series of peptide nucleic acid residues, wherein when the compound is subjected to a plasma protein binding assay, the plasma protein binding assay indicates: (a) conducting a human component of a plasma protein binding assay, the human component of the plasma protein binding assay comprising: (1) spiking a single aliquot of human plasma with a first solution of a compound at 10 mg / mL to obtain at least a second solution of the compound having a concentration of about 1 μg / mL to about 50 μg / mL; (2) using ultracentrifugation of the at least second solution of the compound to separate a mixture containing the compound bound to plasma proteins; and (3) determining the percentage of plasma protein binding in the human plasma using liquid chromatography-tandem mass spectrometry; (b) performing a murine component of a plasma protein binding assay, the murine component of the plasma protein binding assay differing from the human component of the plasma protein binding assay only in that mouse plasma is used instead of human plasma; (c) performing a canine component of a plasma protein binding assay, the canine component of the plasma protein binding assay differing from the human component of the plasma protein binding assay only in that canine plasma is used instead of human plasma; (d) performing a minipig component of a plasma protein binding assay, the minipig component of the plasma protein binding assay differing from the human component of the plasma protein binding assay only in that minipig plasma is used instead of human plasma; (e) performing an ovine component of a plasma protein binding assay, the ovine component of the plasma protein binding assay differing from the human component of the plasma protein binding assay only in that ovine plasma is used instead of human plasma; and (f) performing a monkey component of the plasma protein binding assay, the monkey component of the plasma protein binding assay differing from the human component of the plasma protein binding assay only in that monkey plasma is used instead of human plasma; wherein the compound has a plasma protein binding percentage of at least about 85% in a plasma protein binding assay in humans, mice, dogs, minipigs, sheep, or monkeys.

[0009] In some embodiments, the present disclosure provides a compound having formula (I): [ka] During the ceremony: - each B is independently a nucleobase; - Each R 1 are independently the side chain of a natural amino acid, guanidino(C1-C4) alkyl, or hydrogen; - Each R 2 are independently the side chain of a natural amino acid, guanidino(C1-C4) alkyl, or hydrogen; -R 5 is a sequence comprising at least one alpha amino acid residue, beta amino acid residue, gamma amino acid residue, or combination thereof; hydrogen; or a water-solubilizing group; - n is an integer from 3 to 30; - G is OH, NH2, or [ka] and During the ceremony; -R 3 is hydrogen or amino(C1-C4)alkyl; -R 4 is a sequence comprising at least one alpha amino acid residue, beta amino acid residue, gamma amino acid residue, or combination thereof; or is hydrogen; - m is 0 or 1; containing at least one guanine-cytosine-thymine sequence, The present invention provides a compound, or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, the present disclosure provides a method of treating a condition in a subject, the method comprising administering to the subject a therapeutically effective amount of any compound of the present disclosure. [Brief explanation of the drawings]

[0011] [Figure 1] FIG. 1 illustrates the cumulative excretion of radioactivity following a single intravenous bolus administration of [ 14 C]-Compound 1 at 5 mg / kg to male cynomolgus monkeys (Animal 103).

[0012] [Figure 2] FIG. 2 illustrates the individual blood and plasma profiles of total radioactivity following a single intravenous bolus administration of [C]-Compound 1 at 5 mg / kg to male cynomolgus monkeys: Animal 101 (4 hours post-dose, panel A), Animal 102 (12 hours post-dose, panel B), Animal 103 (24 hours post-dose, panel C), and Animal 103 (168 hours post-dose, panel D).

[0013] [Figure 3] FIG. 3 illustrates the concentration of total radioactivity in representative organs and tissues at various times following a single intravenous bolus administration of [ 14 C]-Compound 1 at 5 mg / kg to male cynomolgus monkeys.

[0014] [Figure 4] FIG. 4 illustrates the concentration of total radioactivity in representative organs and tissues at various times following a single intravenous bolus administration of [ 14 C]-Compound 1 at 5 mg / kg to male cynomolgus monkeys.

[0015] [Figure 5] FIG. 5 illustrates the tissue to blood ratios at various times following a single intravenous bolus administration of [ 14 C]-Compound 1 at 5 mg / kg to male cynomolgus monkeys.

[0016] [Figure 6] FIG. 6 illustrates the tissue to blood ratios at various times following a single intravenous bolus administration of [ 14 C]-Compound 1 at 5 mg / kg to male cynomolgus monkeys.

[0017] [Figure 7A] Figures 7A and 7B are autoradiographs showing representative tissue distribution of total radioactivity in parasagittal sections of animal 101 after a single intravenous bolus dose of 5 mg / kg of [C]-Compound 1. Any gray signal above background indicates the presence of compound in the tissue. [Figure 7B] Same as above.

[0018] [Figure 8A] Figures 8A and 8B are autoradiographs showing representative tissue distribution of total radioactivity in sagittal sections of animal 101 after a single intravenous bolus dose of 5 mg / kg of [C]-Compound 1. Any gray signal above background indicates the presence of compound in the tissue. [Figure 8B] Same as above.

[0019] [Figure 9A] Figures 9A and 9B are autoradiographs showing representative tissue distribution of total radioactivity in sagittal sections of animal 101 after a single intravenous bolus dose of 5 mg / kg of [C]-Compound 1. Any gray signal above background indicates the presence of compound in the tissue. [Figure 9B] Same as above.

[0020] [Figure 10A]Figures 10A and 10B are autoradiographs showing representative tissue distribution of total radioactivity in sagittal sections of animal 101 after a single intravenous bolus dose of 5 mg / kg of [C]-Compound 1. Any gray signal above background indicates the presence of compound in the tissue. [Figure 10B] Same as above.

[0021] [Figure 11] Figure 11 is an autoradiograph showing representative tissue distribution of total radioactivity in a midsagittal section of animal 101 after a single intravenous bolus dose of 5 mg / kg of [C]-Compound 1. Any gray signal above background indicates the presence of compound in the tissue.

[0022] [Figure 12A] Figures 12A and 12B are autoradiographs showing representative tissue distribution of total radioactivity in sagittal sections of Animal 101 (4 hours after administration), Animal 102 (12 hours after administration), and Animal 103 (7 days after administration) following a single intravenous bolus dose of 5 mg / kg of [C]-Compound 1. Any gray signal above background indicates the presence of compound in the tissue. [Figure 12B] Same as above.

[0023] [Figure 13] Figure 13 is an autoradiograph showing representative cranial tissue distribution of total radioactivity in selected sagittal sections of Animal 101 (4 hours post-dose), Animal 102 (12 hours post-dose), and Animal 103 (7 days post-dose) following a single intravenous bolus dose of 5 mg / kg of [C]-Compound 1. Any gray signal above background indicates the presence of compound in the tissue.

[0024] [Figure 14]Figure 14 is an autoradiograph showing representative pelvic region tissue distribution of total radioactivity in selected sagittal sections of Animal 101 (4 hours post-dose), Animal 102 (12 hours post-dose), and Animal 103 (7 days post-dose) after a single intravenous bolus dose of 5 mg / kg of [C]-Compound 1. Any gray signal above background indicates the presence of compound in the tissue.

[0025] [Figure 15A] Figure 15A illustrates the mean brain concentration versus time profile of Compound 1 in C57BL6J mice administered a dose of 0.3 mg / kg, Figure 15B illustrates the mean brain concentration versus time profile of Compound 1 in mice administered a dose of 0.6 mg / kg, and Figure 15C illustrates the mean brain concentration versus time profile of Compound 1 in C57BL6J mice administered a dose of 1 mg / kg. [Figure 15B] Same as above. [Figure 15C] Same as above.

[0026] [Figure 16A] Figure 16A illustrates the mean spleen concentration versus time profile of Compound 1 in C57BL6J mice administered a dose of 0.3 mg / kg, Figure 16B illustrates the mean spleen concentration versus time profile of Compound 1 in mice administered a dose of 0.6 mg / kg, and Figure 16C illustrates the mean spleen concentration versus time profile of Compound 1 in C57BL6J mice administered a dose of 1 mg / kg. [Figure 16B] Same as above. [Figure 16C] Same as above.

[0027] [Figure 17] FIG. 17 illustrates the mean cardiac concentration versus time profile of Compound 1 in C57BL6J mice administered a dose of 0.3 mg / kg.

[0028] [Figure 18A]Figure 18A illustrates the mean brain, spleen, and heart concentrations versus time profile of Compound 1 in C57BL6J mice administered a dose of 0.3 mg / kg, Figure 18B illustrates the mean brain, spleen, and heart concentrations versus time profile of Compound 1 in C57BL6J mice administered a dose of 0.6 mg / kg, and Figure 18C illustrates the mean brain, spleen, and heart concentrations versus time profile of Compound 1 in C57BL6J mice administered a dose of 1 mg / kg. [Figure 18B] Same as above. [Figure 18C] Same as above.

[0029] [Figure 19A] FIG. 19A shows the relative expression of wtHTT (dark bars) and mHTT (light bars) by GM09197 cells after treatment with 1 or 5 μM of Compound 2.

[0030] [Figure 19B] FIG. 19B shows the relative expression of wtHTT (dark bars) and mHTT (light bars) by GM09197 cells after treatment with 1 or 5 μM of Compound 3.

[0031] [Figure 19C] Figure 19C shows the relative expression of wtHTT (dark bars) and mHTT (light bars, not visible) by GM09197 cells after treatment with 1 or 5 μM of compound 4. The mHTT bar is not visible because mHTT was below the detection limit.

[0032] [Figure 20A] FIG. 20A shows the results of a cytotoxicity assay assessing the percent of dead GM09197 cells present after mock treatment (PBS, control) or treatment with 1 or 5 μM of Compound 2.

[0033] [Figure 20B]FIG. 20B shows the results of a cytotoxicity assay assessing the percent of dead GM09197 cells present after mock treatment (PBS, control) or treatment with 1 or 5 μM of Compound 3.

[0034] [Figure 20C] FIG. 20C shows the results of a cytotoxicity assay assessing the percent of dead GM09197 cells present after mock treatment (PBS, control) or treatment with 1 or 5 μM of Compound 4.

[0035] [Figure 21A] Figure 21A shows the structural formula of Compound 1. Figure 21B shows the structural formula of [14C] Compound 1. [Figure 21B] Same as above.

[0036] [Figure 22A] Figure 22A shows the structural formula of Compound 2. Figure 22B shows the structural formula of Compound 4. [Figure 22B] Same as above.

[0037] [Figure 23] FIG. 23 shows the structural formula of compound 3. DETAILED DESCRIPTION OF THE INVENTION

[0038] Detailed Description Huntington's disease (HD) is a genetic disorder associated with abnormally long CAG repeat expansions in the huntingtin gene (HTT), which encodes the huntingtin protein (HTT). HTT gene repeats exceeding a certain threshold produce mutant huntingtin protein (mHTT), which can induce pathological changes in the central nervous system. The risk, penetrance, and age of disease onset can be correlated with the length of the HTT repeat expansion. CAG triads with fewer than 27 repeats are associated with a normal phenotype, whereas repeats of 27-35 generally confer a normal phenotype but increase the risk of disease in offspring. Repeats of 36-39 are associated with incomplete or reduced penetrance, with disease symptoms manifesting later in adulthood. Repeat lengths greater than 40 confer complete penetrance, while repeats greater than 60 result in disease that can manifest in early childhood. Compounds of the Disclosure

[0039] The present disclosure relates to compounds that are useful for detecting or modulating target nucleic acids, including DNA and RNA.The present disclosure also relates to the method for treating trinucleotide repeat disorders, which can comprise administering oligonucleotide analogs that can bind to the pathogenic nucleotide repeats in DNA or RNA.In some embodiments, the compound of the present disclosure binds to the CAG repeats in the mutant mHTT transcript present in Huntington's disease, thereby modulating the expression of mHTT protein.

[0040] In some embodiments, the present disclosure provides a compound comprising a chain. The chain can include a series of atoms connected to form a chain. The atoms connected to form the chain can be independently substituted with a substituent having a polar group, which can be, for example, a guanidino group. The chain can have a pattern in which one atom is independently substituted with a substituent having a polar group, followed by five consecutive atoms that are not substituted with a substituent having a polar group, followed by a second atom that is independently substituted with a substituent having a polar group, followed by another five consecutive atoms that are not substituted with a substituent having a polar group, followed by a third atom that is independently substituted with a substituent having a polar group.

[0041] In some embodiments, the chain has a pattern of one atom independently substituted with a substituent having a polar group (e.g., a guanidino group), followed by 17 consecutive atoms not substituted with a substituent having a polar group, followed by a second atom independently substituted with a substituent having a polar group, followed by another 17 consecutive atoms not substituted with a substituent having a polar group, followed by a third atom independently substituted with a substituent having a polar group. In some embodiments, the third atom independently substituted with a substituent having a polar group (e.g., a guanidino group) is followed by 11 consecutive atoms not substituted with a substituent having a polar group, followed by a fourth atom independently substituted with a substituent having a polar group. In some embodiments, the fourth atom independently substituted with a substituent having a polar group is followed by another 11 consecutive atoms not substituted with a substituent having a polar group. In some embodiments, the first atom, second atom, and third atom are each gamma carbons of the peptide nucleic acid oligomer. In some embodiments, the first atom, the second atom, and the third atom are each an alpha carbon of the peptide nucleic acid oligomer.

[0042] In some embodiments, the chain consists of one atom independently substituted with a substituent having a polar group (e.g., a guanidino group), followed by 11 consecutive atoms that are not substituted with a substituent having a polar group, followed by a second atom independently substituted with a substituent having a polar group, followed by another 11 consecutive atoms that are not substituted with a substituent having a polar group, followed by a third atom independently substituted with a substituent having a polar group.

[0043] Suitable polar groups may include groups that have a formal charge at physiological pH, such as a guanidino group. In some embodiments, each substituent having a guanidino group is independently guanidinoalkyl. In some embodiments, each substituent having a guanidino group is independently guanidino(C1-C4)alkyl. In some embodiments, each substituent having a guanidino group is 2-guanidino-eth-1-yl. In some embodiments, each substituent having a guanidino group is 3-guanidino-prop-1-yl. In some embodiments, each substituent having a guanidino group is 4-guanidino-but-1-yl.

[0044] The compound of the present disclosure can comprise nucleobase or nucleobase analogue.In some embodiments, the pattern can comprise: one atom that is independently substituted by the substituent with the first nucleobase, followed by five consecutive atoms that are not substituted by the substituent with the nucleobase, followed by a second atom that is independently substituted by the substituent with the second nucleobase, followed by another five consecutive atoms that are not substituted by the substituent with the nucleobase, followed by a third atom that is independently substituted by the substituent with the third nucleobase.

[0045] In some embodiments, the substituent with the first nucleobase, the substituent with the second nucleobase, and the substituent with the third nucleobase are each independently purinyl acyl, purinyl alkylene, pyrimidinyl acyl, or pyrimidinyl alkylene.In some embodiments, the substituent with the first nucleobase, the substituent with the second nucleobase, and the substituent with the third nucleobase are each independently guanidinyl acyl, adeninyl acyl, cytosinyl acyl, thyminyl acyl, or uracilyl acyl.In some embodiments, the first nucleobase, the second nucleobase, and the third nucleobase form the sequence CTG, TGC, or GCT.

[0046] In some embodiments, compounds of the present disclosure may be resistant to degradation by enzymes (e.g., nucleases or proteases). In some embodiments, compounds may be stable in a subject. In some embodiments, compounds of the present disclosure may be water soluble. In some embodiments, compounds may be endocytosed by cells containing the compound's target sequence. In some embodiments, compounds are endocytosed, pinocytosed, or phagocytosed in cells that do not contain the target sequence. In some embodiments, compounds are transcytosed across the endothelial lining of cerebral blood vessels or the "blood-brain barrier." peptide nucleic acid

[0047] The peptide nucleic acid analogs of the present disclosure and their pharmaceutically acceptable salts. In some embodiments, the compound comprises a peptide nucleic acid domain. Peptide nucleic acids are oligonucleotide analogs comprising a chain of repeating N-(2-aminoethyl)-glycine units linked by peptide bonds, and the glycyl nitrogen of one or more units is functionalized with an alkylene or acyl group bearing a nucleic acid base. Peptide nucleic acids can optionally include substitutions on the N-(2-aminoethyl)-glycine backbone, for example: [ka] In the formula, the substituent R α , R β , R γare alpha, beta, and gamma substituents, respectively. In some embodiments, the peptide nucleic acid chain is substituted with a polar group, such as a group containing a guanidino moiety. The polar group can be attached to the alpha or gamma position of at least one peptide nucleic acid subunit.

[0048] The compounds (e.g., peptide nucleic acids) of the present disclosure may comprise a chain of atoms with substituted or unsubstituted termini. For example, the first terminus of the chain and the second terminus of the chain may each independently be unsubstituted or substituted by an amino acid. For example, the first terminus of the chain and the second terminus of the chain may each independently be unsubstituted or substituted by a peptide. In some embodiments, the compound is a peptide nucleic acid oligomer, and the first terminus of the chain is the N-terminus of the peptide nucleic acid oligomer, and the second terminus of the chain is the C-terminus of the peptide nucleic acid oligomer. In some embodiments, the C-terminus of the peptide nucleic acid oligomer is linked by a peptide bond to a peptide that may be, for example, a sequence containing alpha amino acid residues, beta amino acid residues, gamma amino acid residues, or a combination thereof. In some embodiments, the C-terminus of the peptide nucleic acid oligomer is linked by a peptide bond to an amidated lysine. In some embodiments, the C-terminus of the peptide nucleic acid oligomer is linked by a peptide bond to an amidated beta lysine.

[0049] In some embodiments, the C-terminus or N-terminus of the peptide nucleic acid is substituted with a cell-permeabilizing group. In some embodiments, the cell-permeabilizing group is a polypeptide containing 3 to 8 lysine residues. In some embodiments, the polypeptide is linked to the peptide nucleic acid via an amide bond. In some embodiments, the polypeptide is linked to the peptide nucleic acid via a peptide bond, a disulfide bond, or a linker containing two penicillamine residues linked by a disulfide bond.

[0050] In some embodiments, the compound may contain 4 to 10 guanidino groups. In some embodiments, the compound may contain 6 to 8 guanidino groups. In some embodiments, the compound may contain 7 to 9 guanidino groups. In some embodiments, the compound may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more guanidino groups. Each of the three guanidino groups can independently bind to a peptide nucleic acid chain. In some embodiments, the group containing the guanidino moiety is a 4-guanidino-but-1-yl group, a 3-guanidino-prop-1-yl group, or a 2-guanidino-eth-1-yl group. In some embodiments, the sequence of the peptide nucleic acid domain is (GCT) n wherein n is 1 to 10. In some embodiments, the sequence of the peptide nucleic acid domain is the domain (GCT)6G. In some embodiments, the sequence of the peptide nucleic acid domain is GCTGCT. In some embodiments, the sequence of the peptide nucleic acid domain is CTGCTG.

[0051] In some embodiments, compounds of the present disclosure may include a moiety that improves the cell permeability of the compound compared to an otherwise identical molecule without the moiety, e.g., compounds of the present disclosure may reach intracellular targets in the cytoplasm or nucleus.

[0052] In some embodiments, the present disclosure provides a compound comprising a pharmacophore region bound to a plurality of positively charged regions, the compound comprising: a) the pharmacophore region comprises several peptide nucleic acid residues, and the number of peptide nucleic acid residues is at least 7 and not a multiple of 3; b) each peptide nucleic acid residue of the pharmacophore region independently comprises a backbone moiety and a side chain moiety attached to the backbone moiety; c) none of the backbone moieties of the peptide nucleic acid residues in the pharmacophore region bear a positive formal charge at neutral pH; d) each side chain moiety independently has a nucleobase; e) the nucleobases of each side chain moiety collectively form a sequence; f) the sequence is complementary to a naturally occurring human nucleic acid sequence associated with Huntington's disease; g) the sequence comprises a subsequence of cytosine-thymine-guanine-cytosine-thymine-guanine; and h) the plurality of positively charged regions comprises at least six consecutive building blocks, each of the consecutive building blocks independently comprising a side chain having a formal positive charge at neutral pH; A compound is provided.

[0053] In some embodiments, the present disclosure provides a compound represented by the structure of Formula (I): [ka] During the ceremony, - each B is independently a nucleobase; - Each R 1 are independently the side chain of a natural amino acid, guanidino(C1-C4) alkyl, or hydrogen; - Each R 2 are independently the side chain of a natural amino acid, guanidino(C1-C4) alkyl, or hydrogen; -R 5 is a sequence comprising at least one alpha amino acid residue, beta amino acid residue, gamma amino acid residue, or combination thereof; hydrogen; or a water-solubilizing group; - n is an integer from 3 to 30; - G is OH, NH2, or [ka] and; During the ceremony, -R 3 is hydrogen or amino(C1-C4)alkyl; -R 4 is a sequence comprising at least one alpha amino acid residue, beta amino acid residue, gamma amino acid residue, or combination thereof; or is hydrogen; - m is 0 or 1; containing at least one guanine-cytosine-thymine sequence, The present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a radiolabeled derivative thereof.

[0054] In some embodiments, each nucleobase B is independently guanine, thymine, or cytosine. In some embodiments, B is guanine. In some embodiments, B is thymine. In some embodiments, B is cytosine. In some embodiments, B is adenine. In some embodiments, B is uracil. In some embodiments, each nucleobase B is an analog of a naturally occurring nucleobase.

[0055] In some embodiments, at least one R 1 is guanidino(C-C)alkyl. In some embodiments, more than one R 1 is guanidino(C-C)alkyl. In some embodiments, at least one out of every two R 1 is guanidino(C-C)alkyl. In some embodiments, at least one third R 1 is guanidino(C-C)alkyl. In some embodiments, at least every two or every three R 1 is guanidino(C-C)alkyl. In some embodiments, each R 1 is guanidino(C-C)alkyl. In some embodiments, at least one R 1 is 4-guanidinobuta-1-yl. In some embodiments, at least one R 1 is 3-guanidinoprop-1-yl. In some embodiments, at least one R 1 is 2-guanidino-eth-1-yl. In some embodiments, at least one R 1 is hydrogen. In some embodiments, each R 1 is hydrogen.

[0056] In some embodiments, at least one R 2 is guanidino(C-C)alkyl. In some embodiments, more than one R 2is guanidino(C-C)alkyl. In some embodiments, at least one out of every two R 2 is guanidino(C-C)alkyl. In some embodiments, at least one in three R 2 is guanidino(C-C)alkyl. In some embodiments, at least every two or every three R 2 is guanidino(C-C)alkyl. In some embodiments, each R 2 is guanidino(C-C)alkyl. In some embodiments, at least one R 2 is 4-guanidinobuta-1-yl. In some embodiments, at least one R 2 is 3-guanidinoprop-1-yl. In some embodiments, at least one R 2 is 2-guanidino-eth-1-yl. In some embodiments, at least one R 2 is hydrogen. In some embodiments, each R 2 is hydrogen.

[0057] In some embodiments, G is [ka] is.

[0058] In some embodiments, R 5 is a water-solubilizing group. In some embodiments, the water-solubilizing group is a plurality of positively charged regions comprising at least six consecutive building blocks. In some embodiments, each consecutive building block independently comprises a side chain that has a formal positive charge at neutral pH.

[0059] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is amino(C1-C4)alkyl. In some embodiments, R 3 is 4-aminobut-1-yl. In some embodiments, R 3is 3-aminoprop-1-yl. In some embodiments, m is 0. In some embodiments, m is 1.

[0060] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is a sequence comprising at least one alpha amino acid residue. 4 is a sequence comprising at least one beta amino acid residue. 4 is a sequence comprising at least one gamma amino acid residue. 4 teeth, [ka] and During the ceremony, - p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; - Each R 6 are independently hydrogen or amino(C1-C4)alkyl.

[0061] In some embodiments, R 4 teeth, [ka] is.

[0062] In some embodiments, p is 3, 4, 5, 6, 7, or 8. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6. In some embodiments, p is 7. In some embodiments, p is 8.

[0063] In some embodiments, R 5 is hydrogen.

[0064] In some embodiments, R 5 teeth, [ka] and During the ceremony, - Each R 7 are independently the side chains of natural amino acids; - q is 0 or 1.

[0065] In some embodiments, R 7 is the side chain of an alpha amino acid. In some embodiments, R 7 is the side chain of a beta amino acid. 7 is the side chain of a gamma amino acid. In some embodiments, q is 0. In some embodiments, q is 1.

[0066] In some embodiments, R 5 teeth, [ka] is.

[0067] In some embodiments, R 5 teeth, [ka] is.

[0068] In some embodiments, the water-solubilizing group comprises a structure that has multiple formal charges at physiological pH. 5 are the formal charges that are positive.

[0069] In some embodiments, when G is OH or NH, R 1 and R 2 at least one of R is a side chain of a natural amino acid or guanidino(C1-C4) alkyl; 5 is not hydrogen.

[0070] In some embodiments, R 1 and R 2 are both hydrogen, then G is [ka] is.

[0071] In some embodiments, R 1 and R 2 are both hydrogen, then G is [ka] and R 5 is a sequence containing at least one alpha amino acid residue.

[0072] In some embodiments, the compound has the following formula: [ka] It has.

[0073] In some embodiments, n is 6. In some embodiments, at least one R 1 is 4-guanidinobuta-1-yl. In some embodiments, each R 1 is 4-guanidinobuta-1-yl. In some embodiments, at least one R 2 is hydrogen. In some embodiments, each R 2 is hydrogen. In some embodiments, R 3 is 4-aminobut-1-yl. In some embodiments, R 3 is 3-aminoprop-1-yl. In some embodiments, R 4 is hydrogen. In some embodiments, R 5 is hydrogen. In some embodiments, R 5 teeth, [ka] is.

[0074] In some embodiments, the compound has the formula: [ka] and During the ceremony, - Each B1a , B 2a and B 3a are independently cytosine, guanine, or thymine; -n 1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0075] In some embodiments, n 1 is 2. In some embodiments, the compound comprises the sequence (CTG)2. In some embodiments, at least one R 1 is 4-guanidinobuta-1-yl. In some embodiments, each R 1 is 4-guanidinobuta-1-yl. In some embodiments, at least one R 1 is hydrogen. In some embodiments, R 3 is 4-aminobut-1-yl. In some embodiments, R 3 is 3-aminoprop-1-yl.

[0076] In some embodiments, the compound has the formula: [ka] It has.

[0077] In some embodiments, B 1a is cytosine, and B 2a is thymine, and B 3a is guanine. 1 is 2.

[0078] In some embodiments, the compound has the formula: [ka] It has.

[0079] In some embodiments, the compound has the formula: [ka] It has.

[0080] In some embodiments, n is 6. In some embodiments, the compound comprises the sequence (CTG)2. In some embodiments, at least one R 1 is 4-guanidinobuta-1-yl. In some embodiments, each R 1 is 4-guanidinobuta-1-yl. In some embodiments, at least one R 1 is hydrogen. In some embodiments, R 3 is 4-aminobut-1-yl. In some embodiments, R 3 is 3-aminoprop-1-yl.

[0081] In some embodiments, the compound has the formula: [ka] and During the ceremony, - Each B 1b , B 2b and B 3b are independently cytosine, guanine, or thymine; -n 2 is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0082] In some embodiments, n 2 is 2. In some embodiments, R 1 is 4-guanidinobuta-1-yl. In some embodiments, R 3 is 4-aminobut-1-yl. In some embodiments, R 3 is 3-aminoprop-1-yl.

[0083] In some embodiments, the compound has the formula: [ka] It has.

[0084] In some embodiments, B 1b is cytosine, and B 2b is thymine, and B3b is guanine. In some embodiments, n 2 is 2.

[0085] In some embodiments, the compound has the formula: [ka] It has.

[0086] In some embodiments, the compound has the formula: [ka] It has.

[0087] In some embodiments, the compound has the formula: [ka] and During the ceremony, - p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; - Each R 6 are independently hydrogen or amino(C1-C4)alkyl.

[0088] In some embodiments, n is 10. In some embodiments, n is 11. In some embodiments, n is 12. In some embodiments, n is 13. In some embodiments, n is 14. In some embodiments, n is 15. In some embodiments, n is 16. In some embodiments, n is 17. In some embodiments, n is 18. In some embodiments, n is 19. In some embodiments, n is 20.

[0089] In some embodiments, at least one R 1 In some embodiments, n is greater than 1 and every other R 1 is hydrogen. In some embodiments, at least one R 1 In some embodiments, n is greater than 1 and every other R1 is 4-guanidinobuta-1-yl.

[0090] In some embodiments, at least one R 2 is hydrogen. In some embodiments, each R 2 is hydrogen. In some embodiments, at least one R 2 is 4-guanidinobuta-1-yl. In some embodiments, every other R 2 is 4-guanidinobuta-1-yl.

[0091] In some embodiments, R 3 is 4-aminobut-1-yl. In some embodiments, R 3 is 3-aminoprop-1-yl.

[0092] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 teeth, [ka] and During the ceremony, p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0093] In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6. In some embodiments, p is 7. In some embodiments, p is 8.

[0094] In some embodiments, R 5 is hydrogen. In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] is.

[0095] In some embodiments, R 6 is 4-aminobut-1-yl. In some embodiments, R 6 is 3-aminoprop-1-yl.

[0096] In some embodiments, the compound has the formula: [ka] and During the ceremony, -R 7 is the side chain of a natural amino acid.

[0097] In some embodiments, R 7 is 4-aminobut-1-yl. In some embodiments, R 7 is 3-aminoprop-1-yl.

[0098] In some embodiments, the compound has the structure [ka] and During the ceremony, - Each B 1c , B 2c , B 3c , and B 4c are independently cytosine, guanine, or thymine; -n 3 is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0099] In some embodiments, B 1c is guanine. In some embodiments, B 2c is cytosine. In some embodiments, B 3c is thymine. In some embodiments, B 4c is guanine.

[0100] In some embodiments, n 3 is 6.

[0101] In some embodiments, p is 7.

[0102] In some embodiments, R 3 is 4-aminobut-1-yl. In some embodiments, R 3 is 3-aminoprop-1-yl.

[0103] In some embodiments, R 6 is 4-aminobut-1-yl. In some embodiments, R 6 is 3-aminoprop-1-yl.

[0104] In some embodiments, R 7 is 4-aminobut-1-yl. In some embodiments, R 7 is 3-aminoprop-1-yl.

[0105] In some embodiments, the compound comprises a sequence that includes G(CTG)6.

[0106] In some embodiments, the compound has the structure [ka] It has.

[0107] In some embodiments, the compound has the structure [ka] It has.

[0108] In some embodiments, the compound has the structure [ka] and During the ceremony, -R 7 is the side chain of a natural amino acid.

[0109] In some embodiments, R 7is 4-aminobut-1-yl. In some embodiments, R 7 is 3-aminoprop-1-yl.

[0110] In some embodiments, the compound has the structure [ka] and During the ceremony, - X [ka] and; - Y is [ka] and; - Each B 1d , B 2d , B 3d , B 4d , B 5d , B 6d , B 7d , B 8d , B 9d , and B 10d are independently cytosine, guanine, or thymine; -n 4 is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; -n 5 is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0111] In some embodiments, B 1d is guanine. In some embodiments, B 2d is cytosine. In some embodiments, B 3d is thymine. In some embodiments, B 4d is guanine. In some embodiments, B 5d is cytosine. In some embodiments, B 6d is thymine. In some embodiments, B 7d is guanine. In some embodiments, B 8dis cytosine. In some embodiments, B 9d is thymine. In some embodiments, B 10d is guanine.

[0112] In some embodiments, n 4 is 3. In some embodiments, n 5 is 2.

[0113] In some embodiments, R 3 is 4-aminobut-1-yl. In some embodiments, at least one R 1 is 4-guanidinobuta-1-yl. In some embodiments, each R 1 is 4-guanidinobuta-1-yl.

[0114] In some embodiments, R 3 is 4-aminobut-1-yl. In some embodiments, R 3 is 3-aminoprop-1-yl. In some embodiments,

[0115] In some embodiments, R 7 is 4-aminobut-1-yl. In some embodiments, R 7 is 3-aminoprop-1-yl.

[0116] In some embodiments, the compound has the structure: [ka] and During the ceremony, X 1 teeth, [ka] and; Y 1 teeth, [ka] is.

[0117] In some embodiments, the compound has the structure: [ka] and During the ceremony, X 2 teeth, [ka] and; Y 2 teeth, [ka] is.

[0118] In some embodiments, the compound has the structure: [ka] and During the ceremony, - L [ka] and; - M is [ka] and; - Each B 1e , B 2e , B 3e , B 4e , B 5e , B 6e , B 7e , B 8e , B 9e , and B 10e are independently cytosine, guanine, or thymine; -n 6 is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; -n 7 is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0119] In some embodiments, B1e is guanine. In some embodiments, B 2e is cytosine. In some embodiments, B 3e is thymine. In some embodiments, B 4e is guanine. In some embodiments, B 5e is cytosine. In some embodiments, B 6e is thymine. In some embodiments, B 7e is guanine. In some embodiments, B 8e is cytosine. In some embodiments, B 9e is thymine. In some embodiments, B 10e is guanine.

[0120] In some embodiments, n 6 is 3. In some embodiments, n 7 is 2.

[0121] In some embodiments, at least one R 2 is 3-guanidinoprop-1-yl. In some embodiments, each R 2 is 3-guanidinoprop-1-yl. In some embodiments, at least one R 2 is 4-guanidinobuta-1-yl. In some embodiments, each R 2 is 4-guanidinobuta-1-yl.

[0122] In some embodiments, R 3 is 4-aminobut-1-yl. In some embodiments, R 3 is 3-aminoprop-1-yl.

[0123] In some embodiments, R 7 is 4-aminobut-1-yl. In some embodiments, R 7 is 3-aminoprop-1-yl.

[0124] In some embodiments, the compound has the structure: [ka] and During the ceremony, L 1 teeth, [ka] and; M 1 teeth, [ka] is.

[0125] In some embodiments, the compound has the structure: [ka] and During the ceremony, L 2 teeth, [ka] and; M 2 teeth, [ka] is. chemical group

[0126] Each chemical group disclosed herein may be unsubstituted or substituted. Non-limiting examples of optional substituents include hydroxyl groups, sulfhydryl groups, halogens, amino groups, nitro groups, nitroso groups, cyano groups, azide groups, sulfoxide groups, sulfone groups, sulfonamide groups, carboxyl groups, carboxaldehyde groups, imine groups, alkyl groups, halo-alkyl groups, alkenyl groups, halo-alkenyl groups, alkynyl groups, halo-alkynyl groups, alkoxy groups, aryl groups, aryloxy groups, aralkyl groups, arylalkoxy groups, heterocyclyl groups, acyl groups, hydrocarbyl groups, acyloxy groups, carbamate groups, amide groups, and ester groups.

[0127] Non-limiting examples of alkyl and alkylene groups include straight-chain, branched-chain, and cyclic alkyl and alkylene groups. Alkyl groups include, for example, substituted or unsubstituted C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 , C 38 , C 39 , C 40 , C 41 , C 42 , C 43 , C 44 , C 45 , C 46 , C 47 , C 48 , C 49 , or C 50 A (C1-C4) alkyl group is an alkyl group containing between 1 and 4 carbon atoms.

[0128] Non-limiting examples of straight chain alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.

[0129] Branched chain alkyl groups include any straight chain alkyl group substituted with any number of alkyl groups. Non-limiting examples of branched chain alkyl groups include isopropyl, isobutyl, sec-butyl, and t-butyl.

[0130] Non-limiting examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. Cyclic alkyl groups also include fused, bridged, and spiro bicyclic rings, as well as higher order fused, bridged, and spiro systems. Cyclic alkyl groups can be substituted with any number of straight-chain, branched, or cyclic alkyl groups.

[0131] Non-limiting examples of alkenyl and alkenylene groups include straight-chain, branched-chain, and cyclic alkenyl groups. The olefin or olefins of the alkenyl group can be, for example, E, Z, cis, trans, terminal, or exo-methylene. The alkenyl or alkenylene group can be, for example, substituted or unsubstituted C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C53, C54, C55, C56, C57, C58, C59, C60, C61, C62, C63, C64, C65, C66, C78, ​​C79, C80, C81, C82, C83, C84, C85, C86, C87, C88, C89, C90, C91, C92, C93, C94, C95, C96, C97, C98, C99, C99, C91, C92, C93, C94, C95, C96, C97, C98, C99, C99, C109, C111, C121, C131, C132, C142, C143, C14 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 , C 38 , C 39 , C 40 , C 41, C 42 , C 43 , C 44 , C 45 , C 46 , C 47 , C 48 , C 49 , or C 50 It can be a group.

[0132] Non-limiting examples of alkynyl or alkynylene groups include straight-chain, branched-chain, or cyclic alkynyl groups. The triple bond of an alkynyl or alkynylene group can be internal or terminal. An alkynyl or alkynylene group can be, for example, a substituted or unsubstituted C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C53, C54, C55, C56, C57, C58, C59, C60, C61, C62, C63, C64, C65, C66, C78, ​​C79, C80, C81, C82, C83, C84, C85, C86, C87, C88, C89, C90, C91, C92, C93, C94, C95, C96, C97, C98, C9 ...101, C10 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 , C 38 , C 39 , C 40 , C 41 , C 42 , C 43 , C 44 , C 45 , C 46 , C 47 , C 48 , C 49 , or C 50 It can be a group.

[0133] A halo-alkyl group can be any alkyl group substituted with any number of halogen atoms, such as fluorine, chlorine, bromine, and iodine atoms. A halo-alkenyl group can be any alkenyl group substituted with any number of halogen atoms. A halo-alkynyl group can be any alkynyl group substituted with any number of halogen atoms.

[0134] An alkoxy group can be, for example, an oxygen atom substituted with any alkyl, alkenyl, or alkynyl group. An ether or ether group comprises an alkoxy group. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and isobutoxy.

[0135] The aryl group can be heterocyclic or non-heterocyclic. The aryl group can be monocyclic or polycyclic. The aryl group can be substituted with any number of substituents described herein, such as hydrocarbyl groups, alkyl groups, alkoxy groups, and halogen atoms. Non-limiting examples of aryl groups include phenyl, toluyl, naphthyl, pyrrolyl, pyridyl, imidazolyl, thiophenyl, and furyl.

[0136] An aryloxy group can be, for example, an oxygen atom substituted by any aryl group, such as phenoxy.

[0137] An aralkyl group can be, for example, any alkyl group substituted by any aryl group, such as benzyl.

[0138] An arylalkoxy group can be, for example, an oxygen atom substituted by any aralkyl group, such as benzyloxy.

[0139] Heterocycles can be any ring containing non-carbon ring atoms, such as N, O, S, P, Si, B, or any other heteroatom. Heterocycles can be substituted with any number of substituents, such as alkyl groups and halogen atoms. Heterocycles can be aromatic (heteroaryl) or non-aromatic. Non-limiting examples of heterocycles include pyrrole, pyrrolidine, pyridine, piperidine, succinamide, maleimide, morpholine, imidazole, thiophene, furan, tetrahydrofuran, pyran, and tetrahydropyran.

[0140] The acyl group can be, for example, a carbonyl group substituted with a hydrocarbyl, alkyl, hydrocarbyloxy, alkoxy, aryl, aryloxy, aralkyl, arylalkoxy, or heterocycle. Non-limiting examples of acyl include acetyl, benzoyl, benzyloxycarbonyl, phenoxycarbonyl, methoxycarbonyl, and ethoxycarbonyl.

[0141] An acyloxy group can be an oxygen atom replaced by an acyl group. An ester or ester group includes an acyloxy group. A non-limiting example of an acyloxy or ester group is acetate.

[0142] A carbamate group can be an oxygen atom substituted with a carbamoyl group, the nitrogen atom of which is unsubstituted, mono- or disubstituted with one or more of hydrocarbyl, alkyl, aryl, heterocyclyl, or aralkyl. When the nitrogen atom is disubstituted, the two substituents together with the nitrogen atom can form a heterocyclic ring.

[0143] The hydrocarbyl group can be any group consisting of carbon and hydrogen atoms and can include alkyl, alkenyl, alkynyl, and aryl groups. The hydrocarbyl group can be, for example, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 , C 38 , C 39 , C 40 , C 41 , C 42 , C 43 , C 44 , C 45 , C 46 , C 47 , C 48 , C 49 , or C 50 It can be a group.

[0144] The hydrocarbyl carbonyl group may be a carbonyl group substituted with a hydrocarbyl group, such as benzoyl, acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridencanoyl, myristoyl, pentadecenoyl, palmitoyl, heptadecanoyl, stearoyl, nondecanoyl, arachidoyl, and acyl groups derived from saturated, monounsaturated, and polyunsaturated fatty acids, such as myristoleoyl, palmitoleoyl, sapienoyl, oleoyl, elaidoyl, vaccenoyl, linoleoyl, linoleidoyl, α-linolenoyl, or arachidonoyl. The hydrocarbyl carbonyl group may be, for example, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 , C 13, C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 , C 38 , C 39 , C 40 , C 41 , C 42 , C 43 , C 44 , C 45 , C 46 , C 47 , C 48 , C 49 , or C 50 It can be a group.

[0145] The aminoalkylene group can be an alkyl group substituted with an amino group, such as aminomethyl, 2-aminoeth-1-yl, 3-aminoprop-1-yl, 2-aminoprop-1-yl, 4-aminobut-1-yl, 3-aminobut-1-yl, 2-aminobut-1-yl, 5-aminopen-1-yl, 4-aminopent-1-yl, 4-aminopent-1-yl, 3-aminopent-1-yl, 2-aminopent-1-yl, a lysine side chain, or an ornithine side chain.

[0146] The guanidinoalkylene group can be an alkyl group substituted with a guanidino group, such as guanidinomethyl, 2-guanidinoeth-1-yl, 3-guanidinoprop-1-yl, 2-guanidinoprop-1-yl, 4-guanidinobut-1-yl, 3-guanidinobut-1-yl, 2-guanidinobut-1-yl, 5-guanidinopent-1-yl, 4-guanidinopent-1-yl, 4-guanidinopent-1-yl, 3-guanidinopent-1-yl, 2-guanidinopent-1-yl, an arginine side chain, or a homoarginine side chain.

[0147] "Polypeptide," "peptide," and grammatical equivalents thereof, as used herein, refer to a polymer of amino acid residues. The polypeptides and proteins disclosed herein (including functional portions and functional variants thereof) may contain synthetic amino acids in place of one or more naturally occurring amino acids. The present disclosure contemplates both L- and D-forms of amino acid residues.

[0148] The compounds of the present disclosure can be radiolabeled. One or more atoms of the compounds of the present disclosure can be radiolabeled with a radioactive or non-radioactive isotope, e.g. 2 H, 3 H, 11 C. 13 C. 14 C, 13N, 15 N, 15 O. 17 O. 18 In one embodiment, at least one carbon of the compounds of the present disclosure may be substituted with: 14 It may be replaced by C. Treatment method

[0149] The present disclosure describes the use of compounds and methods for treating conditions or genetic diseases, including trinucleotide repeat disorders. The method may include administering a therapeutically effective amount of a compound of the present disclosure to a subject. In some embodiments, the genetic disease is a polyglutamine (polyQ) disease. Polyglutamine diseases include trinucleotide repeat disorders involving genes containing an abnormally large number of CAG repeats. In some embodiments, the polyglutamine disease is SCA1 (Spinocerebellar Ataxia Type 1), SCA2 (Spinocerebellar Ataxia Type 2), SCA3 (Spinocerebellar Ataxia Type 3 or Machado-Joseph Disease), SCA6 (Spinocerebellar Ataxia Type 6), SCA7 (Spinocerebellar Ataxia Type 7), SCA12 (Spinocerebellar Ataxia Type 12), SCA17 (Spinocerebellar Ataxia Type 17), DRPLA (Dentatorubral-Pallidoluysian Atrophy), SBMA (Spinobulbar Muscular Atrophy), or Huntington's Disease.

[0150] In some embodiments, the condition is a neurological condition. In some embodiments, the neurological condition is Huntington's disease. In some embodiments, the condition is a central nervous system condition. In some embodiments, the condition is associated with aging. In some embodiments, the condition is associated with cognitive impairment. In some embodiments, the condition is associated with memory loss. In some embodiments, the condition is associated with deterioration of motor skills.

[0151] In some embodiments, polyglutamine disease is Huntington's disease.Treatment can be administered based on the number of CAG repeats in the HTT gene of the subject.For example, the subject who is administered the compound of the present disclosure can have the HTT gene that contains more than 27 CAG repeats.In some embodiments, the HTT gene of the subject contains at least 36 repeats, at least 40 repeats, at least 50 repeats, or at least 60 repeats. In some embodiments, the HTT gene of interest contains 27-36 repeats, 27-36 repeats, 27-40 repeats, 27-60 repeats, 27-80 repeats, 27-90 repeats, 36-40 repeats, 36-60 repeats, 36-80 repeats, 36-90 repeats, 40-60 repeats, 40-80 repeats, 40-90 repeats, or 60-90 repeats.

[0152] In some embodiments, the administration of the disclosed compound does not exhibit immunogenicity.In some embodiments, the administration of the disclosed compound does not promote the production of neutralizing antibodies, cofactors, pro-inflammatory cytokines, or type 1 interferons when or after administering the compound to a subject.In some embodiments, the compound does not activate TLR9 receptor and is not presented to the immune system in MHC1 or MHCII complexes.

[0153] The compound of the present disclosure can be administered to a subject in need of a therapeutically effective amount of a compound that binds to repeat codons systemically.The subject can include bloodstream, brain, and blood-brain barrier.The compound that binds to repeat codons can enter the brain by passing from the bloodstream into the brain through the blood-brain barrier. Mode of administration

[0154] The compounds of the present disclosure or compositions comprising the compounds of the present disclosure (eg, pharmaceutical compositions) can be administered to a subject in a variety of forms and by a variety of suitable routes of administration.

[0155] The compounds of the present disclosure or compositions comprising the compounds of the present disclosure (e.g., pharmaceutical compositions) can be administered locally, for example, via injection of the compound directly into an organ, optionally in a depot or sustained release formulation or implant. The compounds of the present disclosure or compositions comprising the compounds of the present disclosure (e.g., pharmaceutical compositions) can be administered systemically.

[0156] In some embodiments, the compounds of the present disclosure or compositions (e.g., pharmaceutical compositions) comprising the compounds of the present disclosure are administered parenterally. Parenteral administration can be, for example, by bolus injection, or gradual infusion, or by perfusion over time. Administration can also be by surgical placement of a bolus or placement of a medical device.

[0157] In some embodiments, a compound of the present disclosure or a composition comprising a compound of the present disclosure (e.g., a pharmaceutical composition) is administered orally. In some embodiments, a compound of the present disclosure or a composition comprising a compound of the present disclosure (e.g., a pharmaceutical composition) is administered by intravenous, intratumoral, subcutaneous, intramuscular, intracerebral, intraventricular, intraarticular, intraperitoneal, intracranial, intrathecal, intranasal, intrabuccal, sublingual, oral, or rectal administration. In some embodiments, a compound of the present disclosure or a composition comprising a compound of the present disclosure (e.g., a pharmaceutical composition) is administered intravenously. In some embodiments, a compound of the present disclosure or a composition comprising a compound of the present disclosure (e.g., a pharmaceutical composition) is administered subcutaneously. In some embodiments, a compound of the present disclosure or a composition comprising a compound of the present disclosure (e.g., a pharmaceutical composition) is administered intraventricularly. In some embodiments, a compound of the present disclosure or a composition comprising a compound of the present disclosure (e.g., a pharmaceutical composition) is administered orally. In some embodiments, a compound of the present disclosure or a composition comprising a compound of the present disclosure (eg, a pharmaceutical composition) is administered by intrathecal administration.

[0158] Any of the above-mentioned administration routes can be combined with another administration route.For example, the compound of the present disclosure can be delivered by a first administration route, and one or more subsequent maintenance doses of the compound can be delivered by the same or different administration route.In some embodiments, the compound of the present disclosure or the composition (for example, pharmaceutical composition) comprising the compound of the present disclosure is administered by intrathecal administration, and one or more subsequent maintenance doses of the compound or the composition comprising the compound are delivered by subcutaneous administration or intravenous administration.

[0159] Non-limiting examples of suitable modes and routes of administration include oral, topical application, parenteral, intravenous injection, intravenous infusion, subcutaneous injection, subcutaneous injection, intramuscular injection, intradermal injection, intradermal injection, intraperitoneal injection, intracerebral injection, intracranial injection, intrathecal injection, intrathecal injection, intraocular injection, intraspinal injection, intrasternal injection, ocular administration, endodermal administration, topical administration, intranasal administration, intrapulmonary administration, rectal administration, intraarterial administration, intrathecal administration, inhalation, intralesional administration, intradermal administration, epidural administration, absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa), intracisternal administration, subcapsular administration, intracardiac administration, transtracheal administration, subcuticular administration, subarachnoid administration, subcapsular administration, intraspinal administration, and intrasternal administration.

[0160] The compound of the present disclosure or the composition (for example, pharmaceutical composition) comprising the compound of the present disclosure can be administered by non-invasive method.Examples of non-invasive administration modes can include needleless injection device and topical application administration, for example, eye drops.Multiple administration routes can be used for efficient delivery.

[0161] Depending on the intended mode of administration, the composition may be in the form of a solid, semi-solid, or liquid dosage form, such as a tablet, suppository, pill, capsule, powder, liquid, suspension, lotion, cream, or gel, in a unit dosage form suitable for single administration of a precise dosage. The composition can be formulated into any suitable dosage form for administration, such as aqueous dispersions, solutions, gels, syrups, elixirs, slurries, and suspensions for administration to a subject or patient.

[0162] Solid compositions include, for example, powders, tablets, dispersible granules, capsules, and cachets. Liquid compositions include, for example, solutions in which the compound is dissolved, emulsions containing the compound, or solutions containing liposomes, micelles, or nanoparticles containing the compound disclosed herein. Semi-solid compositions include, for example, gels, suspensions, and creams. The composition can be a liquid solution or suspension, a solid dosage form suitable for dissolving or suspending in liquid before use, or an emulsion. These compositions can also contain minor amounts of non-toxic auxiliary substances, such as wetting agents or emulsifying agents, pH buffering agents, and other pharmaceutically acceptable additives.

[0163] In some embodiments, the composition is formulated into a solution (e.g., for IV administration). In some cases, the pharmaceutical composition is formulated as an infusion. In some cases, the pharmaceutical composition is formulated as an injection.

[0164] The compounds of the present disclosure or compositions (e.g., pharmaceutical compositions) comprising the compounds of the present disclosure can be administered in the form of a rapid release formulation, a sustained release formulation, or an intermediate release formulation. Rapid release formulations can provide immediate release. Sustained release formulations can provide controlled release or sustained delayed release.

[0165] Compositions comprising the compounds of the present disclosure can be, for example, immediate release dosage forms or controlled release formulations. Immediate release formulations can be formulated to allow the compound to act rapidly. Non-limiting examples of immediate release formulations include readily soluble formulations. Controlled release formulations can be pharmaceutical formulations in which the release rate and release profile of the active agent are adapted to meet physiological and chronotherapeutic requirements, or are formulated to release the active agent at a programmed rate. Non-limiting examples of controlled release formulations include granules, delayed-release granules, hydrogels (e.g., synthetic or natural origin), other gelling agents (e.g., gel-forming dietary fiber), matrix-based formulations (e.g., formulations comprising polymeric materials in which at least one active ingredient is dispersed), granules in a matrix, polymer mixtures, and granular agglomerates.

[0166] In some embodiments, the controlled release formulation is a delayed release dosage form.The delayed release dosage form can be formulated to delay the action of the compound for a long period of time.The delayed release dosage form can be formulated to delay the release of the effective dose of one or more compounds for, for example, about 4, about 8, about 12, about 16, or about 24 hours.The controlled release formulation can be a sustained release dosage form.The sustained release dosage form can be formulated to, for example, maintain the action of the compound for a long period of time.The sustained release dosage form can be formulated to provide the effective dose of any compound described herein for about 4, about 8, about 12, about 16, or about 24 hours (for example, to provide a physiologically effective blood profile).

[0167] The pharmaceutical compositions disclosed herein can target any suitable tissue or cell type.The manner, route and composition of the present disclosure can be suitable for targeting the compounds of the present disclosure to specific tissue or tissue subset.Non-limiting examples of tissues that can be targeted include kidney (e.g., renal cortex), joint, cartilage, liver, salivary gland, bone (e.g., bone surface), skin, lung, muscle, pancreas, hair follicle, colon mucosa, aortic wall, small intestinal mucosa, adrenal gland, gastric mucosa, spleen, bone marrow, lymph node, thymus, brain, cerebellum, olfactory bulb, thalamus, caudate nucleus, putamen, cerebral cortex, substantia nigra, lateral ventricle, choroidal plexus, and combinations thereof. dosage

[0168] The pharmaceutical composition described herein can be in a unit dosage form suitable for single administration of precise dosage.In the unit dosage form, the preparation is divided into unit doses that contain appropriate amounts of one or more compounds.The dosage (for example, therapeutically effective amount) of the compound described herein can be any amount required.

[0169] The compounds described herein may be administered in a composition or unit dose in an amount of from about 1 mg to about 2000 mg; from about 5 mg to about 1000 mg, from about 10 mg to about 25 mg, from about 50 mg to about 250 mg, from about 100 mg to about 200 mg, from about 1 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 150 mg, from about 150 mg to about 200 mg, from about 200 mg to about 250 mg, from about 250 mg to about 300 mg, from about 300 mg to about 350 mg, from about 350 mg to about 400 mg, from about 400 mg to about 500 mg, from about 400 mg to about 500 mg, from about 400 mg to about 500 mg, from about 400 mg to about 600 mg, from about 400 mg to about 600 mg, from about 400 mg to about 700 mg, from about 400 mg to about 700 mg, from about 400 mg to about 800 mg, from about 400 mg to about 800 mg, from about 400 mg to about 9 ... The amount may be present in the range of about 400 mg to about 450 mg, about 450 mg to about 500 mg, about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700 mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1000 mg.

[0170] The compounds described herein may be administered in a composition or unit dose in an amount of from about 1 μg to about 2000 μg; from about 5 μg to about 1000 μg, from about 10 μg to about 25 μg, from about 50 μg to about 250 μg, from about 100 μg to about 200 μg, from about 1 μg to about 50 μg, from about 50 μg to about 100 μg, from about 100 μg to about 150 μg, from about 150 μg to about 200 μg, from about 200 μg to about 250 μg, from about 250 μg to about 300 μg, from about 300 μg to about 350 μg, from about 350 μg to about 400 μg, from about 400 μg to about 500 μg, from about 400 μg to about 500 μg, from about 400 μg to about 500 μg, from about 400 μg to about 600 μg, from about 400 μg to about 650 μg, from about 400 μg to about 700 μg, from about 400 μg to about 750 μg, from about 400 μg to about 800 μg, from about 400 μg to about 850 μg, from about 400 μg to about 900 μg, from about 400 μg to about 950 μg, from about 400 μg to about 950 μg, from about 400 μg to about 1000 μg, from about 400 μg to about 1200 μg, from about 400 μg to about 1300 μg, from about 400 μg to about 1400 μg, from about 400 The amount of ATP may be present in the range of about 400 μg to about 450 μg, about 450 μg to about 500 μg, about 500 μg to about 550 μg, about 550 μg to about 600 μg, about 600 μg to about 650 μg, about 650 μg to about 700 μg, about 700 μg to about 750 μg, about 750 μg to about 800 μg, about 800 μg to about 850 μg, about 850 μg to about 900 μg, about 900 μg to about 950 μg, or about 950 μg to about 1000 μg.

[0171] The compounds described herein may be present in a composition or unit dose at about 0.001 mg, about 0.002 mg, about 0.003 mg, about 0.004 mg, about 0.005 mg, about 0.006 mg, about 0.007 mg, about 0.008 mg, about 0.009 mg, about 0.01 mg, about 0.02 mg, about 0.03 mg, about 0.04 mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, about 0.09mg, about 0.1mg, about 0.2mg, about 0.3mg, about 0.4mg, about 0.5mg, about 0.6mg, about 0.7mg, about 0.8mg, about 0.9mg, about 1mg, about 2mg, about 3mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 125mg, about 150mg, about 175mg, about 200mg, about 250mg, about 300mg, about 350mg, about 4 00mg, about 450mg, about 500mg, about 550mg, about 600mg, about 650mg, about 700mg, about 750mg, about 800mg, about 850mg, about 900mg, about 950mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, or about 2000 mg.

[0172] In some embodiments, the composition provides a concentration of at least about 0.001 mg, at least about 0.002 mg, at least about 0.003 mg, at least about 0.004 mg, at least about 0.005 mg, at least about 0.006 mg, at least about 0.007 mg, at least about 0.008 mg, at least about 0.009 mg, at least about 0.01 mg, at least about 0.02 mg, at least about 0.03 mg, at least about 0.04 mg, at least about 0.05 mg, at least about 0.06 mg, at least about 0.07 mg, at least about 0.08 mg, at least about 0.09 mg, at least about 0.1 mg, at least about 0.2 mg, at least about 0.3 mg, at least about 0.4 mg, at least about 0.5 mg, at least about 0.6 mg, at least about 0.7 mg, at least about 0.8 mg, at least about 0.9 mg, at least about 1 mg, at least about 2 mg, at least about 3 mg, at least about 4 mg, at least about 5 mg, at least about 10 mg, at least about 15 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 35 mg, at least about 40 mg, at least about 45 mg, at least about 50 mg, at least about 55 mg, at least about 60 mg, at least about 65 mg, at least about 70 mg, at least about 75 mg, at least about 80 mg, at least about 85 mg, at least about 90 mg, at least about 95 mg, at least about 100 mg, at least about 125 mg, at least about 150 mg, at least about 175 mg, at least about 200 mg, at least about 250 mg, at least about 300 mg, at least about 350 mg, at least about 400 mg, at least about 450 mg, at least about 500 mg, and at least about 550 mg, at least about 600 mg, at least about 650 mg, at least about 700 mg, at least about 750 mg, at least about 800 mg, at least about 850 mg, at least about 900 mg, at least about 950 mg, at least about 1000 mg, at least about 1050 mg, at least about 1100 mg, at least about 1150 mg, at least about 1200 mg, at least about 1250 mg, at least about 1300 mg, at least about 1350 mg, at least about 1400 mg, at least about 1450 mg, at least about 1500 mg, at least about 1550 mg, at least about 1600 mg, at least about 1650 mg, at least about 1700 mg, at least about 1750 mg, at least about 1800 mg, at least about 1850 mg, at least about 1900 mg, at least about 1950 mg, or at least about 2000 mg.

[0173] In some embodiments, the compositions provide an amount of α- or β-glucan in the composition or unit dose that is at most about 0.001 mg, at most about 0.002 mg, at most about 0.003 mg, at most about 0.004 mg, at most about 0.005 mg, at most about 0.006 mg, at most about 0.007 mg, at most about 0.008 mg, at most about 0.009 mg, at most about 0.01 mg, at most about 0.02 mg, at most about 0.03 mg, at most about 0.04 mg, at most about 0.05 mg, at most about 0.06 mg, at most about 0.07 mg, at most about 0.08 mg, at most about 0.09 mg, at most about 0.1 mg, mg, maximum approximately 0.2mg, maximum approximately 0.3mg, maximum approximately 0.4mg, maximum approximately 0.5mg, maximum approximately 0.6mg, maximum approximately 0.7mg, maximum approximately 0.8mg, maximum approximately 0.9mg, maximum approximately 1mg, maximum approximately 2mg, maximum approximately 3mg, maximum approximately 4mg, maximum approximately 5mg, maximum approximately 10mg, maximum approximately 15mg, maximum approximately 20mg, maximum approximately 25mg, maximum approximately 30mg, maximum approximately 35mg, maximum approximately 40mg, maximum approximately 45mg, maximum approximately 50mg, maximum approximately 55mg, maximum approximately 60mg, maximum approximately 65mg, maximum approximately 70mg, maximum approximately 75 mg, maximum approximately 80 mg, maximum approximately 85 mg, maximum approximately 90 mg, maximum approximately 95 mg, maximum approximately 100 mg, maximum approximately 125 mg, maximum approximately 150 mg, maximum approximately 175 mg, maximum approximately 200 mg, maximum approximately 250 mg, maximum approximately 300 mg, maximum approximately 350 mg, maximum approximately 400 mg, maximum approximately 450 mg, maximum approximately 500 mg, maximum approximately 550 mg, maximum approximately 600 mg, maximum approximately 650 mg, maximum approximately 700 mg, maximum approximately 750 mg, maximum approximately 800 mg, maximum approximately 850 mg, maximum approximately 900 mg, maximum approximately 950 mg , up to about 1000 mg, up to about 1050 mg, up to about 1100 mg, up to about 1150 mg, up to about 1200 mg, up to about 1250 mg, up to about 1300 mg, up to about 1350 mg, up to about 1400 mg, up to about 1450 mg, up to about 1500 mg, up to about 1550 mg, up to about 1600 mg, up to about 1650 mg, up to about 1700 mg, up to about 1750 mg, up to about 1800 mg, up to about 1850 mg, up to about 1900 mg, up to about 1950 mg, or up to about 2000 mg.

[0174] In some embodiments, the dose (e.g., unit dose) is about 0.001 mg / kg, about 0.002 mg / kg, about 0.003 mg / kg, about 0.004 mg / kg, about 0.005 mg / kg, about 0.006 mg / kg, about 0.007 mg / kg, about 0.008 mg / kg, about 0.009 mg / kg, about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, based on the body mass of the subject or patient. g / kg, approximately 0.1 mg / kg, approximately 0.2 mg / kg, approximately 0.3 mg / kg, approximately 0.4 mg / kg, approximately 0.5 mg / kg, approximately 0.6 mg / kg, approximately 0.7 mg / kg, approximately 0.8 mg / kg, approximately 0.9 mg / kg, approximately 1 mg / kg, approximately 2 mg / kg, approximately 3 mg / kg, approximately 4 m g / kg, approximately 5 mg / kg, approximately 10 mg / kg, approximately 15 mg / kg, approximately 20 mg / kg, approximately 25 mg / kg, approximately 30 mg / kg, approximately 35 mg / kg, approximately 40 mg / kg, approximately 45 mg / kg, approximately 50 mg / kg, approximately 55 mg / kg, approximately 60 mg / kg, approximately 65 mg / kg, approximately 7 0mg / kg, about 75mg / kg, about 80mg / kg, about 85mg / kg, about 90mg / kg, about 95mg / kg, about 100mg / kg, about 125mg / kg, about 150mg / kg, about 175mg / kg, about 200mg / kg, about 250mg / kg, about 300mg / kg, About 350mg / kg, about 400mg / kg, about 450mg / kg, about 500mg / kg, about 550mg / kg, about 600mg / kg, about 650mg / kg, about 700mg / kg, about 750mg / kg, about 800mg / kg, about 850mg / kg, about 900mg / kg, about 9 50 mg / kg, about 1000 mg / kg, about 1050 mg / kg, about 1100 mg / kg, about 1150 mg / kg, about 1200 mg / kg, about 1250 mg / kg, about 1300 mg / kg, about 1350 mg / kg, about 1400 mg / kg, about 1450 mg / kg, about 1500 mg / kg, about 1550 mg / kg, about 1600 mg / kg, about 1650 mg / kg, about 1700 mg / kg, about 1750 mg / kg, about 1800 mg / kg, about 1850 mg / kg, about 1900 mg / kg, about 1950 mg / kg, or about 2000 mg / kg.

[0175] In some embodiments, the dose (e.g., unit dose) is at least about 0.001 mg / kg, at least about 0.002 mg / kg, at least about 0.003 mg / kg, at least about 0.004 mg / kg, at least about 0.005 mg / kg, at least about 0.006 mg / kg, at least about 0.007 mg / kg, at least about 0.008 mg / kg, at least about 0.009 mg / kg, at least about 0.01 mg / kg, at least about 0.02 mg / kg, at least about 0.03mg / kg, at least about 0.04mg / kg, at least about 0.05mg / kg, at least about 0.06mg / kg, at least about 0.07mg / kg, at least about 0.08mg / kg, at least about 0.09mg / kg, at least about 0.1mg / kg, at least about 0.2mg / kg, at least about 0.3mg / kg, at least about 0.4mg / kg, at least about 0.5mg / kg, at least about 0.6mg / kg, at least about 0.7mg / kg, at least about 0.8mg / kg, at least about 0.9 mg / kg, at least about 1 mg / kg, at least about 2 mg / kg, at least about 3 mg / kg, at least about 4 mg / kg, at least about 5 mg / kg, at least about 10 mg / kg, at least about 15 mg / kg, at least about 20 mg / kg, at least about 25 mg / kg, at least about 30 mg / kg, at least about 35 mg / kg, at least about 40 mg / kg, at least about 45 mg / kg, at least about 50 mg / kg, at least about 55 mg / kg, at least about 60 mg / kg, at least about 65 mg / kg, at least about 70 mg / kg, at least about 75 mg / kg, at least about 80 mg / kg, at least about 85 mg / kg, at least about 90 mg / kg, at least about 95 mg / kg, at least about 100 mg / kg, at least about 125 mg / kg, at least about 150 mg / kg, at least about 175 mg / kg, at least about 200 mg / kg, at least about 250 mg / kg, at least about 300 mg / kg, at least about 350 mg / kg, at least about 400 mg / kg, at least about 450 mg / kg, at least about 500 mg / kg, at least about 600 mg / kg, at least about 750 mg / kg, at least about 800 mg / kg, at least about 850 mg / kg, at least about 90 mg / kg, at least about 95 mg / kg, at least about 100 mg / kg, at least about 125 mg / kg, at least about 150 mg / kg, at least about 175 mg / kg, at least about 200 mg / kg, at least about 250 mg / kg, at least about 300 mg / kg, at least about 350 mg / kg, at least about 400 mg / kg, at least about 450 mg / kg, at least about 500 mg / kg, at least about 600 mg / kg, at least about 750 mg / kg, at least about 800 mg / kg, at least about 900 mg / kg, at least about 1000 mg / kg, at least about 125 mg / kg, at least about 150 mg / kg, at least about 175 mg / kg, at least about 200 mg / kg, at least about 250 mg / kg, at least about 300 mg / kg, at least about 350 mg / kg, at least about 400 mg / kg, at mg / kg, at least about 550 mg / kg, at least about 600 mg / kg, at least about 650 mg / kg, at least about 700 mg / kg, at least about 750 mg / kg, at least about 800 mg / kg, at least about 850 mg / kg, at least about 900 mg / kg, at least about 950 mg / kg, at least about 1000 mg / kg, at least about 1050 mg / kg, at least about 1100 mg / kg, at least about 1150 mg / kg, at least about 1200 mg / kg, at least about 1250 mg / kg, or at least about 1300 mg / kg, at least about 1350 mg / kg, at least about 1400 mg / kg, at least about 1450 mg / kg, at least about 1500 mg / kg, at least about 1550 mg / kg, at least about 1600 mg / kg, at least about 1650 mg / kg, at least about 1700 mg / kg, at least about 1750 mg / kg, at least about 1800 mg / kg, at least about 1850 mg / kg, at least about 1900 mg / kg, at least about 1950 mg / kg, or at least about 2000 mg / kg.

[0176] In some embodiments, the dose (e.g., unit dose) is up to about 0.001 mg / kg, up to about 0.002 mg / kg, up to about 0.003 mg / kg, up to about 0.004 mg / kg, up to about 0.005 mg / kg, up to about 0.006 mg / kg, up to about 0.007 mg / kg, up to about 0.008 mg / kg, up to about 0.009 mg / kg, up to about 0.01 mg / kg, up to about 0.02 ...09 mg / kg, up to about 0.01 mg / kg, up to about 0.02 mg / kg, up to about 0.009 mg / kg, up to about 0.009 mg / kg, up to about The maximum is approximately 0.03mg / kg, maximum is approximately 0.04mg / kg, maximum is approximately 0.05mg / kg, maximum is approximately 0.06mg / kg, maximum is approximately 0.07mg / kg, maximum is approximately 0.08mg / kg, maximum is approximately 0.09mg / kg, maximum is approximately 0.1mg / kg, maximum is approximately 0.2mg / kg, maximum is approximately 0.3mg / kg, maximum is approximately 0.4mg / kg, maximum is approximately 0.5mg / kg, maximum is approximately 0.6mg / kg, maximum is approximately 0.7mg / kg, maximum is approximately 0.8mg / kg, maximum is approximately 0.9mg / kg, up to about 1mg / kg, up to about 2mg / kg, up to about 3mg / kg, up to about 4mg / kg, up to about 5mg / kg, up to about 10mg / kg, up to about 15mg / kg, up to about 20mg / kg, up to about 25mg / kg, up to about 30mg / kg, up to about 35mg / kg, up to about 40mg / kg, up to about 45mg / kg, up to about 50mg / kg, up to about 55mg / kg, up to about 60mg / kg, up to about 65mg / kg, up to Approximately 70mg / kg, up to approximately 75mg / kg, up to approximately 80mg / kg, up to approximately 85mg / kg, up to approximately 90mg / kg, up to approximately 95mg / kg, up to approximately 100mg / kg, up to approximately 125mg / kg, up to approximately 150mg / kg, up to approximately 175mg / kg, up to approximately 200mg / kg, up to approximately 250mg / kg, up to approximately 300mg / kg, up to approximately 350mg / kg, up to approximately 400mg / kg, up to approximately 450mg / kg, up to approximately 500mg / kg g, up to about 550mg / kg, up to about 600mg / kg, up to about 650mg / kg, up to about 700mg / kg, up to about 750mg / kg, up to about 800mg / kg, up to about 850mg / kg, up to about 900mg / kg, up to about 950mg / kg, up to about 1000mg / kg, up to about 1050mg / kg, up to about 1100mg / kg, up to about 1150mg / kg, up to about 1200mg / kg, up to about 1250mg / kg, up to about 13 00mg / kg, up to about 1350mg / kg, up to about 1400mg / kg, up to about 1450mg / kg, up to about 1500mg / kg, up to about 1550mg / kg, up to about 1600mg / kg, up to about 1650mg / kg, up to about 1700mg / kg, up to about 1750mg / kg, up to about 1800mg / kg, up to about 1850mg / kg, up to about 1900mg / kg, up to about 1950mg / kg, or up to about 2000mg / kg.

[0177] In some embodiments, the dose (e.g., unit dose) is based on the body mass of the subject or patient and is between about 1 mg / kg and about 2000 mg / kg; between about 5 mg / kg and about 1000 mg / kg, between about 10 mg / kg and about 25 mg / kg, between about 50 mg / kg and about 250 mg / kg, between about 100 mg / kg and about 200 mg / kg, between about 1 mg / kg and about 50 mg / kg, between about 50 mg / kg and about 100 mg / kg, between about 100 mg / kg and about 150 mg / kg, between about 150 mg / kg and about 200 mg / kg, between about 200 mg / kg and about 250 mg / kg, between about 250 mg / kg and about 300 mg / kg, between about 300 mg / kg and about 350 mg / kg, between about 350 mg / kg and about 400 mg / kg, between about 400 mg / kg and about 550 mg / kg, between about 45 ... 0mg / kg~Approx. 400mg / kg, Approx. 400mg / kg~Approx. 450mg / kg, Approx. 450mg / kg~Approx. 500mg / kg, Approx. 500mg / kg~Approx. 550mg / kg, Approx. 550mg / kg~Approx. 600mg / kg, Approx. 700mg / kg to about 750mg / kg, about 750mg / kg to about 800mg / kg, about 800mg / kg to about 850mg / kg, about 850mg / kg to about 900mg / kg, about 900mg / kg to about 950mg / kg, about 950mg / kg to about 1000mg / kg, about 1μg / kg to about 2000μg / kg;Approximately 5μg / kg to approximately 1000μg / kg, approximately 10μg / kg to approximately 25μg / kg, approximately 50μg / kg to approximately 250μg / kg, approximately 100μg / kg to approximately 200μg / kg, approximately 1μg / kg to approximately 50μg / kg, approximately 50μg / kg to approximately 100μg / kg, approximately 100μg / kg kg ~ approx. 150 μg / kg, approx. 150 μg / kg ~ approx. 200 μg / kg, approx. 200 μg / kg ~ approx. 250 μg / kg, approx. 250 μg / kg ~ approx. 300 μg / kg, approx. 300 μg / kg ~ approx. kg to about 450 μg / kg, about 450 μg / kg to about 500 μg / kg, about 500 μg / kg to about 550 μg / kg, about 550 μg / kg to about 600 μg / kg, about 600 μg / kg to about 650 μg / kg, about 650 μg / kg to about 700 μg / kg, about 700 μg / kg to about 750 μg / kg, about 750 μg / kg to about 800 μg / kg, about 800 μg / kg to about 850 μg / kg, about 850 μg / kg to about 900 μg / kg, about 900 μg / kg to about 950 μg / kg, or about 950 μg / kg to about 1000 μg / kg;

[0178] The pharmaceutical compositions and formulations described herein may, for example, contain the compounds of the present disclosure in any suitable concentration.Formulations may include, for example, about 0.001 mg / mL, about 0.002 mg / mL, about 0.003 mg / mL, about 0.004 mg / mL, about 0.005 mg / mL, about 0.006 mg / mL, about 0.007 mg / mL, about 0.008 mg / mL, about 0.009 mg / mL, about 0.01 mg / mL, about 0.02 mg / mL, about 0.03 mg / mL, about 0.04 mg / mL, about 0.05 mg / mL, about 0.06 mg / mL, about 0.07 mg / mL, about 0.08 mg / mL, about 0.09 mg / mL, about 0.1 mg / mL, about 0.2 mg / mL, about 0.3 mg / mL, g / mL, approximately 0.4 mg / mL, approximately 0.5 mg / mL, approximately 0.6 mg / mL, approximately 0.7 mg / mL, approximately 0.8 mg / mL, approximately 0.9 mg / mL, approximately 1 mg / mL, approximately 2 mg / mL, approximately 3 mg / mL, approximately 4 mg / mL, approximately 5 mg / mL, approximately 10 mg / mL, approximately 15 mg / mL, approximately 20mg / mL, approximately 25mg / mL, approximately 30mg / mL, approximately 35mg / mL, approximately 40mg / mL, approximately 45mg / mL, approximately 50mg / mL, approximately 55mg / mL, approximately 60mg / mL, approximately 65mg / mL, approximately 70mg / mL, approximately 75mg / mL, approximately 80mg / mL , about 85 mg / mL, about 90 mg / mL, about 95 mg / mL, about 100 mg / mL, about 125 mg / mL, about 150 mg / mL, about 175 mg / mL, about 200 mg / mL, about 250 mg / mL, about 300 mg / mL, about 350 mg / mL, about 400 mg / mL, about 450mg / mL, about 500mg / mL, about 550mg / mL, about 600mg / mL, about 650mg / mL, about 700mg / mL, about 750mg / mL, about 800mg / mL, about 850mg / mL, about 900mg / mL, about 950mg / mL, about 1000mg / mL, The compositions of the present disclosure may be comprised in a concentration of about 1050 mg / mL, about 1100 mg / mL, about 1150 mg / mL, about 1200 mg / mL, about 1250 mg / mL, about 1300 mg / mL, about 1350 mg / mL, about 1400 mg / mL, about 1450 mg / mL, about 1500 mg / mL, about 1550 mg / mL, about 1600 mg / mL, about 1650 mg / mL, about 1700 mg / mL, about 1750 mg / mL, about 1800 mg / mL, about 1850 mg / mL, about 1900 mg / mL, about 1950 mg / mL, or about 2000 mg / mL.

[0179] In some embodiments, the formulations of the present disclosure have a concentration of at least about 0.001 mg / mL, at least about 0.002 mg / mL, at least about 0.003 mg / mL, at least about 0.004 mg / mL, at least about 0.005 mg / mL, at least about 0.006 mg / mL, at least about 0.007 mg / mL, at least about 0.008 mg / mL, at least about 0.009 mg / mL, at least about 0.01 mg / mL, at least about 0.02 mg / mL, at least about 0.03 mg / mL, at least about 0.04 mg / mL, at least about 0.05 mg / mL, at least about 0. ...7 mg / mL, at least about 0.008 mg / mL, at least about 0.009 mg / mL, at least about 0.01 mg / mL, at least about 0.02 mg / mL, at least about 0.03 mg / mL, at least about 0.04 mg / mL, at least about 0.05 mg / mL, at least about 0.06 mg / mL, at least about 0.07 mg / mL, at least about 0.08 mg / mL, at least about 0.08 mg / mL, at least about 0.09 mg / mL, at least about 0.01 mg / mL, at least about 0.02 mg / mL, at least about 0.03 mg / mL, at least At least about 0.04 mg / mL, at least about 0.05 mg / mL, at least about 0.06 mg / mL, at least about 0.07 mg / mL, at least about 0.08 mg / mL, at least about 0.09 mg / mL, at least about 0.1 mg / mL, at least about 0.2 mg / mL, at least about 0.3 mg / mL, at least about 0.4 mg / mL, at least about 0.5 mg / mL, at least about 0.6 mg / mL, at least about 0.7 mg / mL, at least about 0.8 mg / mL, at least about 0.9 mg / mL, at least about 1 mg / mL, at least about 2 mg / mL, at least about 3 mg / mL, at least about 4 mg / mL, at least about 5 mg / mL, at least about 10 mg / mL, at least about 15 mg / mL, at least about 20 mg / mL, at least about 25 mg / mL, at least about 30 mg / mL, at least about 35 mg / mL, at least about 40 mg / mL, at least about 45 mg / mL, at least about 50 mg / mL, at least about 55 mg / mL, at least about 60 mg / mL, at least about 65 mg / mL, at least Also about 70 mg / mL, at least about 75 mg / mL, at least about 80 mg / mL, at least about 85 mg / mL, at least about 90 mg / mL, at least about 95 mg / mL, at least about 100 mg / mL, at least about 125 mg / mL, at least about 150 mg / mL, at least about 175 mg / mL, at least about 200 mg / mL, at least about 250 mg / mL, at least about 300 mg / mL, at least about 350 mg / mL, at least about 400 mg / mL, at least about 450 mg / mL, at least about 500 mg / mL , at least about 550 mg / mL, at least about 600 mg / mL, at least about 650 mg / mL, at least about 700 mg / mL, at least about 750 mg / mL, at least about 800 mg / mL, at least about 850 mg / mL, at least about 900 mg / mL, at least about 950 mg / mL, at least about 1000 mg / mL, at least about 1050 mg / mL, at least about 1100 mg / mL, at least about 1150 mg / mL, at least about 1200 mg / mL, at least about 1250 mg / mL, at least about 1300 mg at least about 1350 mg / mL, at least about 1400 mg / mL, at least about 1450 mg / mL, at least about 1500 mg / mL, at least about 1550 mg / mL, at least about 1600 mg / mL, at least about 1650 mg / mL, at least about 1700 mg / mL, at least about 1750 mg / mL, at least about 1800 mg / mL, at least about 1850 mg / mL, at least about 1900 mg / mL, at least about 1950 mg / mL, or at least about 2000 mg / mL.

[0180] In some embodiments, the formulations of the present disclosure have a saturation concentration of up to about 0.002 mg / mL, up to about 0.003 mg / mL, up to about 0.004 mg / mL, up to about 0.005 mg / mL, up to about 0.006 mg / mL, up to about 0.007 mg / mL, up to about 0.008 mg / mL, up to about 0.009 mg / mL, up to about 0.01 mg / mL, up to about 0.02 mg / mL, up to about 0.03 mg / mL, up to about 0.0 4mg / mL, maximum approximately 0.05mg / mL, maximum approximately 0.06mg / mL, maximum approximately 0.07mg / mL, maximum approximately 0.08mg / mL, maximum approximately 0.09mg / mL, maximum approximately 0.1mg / mL, maximum approximately 0.2mg / mL, maximum approximately 0.3mg / mL, maximum approximately 0.4mg / mL, maximum approximately 0.5mg / mL, maximum approximately 0.6mg / mL, maximum approximately 0.7mg / mL, maximum approximately 0.8mg / mL, maximum approximately 0.9mg / mL, up to about 1mg / mL, up to about 2mg / mL, up to about 3mg / mL, up to about 4mg / mL, up to about 5mg / mL, up to about 10mg / mL, up to about 15mg / mL, up to about 20mg / mL, up to about 25mg / mL, up to about 30mg / mL, up to about 35mg / mL, up to about 40mg / mL, up to about 45mg / mL, up to about 50mg / mL, up to about 55mg / mL, up to about 60mg / mL, up to about 65mg / mL, up to about 70 mg / mL, up to about 75 mg / mL, up to about 80 mg / mL, up to about 85 mg / mL, up to about 90 mg / mL, up to about 95 mg / mL, up to about 100 mg / mL, up to about 125 mg / mL, up to about 150 mg / mL, up to about 175 mg / mL, up to about 200 mg / mL, up to about 250 mg / mL, up to about 300 mg / mL, up to about 350 mg / mL, up to about 400 mg / mL, up to about 450 mg / mL, up to about 500 mg / mL, up to about 550 mg / mL, up to about 600 mg / mL, up to about 650 mg / mL, up to about 700 mg / mL, up to about 750 mg / mL, up to about 800 mg / mL, up to about 850 mg / mL, up to about 900 mg / mL, up to about 950 mg / mL, up to about 1000 mg / mL, up to about 1050 mg / mL, up to about 1100 mg / mL, up to about 1150 mg / mL, up to about 1200 mg / mL, up to about 1250 mg / mL, up to about 1300 mg / mL, and comprising a compound of the present disclosure at a concentration of up to about 1350 mg / mL, up to about 1400 mg / mL, up to about 1450 mg / mL, up to about 1500 mg / mL, up to about 1550 mg / mL, up to about 1600 mg / mL, up to about 1650 mg / mL, up to about 1700 mg / mL, up to about 1750 mg / mL, up to about 1800 mg / mL, up to about 1850 mg / mL, up to about 1900 mg / mL, up to about 1950 mg / mL, or up to about 2000 mg / mL.

[0181] In some embodiments, the formulations of the present disclosure have a concentration of about 1 mg / mL to about 2000 mg / mL; about 5 mg / mL to about 1000 mg / mL, about 10 mg / mL to about 25 mg / mL, about 50 mg / mL to about 250 mg / mL, about 100 mg / mL to about 200 mg / mL, about 1 mg / mL to about 50 mg / mL, about 50 mg / mL to about 100 mg / mL, about 100 mg / mL to about 150 mg / mL, about 150 mg / mL to about 200 mg / mL, about 200 mg / mL to about 250 mg / mL, about 250 mg / mL to about 300 mg / mL, about 300 mg / mL to about 350 mg / mL, about 350 mg / mL to about 400 mg / mL g / mL, approx. 400 mg / mL to approx. 450 mg / mL, approx. 450 mg / mL to approx. 500 mg / mL, approx. 500 mg / mL to approx. 550 mg / mL, approx. 550 mg / mL to approx. 600 mg / mL, approx. mL~about 750mg / mL, about 750mg / mL~about 800mg / mL, about 800mg / mL~about 850mg / mL, about 850mg / mL~about 900mg / mL, about 900mg / mL~about 950mg / mL, about 950mg / mL~about 1000mg / mL, about 1μg / mL~about 2000μg / mL;Approximately 5μg / mL to approximately 1000μg / mL, approximately 10μg / mL to approximately 25μg / mL, approximately 50μg / mL to approximately 250μg / mL, approximately 100μg / mL to approximately 200μg / mL, approximately 1μg / mL to approximately 50μg / mL, approximately 50μg / mL to approximately 100μg / mL, approximately 100μg / mL Approximately 150μg / mL, approximately 150μg / mL to approximately 200μg / mL, approximately 200μg / mL to approximately 250μg / mL, approximately 250μg / mL to approximately 300μg / mL, approximately 300μg / mL to approximately 350μg / mL, approximately 350μg / mL to approximately 400μg / mL, approximately 400μg / mL to approximately 45 0 μg / mL, about 450 μg / mL to about 500 μg / mL, about 500 μg / mL to about 550 μg / mL, about 550 μg / mL to about 600 μg / mL, about 600 μg / mL to about 650 μg / mL, about 650 μg / mL to about 700 μg / mL, about 700 μg / mL to about 750 μg / mL, about 750 μg / mL to about 800 μg / mL, about 800 μg / mL to about 850 μg / mL, about 850 μg / mL to about 900 μg / mL, about 900 μg / mL to about 950 μg / mL, or about 950 μg / mL to about 1000 μg / mL; Treatment effect Tissue distribution and pharmacokinetics

[0182] The compounds disclosed herein may have favorable properties for administration to a subject or patient, such as favorable pharmacokinetic or tissue distribution parameters.

[0183] In some embodiments, when a study or assay (e.g., a tissue distribution study) is performed, the study or assay includes administering (e.g., intracerebroventricularly) a compound of the present disclosure (e.g., Compound 1) to a study patient or subject at a dose of about 0.1 mg / kg to about 1.5 mg / kg, wherein the compound accumulates in the brain of the study patient for up to about one month after administration. In some embodiments, the compound is not observed at detectable levels, or is barely observed, in the plasma, intestine, liver, lungs, kidneys, and / or muscle of the study patient during that one month period.

[0184] In some embodiments, the compound may be subjected to an assay or study (e.g., a tissue distribution study) in which the compound may be observed to accumulate in the brain of a study patient (e.g., a mouse) for a period of time (e.g., up to about one month) after the administering step. In some embodiments, the compound is not observed at detectable levels in the plasma, intestine, liver, lung, kidney, and / or muscle of the study patient during that period. In some embodiments, the assay may include administering (e.g., intracerebroventricularly) a dose of the compound (e.g., about 0.1 mg / kg to about 1.5 mg / kg) to a study patient (e.g., a mouse). A blood sample may be collected from the study patient (e.g., from the vena cava) at a time point (e.g., between about 1 hour and 28 days) after administration. After collecting the blood sample, the study patient may be euthanized at a time point (e.g., between about 1 hour and 28 days) after administration. After euthanasia, various tissues (e.g., brain, intestine, liver, lung, kidney, and / or muscle tissue) may be collected from the study patient.

[0185] A variety of analytical techniques can be used to determine the concentration of compounds in tissue and / or other samples (eg, blood, plasma, urine, feces, etc.) collected from study patients. Non-limiting examples of techniques that can be used to determine the concentration of a compound include mass spectrometry, such as liquid chromatography mass spectrometry (LC-MS), gas chromatography mass spectrometry (GC-MS), tandem MS (MS / MS, e.g., LC-MS / MS or GC-MS / MS), matrix-assisted laser desorption / ionization-time of flight mass spectrometry (MALDI-TOF MS), triple quadrupole mass spectrometry (TQMS), quadrupole trap MS, hybrid linear trap orbitrap MS, quadrupole-orbitrap mass spectrometry, high performance or ultra-high performance liquid chromatography (HPLC or UHPLC, e.g., with MS or ultraviolet detection), time of flight (TOF) MS, selected reaction monitoring (SRM), multiple reaction monitoring (MRM), nuclear magnetic resonance (NMR, e.g., continuous wave (cw), pulsed or Fourier transform, 1H, 13C, 19F, 31P or other nuclei), variations thereof or combinations thereof.

[0186] In some embodiments, if an assay or study is performed, the study or assay includes administering (e.g., via intracerebroventricular administration) a compound of the disclosure (e.g., Compound 1) to a study patient (e.g., a mouse) or subject at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg), wherein the compound accumulates in the brain of the study patient or subject for a period of up to about 1 month (e.g., up to about 3 days, up to about 7 days, up to about 14 days, up to about 21 days, up to about 27 days, or up to about 28 days) after administration. In some embodiments, the compound is not observed at detectable levels, or is barely observed, in the plasma, intestine, liver, lungs, kidneys, and / or muscle of the study patient or subject during this period.

[0187] In some embodiments, if an assay or study is performed, the study or assay includes administering (e.g., via intracerebroventricular administration) a compound of the disclosure (e.g., Compound 1) to a study patient or subject at a dosage of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg), wherein the compound accumulates in the brain of the study patient or subject for a period of at least about 1 day (e.g., at least about 1 day, at least about 3 days, at least about 7 days, at least about 14 days, at least about 21 days, at least about 27 days, at least about 28 days, at least about 1 month, at least about 2 months, or at least about 3 months) after administration. In some embodiments, the compound is not observed at detectable levels, or is barely observed, in the plasma, intestine, liver, lungs, kidneys, and / or muscle of the study patient or subject during this period.

[0188] In some embodiments, if an assay or study is performed, the study or assay includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure (e.g., Compound 1) to a study patient or subject at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg), wherein the compound accumulates in the spleen of the study patient or subject for a period of up to about 1 month (e.g., up to about 3 days, up to about 7 days, up to about 14 days, up to about 21 days, up to about 27 days, or up to about 28 days) after administration. In some embodiments, the compound is not observed at detectable levels, or is barely observed, in the plasma, intestine, liver, lungs, kidneys, and / or muscle of the study patient or subject during this period.

[0189] In some embodiments, if an assay or study is performed, the study or assay includes administering (e.g., via intracerebroventricular administration) a compound of the disclosure (e.g., Compound 1) to a study patient or subject at a dosage of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg), wherein the compound accumulates in the spleen of the study patient or subject for a period of at least about 1 day (e.g., at least about 1 day, at least about 3 days, at least about 7 days, at least about 14 days, at least about 21 days, at least about 27 days, at least about 28 days, at least about 1 month, at least about 2 months, or at least about 3 months) after administration. In some embodiments, the compound is not observed at detectable levels, or is barely observed, in the plasma, intestine, liver, lungs, kidneys, and / or muscle of the study patient or subject during this period.

[0190] In some embodiments, if an assay or study is performed, the study or assay includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure (e.g., Compound 1) to a study patient or subject at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg), wherein the compound accumulates in the heart of the study patient or subject for a timer period of up to about 1 month (e.g., up to about 3 days, up to about 7 days, up to about 14 days, up to about 21 days, up to about 27 days, or up to about 28 days) after administration. In some embodiments, the compound is not observed at detectable levels, or is barely observed, in the plasma, intestine, liver, lungs, kidneys, and / or muscle of the study patient or subject during this period.

[0191] In some embodiments, if an assay or study is performed, the study or assay includes administering (e.g., via intracerebroventricular administration) a compound of the disclosure (e.g., Compound 1) to a study patient or subject at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg), wherein the compound accumulates in the heart of the study patient or subject for a period of at least about 1 day (e.g., at least about 1 day, at least about 3 days, at least about 7 days, at least about 14 days, at least about 21 days, at least about 27 days, at least about 28 days, at least about 1 month, at least about 2 months, or at least about 3 months) after administration. In some embodiments, the compound is not observed at detectable levels, or is barely observed, in the plasma, intestine, liver, lungs, kidneys, and / or muscle of the study patient or subject during this period.

[0192] In some embodiments, if an assay or study is performed, the study or assay includes administering (e.g., via intracerebroventricular administration) a compound of the disclosure (e.g., Compound 1) to a study patient or subject at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg), wherein the compound accumulates in the brain of the study patient or subject for a period of up to about 1 month (e.g., up to about 3 days, up to about 7 days, up to about 14 days, up to about 21 days, up to about 27 days, or up to about 28 days) after administration. In some embodiments, the compound is not observed at detectable levels, or is barely observed, in the plasma, intestine, liver, lungs, kidneys, and / or muscle of the study patient or subject during this period.

[0193] In some embodiments, if an assay or study is performed, the study or assay includes administering (e.g., via intracerebroventricular administration) a compound of the disclosure (e.g., Compound 1) to a study patient or subject at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg), wherein the compound accumulates in the brain of the study patient or subject for a period of at least about 1 day (e.g., at least about 1 day, at least about 3 days, at least about 7 days, at least about 14 days, at least about 21 days, at least about 27 days, at least about 28 days, at least about 1 month, at least about 2 months, or at least about 3 months) after administration. In some embodiments, the compound is not observed at detectable levels, or is barely observed, in the plasma, intestine, liver, lungs, kidneys, and / or muscle of the study patient or subject during this period.

[0194] In some embodiments, if an assay or study is performed, the study or assay includes administering (e.g., via intracerebroventricular administration) a compound of the disclosure (e.g., Compound 1) to a study patient or subject at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg), wherein the compound accumulates in the spleen of the study patient or subject for a period of up to about 1 month (e.g., up to about 3 days, up to about 7 days, up to about 14 days, up to about 21 days, up to about 27 days, or up to about 28 days) after administration. In some embodiments, the compound is not observed at detectable levels, or is barely observed, in the plasma, intestine, liver, lungs, kidneys, and / or muscle of the study patient or subject during this period.

[0195] In some embodiments, if an assay or study is performed, the study or assay includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure (e.g., Compound 1) to a study patient or subject at a dosage of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg), wherein the compound accumulates in the spleen of the study patient or subject for a period of at least about 1 day (e.g., at least about 1 day, at least about 3 days, at least about 7 days, at least about 14 days, at least about 21 days, at least about 27 days, at least about 28 days, at least about 1 month, at least about 2 months, or at least about 3 months) after administration. In some embodiments, the compound is not observed at detectable levels, or is barely observed, in the plasma, intestine, liver, lungs, kidneys, and / or muscle of the study patient or subject during this period.

[0196] In some embodiments, if an assay or study is performed, the study or assay includes administering (e.g., via intracerebroventricular administration) a compound of the disclosure (e.g., Compound 1) to a study patient or subject at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg), wherein the compound accumulates in the heart of the study patient or subject for a period of up to about 1 month (e.g., up to about 3 days, up to about 7 days, up to about 14 days, up to about 21 days, up to about 27 days, or up to about 28 days) after administration. In some embodiments, the compound is not observed at detectable levels, or is barely observed, in the plasma, intestine, liver, lungs, kidneys, and / or muscle of the study patient or subject during this period.

[0197] In some embodiments, if an assay or study is performed, the study or assay includes administering (e.g., via intracerebroventricular administration) a compound of the disclosure (e.g., Compound 1) to a study patient or subject at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg), wherein the compound accumulates in the heart of the study patient or subject for a period of at least about 1 day (e.g., at least about 1 day, at least about 3 days, at least about 7 days, at least about 14 days, at least about 21 days, at least about 27 days, at least about 28 days, at least about 1 month, at least about 2 months, or at least about 3 months) after administration. In some embodiments, the compound is not observed at detectable levels, or is barely observed, in the plasma, intestine, liver, lungs, kidneys, and / or muscle of the study patient or subject during this period.

[0198] In some embodiments, the dose can be modulated to achieve a desired pharmacokinetic or pharmacodynamic profile, for example, a desired or effective hematological profile as described herein.

[0199] Pharmacokinetic and pharmacodynamic data can be obtained by various experimental techniques. The appropriate pharmacokinetic and pharmacodynamic profile components that describe a particular composition may vary due to variations in drug metabolism in human subjects. Pharmacokinetic and pharmacodynamic profiles can be based on determining the average parameters of a group of subjects. The group of subjects includes any reasonable number of subjects suitable for determining a representative average, for example, 5 subjects, 10 subjects, 15 subjects, 20 subjects, 25 subjects, 30 subjects, 35 subjects, or more subjects. The average is determined, for example, by calculating the average value of all subjects' measurements for each parameter measured. Dosage can be adjusted to achieve a desired pharmacokinetic or pharmacodynamic profile, for example, the desired or effective blood profile described herein.

[0200] In some embodiments, the subject is a vertebrate. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is a primate, ape, monkey, sheep, horse, cow, pig, minipig, dog, cat, goat, camel, rodent, rabbit, mouse, rat, hamster, gerbil, hamster, chinchilla, fancy rat, guinea pig, C57BL6J mouse, beagle dog, Gottingen minipig, or cynomolgus monkey. In some embodiments, the subject is a non-human subject. In some embodiments, the subject is a veterinary subject.

[0201] In some embodiments, the patient is a vertebrate. In some embodiments, the patient is a mammal. In some embodiments, the patient is a human. In some embodiments, the patient is a primate, ape, monkey, sheep, horse, cow, pig, minipig, dog, cat, goat, camel, rodent, rabbit, mouse, rat, hamster, gerbil, hamster, chinchilla, fancy rat, guinea pig, C57BL6J mouse, beagle dog, Gottingen minipig, or cynomolgus monkey. In some embodiments, the patient is a non-human patient. In some embodiments, the patient is a veterinary patient.

[0202] In some embodiments, the patient and subject are of the same species, hi some embodiments, the subject and patient are human.

[0203] In some embodiments, the patient and the subject are of different species.In some embodiments, the subject is a human, and the patient is a non-human, for example, a non-human vertebrate, a non-human mammal, a non-human primate, an ape, a monkey, a sheep, a horse, a cow, a pig, a miniature pig, a dog, a cat, a goat, a camel, a rodent, a rabbit, a mouse, a rat, a hamster, a gerbil, a hamster, a chinchilla, a fancy rat, or a guinea pig.In some embodiments, the patient is a human, and the subject is a non-human, for example, a non-human vertebrate, a non-human mammal, a non-human primate, an ape, a monkey, a sheep, a horse, a cow, a pig, a miniature pig, a dog, a cat, a goat, a camel, a rodent, a rabbit, a mouse, a rat, a hamster, a gerbil, a hamster, a chinchilla, a fancy rat, or a guinea pig.

[0204] The pharmacokinetic parameters can be any parameters suitable for describing the compound. Non-limiting examples of pharmacodynamic and pharmacokinetic parameters that can be calculated for compounds administered by the methods of the present invention include the following: a) Drug administration, which can be expressed as dose D; b) the dosing interval, which can be expressed as τ; c) Volume of distribution V d , where V d= the apparent volume into which the drug is distributed, which can be expressed as D / C0; d) Concentration C0 or C ss , where C0 or C ss = the amount of drug in a given volume of plasma, which can be expressed as D / Vd and can be expressed as the average plasma concentration over multiple samples; e) Drug half-life t 1 / 2 , where t 1 / 2 =ln(2) / k e ; f) The rate at which the drug is eliminated from the body, k e , where k e =ln(2) / t 1 / 2 =CL / V d ;g)Formula K in , where K in =C ss .The injection rate required for CL equilibrium; h) AUC 0-∞ , where

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[0205] In some embodiments, when a compound is subjected to a study or assay (e.g., a pharmacokinetic study), an average peak brain concentration (e.g., 3,000 ng / mL to about 22,000 ng / mL) may be observed in a study patient (e.g., a mouse) in a time to peak brain concentration (e.g., about 1 hour to about 50 hours after administration). In some embodiments, the assay may include administering (e.g., intracerebroventricularly) a dose of about 0.1 mg / kg to about 2 mg / kg of the compound to the study patient (e.g., a mouse). The mouse may be euthanized at a time point after administration (e.g., between about 1 hour and 28 days). Various tissues (e.g., brain tissue) may be collected from the study patient after euthanasia. The concentration in the study patient's tissue may be determined using various techniques disclosed herein, such as liquid chromatography-tandem mass spectrometry. Brain Pharmacokinetics

[0206] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg) to a study patient or subject, where the mean T maxis at least 0.5, at least 1, at least 2, at least 4, at least 8, at least 12, at least 16, at least 20, at least 24, at least 28, at least 32, at least 36, at least 40, at least 44, or at least 48 hours.

[0207] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg) to a study patient or subject, where the mean T max is a maximum of 6, a maximum of 12, a maximum of 16, a maximum of 20, a maximum of 24, a maximum of 28, a maximum of 32, a maximum of 36, a maximum of 40, a maximum of 44, a maximum of 48, a maximum of 72, a maximum of 96, or a maximum of 120 hours.

[0208] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg) to a study patient or subject, where the mean T max is about 0.5 to about 120, about 1 to about 24, about 1 to about 36, about 1 to about 48, about 2 to about 36, about 6 to about 24, about 1 to about 6, about 6 to about 12, about 12 to about 24, about 12 to about 18, about 18 to about 48, about 18 to about 36, or about 24 to about 48 hours.

[0209] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg) to a study patient or subject, wherein the mean C max is at least about 1, at least about 1000, at least about 2000, at least about 3000, at least about 4000, at least about 5000, at least about 6000, at least about 7000, at least about 8000, at least about 9000, at least about 10000, at least about 12000, at least about 14000, at least about 16000, at least about 18000, at least about 20000, at least about 22000, or at least about 25000 ng / mL.

[0210] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg) to a study patient or subject, wherein the mean C max is at most about 3000, at most about 4000, at most about 5000, at most about 6000, at most about 7000, at most about 8000, at most about 9000, at most about 10000, at most about 12000, at most about 14000, at most about 16000, at most about 18000, at most about 20000, at most about 22000, at most about 25000, at most about 30000, or at most about 50000 ng / mL.

[0211] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg) to a study patient or subject, wherein the mean C max is about 1,000 to about 50,000, about 2,000 to about 25,000, about 3,000 to about 22,000, about 2,000 to about 5,000, about 5,000 to about 15,000, or about 10,000 to about 25,000 ng / mL.

[0212] In some embodiments, at a dose of 0.3 mg / kg, the mean peak brain concentration is about 3,000 ng / mL to about 4,000 ng / mL. In some embodiments, at a dose of 0.6 mg / kg, the mean peak brain concentration is about 6,000 ng / mL to about 12,000 ng / mL. In some embodiments, at a dose of 1 mg / kg, the mean peak brain concentration is about 15,000 ng / mL to about 22,000 ng / mL.

[0213] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg) to a study patient or subject, where the mean AUC of the compound in the brain is last is at least about 0.5×10^6, at least about 1×10^6, at least about 1.5×10^6, at least about 2×10^6, at least about 2.5×10^6, at least about 3×10^6, at least about 4×10^6, at least about 5×10^6, at least about 6×10^6, at least about 7×10^6, at least about 8×10^6, or at least about 10×10^6 ng·h / mL.

[0214] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg) to a study patient or subject, where the mean AUC of the compound in the brain is last is at most about 1.5×10^6, at most about 2×10^6, at most about 2.5×10^6, at most about 3×10^6, at most about 4×10^6, at most about 5×10^6, at most about 6×10^6, at most about 7×10^6, at most about 8×10^6, at most about 10×10^6, at most about 15×10^6, or at most about 20×10^6ng·h / mL.

[0215] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg) to a study patient or subject, where the mean AUC of the compound in the brain is last is about 0.5 x 10^6 to about 20 x 10^6, about 1 x 10^6 to about 15 x 10^6, about 1 x 10^6 to about 10 x 10^6, about 1.5 x 10^6 to about 8 x 10^6, about 1 x 10^6 to about 5 x 10^6, about 5 x 10^6 to about 10 x 10^6, about 1 x 10^6 to about 3 x 10^6, or about 2 x 10^6 to about 5 x 10^6 ng·h / mL. In some embodiments, the AUC last is approximately 1,400,000 hours * ng / mL~about 7500000h * ng / mL.

[0216] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure to a study patient or subject at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg), where the mean T last is at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 10, at least about 12, at least about 14, at least about 21, at least about 28, at least about 35, at least about 42, at least about 49, or at least about 100 days.

[0217] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure to a study patient or subject at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg), where the mean T last is up to about 1, up to about 2, up to about 3, up to about 4, up to about 5, up to about 6, up to about 7, up to about 10, up to about 12, up to about 14, up to about 21, up to about 28, up to about 35, up to about 42, up to about 49, up to about 100 days, up to about 200, or up to about 300 days.

[0218] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure to a study patient or subject at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg), where the mean T lastis about 1 to about 300, about 2 to about 100, about 5 to about 50, about 10 to about 30, about 1 to about 20, about 20 to about 40, about 40 to about 60, about 60 to about 80, or about 80 to about 100 days.

[0219] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure to a study patient or subject at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg), where the mean T 1 / 2 is at least 6, at least 24, at least 48, at least 100, at least 200, at least 500, at least 1000, at least 1500, at least 2000, at least 2500, at least 3000, or at least 5000 hours.

[0220] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure to a study patient or subject at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg), where the mean T 1 / 2 is up to 24, up to 48, up to 100, up to 200, up to 500, up to 1000, up to 1500, up to 2000, up to 2500, up to 3000, up to 5000, up to 10000, or up to 20000 hours.

[0221] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure to a study patient or subject at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg), where the mean T 1 / 2 is about 24 to about 20,000, about 100 to about 15,000, about 500 to about 10,000, about 500 to about 5,000, about 100 to about 1,000, about 1,000 to about 2,000, or about 3,000 to about 5,000 hours.

[0222] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg) to a study patient or subject, wherein the mean T max is at least 0.5, at least 1, at least 2, at least 4, at least 8, at least 12, at least 16, at least 20, at least 24, at least 28, at least 32, at least 36, at least 40, at least 44, or at least 48 hours.

[0223] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg) to a study patient or subject, wherein the mean Tmax is a maximum of 6, a maximum of 12, a maximum of 16, a maximum of 20, a maximum of 24, a maximum of 28, a maximum of 32, a maximum of 36, a maximum of 40, a maximum of 44, a maximum of 48, a maximum of 72, a maximum of 96, or a maximum of 120 hours.

[0224] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg) to a study patient or subject, wherein the mean T max is about 0.5 to about 120, about 1 to about 24, about 1 to about 36, about 1 to about 48, about 2 to about 36, about 6 to about 24, about 1 to about 6, about 6 to about 12, about 12 to about 24, about 12 to about 18, about 18 to about 48, about 18 to about 36, or about 24 to about 48 hours.

[0225] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg) to a study patient or subject, wherein the mean C maxis at least about 1, at least about 1000, at least about 2000, at least about 3000, at least about 4000, at least about 5000, at least about 6000, at least about 7000, at least about 8000, at least about 9000, at least about 10000, at least about 12000, at least about 14000, at least about 16000, at least about 18000, at least about 20000, at least about 22000, or at least about 25000 ng / mL.

[0226] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg) to a study patient or subject, wherein the mean C max is at most about 3000, at most about 4000, at most about 5000, at most about 6000, at most about 7000, at most about 8000, at most about 9000, at most about 10000, at most about 12000, at most about 14000, at most about 16000, at most about 18000, at most about 20000, at most about 22000, at most about 25000, at most about 30000, or at most about 50000 ng / mL.

[0227] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg) to a study patient or subject, wherein the mean C maxis about 1,000 to about 50,000, about 2,000 to about 25,000, about 3,000 to about 22,000, about 2,000 to about 5,000, about 5,000 to about 15,000, or about 10,000 to about 25,000 ng / mL.

[0228] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg) to a study patient or subject, wherein the mean AUC of the compound in the brain is last is at least about 0.5×10^6, at least about 1×10^6, at least about 1.5×10^6, at least about 2×10^6, at least about 2.5×10^6, at least about 3×10^6, at least about 4×10^6, at least about 5×10^6, at least about 6×10^6, at least about 7×10^6, at least about 8×10^6, or at least about 10×10^6 ng·h / mL.

[0229] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg) to a study patient or subject, wherein the mean AUC of the compound in the brain is lastis at most about 1.5×10^6, at most about 2×10^6, at most about 2.5×10^6, at most about 3×10^6, at most about 4×10^6, at most about 5×10^6, at most about 6×10^6, at most about 7×10^6, at most about 8×10^6, at most about 10×10^6, at most about 15×10^6, or at most about 20×10^6ng·h / mL.

[0230] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg) to a study patient or subject, wherein the mean AUC of the compound in the brain is last is about 0.5x10^6 to about 20x10^6, about 1x10^6 to about 15x10^6, about 1x10^6 to about 10x10^6, about 1.5x10^6 to about 8x10^6, about 1x10^6 to about 5x10^6, about 5x10^6 to about 10x10^6, about 1x10^6 to about 3x10^6, or about 2x10^6 to about 5x10^6 ng·h / mL.

[0231] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg) to a study patient or subject, where the mean T lastis at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 10, at least about 12, at least about 14, at least about 21, at least about 28, at least about 35, at least about 42, at least about 49, or at least about 100 days.

[0232] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg) to a study patient or subject, where the mean T last is up to about 1, up to about 2, up to about 3, up to about 4, up to about 5, up to about 6, up to about 7, up to about 10, up to about 12, up to about 14, up to about 21, up to about 28, up to about 35, up to about 42, up to about 49, up to about 100 days, up to about 200, or up to about 300 days.

[0233] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg) to a study patient or subject, where the mean T last is about 1 to about 300, about 2 to about 100, about 5 to about 50, about 10 to about 30, about 1 to about 20, about 20 to about 40, about 40 to about 60, about 60 to about 80, or about 80 to about 100 days.

[0234] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg) to a study patient or subject, where the mean T 1 / 2 is at least 6, at least 24, at least 48, at least 100, at least 200, at least 500, at least 1000, at least 1500, at least 2000, at least 2500, at least 3000, or at least 5000 hours.

[0235] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg) to a study patient or subject, where the mean T 1 / 2 is up to 24, up to 48, up to 100, up to 200, up to 500, up to 1000, up to 1500, up to 2000, up to 2500, up to 3000, up to 5000, up to 10000, or up to 20000 hours.

[0236] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg) to a study patient or subject, where the mean T 1 / 2 is about 24 to about 20,000, about 100 to about 15,000, about 500 to about 10,000, about 500 to about 5,000, about 100 to about 1,000, about 1,000 to about 2,000, or about 3,000 to about 5,000 hours.

[0237] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average T max However, after administration of a single dose to male subjects, the T max The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0238] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average T max However, after administration of a single dose to female subjects, the 48-hour T max The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0239] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average T max However, after administration of a single dose to male subjects, the 4-hour T max The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0240] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average T max However, after administration of a single dose to female subjects, the T max The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0241] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average T max However, after administration of a single dose to male subjects, the 24-hour T max The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0242] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average T max However, after administration of a single dose to female subjects, the 8-hour T max The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0243] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average C max However, after administration of a single dose to male subjects, a C of 3110 ng / mL was observed at 0.3 mg / kg. max The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0244] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average C max However, after a single dose in female subjects, a C of 3930 ng / mL was observed at 0.3 mg / kg. max The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0245] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average C max However, after a single dose in male subjects, a C of 6490 ng / mL was observed at 0.6 mg / kg. max The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0246] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average C max However, after a single dose in female subjects, a C of 11400 ng / mL was observed at 0.6 mg / kg. max The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0247] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average C max However, after administration of a single dose to male subjects, a C of 15500 ng / mL at 1 mg / kg was observed. max The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0248] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average C max However, after a single dose in female subjects, a C of 21500 ng / mL was observed at 1 mg / kg. max The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0249] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having a mean AUC last However, after administration of a single dose to male subjects, the AUC last The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0250] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having a mean AUC last However, after administration of a single dose to female subjects, the AUC last The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0251] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having a mean AUC last However, after administration of a single dose to male subjects, the AUC last The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0252] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having a mean AUC last However, after administration of a single dose to female subjects, the AUC last The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0253] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having a mean AUC last However, after administration of a single dose to male subjects, the AUC last The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0254] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having a mean AUC last However, after administration of a single dose to female subjects, the AUC last The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0255] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average T last However, after administration of a single dose to subjects, the T last The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above. Splenic Pharmacokinetics

[0256] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg) to a study patient or subject, where the mean T max is at least 0.5, at least 1, at least 2, at least 4, at least 8, at least 12, at least 16, at least 20, at least 24, at least 28, at least 32, at least 36, at least 40, at least 44, or at least 48 hours.

[0257] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg) to a study patient or subject, where the mean T max is a maximum of 6, a maximum of 12, a maximum of 16, a maximum of 20, a maximum of 24, a maximum of 28, a maximum of 32, a maximum of 36, a maximum of 40, a maximum of 44, a maximum of 48, a maximum of 72, a maximum of 96, or a maximum of 120 hours.

[0258] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg) to a study patient or subject, where the mean T max is about 0.5 to about 120, about 1 to about 24, about 1 to about 36, about 1 to about 48, about 2 to about 36, about 6 to about 24, about 1 to about 6, about 6 to about 12, about 12 to about 24, about 12 to about 18, about 18 to about 48, about 18 to about 36, or about 24 to about 48 hours.

[0259] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg) to a study patient or subject, where the mean C max is at least about 1, at least about 50, at least about 100, at least about 250, at least about 500, at least about 750, at least about 1250, at least about 1500, at least about 2000, at least about 2500, at least about 3000, at least about 5000, or at least about 10000 ng / mL.

[0260] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg) to a study patient or subject, where the mean C maxis at most about 1000, at most about 1500, at most about 2000, at most about 2500, at most about 3000, at most about 4000, at most about 5000, or at most about 10000 ng / mL.

[0261] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg) to a study patient or subject, where the mean C max is about 100 to about 50,000, about 200 to about 5,000, about 300 to about 4,000, about 500 to about 3,000, about 500 to about 1,000, about 1,000 to about 2,000, about 1,000 to about 3,000, or about 2,000 to about 4,000 ng / mL.

[0262] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure to a study patient or subject at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg), where the mean AUC of the compound in the spleen is last is at least about 0.01×10^6, at least about 0.05×10^6, at least about 0.08×10^6, at least about 0.1×10^6, at least about 0.2×10^6, at least about 0.3×10^6, at least about 0.4×10^6, at least about 0.5×10^6, at least about 0.75×10^6, at least about 1×10^6, at least about 3×10^6 or at least about 5×10^6 ng·h / mL.

[0263] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure to a study patient or subject at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg), where the mean AUC of the compound in the spleen is last is at most about 0.08×10^6, at most about 0.1×10^6, at most about 0.2×10^6, at most about 0.3×10^6, at most about 0.4×10^6, at most about 0.5×10^6, at most about 0.75×10^6, at most about 1×10^6, at most about 1.5×10^6, at most about 2×10^6, or at most about 5×10^6ng·h / mL.

[0264] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure to a study patient or subject at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg), where the mean AUC of the compound in the spleen is last is about 0.01x10^6 to about 5x10^6, about 0.05x10^6 to about 3x10^6, about 0.075x10^6 to about 2x10^6, about 0.09x10^6 to about 1.1x10^6, about 0.1x10^6 to about 0.8x10^6, about 0.1x10^6 to about 0.5x10^6, about 0.1x10^6 to about 0.3x10^6, about 0.3x10^6 to about 1x10^6, about 0.5x10^6 to about 1x10^6, about 0.1x10^6 to about 0.2x10^6, about 0.2x10^6 to about 0.3x10^6, or about 0.3x10^6 to about 0.5x10^6 ng·h / mL.

[0265] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure to a study patient or subject at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg), where the mean T last is at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 10, at least about 12, at least about 14, at least about 21, at least about 28, at least about 35, at least about 42, at least about 49, or at least about 100 days.

[0266] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure to a study patient or subject at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg), where the mean T last is up to about 1, up to about 2, up to about 3, up to about 4, up to about 5, up to about 6, up to about 7, up to about 10, up to about 12, up to about 14, up to about 21, up to about 28, up to about 35, up to about 42, up to about 49, up to about 100 days, up to about 200, or up to about 300 days.

[0267] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure to a study patient or subject at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg), where the mean Tlast is about 1 to about 300, about 2 to about 100, about 5 to about 50, about 10 to about 30, about 1 to about 20, about 20 to about 40, about 40 to about 60, about 60 to about 80, or about 80 to about 100 days.

[0268] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure to a study patient or subject at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg), where the mean T 1 / 2 is at least 6, at least 24, at least 48, at least 100, at least 150, at least 200, at least 250, at least 300, at least 400, at least 500, or at least 1000 hours.

[0269] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure to a study patient or subject at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg), where the mean T 1 / 2 is up to 24, up to 48, up to 100, up to 200, up to 300, up to 400, up to 500, up to 600, up to 750, up to 1000, or up to 5000 hours.

[0270] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure to a study patient or subject at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg), where the mean T 1 / 2 is about 24 to about 20,000, about 50 to about 15,000, about 50 to about 1,000, about 100 to about 500, about 100 to about 300, about 100 to about 200, about 200 to about 300, about 300 to about 400, about 400 to about 500, or about 3,000 to about 5,000 hours.

[0271] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg) to a study patient or subject, wherein the mean T max is at least 0.5, at least 1, at least 2, at least 4, at least 8, at least 12, at least 16, at least 20, at least 24, at least 28, at least 32, at least 36, at least 40, at least 44, or at least 48 hours.

[0272] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg) to a study patient or subject, wherein the mean T max is a maximum of 6, a maximum of 12, a maximum of 16, a maximum of 20, a maximum of 24, a maximum of 28, a maximum of 32, a maximum of 36, a maximum of 40, a maximum of 44, a maximum of 48, a maximum of 72, a maximum of 96, or a maximum of 120 hours.

[0273] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg) to a study patient or subject, wherein the mean T max is about 0.5 to about 120, about 1 to about 24, about 1 to about 36, about 1 to about 48, about 2 to about 36, about 6 to about 24, about 1 to about 6, about 6 to about 12, about 12 to about 24, about 12 to about 18, about 18 to about 48, about 18 to about 36, or about 24 to about 48 hours.

[0274] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg) to a study patient or subject, wherein the mean C max is at least about 1, at least about 50, at least about 100, at least about 250, at least about 500, at least about 750, at least about 1250, at least about 1500, at least about 2000, at least about 2500, at least about 3000, at least about 5000, or at least about 10000 ng / mL.

[0275] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg) to a study patient or subject, wherein the mean C max is at most about 1000, at most about 1500, at most about 2000, at most about 2500, at most about 3000, at most about 4000, at most about 5000, or at most about 10000 ng / mL.

[0276] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg) to a study patient or subject, wherein the mean C max is about 100 to about 50,000, about 200 to about 5,000, about 300 to about 4,000, about 500 to about 3,000, about 500 to about 1,000, about 1,000 to about 2,000, about 1,000 to about 3,000, or about 2,000 to about 4,000 ng / mL.

[0277] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure to a study patient or subject at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg), wherein the mean AUC of the compound in the spleen is last is at least about 0.01×10^6, at least about 0.05×10^6, at least about 0.08×10^6, at least about 0.1×10^6, at least about 0.2×10^6, at least about 0.3×10^6, at least about 0.4×10^6, at least about 0.5×10^6, at least about 0.75×10^6, at least about 1×10^6, at least about 3×10^6, or at least about 5×10^6 ng·h / mL.

[0278] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure to a study patient or subject at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg), wherein the mean AUC of the compound in the spleen is last is at most about 0.08×10^6, at most about 0.1×10^6, at most about 0.2×10^6, at most about 0.3×10^6, at most about 0.4×10^6, at most about 0.5×10^6, at most about 0.75×10^6, at most about 1×10^6, at most about 1.5×10^6, at most about 2×10^6, or at most about 5×10^6ng·h / mL.

[0279] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure to a study patient or subject at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg), wherein the mean AUC of the compound in the spleen is last is about 0.01x10^6 to about 5x10^6, about 0.05x10^6 to about 3x10^6, about 0.075x10^6 to about 2x10^6, about 0.09x10^6 to about 1.1x10^6, about 0.1x10^6 to about 0.8x10^6, about 0.1x10^6 to about 0.5x10^6, about 0.1x10^6 to about 0.3x10^6, about 0.3x10^6 to about 1x10^6, about 0.5x10^6 to about 1x10^6, about 0.1x10^6 to about 0.2x10^6, about 0.2x10^6 to about 0.3x10^6, or about 0.3x10^6 to about 0.5x10^6 ng·h / mL.

[0280] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure to a study patient or subject at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg), where the mean T last is at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 10, at least about 12, at least about 14, at least about 21, at least about 28, at least about 35, at least about 42, at least about 49, or at least about 100 days.

[0281] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure to a study patient or subject at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg), where the mean T last is up to about 1, up to about 2, up to about 3, up to about 4, up to about 5, up to about 6, up to about 7, up to about 10, up to about 12, up to about 14, up to about 21, up to about 28, up to about 35, up to about 42, up to about 49, up to about 100 days, up to about 200, or up to about 300 days.

[0282] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure to a study patient or subject at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg), where the mean T last is about 1 to about 300, about 2 to about 100, about 5 to about 50, about 10 to about 30, about 1 to about 20, about 20 to about 40, about 40 to about 60, about 60 to about 80, or about 80 to about 100 days.

[0283] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure to a study patient or subject at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg), where the mean T 1 / 2 is at least 6, at least 24, at least 48, at least 100, at least 150, at least 200, at least 250, at least 300, at least 400, at least 500, or at least 1000 hours.

[0284] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure to a study patient or subject at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg), where the mean T 1 / 2is up to 24, up to 48, up to 100, up to 200, up to 300, up to 400, up to 500, up to 600, up to 750, up to 1000, or up to 5000 hours.

[0285] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure to a study patient or subject at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg), where the mean T 1 / 2 is about 24 to about 20,000, about 50 to about 15,000, about 50 to about 1,000, about 100 to about 500, about 100 to about 300, about 100 to about 200, about 200 to about 300, about 300 to about 400, about 400 to about 500, or about 3,000 to about 5,000 hours.

[0286] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average T max However, after administration of a single dose to male subjects, the 4-hour T max The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0287] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average T max However, after administration of a single dose to female subjects, the 8-hour T max The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0288] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average T maxHowever, after administration of a single dose to male subjects, the 24-hour T max The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0289] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average T max However, after administration of a single dose to female subjects, the 24-hour T max The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0290] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average T max However, after administration of a single dose to male subjects, the 48-hour T max The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0291] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average T max However, after administration of a single dose to female subjects, the 48-hour T max The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0292] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average C max However, after administration of a single dose to male subjects, a C of 756 ng / mL was observed at 0.3 mg / kg. max The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0293] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average C max However, after a single dose in female subjects, a C of 586 ng / mL was observed at 0.3 mg / kg.max The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0294] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average C max However, after administration of a single dose to male subjects, a C of 1530 ng / mL was observed at 0.6 mg / kg. max The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0295] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average C max However, after a single dose in female subjects, a C of 984 ng / mL was observed at 0.6 mg / kg. max The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0296] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average C max However, after a single dose in male subjects, a C of 2940 ng / mL at 1 mg / kg was observed. max The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0297] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average C max However, after a single dose in female subjects, a C of 2270 ng / mL at 1 mg / kg was observed. max The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0298] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having a mean AUC last However, after administration of a single dose to male subjects, the AUC lastThe pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0299] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having a mean AUC last However, after administration of a single dose to female subjects, the AUC last The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0300] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having a mean AUC last However, after administration of a single dose to male subjects, the AUC last The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0301] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having a mean AUC last However, after administration of a single dose to female subjects, the AUC last The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0302] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having a mean AUC last However, after administration of a single dose to male subjects, the AUC last The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0303] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having a mean AUC lastHowever, after administration of a single dose to female subjects, the AUC last The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0304] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average T last However, after administration of a single dose to male subjects, the 144-hour T last The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0305] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average T last However, after administration of a single dose to female subjects, the T last The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0306] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average T last However, after administration of a single dose to male subjects, the T last The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0307] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average T last However, after administration of a single dose to female subjects, the T last The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0308] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average T last However, after administration of a single dose to male subjects, the Tlast The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0309] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average T last However, after administration of a single dose to female subjects, the T last The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above. Cardiac Pharmacokinetics

[0310] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg) to a test patient or subject, wherein the mean T max is at least 0.5, at least 1, at least 2, at least 4, at least 8, at least 12, at least 16, at least 20, at least 24, at least 28, at least 32, at least 36, at least 40, at least 44, or at least 48 hours.

[0311] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg) to a test patient or subject, wherein the mean T max is a maximum of 6, a maximum of 12, a maximum of 16, a maximum of 20, a maximum of 24, a maximum of 28, a maximum of 32, a maximum of 36, a maximum of 40, a maximum of 44, a maximum of 48, a maximum of 72, a maximum of 96, or a maximum of 120 hours.

[0312] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg) to a test patient or subject, wherein the mean T max is about 0.5 to about 120, about 1 to about 24, about 1 to about 36, about 1 to about 48, about 2 to about 36, about 6 to about 24, about 1 to about 6, about 6 to about 12, about 12 to about 24, about 12 to about 18, about 18 to about 48, about 18 to about 36, or about 24 to about 48 hours.

[0313] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg) to a test patient or subject, wherein the mean C max is at least about 1, at least about 50, at least about 100, at least about 250, at least about 500, at least about 750, at least about 1250, at least about 1500, at least about 2000, at least about 2500, at least about 3000, at least about 5000, or at least about 10000 ng / mL.

[0314] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg) to a test patient or subject, wherein the mean C max is at most about 750, at most about 1000, at most about 1500, at most about 2000, at most about 2500, at most about 3000, at most about 4000, at most about 5000, or at most about 10000 ng / mL.

[0315] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg) to a test patient or subject, wherein the mean C max is about 100 to about 50,000, about 200 to about 5,000, about 300 to about 4,000, about 300 to about 3,000, about 300 to about 1,000, about 100 to about 2,000, about 1,000 to about 3,000, or about 2,000 to about 4,000 ng / mL.

[0316] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg) to a test patient or subject, wherein the mean AUC of the compound in the heart is lastis at least about 0.01×10^6, at least about 0.05×10^6, at least about 0.08×10^6, at least about 0.1×10^6, at least about 0.2×10^6, at least about 0.3×10^6, at least about 0.4×10^6, at least about 0.5×10^6, at least about 0.75×10^6, at least about 1×10^6, at least about 3×10^6, or at least about 5×10^6 ng·h / mL.

[0317] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg) to a test patient or subject, wherein the mean AUC of the compound in the heart is last is at most about 0.08×10^6, at most about 0.1×10^6, at most about 0.2×10^6, at most about 0.3×10^6, at most about 0.4×10^6, at most about 0.5×10^6, at most about 0.75×10^6, at most about 1×10^6, at most about 1.5×10^6, at most about 2×10^6, or at most about 5×10^6ng·h / mL.

[0318] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg) to a test patient or subject, wherein the mean AUC of the compound in the heart is lastis about 0.01x10^6 to about 5x10^6, about 0.05x10^6 to about 3x10^6, about 0.075x10^6 to about 2x10^6, about 0.09x10^6 to about 1.1x10^6, about 0.1x10^6 to about 0.8x10^6, about 0.1x10^6 to about 0.5x10^6, about 0.1x10^6 to about 0.3x10^6, about 0.3x10^6 to about 1x10^6, about 0.5x10^6 to about 1x10^6, about 0.1x10^6 to about 0.2x10^6, about 0.2x10^6 to about 0.3x10^6, or about 0.3x10^6 to about 0.5x10^6 ng·h / mL.

[0319] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the disclosure to a test patient or subject at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg), wherein the mean T last is at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 10, at least about 12, at least about 14, at least about 21, at least about 28, at least about 35, at least about 42, at least about 49, or at least about 100 days.

[0320] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the disclosure to a test patient or subject at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg), wherein the mean T lastis up to about 1, up to about 2, up to about 3, up to about 4, up to about 5, up to about 6, up to about 7, up to about 10, up to about 12, up to about 14, up to about 21, up to about 28, up to about 35, up to about 42, up to about 49, up to about 100 days, up to about 200, or up to about 300 days.

[0321] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the disclosure to a test patient or subject at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg), wherein the mean T last is about 1 to about 300, about 2 to about 100, about 5 to about 50, about 10 to about 30, about 1 to about 20, about 20 to about 40, about 40 to about 60, about 60 to about 80, or about 80 to about 100 days.

[0322] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the disclosure to a test patient or subject at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg), wherein the mean T 1 / 2 is at least 6, at least 24, at least 48, at least 100, at least 150, at least 200, at least 250, at least 300, at least 400, at least 500, or at least 1000 hours.

[0323] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the disclosure to a test patient or subject at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg), wherein the mean T 1 / 2 is up to 24, up to 48, up to 100, up to 200, up to 300, up to 400, up to 500, up to 600, up to 750, up to 1000, or up to 5000 hours.

[0324] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the disclosure to a test patient or subject at a dose of about 0.01 mg / kg to about 5 mg / kg (e.g., about 0.1 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.3 to about 1.2 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.6 mg / kg, or about 0.6 to about 1 mg / kg), wherein the mean T 1 / 2 is about 24 to about 20,000, about 50 to about 15,000, about 50 to about 1,000, about 100 to about 500, about 100 to about 300, about 100 to about 200, about 200 to about 300, about 300 to about 400, about 400 to about 500, or about 3,000 to about 5,000 hours.

[0325] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg) to a test patient or subject, wherein the mean T maxis at least 0.5, at least 1, at least 2, at least 4, at least 8, at least 12, at least 16, at least 20, at least 24, at least 28, at least 32, at least 36, at least 40, at least 44, or at least 48 hours.

[0326] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg) to a test patient or subject, wherein the mean T max is a maximum of 6, a maximum of 12, a maximum of 16, a maximum of 20, a maximum of 24, a maximum of 28, a maximum of 32, a maximum of 36, a maximum of 40, a maximum of 44, a maximum of 48, a maximum of 72, a maximum of 96, or a maximum of 120 hours.

[0327] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg) to a test patient or subject, wherein the mean T max is about 0.5 to about 120, about 1 to about 24, about 1 to about 36, about 1 to about 48, about 2 to about 36, about 6 to about 24, about 1 to about 6, about 6 to about 12, about 12 to about 24, about 12 to about 18, about 18 to about 48, about 18 to about 36, or about 24 to about 48 hours.

[0328] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg) to a test patient or subject, wherein the mean C max is at least about 1, at least about 50, at least about 100, at least about 250, at least about 500, at least about 750, at least about 1250, at least about 1500, at least about 2000, at least about 2500, at least about 3000, at least about 5000, or at least about 10000 ng / mL.

[0329] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg) to a test patient or subject, wherein the mean C max is at most about 1000, at most about 1500, at most about 2000, at most about 2500, at most about 3000, at most about 4000, at most about 5000, or at most about 10000 ng / mL.

[0330] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg) to a test patient or subject, wherein the mean C max is about 100 to about 50,000, about 200 to about 5,000, about 300 to about 4,000, about 500 to about 3,000, about 500 to about 1,000, about 1,000 to about 2,000, about 1,000 to about 3,000, or about 2,000 to about 4,000 ng / mL.

[0331] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg) to a test patient or subject, wherein the mean AUC of the compound in the heart is last is at least about 0.01×10^6, at least about 0.05×10^6, at least about 0.08×10^6, at least about 0.1×10^6, at least about 0.2×10^6, at least about 0.3×10^6, at least about 0.4×10^6, at least about 0.5×10^6, at least about 0.75×10^6, at least about 1×10^6, at least about 3×10^6, or at least about 5×10^6 ng·h / mL.

[0332] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg) to a test patient or subject, wherein the mean AUC of the compound in the heart is last is at most about 0.08×10^6, at most about 0.1×10^6, at most about 0.2×10^6, at most about 0.3×10^6, at most about 0.4×10^6, at most about 0.5×10^6, at most about 0.75×10^6, at most about 1×10^6, at most about 1.5×10^6, at most about 2×10^6, or at most about 5×10^6ng·h / mL.

[0333] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg) to a test patient or subject, wherein the mean AUC of the compound in the heart is last is about 0.01x10^6 to about 5x10^6, about 0.05x10^6 to about 3x10^6, about 0.075x10^6 to about 2x10^6, about 0.09x10^6 to about 1.1x10^6, about 0.1x10^6 to about 0.8x10^6, about 0.1x10^6 to about 0.5x10^6, about 0.1x10^6 to about 0.3x10^6, about 0.3x10^6 to about 1x10^6, about 0.5x10^6 to about 1x10^6, about 0.1x10^6 to about 0.2x10^6, about 0.2x10^6 to about 0.3x10^6, or about 0.3x10^6 to about 0.5x10^6 ng·h / mL.

[0334] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg) to a test patient or subject, wherein the mean T last is at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 10, at least about 12, at least about 14, at least about 21, at least about 28, at least about 35, at least about 42, at least about 49, or at least about 100 days.

[0335] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg) to a test patient or subject, wherein the mean T last is up to about 1, up to about 2, up to about 3, up to about 4, up to about 5, up to about 6, up to about 7, up to about 10, up to about 12, up to about 14, up to about 21, up to about 28, up to about 35, up to about 42, up to about 49, up to about 100 days, up to about 200, or up to about 300 days.

[0336] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg) to a test patient or subject, wherein the mean T last is about 1 to about 300, about 2 to about 100, about 5 to about 50, about 10 to about 30, about 1 to about 20, about 20 to about 40, about 40 to about 60, about 60 to about 80, or about 80 to about 100 days.

[0337] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg) to a test patient or subject, wherein the mean T 1 / 2 is at least 6, at least 24, at least 48, at least 100, at least 150, at least 200, at least 250, at least 300, at least 400, at least 500, or at least 1000 hours.

[0338] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg) to a test patient or subject, wherein the mean T 1 / 2is up to 24, up to 48, up to 100, up to 200, up to 300, up to 400, up to 500, up to 600, up to 750, up to 1000, or up to 5000 hours.

[0339] In some embodiments, if a pharmacokinetic study is performed, the pharmacokinetic study includes administering (e.g., via intracerebroventricular administration) a compound of the present disclosure at a dose of about 0.001 mg / kg to about 0.5 mg / kg (e.g., about 0.008 to about 0.163 mg / kg, about 0.016 to about 0.125 mg / kg, about 0.025 to about 0.1 mg / kg, about 0.025 to about 0.08 mg / kg, about 0.025 to about 0.05 mg / kg, or about 0.05 to about 0.08 mg / kg) to a study patient or subject, wherein the mean T 1 / 2 is about 24 to about 20,000, about 50 to about 15,000, about 50 to about 1,000, about 100 to about 500, about 100 to about 300, about 100 to about 200, about 200 to about 300, about 300 to about 400, about 400 to about 500, or about 3,000 to about 5,000 hours.

[0340] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average T max However, after administration of a single dose to male subjects, the 48-hour T max The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0341] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average T max However, after administration of a single dose to female subjects, the 24-hour T max The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0342] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average C maxHowever, after administration of a single dose to male subjects, a C of 416 ng / mL was observed at 0.3 mg / kg. max The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0343] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average C max However, after a single dose in female subjects, a C of 729 ng / mL was observed at 0.3 mg / kg. max The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0344] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having a mean AUC last However, after administration of a single dose to male subjects, the AUC last The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0345] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having a mean AUC last However, after administration of a single dose to female subjects, the AUC last The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0346] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average T last However, after administration of a single dose to male subjects, the T last The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0347] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intraventricular delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average T lastHowever, after administration of a single dose to female subjects, the T last The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above. Biodistribution

[0348] The biodistribution of the compounds of the present disclosure can be evaluated through a method that can directly or indirectly detect the presence of the compound in tissue.For example, the tissue of the subject that has been administered with the compounds of the present disclosure can be evaluated by mass spectrometry, for example, tandem mass spectrometry, and the presence of the compound in tissue samples can be evaluated based on the intensity of the signal corresponding to the mass of ionized compound or compound fragment.Other methods suitable for determining biodistribution include administering a radiolabeled analog of the compound, and evaluating the radiosignature of the analog in the subject through imaging techniques, for example, autoradiography, positron emission tomography, or single-photon emission computed tomography.

[0349] In some embodiments, the biodistribution of radiolabeled analogs is evaluated through quantitative whole-body autoradiography (QWBA). In quantitative whole-body autoradiography, animal subjects are administered a radiolabeled analog, euthanized at designated times after administration, frozen, and suspended in an embedding medium, such as aqueous carboxymethylcellulose. The suspended carcasses are sectioned in a cryomacrotome, and the resulting sections are mounted on adhesive supports and can be placed on imaging plates sensitive to the specific radioisotope used in the radiolabeled analog, such as carbon-14. The exposed imaging plate can then be converted into electronic form using a phosphor imager system, and selected regions of the image file can be electronically integrated to provide the concentration of the analog, expressed as ng equivalents of compound per gram of tissue (ng-equivalents / g).

[0350] QWBA assay can be repeated for multiple animal subjects, or selected parameters of the assay, such as dosage, route of administration, or the time from compound administration to euthanasia, can be varied for each animal.For example, QWBA can include three components: one animal is euthanized 4 hours after administration of radiolabeled analogue, a second animal is euthanized 12 hours after administration of radiolabeled analogue, and a third animal is euthanized 7 days after administration of radiolabeled analogue.Then, the concentration of analogue in various tissues of each animal can be determined and compared for each animal, thereby providing insight into the time course of biodistribution of radiolabeled analogue and compound.In each study component, urine and feces of each subject animal can be collected and evaluated for radiolabeled analogue content.

[0351] Upon systemic administration, a compound of the present disclosure or a radiolabeled analog thereof can exhibit distribution to certain tissues as determined, for example, by quantitative whole-body autoradiography (QWBA).

[0352] In some embodiments, where assays (e.g., tissue distribution studies) are performed, the assays may be performed using radiolabeled analogs of compounds of the present disclosure (e.g., [ 14C]-Compound 1) to a study patient (e.g., monkey) or subject at a dose of about 5 mg / kg (e.g., about 0.05 to about 500 mg / kg, about 0.5 to about 50 mg / kg, about 1 to about 10 mg / kg, about 2 to about 8 mg / kg, about 3 to about 7 mg / kg, or about 4 to about 6 mg / kg), wherein the compound is capable of distributing to, for example, the renal cortex, joints, cartilage, liver, salivary glands, bone surfaces, pancreas, hair follicles, colonic mucosa, aortic wall, small intestinal mucosa, adrenal glands, gastric mucosa, spleen, bone marrow, lymph nodes, thymus, brain, cerebellum, olfactory bulb, thalamus, caudate nucleus, putamen, cerebral cortex, substantia nigra, lateral ventricles, choroid plexus, or combinations thereof, as determined, for example, by quantitative whole-body autoradiography (QWBA). In some embodiments, the compound is distributed in the tissue for at least 6, at least 24, at least 48, at least 100, at least 125, at least 150, at least 200, at least 250, at least 300, at least 400, at least 500, or at least 1000 hours.

[0353] In some embodiments, when a study or assay (e.g., a tissue distribution study) is performed, the compound is administered (e.g., via a single intravenous dose) to a study patient or subject at a dose of about 5 mg / kg (e.g., about 0.05 to about 500 mg / kg, about 0.5 to about 50 mg / kg, about 1 to about 10 mg / kg, about 2 to about 8 mg / kg, about 3 to about 7 mg / kg, or about 4 to about 6 mg / kg), where the compound is administered ... e.g., via a single intravenous dose, where the compound is administered to a study patient or subject at a dose of about 5 mg / kg (e.g., about 0.05 to about 500 mg / kg, about 0.5 to about 50 mg / kg, about 1 to about 10 mg / kg, about 2 to about 8 mg / kg, about 3 to about 7 mg / kg, or about 4 to about 6 mg / kg), e.g., to a study subject at a dose of about 5 mg / kg (e.g., about 0.05 to about 500 mg / kg, about 0.5 to about 5 , adrenal medulla, aortic wall, bone interior, bone surface, bone marrow, caudate nucleus, cerebellum, cerebral cortex, lateral ventricles, olfactory bulb, putamen, substantia nigra, thalamus, brown fat, ophthalmic duct (choroid plexus + RPE), hair follicles, cardiac blood, cardiac muscle, joints (cartilage), renal cortex, renal medulla, large intestine contents, large intestine mucosa, large intestine wall, liver, lungs, lymph nodes, pancreas, pituitary gland, salivary gland - parotid gland, salivary gland - other, skeletal muscle, skin, small intestine contents, small intestine mucosa, small intestine wall, spinal cord, spleen, stomach contents, stomach mucosa, stomach wall, testes, thymus, thyroid gland, bladder, urine, white fat, whole blood, or a combination thereof. In some embodiments, the compound is distributed to the tissue for at least 6, at least 24, at least 48, at least 100, at least 125, at least 150, at least 200, at least 250, at least 300, at least 400, at least 500, or at least 1000 hours.

[0354] In some embodiments, the present disclosure provides a compound comprising a peptide nucleic acid sequence and a cell permeabilizing group linked to the peptide nucleic acid sequence. In an assay for the retention of the compound in the brain of a subject after administration of the compound, the amount of the compound in the brain 7, 8, 9, or 10 days after administration can be equivalent to at least 80% of the amount of the compound in the brain 4 hours after administration. In some embodiments, the amount of the compound in the brain 7, 8, 9, or 10 days after administration can be equivalent to at least 100% of the amount of the compound in the brain 4 hours after administration. In some embodiments, the amount of the compound in the brain 7, 8, 9, or 10 days after administration can be equivalent to at least 150% of the amount of the compound in the brain 4 hours after administration. In some embodiments, the amount of the compound in the brain 7, 8, 9, or 10 days after administration can be equivalent to at least 200% of the amount of the compound in the brain 4 hours after administration.

[0355] In some embodiments, the present disclosure provides a compound comprising a peptide nucleic acid sequence and a cell permeabilizing group linked to the peptide nucleic acid sequence.After administering the compound to a subject, in the test for the retention of the compound in the brain of the subject, at least 80% of the compound present in the brain 4 hours after administration can remain in the brain for at least 7 days after administration.In some embodiments, the test is a quantitative whole-body autoradiography test.

[0356] In some embodiments, the present disclosure provides a compound comprising a peptide nucleic acid sequence and a cell-permeabilizing group linked to the peptide nucleic acid sequence. In an assay for the retention of the compound in the skeletal muscle of a subject after administration of the compound, the amount of the compound in the skeletal muscle 7, 8, 9, or 10 days after administration can be equivalent to at least 40% of the amount of the compound in the skeletal muscle 4 hours after administration. In some embodiments, the amount of the compound in the skeletal muscle 7, 8, 9, or 10 days after administration can be equivalent to at least 60% of the amount of the compound in the skeletal muscle 4 hours after administration. In some embodiments, the amount of the compound in the skeletal muscle 7, 8, 9, or 10 days after administration can be equivalent to at least 80% of the amount of the compound in the skeletal muscle 4 hours after administration. In some embodiments, the amount of the compound in the skeletal muscle 7, 8, 9, or 10 days after administration can be equivalent to at least 90% of the amount of the compound in the skeletal muscle 4 hours after administration. In some embodiments, the assay is quantitative whole-body autoradiography.

[0357] In some embodiments, the present disclosure provides a compound comprising a peptide nucleic acid sequence and a cell permeabilizing group linked to the peptide nucleic acid sequence.After administering the compound to a subject, in the test of the retention of the compound in the skeletal muscle of the subject, at least 80% of the compound present in the skeletal muscle 4 hours after administration can remain in the skeletal muscle for at least 7 days after administration.In some embodiments, the test is a quantitative whole-body autoradiography test.

[0358] In some embodiments, the concentration of the compound in the subject's brain is at least about 100 nanograms of compound per gram of wet brain tissue, 200 nanograms of compound per gram of wet brain tissue, 300 nanograms of compound per gram of wet brain tissue, 400 nanograms of compound per gram of wet brain tissue, 500 nanograms of compound per gram of wet brain tissue, 600 nanograms of compound per gram of wet brain tissue, 700 nanograms of compound per gram of wet brain tissue, 800 nanograms of compound per gram of wet brain tissue, 900 nanograms of compound per gram of wet brain tissue, or 1000 nanograms of compound per gram of wet brain tissue about 4 hours after the administering step.

[0359] In some embodiments, the concentration of the compound in the subject's brain is at least about 100 nanograms of compound per gram of wet brain tissue, 200 nanograms of compound per gram of wet brain tissue, 300 nanograms of compound per gram of wet brain tissue, 400 nanograms of compound per gram of wet brain tissue, 500 nanograms of compound per gram of wet brain tissue, 600 nanograms of compound per gram of wet brain tissue, 700 nanograms of compound per gram of wet brain tissue, 800 nanograms of compound per gram of wet brain tissue, 900 nanograms of compound per gram of wet brain tissue, or 1000 nanograms of compound per gram of wet brain tissue about 7 days after the administering step.

[0360] In some embodiments, the concentration of the compound in the subject's brain is at least about 200 nanograms of compound per gram of wet brain tissue about 4 hours after the administering step. In some embodiments, the concentration of the compound in the subject's brain is at least about 200 nanograms of compound per gram of wet brain tissue about 7 days after the administering step. In some embodiments, the concentration of the compound in the subject's brain is at least about 100 nanomoles of compound per liter about 4 hours after the administering step. In some embodiments, the concentration of the compound in the subject's brain is at least about 100 nanomoles of compound per liter about 7 days after the administering step.

[0361] Upon systemic administration, compounds of the present disclosure or radiolabeled analogs thereof may exhibit low excretion rates.

[0362] In some embodiments, when an assay (e.g., tissue distribution study) is performed, the assay may involve administering to a subject a compound of the present disclosure (e.g., Compound 1) or a radiolabeled analog thereof (e.g., [ 14C]-Compound 1) to a study patient (e.g., monkey) or subject at a dose of about 5 mg / kg (e.g., about 0.05 to about 500 mg / kg, about 0.5 to about 50 mg / kg, about 1 to about 10 mg / kg, about 2 to about 8 mg / kg, about 3 to about 7 mg / kg, or about 4 to about 6 mg / kg), wherein less than about 20% of the dose, about Less than 15%, less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2.5%, less than about 2%, less than about 1.9%, less than about 1.8%, less than about 1.7%, less than about 1.6%, less than about 1.5%, less than about 1.4%, less than about 1.3%, less than about 1.2%, less than about 1.1%, or less than about 1% may be recovered from urine, for example, during about 168 hours.

[0363] In some embodiments, when an assay (e.g., tissue distribution study) is performed, the assay may involve administering to a subject a compound of the present disclosure (e.g., Compound 1) or a radiolabeled analog thereof (e.g., [ 14 C]-Compound 1) to a study patient (e.g., monkey) or subject at a dose of about 5 mg / kg (e.g., about 0.05 to about 500 mg / kg, about 0.5 to about 50 mg / kg, about 1 to about 10 mg / kg, about 2 to about 8 mg / kg, about 3 to about 7 mg / kg, or about 4 to about 6 mg / kg), wherein less than about 20% of the dose, about 1 Less than 5%, less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2.5%, less than about 2%, less than about 1.9%, less than about 1.8%, less than about 1.7%, less than about 1.6%, less than about 1.5%, less than about 1.4%, less than about 1.3%, less than about 1.2%, less than about 1.1%, or less than about 1% may be recovered from the feces over, for example, about 168 hours.

[0364] In some embodiments, when an assay (e.g., tissue distribution study) is performed, the assay may involve administering to a subject a compound of the present disclosure (e.g., Compound 1) or a radiolabeled analog thereof (e.g., [ 14C]-Compound 1) to a study patient (e.g., monkey) or subject at a dosage of about 5 mg / kg (e.g., about 0.05 to about 500 mg / kg, about 0.5 to about 50 mg / kg, about 1 to about 10 mg / kg, about 2 to about 8 mg / kg, about 3 to about 7 mg / kg, or about 4 to about 6 mg / kg), wherein less than about 20% of the dose, Less than about 15%, less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2.5%, less than about 2%, less than about 1.9%, less than about 1.8%, less than about 1.7%, less than about 1.6%, less than about 1.5%, less than about 1.4%, less than about 1.3%, less than about 1.2%, less than about 1.1%, or less than about 1% may be excreted, for example, over a period of about 168 hours.

[0365] In some embodiments, when a study or assay (e.g., tissue distribution study) is performed, the assay may involve administering to a subject a compound of the disclosure (e.g., Compound 1) or a radiolabeled analog thereof (e.g., [ 14 C]-Compound 1) to a study patient (e.g., monkey) or subject at a dose of about 5 mg / kg (e.g., about 0.05 to about 500 mg / kg, about 0.5 to about 50 mg / kg, about 1 to about 10 mg / kg, about 2 to about 8 mg / kg, about 3 to about 7 mg / kg, or about 4 to about 6 mg / kg), wherein the mean T 1 / 2 is at least 6, at least 24, at least 48, at least 100, at least 125, at least 150, at least 200, at least 250, at least 300, at least 400, at least 500, or at least 1000 hours.

[0366] In some embodiments, when a study or assay (e.g., tissue distribution study) is performed, the assay may involve administering to a subject a compound of the disclosure (e.g., Compound 1) or a radiolabeled analog thereof (e.g., [ 14C]-Compound 1) to a study patient (e.g., monkey) or subject at a dose of about 5 mg / kg (e.g., about 0.05 to about 500 mg / kg, about 0.5 to about 50 mg / kg, about 1 to about 10 mg / kg, about 2 to about 8 mg / kg, about 3 to about 7 mg / kg, or about 4 to about 6 mg / kg), wherein the mean T 1 / 2 is up to 24, up to 48, up to 100, up to 200, up to 300, up to 400, up to 500, up to 600, up to 750, up to 1000, or up to 5000 hours.

[0367] In some embodiments, when a study or assay (e.g., tissue distribution study) is performed, the assay may involve administering to a subject a compound of the disclosure (e.g., Compound 1) or a radiolabeled analog thereof (e.g., [ 14 C]-Compound 1) to a study patient (e.g., monkey) or subject at a dose of about 5 mg / kg (e.g., about 0.05 to about 500 mg / kg, about 0.5 to about 50 mg / kg, about 1 to about 10 mg / kg, about 2 to about 8 mg / kg, about 3 to about 7 mg / kg, or about 4 to about 6 mg / kg), wherein the mean T 1 / 2 is about 24 to about 20,000, about 50 to about 15,000, about 50 to about 1,000, about 100 to about 500, about 100 to about 300, about 100 to about 200, about 200 to about 300, about 300 to about 400, about 400 to about 500, or about 3,000 to about 5,000 hours.

[0368] In some embodiments, where studies or assays (e.g., tissue distribution studies) are performed, the assays may be performed using radiolabeled analogs of compounds of the present disclosure (e.g., [ 14 C]-Compound 1) to a study patient (e.g., monkey) or subject at a dose of about 5 mg / kg (e.g., about 0.05 to about 500 mg / kg, about 0.5 to about 50 mg / kg, about 1 to about 10 mg / kg, about 2 to about 8 mg / kg, about 3 to about 7 mg / kg, or about 4 to about 6 mg / kg), wherein the mean C of the compound in plasma is maxis at least about 1, at least about 1000, at least about 2000, at least about 3000, at least about 4000, at least about 5000, at least about 6000, at least about 7000, at least about 8000, at least about 9000, at least about 10000, at least about 12000, at least about 14000, at least about 16000, at least about 18000, at least about 20000, at least about 22000, or at least about 25000 ng-equivalents / g.

[0369] In some embodiments, when a study or assay (e.g., tissue distribution study) is performed, the assay may involve administering to a subject a compound of the disclosure (e.g., Compound 1) or a radiolabeled analog thereof (e.g., [ 14 C]-Compound 1) to a study patient (e.g., monkey) or subject at a dose of about 5 mg / kg (e.g., about 0.05 to about 500 mg / kg, about 0.5 to about 50 mg / kg, about 1 to about 10 mg / kg, about 2 to about 8 mg / kg, about 3 to about 7 mg / kg, or about 4 to about 6 mg / kg), wherein the mean C of the compound in plasma is max is at most about 3000, at most about 4000, at most about 5000, at most about 6000, at most about 7000, at most about 8000, at most about 9000, at most about 10000, at most about 12000, at most about 14000, at most about 16000, at most about 18000, at most about 20000, at most about 22000, at most about 25000, at most about 30000, or at most about 50000 ng-eq / g.

[0370] In some embodiments, where studies or assays (e.g., tissue distribution studies) are performed, the assays may be performed using radiolabeled analogs of compounds of the present disclosure (e.g., [ 14C]-Compound 1) to a study patient (e.g., monkey) or subject at a dose of about 5 mg / kg (e.g., about 0.05 to about 500 mg / kg, about 0.5 to about 50 mg / kg, about 1 to about 10 mg / kg, about 2 to about 8 mg / kg, about 3 to about 7 mg / kg, or about 4 to about 6 mg / kg), wherein the mean C of the compound in plasma is max is about 1,000 to about 50,000, about 2,000 to about 25,000, about 3,000 to about 22,000, about 2,000 to about 5,000, about 5,000 to about 15,000, or about 10,000 to about 25,000 ng-equivalents / g.

[0371] In some embodiments, when a study or assay (e.g., tissue distribution study) is performed, the assay may involve administering to a subject a compound of the disclosure (e.g., Compound 1) or a radiolabeled analog thereof (e.g., [ 14 C]-Compound 1) to a study patient (e.g., monkey) or subject at a dose of about 1.6 mg / kg (e.g., about 0.015 to about 160 mg / kg, about 0.16 to about 16 mg / kg, about 0.3 to about 3.2 mg / kg, about 0.65 to about 2.6 mg / kg, about 1 to about 2.3 mg / kg, or about 1.3 to about 2 mg / kg), wherein the mean T 1 / 2 is at least 6, at least 24, at least 48, at least 100, at least 125, at least 150, at least 200, at least 250, at least 300, at least 400, at least 500, or at least 1000 hours.

[0372] In some embodiments, when a study or assay (e.g., tissue distribution study) is performed, the assay may involve administering to a subject a compound of the disclosure (e.g., Compound 1) or a radiolabeled analog thereof (e.g., [ 14C]-Compound 1) to a study patient (e.g., monkey) or subject at a dose of about 1.6 mg / kg (e.g., about 0.015 to about 160 mg / kg, about 0.16 to about 16 mg / kg, about 0.3 to about 3.2 mg / kg, about 0.65 to about 2.6 mg / kg, about 1 to about 2.3 mg / kg, or about 1.3 to about 2 mg / kg), wherein the mean T 1 / 2 is up to 24, up to 48, up to 100, up to 200, up to 300, up to 400, up to 500, up to 600, up to 750, up to 1000, or up to 5000 hours.

[0373] In some embodiments, when a study or assay (e.g., tissue distribution study) is performed, the assay may involve administering to a subject a compound of the disclosure (e.g., Compound 1) or a radiolabeled analog thereof (e.g., [ 14 C]-Compound 1) to a study patient (e.g., monkey) or subject at a dose of about 1.6 mg / kg (e.g., about 0.015 to about 160 mg / kg, about 0.16 to about 16 mg / kg, about 0.3 to about 3.2 mg / kg, about 0.65 to about 2.6 mg / kg, about 1 to about 2.3 mg / kg, or about 1.3 to about 2 mg / kg), wherein the mean T 1 / 2 is about 24 to about 20,000, about 50 to about 15,000, about 50 to about 1,000, about 100 to about 500, about 100 to about 300, about 100 to about 200, about 200 to about 300, about 300 to about 400, about 400 to about 500, or about 3,000 to about 5,000 hours.

[0374] In some embodiments, where studies or assays (e.g., tissue distribution studies) are performed, the assays may be performed using radiolabeled analogs of compounds of the present disclosure (e.g., [ 14C]-Compound 1) to a study patient (e.g., monkey) or subject at a dose of about 1.6 mg / kg (e.g., about 0.015 to about 160 mg / kg, about 0.16 to about 16 mg / kg, about 0.3 to about 3.2 mg / kg, about 0.65 to about 2.6 mg / kg, about 1 to about 2.3 mg / kg, or about 1.3 to about 2 mg / kg), wherein the mean C of the compound in plasma is max is at least about 1, at least about 1000, at least about 2000, at least about 3000, at least about 4000, at least about 5000, at least about 6000, at least about 7000, at least about 8000, at least about 9000, at least about 10000, at least about 12000, at least about 14000, at least about 16000, at least about 18000, at least about 20000, at least about 22000, or at least about 25000 ng-equivalents / g.

[0375] In some embodiments, where studies or assays (e.g., tissue distribution studies) are performed, the assays may be performed using radiolabeled analogs of compounds of the present disclosure (e.g., [ 14 C]-Compound 1) to a study patient (e.g., monkey) or subject at a dose of about 1.6 mg / kg (e.g., about 0.015 to about 160 mg / kg, about 0.16 to about 16 mg / kg, about 0.3 to about 3.2 mg / kg, about 0.65 to about 2.6 mg / kg, about 1 to about 2.3 mg / kg, or about 1.3 to about 2 mg / kg), wherein the mean C of the compound in plasma is max is at most about 3000, at most about 4000, at most about 5000, at most about 6000, at most about 7000, at most about 8000, at most about 9000, at most about 10000, at most about 12000, at most about 14000, at most about 16000, at most about 18000, at most about 20000, at most about 22000, at most about 25000, at most about 30000, or at most about 50000 ng-eq / g.

[0376] In some embodiments, where studies or assays (e.g., tissue distribution studies) are performed, the assays may be performed using radiolabeled analogs of compounds of the present disclosure (e.g., [ 14 C]-Compound 1) to a study patient (e.g., monkey) or subject at a dose of about 1.6 mg / kg (e.g., about 0.015 to about 160 mg / kg, about 0.16 to about 16 mg / kg, about 0.3 to about 3.2 mg / kg, about 0.65 to about 2.6 mg / kg, about 1 to about 2.3 mg / kg, or about 1.3 to about 2 mg / kg), wherein the mean C of the compound in plasma is max is about 1,000 to about 50,000, about 2,000 to about 25,000, about 3,000 to about 22,000, about 2,000 to about 5,000, about 5,000 to about 15,000, or about 10,000 to about 25,000 ng-equivalents / g.

[0377] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intravenous delivery of a compound comprising a peptide nucleic acid sequence or a radiolabeled analog thereof, wherein the mean AUC 0-t However, after administration of a single dose to subjects, the AUC 0-t The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0378] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intravenous delivery of a compound comprising a peptide nucleic acid sequence or a radiolabeled analog thereof, wherein the compound has an average C max However, after administration of a single dose to subjects, a C of 11500 ng-equivalents / g was observed in plasma. max The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0379] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intravenous delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average t 1 / 2 After administration of a single dose to subjects, the t 1 / 2 The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0380] In some embodiments, the subject is a primate, monkey, or human.

[0381] In some embodiments, when a study or assay (e.g., tissue distribution study) is performed, the assay may involve administering to a subject a compound of the disclosure (e.g., Compound 1) or a radiolabeled analog thereof (e.g., [ 14 C]-Compound 1) to a study patient (e.g., monkey) or subject at a dose of about 5 mg / kg (e.g., about 0.05 to about 500 mg / kg, about 0.5 to about 50 mg / kg, about 1 to about 10 mg / kg, about 2 to about 8 mg / kg, about 3 to about 7 mg / kg, or about 4 to about 6 mg / kg), where the mean T 1 / 2 is at least 6, at least 24, at least 48, at least 100, at least 125, at least 150, at least 200, at least 250, at least 300, at least 400, at least 500, or at least 1000 hours.

[0382] In some embodiments, when a study or assay (e.g., tissue distribution study) is performed, the assay may involve administering to a subject a compound of the disclosure (e.g., Compound 1) or a radiolabeled analog thereof (e.g., [ 14 C]-Compound 1) to a study patient (e.g., monkey) or subject at a dose of about 5 mg / kg (e.g., about 0.05 to about 500 mg / kg, about 0.5 to about 50 mg / kg, about 1 to about 10 mg / kg, about 2 to about 8 mg / kg, about 3 to about 7 mg / kg, or about 4 to about 6 mg / kg), where the mean T 1 / 2 is up to 24, up to 48, up to 100, up to 200, up to 300, up to 400, up to 500, up to 600, up to 750, up to 1000, or up to 5000 hours.

[0383] In some embodiments, when a study or assay (e.g., tissue distribution study) is performed, the assay may involve administering to a subject a compound of the disclosure (e.g., Compound 1) or a radiolabeled analog thereof (e.g., [ 14C]-Compound 1) to a study patient (e.g., monkey) or subject at a dose of about 5 mg / kg (e.g., about 0.05 to about 500 mg / kg, about 0.5 to about 50 mg / kg, about 1 to about 10 mg / kg, about 2 to about 8 mg / kg, about 3 to about 7 mg / kg, or about 4 to about 6 mg / kg), where the mean T 1 / 2 is about 24 to about 20,000, about 50 to about 15,000, about 50 to about 1,000, about 100 to about 500, about 100 to about 300, about 100 to about 200, about 200 to about 300, about 300 to about 400, about 400 to about 500, or about 3,000 to about 5,000 hours.

[0384] In some embodiments, where studies or assays (e.g., tissue distribution studies) are performed, the assays may be performed using radiolabeled analogs of compounds of the present disclosure (e.g., [ 14 C]-Compound 1) to a study patient (e.g., monkey) or subject at a dose of about 5 mg / kg (e.g., about 0.05 to about 500 mg / kg, about 0.5 to about 50 mg / kg, about 1 to about 10 mg / kg, about 2 to about 8 mg / kg, about 3 to about 7 mg / kg, or about 4 to about 6 mg / kg), where the average C of the compound in the blood is max is at least about 1, at least about 1000, at least about 2000, at least about 3000, at least about 4000, at least about 5000, at least about 6000, at least about 7000, at least about 8000, at least about 9000, at least about 10000, at least about 12000, at least about 14000, at least about 16000, at least about 18000, at least about 20000, at least about 22000, or at least about 25000 ng-equivalents / g.

[0385] In some embodiments, where studies or assays (e.g., tissue distribution studies) are performed, the assays may be performed using radiolabeled analogs of compounds of the present disclosure (e.g., [ 14C]-Compound 1) to a study patient (e.g., monkey) or subject at a dose of about 5 mg / kg (e.g., about 0.05 to about 500 mg / kg, about 0.5 to about 50 mg / kg, about 1 to about 10 mg / kg, about 2 to about 8 mg / kg, about 3 to about 7 mg / kg, or about 4 to about 6 mg / kg), where the average C of the compound in the blood is max is at most about 3000, at most about 4000, at most about 5000, at most about 6000, at most about 7000, at most about 8000, at most about 9000, at most about 10000, at most about 12000, at most about 14000, at most about 16000, at most about 18000, at most about 20000, at most about 22000, at most about 25000, at most about 30000, or at most about 50000 ng-eq / g.

[0386] In some embodiments, where studies or assays (e.g., tissue distribution studies) are performed, the assays may be performed using radiolabeled analogs of compounds of the present disclosure (e.g., [ 14 C]-Compound 1) to a study patient (e.g., monkey) or subject at a dose of about 5 mg / kg (e.g., about 0.05 to about 500 mg / kg, about 0.5 to about 50 mg / kg, about 1 to about 10 mg / kg, about 2 to about 8 mg / kg, about 3 to about 7 mg / kg, or about 4 to about 6 mg / kg), where the average C of the compound in the blood is max is about 1,000 to about 50,000, about 2,000 to about 25,000, about 3,000 to about 22,000, about 2,000 to about 5,000, about 5,000 to about 15,000, or about 10,000 to about 25,000 ng-equivalents / g.

[0387] In some embodiments, when a study or assay (e.g., tissue distribution study) is performed, the assay may involve administering to a subject a compound of the disclosure (e.g., Compound 1) or a radiolabeled analog thereof (e.g., [ 14C]-Compound 1) to a study patient or subject at a dose of about 1.6 mg / kg (e.g., about 0.015 to about 160 mg / kg, about 0.16 to about 16 mg / kg, about 0.3 to about 3.2 mg / kg, about 0.65 to about 2.6 mg / kg, about 1 to about 2.3 mg / kg, or about 1.3 to about 2 mg / kg), wherein the mean T 1 / 2 is at least 6, at least 24, at least 48, at least 100, at least 125, at least 150, at least 200, at least 250, at least 300, at least 400, at least 500, or at least 1000 hours.

[0388] In some embodiments, when a study or assay (e.g., tissue distribution study) is performed, the assay may involve administering to a subject a compound of the disclosure (e.g., Compound 1) or a radiolabeled analog thereof (e.g., [ 14 C]-Compound 1) to a study patient or subject at a dose of about 1.6 mg / kg (e.g., about 0.015 to about 160 mg / kg, about 0.16 to about 16 mg / kg, about 0.3 to about 3.2 mg / kg, about 0.65 to about 2.6 mg / kg, about 1 to about 2.3 mg / kg, or about 1.3 to about 2 mg / kg), wherein the mean T 1 / 2 is up to 24, up to 48, up to 100, up to 200, up to 300, up to 400, up to 500, up to 600, up to 750, up to 1000, or up to 5000 hours.

[0389] In some embodiments, when a study or assay (e.g., tissue distribution study) is performed, the assay may involve administering to a subject a compound of the disclosure (e.g., Compound 1) or a radiolabeled analog thereof (e.g., [ 14C]-Compound 1) to a study patient or subject at a dose of about 1.6 mg / kg (e.g., about 0.015 to about 160 mg / kg, about 0.16 to about 16 mg / kg, about 0.3 to about 3.2 mg / kg, about 0.65 to about 2.6 mg / kg, about 1 to about 2.3 mg / kg, or about 1.3 to about 2 mg / kg), wherein the mean T 1 / 2 is about 24 to about 20,000, about 50 to about 15,000, about 50 to about 1,000, about 100 to about 500, about 100 to about 300, about 100 to about 200, about 200 to about 300, about 300 to about 400, about 400 to about 500, or about 3,000 to about 5,000 hours.

[0390] In some embodiments, where studies or assays (e.g., tissue distribution studies) are performed, the assays may be performed using radiolabeled analogs of compounds of the present disclosure (e.g., [ 14 C]-Compound 1) to a study patient or subject at a dose of about 1.6 mg / kg (e.g., about 0.015 to about 160 mg / kg, about 0.16 to about 16 mg / kg, about 0.3 to about 3.2 mg / kg, about 0.65 to about 2.6 mg / kg, about 1 to about 2.3 mg / kg, or about 1.3 to about 2 mg / kg), wherein the mean C of the compound in the blood is max is at least about 1, at least about 1000, at least about 2000, at least about 3000, at least about 4000, at least about 5000, at least about 6000, at least about 7000, at least about 8000, at least about 9000, at least about 10000, at least about 12000, at least about 14000, at least about 16000, at least about 18000, at least about 20000, at least about 22000, or at least about 25000 ng-equivalents / g.

[0391] In some embodiments, where studies or assays (e.g., tissue distribution studies) are performed, the assays may be performed using radiolabeled analogs of compounds of the present disclosure (e.g., [ 14C]-Compound 1) to a study patient or subject at a dose of about 1.6 mg / kg (e.g., about 0.015 to about 160 mg / kg, about 0.16 to about 16 mg / kg, about 0.3 to about 3.2 mg / kg, about 0.65 to about 2.6 mg / kg, about 1 to about 2.3 mg / kg, or about 1.3 to about 2 mg / kg), wherein the mean C of the compound in the blood is max is at most about 3000, at most about 4000, at most about 5000, at most about 6000, at most about 7000, at most about 8000, at most about 9000, at most about 10000, at most about 12000, at most about 14000, at most about 16000, at most about 18000, at most about 20000, at most about 22000, at most about 25000, at most about 30000, or at most about 50000 ng-eq / g.

[0392] In some embodiments, where studies or assays (e.g., tissue distribution studies) are performed, the assays may be performed using radiolabeled analogs of compounds of the present disclosure (e.g., [ 14 C]-Compound 1) to a study patient or subject at a dose of about 1.6 mg / kg (e.g., about 0.015 to about 160 mg / kg, about 0.16 to about 16 mg / kg, about 0.3 to about 3.2 mg / kg, about 0.65 to about 2.6 mg / kg, about 1 to about 2.3 mg / kg, or about 1.3 to about 2 mg / kg), wherein the mean C of the compound in the blood is max is about 1,000 to about 50,000, about 2,000 to about 25,000, about 3,000 to about 22,000, about 2,000 to about 5,000, about 5,000 to about 15,000, or about 10,000 to about 25,000 ng-equivalents / g.

[0393] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intravenous delivery of a compound comprising a peptide nucleic acid sequence, the mean AUC 0-t However, after administration of a single dose to subjects, the AUC 0-t The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0394] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intravenous delivery of a compound comprising a peptide nucleic acid sequence, the compound comprising a radiolabeled analog of the compound having an average C max However, after administration of a single dose to subjects, a C of 7510 ng-equivalents / g was observed in the blood. max The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0395] In some embodiments, provided herein is a pharmaceutical composition in unit dosage form for intravenous delivery of a compound comprising a peptide nucleic acid sequence, the compound having an average t 1 / 2 After administration of a single dose to subjects, the t 1 / 2 The pharmaceutical composition is provided, wherein the content is within 70% to 130% of the above.

[0396] In some embodiments, the subject is a primate, monkey, or human.

[0397] In some embodiments, 2% or less of the therapeutically effective amount of the compound is excreted in urine by the subject over a 7-day period following the administering step. In some embodiments, 2% or less of the therapeutically effective amount of the compound is excreted in feces by the subject over a 7-day period following the administering step.

[0398] In some embodiments, the compound of the present disclosure can achieve complete biodistribution without lipid nanoparticles.For example, the scaffold can be modified by covalent bonding so that the compound exhibits cell permeability that is not different between cell types.For example, the scaffold can be modified by covalent bonding with functional groups (for example, guanidino groups) so that the compound exhibits cell permeability that is not significantly different between cell types.

[0399] In some embodiments, when a compound disclosed herein is subjected to a plasma protein binding assay, the plasma protein binding percentage is at least about 85% in one or more study patients in the plasma protein binding assay. In some embodiments, the plasma protein binding percentage is at least about 85% in each of humans, mice, dogs, minipigs, sheep, and / or monkeys. In some embodiments, the plasma protein binding assay comprises performing a plasma protein binding assay on the study patient. In some embodiments, at a concentration of about 1 μg / mL, the plasma protein binding percentage is at least about 95% in each of humans, mice, dogs, minipigs, sheep, and / or monkeys. In some embodiments, at a concentration of about 1 μg / mL, the plasma protein binding percentage is at least about 95% in each of humans, mice, dogs, minipigs, sheep, and monkeys.

[0400] In some embodiments, the plasma protein binding assay includes spiking a single aliquot of a study patient's plasma with a first solution of the compound (e.g., a 10 mg / mL first solution of the compound) to obtain at least a second solution of the compound (e.g., a concentration of about 1 μg / mL to about 50 μg / mL). In some embodiments, a separation technique (e.g., ultracentrifugation) is used on the at least second solution of the compound to separate a mixture containing the compound bound to plasma proteins. In some embodiments, the plasma protein binding percentage in the study patient's plasma can be determined using various techniques disclosed herein, such as liquid chromatography-tandem mass spectrometry.

[0401] In some embodiments, the plasma protein binding assay includes performing a human component of the plasma protein binding assay. For example, the human component of the plasma protein binding assay includes spiking a single aliquot of human plasma with a first solution of the compound (e.g., a 10 mg / mL first solution of the compound) to obtain at least a second solution of the compound (e.g., a concentration of about 1 μg / mL to about 50 μg / mL). In some embodiments, a separation technique (e.g., ultracentrifugation) is used on the at least second solution of the compound to separate a mixture containing the compound bound to plasma proteins. In some embodiments, the percentage of plasma protein binding in human plasma can be determined using various techniques disclosed herein, such as liquid chromatography-tandem mass spectrometry. In some embodiments, the murine component of the plasma protein binding assay is performed. In some embodiments, the murine component of the plasma protein binding assay differs from the human component of the plasma protein binding assay only in that mouse plasma is used instead of human plasma. In some embodiments, the canine component of the plasma protein binding assay is performed. In some embodiments, the canine component of the plasma protein binding assay differs from the human component of the plasma protein binding assay only in that canine plasma is used instead of human plasma. In some embodiments, the minipig component of the plasma protein binding assay is performed. In some embodiments, the minipig component of the plasma protein binding assay differs from the human component of the plasma protein binding assay only in that minipig plasma is used instead of human plasma. In some embodiments, the sheep component of the plasma protein binding assay is performed. In some embodiments, the sheep component of the plasma protein binding assay differs from the human component of the plasma protein binding assay only in that sheep plasma is used instead of human plasma. In some embodiments, the monkey component of the plasma protein binding assay is performed.In some embodiments, the monkey component of the plasma protein binding assay differs from the human component of the plasma protein binding assay only in that monkey plasma is used instead of human plasma.

[0402] In some embodiments, when a compound is evaluated in plasma from a host species in a plasma binding protein assay (e.g., an in vitro plasma binding protein assay) (e.g., spiked into pooled plasma at a concentration of about 0.01, about 0.1, about 0.5, about 1, about 5, about 10, about 50, about 100, about 500, or about 1000 μg / mL), the % bound to plasma proteins (PPB) of the compound is about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 7 %, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, Approximately 48%, approximately 49%, approximately 50%, approximately 51%, approximately 52%, approximately 53%, approximately 54%, approximately 55%, approximately 56%, approximately 57%, approximately 58%, approximately 59%, approximately 60%, approximately 61%, approximately 62%, approximately 63%, approximately 64%, approximately 65%, approximately 66%, approximately 67%, approximately 68%, approximately 69%, approximately 70%, approximately 71%, approximately 72%, approximately 73%, approximately 74%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, approximately 80%, approximately 81%, approximately 82%, approximately 83%, approximately 84%, approximately 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 95.5%, about 96%, about 96.5%, about 97%, about 97.5%, about 98%, about 98.5%, about 99%, about 99.1%, about 99.1%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, about 99.9%, about 99.95%, or about 99.99%. The host species can be, for example, a mouse (e.g., C57BL6), a dog (e.g., a beagle), a minipig (e.g., a Gottingen minipig), a sheep, a monkey (e.g., a cynomolgus monkey), a human, or any suitable animal disclosed herein.

[0403] In some embodiments, in a plasma binding protein assay (e.g., an in vitro plasma binding protein assay), when a compound is evaluated in plasma from a host species (e.g., spiked into pooled plasma at a concentration of about 0.01, about 0.1, about 0.5, about 1, about 5, about 10, about 50, about 100, about 500, or about 1000 μg / mL), the % bound to plasma proteins (PPB) of the compound is at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 5%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59% %, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%,at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 95.5%, at least about 96%, at least about 96.5%, at least about 97%, at least about 97.5%, at least about 98%, at least about 98.5%, at least about 99%, at least about 99.1%, at least about 99.1%, at least about 99.3%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, at least about 99.9%, at least about 99.95%, or at least about 99.99%. The host species can be, for example, a mouse (e.g., C57BL6), a dog (e.g., a beagle), a minipig (e.g., a Gottingen minipig), a sheep, a monkey (e.g., a cynomolgus monkey), a human, or any suitable animal disclosed herein.

[0404] In some embodiments, when a compound is evaluated in plasma from a host species (e.g., spiked into pooled plasma at a concentration of about 0.01, about 0.1, about 0.5, about 1, about 5, about 10, about 50, about 100, about 500, or about 1000 μg / mL) in a plasma binding protein assay (e.g., an in vitro plasma binding protein assay), the % bound to plasma proteins (PPB) of the compound is at most about 1%, at most about 2%, at most about 3%, at most about 4%, at most about 5%, at most about 6%, at most about 7%, at most about 8%, at most about 9%, at most about 10%, at most about 11%, at most about 12%, at most about 13%, at most about 14%, at most about 15%, at most about 16%, at most about 17%, at most about 18%, at most about 19%, at most about 20%, at most about 21%, at most about 22%, at most about 23%, at most about 24%, at most about 25%, at most about 26%, at most about 27%, at most about 28%, at most about 29%, at most about 30%, at most about 31%, at most about 32%, at most about 33%, at most about 34%, at most about 35%, at most about 36%, at most about 37%, at most about 38%, at most about 39%, at most about 40%, at most about 41%, at most about 42%, at most about 43%, at most about 44%, at most about 45%, at most about 46%, at most about 47%, at most about 48%, at most about 49%, at most about 50%, at most about 51%, at most about 52%, at most about 53%, at most about 54%, at most about 55%, at most about 56%, at %, up to about 14%, up to about 15%, up to about 16%, up to about 17%, up to about 18%, up to about 19%, up to about 20%, up to about 21%, up to about 22%, up to about 23%, up to about 24%, up to about 25%, up to about 26%, up to about 27%, up to about 28%, up to about 29%, up to about 30%, up to about 31%, up to about 32%, up to about 33%, up to about 34%, up to about 35%, up to about 36%, up to about 37%, up to about 38%, up to about 39%, up to about 40%, up to about 41%, up to about 42%, up to about 43 %, up to about 44%, up to about 45%, up to about 46%, up to about 47%, up to about 48%, up to about 49%, up to about 50%, up to about 51%, up to about 52%, up to about 53%, up to about 54%, up to about 55%, up to about 56%, up to about 57%, up to about 58%, up to about 59%, up to about 60%, up to about 61%, up to about 62%, up to about 63%, up to about 64%, up to about 65%, up to about 66%, up to about 67%, up to about 68%, up to about 69%, up to about 70%, up to about 71%, up to about 72%, up to about 7 3%, up to about 74%, up to about 75%, up to about 76%, up to about 77%, up to about 78%, up to about 79%, up to about 80%, up to about 81%, up to about 82%, up to about 83%, up to about 84%, up to about 85%, up to about 86%, up to about 87%, up to about 88%, up to about 89%, up to about 90%, up to about 91%, up to about 92%, up to about 93%, up to about 94%, up to about 95%, up to about 95.5%, up to about 96%, up to about 96.5%, up to about 97%, up to about 97.5%, up to about 98%, up to about 98.99.9%, up to about 99.95%, or up to about 99.99%. The host species can be, for example, a mouse (e.g., C57BL6), a dog (e.g., beagle), a minipig (e.g., Gottingen minipig), a sheep, a monkey (e.g., cynomolgus monkey), a human, or any suitable animal disclosed herein.

[0405] In some embodiments, in a plasma binding protein assay (e.g., an in vitro plasma binding protein assay), when a compound is evaluated in plasma from a host species (e.g., spiked into pooled plasma at a concentration of about 0.01, about 0.1, about 0.5, about 1, about 5, about 10, about 50, about 100, about 500, or about 1000 μg / mL), the % binding of the compound to plasma proteins (PPB) is between about 0% and about 10%, about 10% and about 20%, about 20% and about 30%, about 30% and about 40%, about 40% and about 50%, about 50% and about 60%, about 60% and about 70%, about 70% and about 80%, about 80% and about 90%, about 90% and about 100%. 00%, about 0% to about 20%, about 0% to about 30%, about 0% to about 40%, about 0% to about 50%, about 0% to about 60%, about 0% to about 70%, about 0% to about 80%, about 0% to about 90%, about 10% to about 30%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 80%, about 10% to about 90%, about 10% to about 100%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 20% to about 90%, about 20% to about 100%, about 30% to about 50%, about 30% ~ about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 30% to about 100%, about 40% to about 60%, about 40% to about 70%, about 40% to about 80%, about 40% to about 90%, about 40% to about 100%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 50% to about 100%, about 60% to about 80%, about 60% to about 90%, about 60% to about 100%, about 70% to about 90%, about 70% to about 100%, or about 80% to about 100%, about 85% to about 99%, about 87% to about 99%, about 88% to about 99%, about 89% to about 99% 9%, about 90% to about 99%, about 91% to about 99%, about 92% to about 99%, about 93% to about 99%, about 94% to about 99%, about 95% to about 99%, about 96% to about 99%, about 97% to about 99%, about 98% to about 99%, about 85% to about 98%, about 87% to about 98%, about 88% to about 98%, about 89% to about 98%, about 90% to about 98%, about 91% to about 98%, about 92% to about 98%, about 93% to about 98%, about 94% to about 98%, about 95% to about 98%, about 96% to about 98%, about 97% to about 98%, about 85% to about 97%, about 87% to about 97%, about 88% to about 97%,Approximately 89% to approximately 97%, approximately 90% to approximately 97%, approximately 91% to approximately 97%, approximately 92% to approximately 97%, approximately 93% to approximately 97%, approximately 94% to approximately 97%, approximately 95% to approximately 97%, approximately 96% to approximately 97%, approximately 85% to approximately 96%, approximately 87% to approximately 96%, approximately 88% to approximately 96%, approximately 89% to approximately 96%, approximately 90% to approximately 96%, approximately 91% to approximately 96 %, about 92% to about 96%, about 93% to about 96%, about 94% to about 96%, about 95% to about 96%, about 85% to about 95%, about 87% to about 95%, about 88% to about 95%, about 89% to about 95%, about 90% to about 95%, about 91% to about 95%, about 92% to about 95%, about 93% to about 95%, or about 94% to about 95%. The host species can be, for example, a mouse (e.g., C57BL6), a dog (e.g., a beagle), a minipig (e.g., a Gottingen minipig), a sheep, a monkey (e.g., a cynomolgus monkey), a human, or any suitable animal disclosed herein. [Example]

[0406] Example 1 In vitro plasma protein binding of compound 1 in mice, dogs, minipigs, sheep, monkeys, and humans. This study was designed to determine the in vitro binding of compound 1 to plasma proteins in C57BL6J mice, beagle dogs, Göttingen minipigs, sheep, cynomolgus monkeys, and humans. Plasma protein binding (PPB) was assessed in pooled male plasma at nominal compound 1 concentrations of 1, 10, and 50 μg / mL. The assay was performed using ultrafiltration techniques, and compound 1 concentrations were determined by LC-MS / MS analysis. Warfarin was used as a positive control to validate each ultrafiltration run. Using Busher's classification, the binding of compound 1 to plasma proteins was ranked as high to very high (PPB > 85.0%) at 1 μg / mL and high (85.0% ≤ PPB ≤ 98.0%) at both 10 μg / mL and 50 μg / mL. A slight concentration dependence was observed across the concentration range investigated, suggesting a tendency for the PPB to become nonlinear with increasing concentrations of compound 1. This trend was more evident in mice, dogs, minipigs, and humans. The PPB results for Compound 1 at various concentrations are summarized in Table 1. [Table 1] Test system

[0407] Plasma from male C57BL6J mice, male beagle dogs, male Göttingen minipigs, male sheep, male cynomolgus monkeys, and male humans was purchased from BIOIVT (UK). Preclinical plasma was pooled from at least three different non-fasting animals, while human plasma was obtained from at least three healthy, fasting volunteers. K3EDTA was used as the anticoagulant for both species. All plasma was stored at 20°C and thawed only once on the day of the experiment. No pH correction was applied before the experiment. Experimental design

[0408] In this study, the binding of compound 1 to plasma proteins in mice, dogs, minipigs, sheep, monkeys, and humans was determined in triplicate at nominal concentrations of 1, 10, and 50 μg / mL using ultrafiltration techniques.

[0409] Separation of unbound Compound 1 from plasma proteins was performed using a Centrifree® ultrafiltration device with a 30,000 NMWL regenerated cellulose membrane.

[0410] The suitability of ultrafiltration as a method for determining protein binding of Compound 1 was evaluated.

[0411] A single concentration of 4.1 μM warfarin in male human plasma (n=3) was used as a control compound, and in each ultrafiltration run, the control was tested in parallel with the test article to ensure accurate experimental performance. Methods and Procedures Preparation of phosphate-buffered saline (PBS).

[0412] Phosphate buffered saline (PBS) was prepared at a concentration of 0.146 M. The pH was measured and found to be 7.40. The PBS was stored at 4°C. Compound 1 spike solution.

[0413] A stock solution (SS) containing 10 mg / mL of Compound 1 was prepared. The SS was further diluted in PBS supplemented with 0.2% (v / v) formic acid to obtain a working solution WS1, 100 μg / mL. Compound 1 SS and Compound 1 WS were stored at −80° C. Preparation of warfarin solution.

[0414] A stock solution of warfarin (SS_W) was prepared in water:acetonitrile (50:50, v / v) at a nominal concentration of 3.24 mM (equivalent to 1 mg / mL). This solution was further diluted in the same solvent to obtain a working solution, WS_W, 410 μM, which was used for plasma spiking.

[0415] Warfarin SS_W was stored at 4°C (not to exceed 21 days per method sheet). Warfarin WS_W was prepared fresh for each ultrafiltration. Plasma sample preparation.

[0416] Single aliquots of appropriate volumes of mouse, dog, minipig, sheep, monkey, and human plasma were spiked with 10 mg / mL SS or 100 μg / mL WS to obtain target concentrations of 1, 10, and 50 μg / mL. Each sample was then gently mixed and rotated for approximately 10–15 minutes before being transferred to an ultrafiltration tube.

[0417] The same procedure was followed to prepare a warfarin control sample of 4.1 μM (equivalent to 1265 ng / mL) in male human plasma. Suitability of the method for ultrafiltration.

[0418] To assess the suitability of the ultrafiltration technique, experiments were performed to determine the potential for nonspecific binding to the filtration membrane and the stability of the test articles in plasma and PBS over incubation times. Assessment of nonspecific binding of Compound 1 to ultrafiltration devices.

[0419] An appropriate amount of PBS was spiked with three test article concentrations (1, 10, and 50 μg / mL). The samples were mixed for 1-2 minutes at room temperature.

[0420] Triplicate aliquots of each spiked sample were transferred to ultrafiltration tubes and spun at 1500 g in a Biofuge centrifuge with a fixed-angle rotor at room temperature until the entire load had passed through the filter.

[0421] Before centrifugation (t), triplicate aliquots were collected from each sample and the concentration of Compound 1 (C) was determined by LC-MS / MS analysis. After centrifugation, the bottom ultrafiltrate (C u Triplicate aliquots of ) were retained and then analyzed by LC-MS / MS. Stability assessment of Compound 1 in plasma and PBS.

[0422] The stability of Compound 1 was evaluated at two test article concentrations (1 and 50 μg / mL) in all plasma types and in PBS by incubating each matrix at 37°C for 15 minutes and then at room temperature for 4 hours (a time covering incubation, ultrafiltration, and sample processing for analysis). 4h In both cases, the concentration of Compound 1 was determined by LC-MS / MS analysis. Ultrafiltration procedure.

[0423] The in vitro binding of compound 1 to plasma proteins was determined at three concentrations: 1, 10, and 50 μg / mL.

[0424] To prevent nonspecific binding of Compound 1 to the ultrafiltration tube, the inner wall was rinsed with 10% (v / v) Triton® X-100 solution and allowed to dry for at least 1 hour before use.

[0425] Triplicate aliquots of each spiked plasma were transferred to ultrafiltration tubes, which were spun at 1500 g for 20 minutes at room temperature in a Biofuge centrifuge equipped with a fixed-angle rotor.

[0426] Triplicate aliquots of spiked plasma were retained before centrifugation to obtain the concentration of Compound 1 in plasma after ultracentrifugation (C0). Then, after centrifugation, the upper retentate (C r ) and bottom ultrafiltrate (C u ) was removed for LC-MS / MS analysis.

[0427] The entire ultrafiltration device, the ultrafiltration reservoir and the filtrate cup were weighed before adding the sample, after adding the sample (only for the entire ultrafiltration device) and at the end of centrifugation.

[0428] The same procedure was performed for the warfarin control sample. Determination of protein content in ultrafiltration samples.

[0429] After collection, each ultrafiltrate sample was checked for protein content to assess possible protein contamination and then to confirm the integrity of the filter for ultrafiltration. The Bradford method was used to assess the presence of protein in the ultrafiltrate.

[0430] A calibration standard curve of bovine serum albumin was prepared at the following concentrations: 0, 50, 100, 200, 400, 600, 800, and 1000 μg / mL.

[0431] The calibration standards and ultrafiltrate samples were dispensed (6 μL / well) into a 96-well plate and supplemented with Coomassie Brilliant Blue G solution (300 μL). After 1 minute at room temperature, the absorbance of each well was measured at λ = 595 nm using an absorbance microplate reader. Sample processing and analysis.

[0432] Appropriate aliquots of spiked plasma (collected before and after ultrafiltration) and ultrafiltrated samples (collected after ultrafiltration) were supplemented with an equal volume (matrix-matching) of drug-free PBS or drug-free plasma, respectively.

[0433] After matrix matching, plasma and ultrafiltration samples were extracted and analyzed by LC-MS / MS. Sample storage.

[0434] All samples were collected in uniquely identifiable containers labeled with study number, sample type, nominal sample concentration, and incubation time. Compound 1 and warfarin samples were stored at -80°C. Data Handling and Analysis Plasma protein binding calculations Non-specific binding (NSB)

[0435] in the PBS sample before centrifugation (C0) and in the ultrafiltration sample collected after centrifugation (C u The NSB into the ultrafiltration tube was determined from the concentration of Compound 1 in the PBS solution.

number

[0436] During the ceremony,

[0437] C0 = Compound 1 concentration before ultrafiltration, ng / mL

[0438] C u = Compound 1 concentration after ultrafiltration, ng / mL Stability evaluation

[0439] In plasma (or PBS), the cells were incubated at room temperature for the duration of the experiment (t 4h ) was calculated as follows:

number

[0440] During the ceremony,

[0441] C0 = concentration in matrix (plasma or PBS) at t0, ng / mL

[0442] C 4h =t 4h Concentration in the matrix (plasma or PBS) after treatment, ng / mL Plasma protein binding.

[0443] The percent binding of Compound 1 to plasma proteins (B% or PPB%) was determined using the following equation:

number

[0444] During the ceremony,

[0445] F=free fraction

[0446] R = recovery rate

[0447] The same calculation was performed for the warfarin control sample. Total recovery rate.

[0448] The concentrations of Compound 1 in the ultrafiltrate and retentate samples (post-ultrafiltration) were compared to the concentration of Compound 1 in the sample before ultrafiltration to obtain percent recovery values ​​as described in the following equation:

number

[0449] NSB ≤ 20% is acceptable. t 4h Compound 1 was considered stable in plasma and PBS when the percentage difference between the concentration after t and the concentration after t0 was within ±15%. The protein binding of warfarin, which is a positive control, should be 98.0% or more. The protein concentration measured after ultrafiltration should be 0.3 mg / mL or less.

[0450] The value of the recovery rate (R) (range of recovery rate, %) was evaluated as detailed below: R ≥ 200 or R ≤ 50 means that the experimental data is not valid; 50 ≤ R < 80 or 120 < R ≤ 200 means potentially unreliable experimental data; and 80 ≤ R ≤ 120 means that the experimental data is valid. Results Evaluation of non-specific binding (NSB).

[0451] Generally, NSB to the filtration membrane was 20.5%, 6.2%, and 2.2% at concentrations of 1, 10, and 50 μg / mL of Compound 1, respectively, indicating that the contribution of NSB increased as the concentration decreased (this is a typical trend for compounds showing NSB). Since NSB did not exceed approximately 20% (even in the worst case), the ultrafiltration technique was considered to be suitable for the purpose.

[0452] The results of the NSB evaluation are shown in Table 2. [Table 2] Determination of the stability of Compound 1 in plasma and PBS.

[0453] Compound 1 was stable (i.e., with a percentage loss not exceeding 15%) in mouse, dog, sheep, monkey, and human plasma as well as in PBS when incubated at room temperature for up to 4 hours at both 1 μg / mL and 50 μg / mL.

[0454] Compound 1 was stable in minipig plasma at 1 μg / mL, but slight instability (characterized by a loss percentage of 22.5%) was observed at 50 μg / mL.

[0455] The stability results of Compound 1 in plasma and PBS samples are shown in Table 3. [Table 3-1] [Table 3-2] [Table 3-3] Determination of plasma protein binding of compound 1.

[0456] The degree of PPB was defined by Busher's classification: very high (PPB ≥ 98.0%), high (85.0% ≤ PPB ≤ 98.0%), and moderate-low (PPB < 85.0%).

[0457] The PPB results for compound 1 at various concentrations (1, 10, and 50 μg / mL) are summarized in Table 1 and reported in full in Table 4. [Table 4-1] [Table 4-2] [Table 4-3]

[0458] A slight concentration dependence was observed over the range of concentrations investigated, suggesting that there is a tendency for the PPB to become nonlinear with increasing concentrations of compound 1, which is more pronounced in mice, dogs, minipigs, and humans.

[0459] The average PPB of warfarin was 99.2% or greater in all experiments, thus validating each ultrafiltration run (see Table 5). [Table 5]

[0460] No protein contamination was detected in any of the ultrafiltered Compound 1 samples. Bioanalysis results.

[0461] Matrix-matched samples were analyzed using three qualified bioanalytical LC-MS / MS methods: one for warfarin and two for Compound 1 (one for minipigs and one for humans, cynomolgus monkeys, dogs, sheep, and mice).

[0462] Carryover was assessed throughout the study phase by injecting one or more blank samples after the high-concentration standard. Carryover was greater than 25% of the response at the LLOQ for Compound 1 and less than 5% for the internal standard. Carryover was greater than 25% of the response at the LLOQ for warfarin and less than 5% for the internal standard. To avoid possible influence on the final results, study samples were analyzed according to expected concentrations.

[0463] Compound 1 and warfarin concentrations in study samples were determined from appropriate calibration plots within BioLims.

[0464] Samples with unexpected results were re-assayed in duplicate. In some cases, the results were not reportable (NR). conclusion

[0465] Consistent with Busher's classification, the binding of compound 1 to plasma proteins was ranked as high to very high (PPB > 85.0%) at 1 μg / mL and high (85.0% ≤ PPB ≤ 98.0%) at both 10 μg / mL and 50 μg / mL. A slight concentration dependence was observed across the concentration range investigated, suggesting a tendency for the PPB to become nonlinear with increasing concentrations of compound 1. This tendency was more evident in mice, dogs, minipigs, and humans. Example 2 Tissue distribution of total radioactivity in cynomolgus monkeys after a single intravenous bolus administration of Compound 1.

[0466] The purpose of this study was to use quantitative whole-body autoradiography (QWBA) to assess the [ 14 The purpose of this study was to evaluate the tissue distribution, disposition, and pharmacokinetics (PK) of [C]-Compound 1, a drug-related substance. Cynomolgus monkeys are representative of human distribution and excretion. After administration, three animals were placed in metabolic cages and housed for 4, 12, and 168 hours post-dose, respectively.

[0467] [ 14 The disposition of [C]-Compound 1 was investigated in only one animal (number 103, 168 h). Total radioactivity was measured in urine, feces, and cage rinses.

[0468] Pharmacokinetic profiles were obtained in blood and plasma collected from each animal from selected time points post-dose through termination.

[0469] After euthanasia at 4, 12, and 168 hours post-dose, quantitative whole-body autoradiography was used to determine the [ 14 The tissue distribution of [C]-Compound 1 was investigated.

[0470] [ 14Following IV bolus administration of [C]-Compound 1, very limited amounts of the administered radioactivity (4.2% of the dose) were excreted over 168 hours after administration. This observation indicated that most of the dose was retained in tissues: 1.5% and 1.7% of the dose were recovered in urine and feces, respectively. Cage rinses, associated with urinary excretion, accounted for an additional 0.9% of the dose.

[0471] Total radioactivity in blood and plasma was quantifiable in all animals until the end of the study period. last Total systemic exposure to radioactivity (AUC) measured as the area under the plasma concentration-time curve (AUC) 0~t ) in blood and plasma were 231000 and 205000 h·ng-eq / g, respectively, while the maximum concentration (C max ) were 7510 ng-eq / g (C09260 ng-eq / g) and 11500 ng-eq / g (C014000 ng-eq / g), respectively. Total radioactivity showed greater distribution in plasma than in blood (blood to plasma ratios of 0.6-0.8), except at 168 hours, where a ratio of 2.1 was observed.

[0472] The clearance (CL) was 6.69 mL / h / kg (blood) and 14.0 mL / h / kg (plasma), significantly lower than the hepatic and renal blood flow rates (approximately 2616 and 1656 mL / h / kg). Consistently, the mean volume of distribution (V ss ) accounted for 2480 mL / kg (blood) and 2780 mL / kg (plasma), which was greater than the total body water in cynomolgus monkeys (approximately 693 mL / kg), and showed a moderate volume of distribution (0.6-5 L / kg).

[0473] in general,[ 14[C]-Compound 1 drug-related substance was widely distributed throughout the body and was quantifiable in all tissues up to the final sampling time point. Tissue distribution patterns were comparable among selected time points over 168 hours post-dose. Highest concentrations were observed in the kidney cortex, joints (most likely connected to cartilage), and liver, suggesting possible accumulation in these tissues.

[0474] Other tissues that showed significant uptake were: salivary glands, bone surfaces, pancreas, hair follicles, large intestinal mucosa, aortic wall, small intestinal mucosa, adrenal glands, gastric mucosa, spleen, bone marrow, lymph nodes, and thymus.

[0475] Moderate brain penetration was observed (brain to blood ratio <1): total radioactivity was distributed quite homogeneously in the relevant subregions (cerebellum, olfactory bulb, thalamus, caudate nucleus, putamen, cerebral cortex, and substantia nigra), but the highest concentrations were measured in the lateral ventricles, most likely within the choroid plexus.

[0476] Finally, radioactivity was also measured in tissues containing melanin (eg, hair follicles and, most importantly, the uveal tract of the eye), indicating possible binding to melanin. Radiolabeled test articles.

[0477] [ 14 C]-Compound 1( 14 (Radiolabeled by conjugation to 1C doubly labeled glycine)

[0478] Specific radioactivity: 29.3μCi / mg (1.08MBq / mg)

[0479] Radiochemical purity: 73.7%

[0480] The radiolabeled test article (88.8 MBq, equivalent to 81.9 mg), supplied as a powder, was dissolved in vehicle (8.9 mL) to obtain a radioactive stock solution (SS) with a nominal concentration of 10 MBq / mL (9.2 mg / mL). The actual radioactivity concentration and radiochemical purity of the SS were determined by liquid scintillation counting (LSC) prior to use. The SS was stored at -80°C. Vehicle (control).

[0481] DPBS: Dulbecco's phosphate buffered saline (modified, calcium chloride and magnesium chloride free, liquid, sterile filtered).

[0482] pH 7.1 to 7.5

[0483] Osmolality: 275-304 mOs / kg.

[0484] Storage conditions: Below 30°C (ambient temperature, AT), 2-8°C when opened. Test article formulation.

[0485] Target dose level: 5.0 mg / kg

[0486] Target radioactivity dose: 147μCi / kg (5.42MBq / kg)

[0487] Dosage volume: 2.0 mL / kg

[0488] Nominal concentration: 2.5 mg / mL

[0489] Nominal radioactivity concentration: 73.3μCi / mL (2.71MBq / mL)

[0490] Methods: The final formulation was prepared the day before administration. The SS was thawed at ambient temperature, heated to approximately 65°C for 5 minutes, and then allowed to cool to room temperature under magnetic stirring. An appropriate aliquot of the SS was diluted with the required volume of vehicle and kept at room temperature overnight under magnetic stirring. At the stated specific activities, no additional isotope dilution with non-radiolabeled test articles was required.

[0491] Stability of the final formulation: 14 The heating step was evaluated beforehand to ensure that the stability of [C]-Compound 1 was not affected. Stability at ambient temperature was evaluated over 24 hours, allowing for formulation preparation the day before administration.

[0492] Storage conditions for final formulation: Ambient temperature for up to 24 hours prior to administration.

[0493] Residual test article formulation: The residual formulation was stored at -20°C. Test system Characterization of the test system.

[0494] Number of studies: 3 males

[0495] Age: Between 2 and 2.5 years old

[0496] Weight: 2.40kg, 2.24kg, 2.29kg

[0497] Minimum acclimation: At least 21 days (before Day 1)

[0498] Monkeys were used as one of the non-rodent species required for toxicity studies per study guidance. Cynomolgus monkeys were chosen because the blood-brain barrier of non-human primates is more similar to that of humans than to that of dogs.

[0499] Temperature and humidity were recorded daily during the study phase. The actual mean measurements (including range) were 21.3°C and 52.7%. Average temperature and relative humidity were always within acceptable ranges during the living phase: 21-23°C (20-24°C is acceptable for less than 24 hours) and 45-65% (40-70% is acceptable for less than 24 hours), respectively. Food, water, and environmental enrichment.

[0500] Food was available ad libitum throughout the study, except approximately 1 hour before and 1 hour after dosing. Fruit, vegetable, and feed mix supplements were also provided.

[0501] Filtered water from regular household water was available ad libitum throughout the study.

[0502] Monkeys had access to special environmental enrichment devices in each cage, and social interactions between animals and staff were ensured for appropriate periods twice daily on working days and once daily on weekends. Experimental design

[0503] Three naive male cynomolgus monkeys were each administered a target dose of 5 mg / kg [ 14 C]-Compound 1. After dose administration, animals were placed in metabolic cages and the following matrices were collected as outlined in Table 6: [Table 6]

[0504] Levels of total radioactivity in the following matrices were determined by liquid scintillation counting (LSC): blood, plasma, urine, feces, and cage rinse.

[0505] At the termination time points (4, 12, and 168 hours post-dose, respectively), animals were euthanized and tissue distribution of total radioactivity was assessed using QWBA.

[0506] The organ distribution of total radioactivity was assessed in the brain (cerebellum, olfactory bulb, thalamus, caudate nucleus, putamen, cerebral cortex, and substantia nigra), eyes, and kidneys. Sections were collected using a cryomacrotome, lyophilized, and exposed to imaging plates. The resulting whole-body electron autoradiograms were evaluated for quantitative assessment of radioactivity within the tissues.

[0507] Where possible, radioactivity data in blood, plasma and tissues were subjected to non-compartmental analysis for assessment of relevant pharmacokinetic parameters. Methods and Procedures Assessment of test article stability.

[0508] Prior to initiating in-vivo experimental activities, the stability of the test article was assessed by measuring radiochemical purity under the following conditions:

[0509] An aliquot of SS was heated to approximately 65°C for 5 minutes to ensure this step was completed during formulation preparation. 14 It was confirmed that this does not affect the stability of the C label.

[0510] The stability of the final formulation was evaluated at room temperature for 4 and 24 hours.

[0511] In monkey blood 14 A preliminary evaluation of the stability of [C]-Compound 1 was also performed: a fixed volume of blank monkey blood was spiked with an appropriate aliquot of radiolabeled SS and incubated at 37°C for 4 and 24 hours.

[0512] Measurement of radiochemical purity after incubation in blood and assessment of stability in biological matrices were not possible because radioactivity could not be extracted using standard approaches. Characterization of stock solutions and formulations.

[0513] The radioactivity concentrations of the stock solutions and dose formulations were determined as follows: three weighed aliquots were dispensed into glass vials and diluted appropriately with DPBS. Three weighed aliquots were then removed from each dilution, replenished with liquid scintillant, and radioassayed on an LSC to determine the actual radioactivity concentration and homogeneity of the solution. Dose administration.

[0514] The dose formulation was administered intravenously as a bolus via the tail vein.

[0515] The individual dose volume was adjusted based on the animal's body weight on the day of dose administration. The dose was dispensed into pre-weighed syringes, which were weighed before and after dose administration. The actual dose that each animal received was calculated from the dose concentration, the weight of the administered dose and the animal's body weight. Sample collection. Phase 1: Excretory balance.

[0516] Following dosing, urine and feces were quantitatively collected at selected time points post-dose and kept refrigerated on wet ice during collection.

[0517] Every day and / or at the end of the collection period, metabolic cages were rinsed with ethanol / water (50:50, v / v) and the washings were retained for quantitative determination of radioactivity.

[0518] Cage debris was collected and pooled per animal for the entire collection period. Phase 2: Pharmacokinetics.

[0519] After administration, whole blood was removed from the cephalic vein at each selected time point after administration and transferred to tubes containing K3EDTA as an anticoagulant (the actual time of blood collection was recorded). After collection, all blood samples were thoroughly mixed and placed on wet ice. Plasma samples were prepared within 2 hours of blood collection. Liquid scintillation counting analysis

[0520] Triplicate aliquots of liquid samples (eg, dose formulation, urine, plasma, and cage washes) were counted directly in liquid scintillant.

[0521] Feces were homogenized in a suitable volume of ultrapure water (approximate ratio 1:2, w / v) using a Stomacher homogenizer. Quadrilateral aliquots (0.2–0.4 g) of the homogenate were solubilized by adding 1 mL of Solvable tissue solubilizer, supplemented twice with 200 μL of 30% hydrogen peroxide (HO), and incubated at approximately 50°C until a suitable color change was achieved before adding scintillant.

[0522] Triplicate weighed aliquots (100 μL) of blood were processed as fecal homogenates.

[0523] The remaining blood was centrifuged at 2000 g for 10 minutes at approximately 4° C. within 2 hours of collection, and the plasma was decanted into plastic tubes. An aliquot of the plasma was radioassayed on an LSC. The blood pellet was discarded.

[0524] Radioactivity was determined in a Tricarb Series liquid scintillation analyzer. Quench correction was achieved during sample counting by automatically assigning a quench index (tSIE / AEC) value to the sample. This value was used to interpolate sample counting efficiencies from instrument-stored quench curves generated from a sealed series of quenched standards. The interpolated efficiency values ​​were used to automatically correct counts per minute (cpm) for LSC data to obtain disintegrations per minute (dpm). A suitable scintillation fluid (Ultima Gold) was added to each sample, which was then radioassayed by LSC for the appropriate time. Background counts were subtracted from the quench-corrected sample counts. The limit of quantitation was calculated based on the background value and counting time. Tissue distribution.

[0525] At the final time points (4, 12, and 168 hours post-dose, respectively), animals were euthanized and whole-body quantitative autoradiography was used to assess tissue distribution of total radioactivity. Sample collection and embedding.

[0526] After euthanasia, the animals were frozen by immersion in a hexane / solid CO2 freezing mixture. The animals were left in the freezing mixture for at least 2 hours until completely frozen.

[0527] Frozen carcasses were embedded left side up in blocks of sodium carboxymethylcellulose (approximately 2% w / v in water). Sectioning.

[0528] Each block was mounted in a CM3600 cryomacrotome (Leica Microsystems) maintained at approximately -20°C. After initial trimming of the blocks, sagittal whole-body sections (40 μm) were obtained at various levels throughout the carcass. The desired sections, mounted on pressure-sensitive tape, were dehydrated for approximately 60 hours in the cryomacrotome chamber at approximately -20°C. Autoradiography.

[0529] The freeze-dried sections were14 The samples were then placed against an imaging plate (IP) suitable for C for approximately 4 days. During the exposure period, the IP was placed in a copper-lead shielding box to minimize external background signals. After exposure, the IP was scanned with a laser beam using a Fuji FLA5000 phosphor imager system, and the latent image was captured and stored in an electronic data file.

[0530] For each set of whole-body images acquired, the system was calibrated using biological standards of known radioactivity.

[0531] Selected tissues were identified on the images and integrated using AIDA software to obtain tissue density values. Triplicate measurements were made across each selected organ / tissue, where possible, either by multiple integrations on a single section or by multiple integrations from several different sections.

[0532] The results from the integration were expressed as Bq / g and then converted to ng-equivalents of Compound 1 per gram of tissue (ng-eq / g) using the specific activity of the dose formulation.

[0533] The limit of quantitation (LOQ) for tissue distribution was set as 3 times the mean background level of radioactivity (mean of 7 determinations per IP).

[0534] For quantification purposes, it was assumed that all analyzed tissues had similar density and quenching characteristics to blood (used as a calibration standard). Exceptions to this rule were bone and white fat, where correction factors of 0.48 and 0.84, respectively, were applied to compensate for radioactive quenching. correction curve

[0535] A block of frozen CMC (approximately 2% w / v in water) containing standards of known radioactivity was prepared separately. A series of paper straws were fixed to this block and increasing amounts of [ 14Monkey blood containing [C]-Compound 1 was aliquoted into straws and frozen. The range of calibration standards was chosen to encompass a range of similar tissue concentration values ​​(actual range: 56.8–32,274 Bq / g).

[0536] A calibration line was generated for each set of sections exposed to a single IP by selecting an area of ​​each standard from the scanned image and assigning the corresponding radioactive concentration previously determined by LSC. result Analysis of stock solutions.

[0537] The radioactivity concentration and radiochemical purity of the stock solution were checked before use. The radioactivity concentration (MBq / mL) was 9.52. The radiochemical purity was 93.2%. Stability assessment of test article.

[0538] Compound 1 was stable under the experimental conditions evaluated. Formulation analysis.

[0539] Compound 1 concentration: 2.33 mg / g (Compound 1 + [ 14 C]-Compound 1 mg)

[0540] Radioactivity concentration: 2.52MBq / g

[0541] Specific radioactivity of the preparation: 1.08MBq / mg

[0542] CV: 1.9% (overall pre- and post-administration)

[0543] Difference between pre- and post-administration: 1.6%

[0544] Radiochemical purity: 91.8% (average of pre- and post-administration)

[0545] The formulation was found to be homogeneous pre-dose and across doses (CV<5%).

[0546] The difference in concentration between pre- and post-administration was within ±10%. The dose administered.

[0547] was administered as a single IV bolus to male cynomolgus monkeys. 14 The actual doses of C]-Compound 1 are shown in Table 7. [Table 7]

[0548] Actual dose average: 4.72 ± 0.05 mg of total Compound 1 per kg (Compound 1 + [ 14 C]-Compound 1 mg)

[0549] Actual mean radioactive dose: 5.09 ± 0.05 MBq / kg

[0550] No clinical signs were observed after administration. excretion.

[0551] Due to early termination time points for animals 101 and 102, it was not possible to collect excreta from these animals. Individual excretion data was obtained from animal 103 and is shown in Table 8. Cumulative data for the same animals is also shown in Table 8. Cumulative excretion is also plotted in Figure 1. [Table 8-1] [Table 8-2] [Table 9-1] [Table 9-2]

[0552] [ 14After IV bolus administration of [C]-Compound 1, very limited amounts of the administered radioactivity (4.2% of the dose) were excreted over 168 hours after administration, with most of the dose being retained in tissues: 1.5% and 1.7% of the dose were recovered in urine and feces, respectively. An additional 0.9% of the dose was recovered in cage rinses associated with urinary excretion. Pharmacokinetics in blood and plasma

[0553] Male cynomolgus monkeys 14 Individual radioactivity concentrations in blood and plasma at various sampling times after a single IV bolus administration of [C]-Compound 1 are shown in Table 9. Individual profiles of total radioactivity in blood and plasma for Animal 101 (Panel A), Animal 102 (Panel B), Animal 103 over 24 hours (Panel C), and Animal 103 over 168 hours (Panel D) are illustrated in Figure 2.

[0554] PK parameters calculated from the continuous concentration-time profiles of total radioactivity are shown in Table 10. [Table 10]

[0555] Total drug-associated radioactivity in blood and plasma was quantifiable in all animals up to the termination time point.

[0556] In animal 103 (168 hours after dosing), AUC 0~t The whole-body exposure to total radioactivity measured as ng / g was 231,000–205,000 h·ng-eq / g in blood and plasma, respectively, whereas the C max were 7510 ng-eq / g (C09260 ng-eq / g) and 11500 ng-eq / g (C014000 ng-eq / g), respectively.

[0557] The CL was 6.69 mL / h / kg (blood) and 14.0 mL / h / kg (plasma), significantly lower than the hepatic and renal blood flow...

Claims

1. formula: 【Chemistry 138】 or a pharmaceutically acceptable salt thereof, During the ceremony: each B is independently guanine, thymine, or cytosine; - Each R １ is hydrogen; - Each R ２ is guanidino (C １ -C ４ ) alkyl, or hydrogen; -R ５ is a sequence comprising at least one alpha amino acid residue, beta amino acid residue, gamma amino acid residue, or combination thereof; hydrogen; or a water-solubilizing group; n is an integer from 12 to 30; -R ３ is hydrogen or amino (C １ -C ４ ) alkyl; -R ４ is a sequence comprising at least one alpha amino acid residue, beta amino acid residue, gamma amino acid residue, or combination thereof; or hydrogen; The compound contains at least one guanine-cytosine-thymine sequence and 7 to 9 guanidino groups, and at least one R ２ is guanidino (C １ -C ４ ) alkyl; The compound, or a pharmaceutically acceptable salt thereof.

2. At least one R ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is 4-guanidinobut-1-yl.

3. At least one R ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is 3-guanidinoprop-1-yl.

4. R ３ The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is 4-aminobut-1-yl.

5. R ３ The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is 3-aminoprop-1-yl.

6. R ４ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

7. R ４ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: is a sequence comprising at least one alpha amino acid residue.

8. R ４ but, 【Chem.98】 and During the ceremony, - p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; - Each R ６ are independently hydrogen or amino (C １ -C ４ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

9. R ４ but, 【Chem.99】 9. The compound of claim 8, wherein:

10. 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein p is 3, 4, 5, 6, 7, or 8.

11. 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein p is 7.

12. R ５ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

13. R ５ but, 【Chemistry 100】 and During the ceremony, - Each R ７ are independently the side chains of natural amino acids; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein q is 0 or 1.

14. R ５ but, 【Chemistry 101】 2. The compound of claim 1, wherein:

15. R ５ but, 【Chemical Engineering 102】 2. The compound of claim 1, wherein:

16. At least one R ２ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

17. R ５ but, 【Chemical 104】 2. The compound of claim 1, wherein:

18. formula 【Chemistry 108】 2. The compound of claim 1, wherein:

19. formula: 【Chemistry 112】 and During the ceremony; - p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; - Each R ６ are independently hydrogen or amino (C １ -C ４ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

20. 20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein n is 12, 13, 14, 15, 16, 17, 18, 19, or 20.

21. 21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein n is 19.

22. At least one R ２ 20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

23. At least one R ２ 20. The compound according to claim 19, or a pharmaceutically acceptable salt thereof, wherein is 4-guanidinobut-1-yl.

24. R ３ 20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein is 4-aminobut-1-yl.

25. R ３ 20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein is 3-aminoprop-1-yl.

26. R ５ 20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

27. R ５ but 【Chemistry 113】 20. The compound of claim 19, wherein:

28. R ５ but, 【Chemical 114】 20. The compound of claim 19, wherein:

29. R ６ 20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein is 4-aminobut-1-yl.

30. R ６ 20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein is 3-aminoprop-1-yl.

31. 20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein p is 3, 4, 5, 6, 7, or 8.

32. 20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein p is 7.

33. formula: 【Chemical 115】 and In the formula, R ７ 20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein is a side chain of a natural amino acid.

34. R ７ 34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein is 4-aminobut-1-yl.

35. R ７ 34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein is 3-aminoprop-1-yl.

36. formula: 【Chemical 119】 and In the formula, R ７ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is a side chain of a natural amino acid.

37. R ７ 37. The compound of claim 36, or a pharmaceutically acceptable salt thereof, wherein is 4-aminobut-1-yl.

38. R ７ 37. The compound of claim 36, or a pharmaceutically acceptable salt thereof, wherein is 3-aminoprop-1-yl.

39. structure: 【Chemistry 129】 and During the ceremony: - L, 【Chemistry 130】 and - M. 【Chemistry 131】 and - Each B １ｅ , B ２ｅ , B ３ｅ , B ４ｅ , B ５ｅ , B ６ｅ , B ７ｅ , B ８ｅ , B ９ｅ , and B １０ｅ are independently cytosine, guanine, or thymine; -n ６ is 1, 2, or 3; -n ７ 37. The compound of claim 36, or a pharmaceutically acceptable salt thereof, wherein is 1 or 2.

40. B １ｅ 40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein is guanine.

41. B ２ｅ 40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein is cytosine.

42. B ３ｅ 40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein is thymine.

43. B ４ｅ 40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein is guanine.

44. B ５ｅ 40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein is cytosine.

45. B ６ｅ 40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein is thymine.

46. B ７ｅ 40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein is guanine.

47. B ８ｅ 40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein is cytosine.

48. B ９ｅ 40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein is thymine.

49. B １０ｅ 40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein is guanine.

50. n ６ 40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein:

51. n ７ 40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein:

52. At least one R ２ 40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein is 3-guanidinoprop-1-yl.

53. At least one R ２ 40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein is 4-guanidinobut-1-yl.

54. R ３ 40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein is 4-aminobut-1-yl.

55. R ３ 40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein is 3-aminoprop-1-yl.

56. R ７ 40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein is 4-aminobut-1-yl.

57. R ７ 40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein is 3-aminoprop-1-yl.

58. structure: 【Chemistry 132】 and During the ceremony: - L １ but, 【Chemistry 133】 and -M １ but, 【Chemistry 134】 40. The compound of claim 39, wherein:

59. structure: 【Chemistry 135】 and During the ceremony: - L ２ but, 【Transformation 136】 and -M ２ but, 【Chemistry 137】 59. The compound of claim 58, wherein:

60. 60. A pharmaceutical composition for use in treating a condition in a subject, said pharmaceutical composition comprising a compound according to any one of claims 1 to 59, or a pharmaceutically acceptable salt thereof.

61. 61. The pharmaceutical composition for use according to claim 60, wherein the subject is a human.

62. 61. The pharmaceutical composition for use according to claim 60, wherein the condition is a neurological condition.

63. 61. The pharmaceutical composition for use according to claim 60, wherein the condition is a central nervous system condition.

64. 61. The pharmaceutical composition for use according to claim 60, wherein the condition is a polyglutamine disease.

65. 65. The pharmaceutical composition for use according to claim 64, wherein the polyglutamine disease is Huntington's disease.

66. 61. The pharmaceutical composition for use according to claim 60, wherein said treatment comprises administration of said compound in an amount of about 8 μg / kg to about 200 μg / kg of body weight of said subject.

67. 61. The pharmaceutical composition for use according to claim 60, wherein the compound is administered by intravenous administration.

68. 61. The pharmaceutical composition for use according to claim 60, wherein the compound is administered by subcutaneous administration.

69. 61. The pharmaceutical composition for use according to claim 60, wherein the compound is administered by intracerebroventricular administration.

70. 61. The pharmaceutical composition for use according to claim 60, wherein the compound is administered by oral administration.

71. 61. The pharmaceutical composition for use according to claim 60, wherein the compound is administered by intrathecal administration.

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