Modified peptide nucleic acid composition

Abstract

To provide a modified peptide nucleic acid composition. [Solution] This disclosure relates to compounds useful for the detection or modulation of target nucleic acids, including DNA and RNA. This disclosure further relates to a method for treating trinucleotide repeat disorders, which may include the administration of oligonucleotide analogs capable of binding to pathogenic nucleotide repeats in DNA or RNA. In some embodiments, this disclosure provides a method for treating a condition in a subject, comprising the step of administering a therapeutically effective amount of any compound of this disclosure to the subject.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 002,326, filed on March 30, 2020, which is incorporated herein 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 functions. In people with HD, neurons in the brain are lost over time, often due to the accumulation of toxicity from the defective HTT protein in their cells. Current treatment options work to reduce the motor and psychiatric symptoms of the individual, but there are no treatments for HD that can slow or stop the progression of the disease.

[0003] Inclusion by reference All publications, patents, and patent applications referenced herein are incorporated by reference to the same extent that each individual publication, patent, or patent application is specifically and individually incorporated herein by reference. [Overview of the project] [Means for solving the problem]

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

[0005] In some embodiments, the present disclosure relates to a compound comprising a peptide nucleic acid sequence and a cell permeabilizing group bound to the peptide nucleic acid sequence, wherein when a radiolabeled analog of the compound is subjected to an assay, the assay is: (a) The first component: (i) A step of administering a 5 mg / kg intravenous bolus dose of the radiolabeled analog into the tail vein of a male cynomolgus monkey; (ii) A step in which the monkey is euthanized four hours after the administration step; (iii)(ii) The step of freezing the monkey in a mixture of hexane and solid carbon dioxide for at least two hours and providing the frozen carcass; (iv) The step of burying the frozen corpse with its left side facing up in a 2% w / v sodium carboxymethylcellulose aqueous solution, and providing the buried corpse; (v) The embedded corpse is prepared into 40 μm sagittal whole-body sections using a cryo-macrotome; (vi) A step of placing a 40 μm sagittal whole-body section onto pressure-sensitive tape; (vii) After (vi), whole-body sections were placed in a cryo-macrotome at approximately -20°C for approximately 60 hours. Intermediate dehydration step; (viii)(vii) followed by the step of placing the whole-body section in contact with a carbon-14-sensitive image plate for a period not exceeding 4 days; (ix)(viii) followed by the step of scanning the image plate with a phosphor imager system; and (x)(ix) followed by a step of determining the concentration of the radiolabeled analog in the brain tissue of whole-body sections; The first component includes and (b) A second component which is similar to the first component except that another monkey is used which has been euthanized 168 hours after the administration step. Includes, Radially labeled analog, 14 The N-terminus contains a C-enriched glycine residue, and the radiolabeled analog is the compound of the radiolabeled analog. 14 The only structural difference from the compound is the absence of a C-enriched glycine residue. In this case, the present invention provides a compound in which, in the assay, the concentration of the radiolabeled analog in the brain tissue determined in the second component is equivalent to at least about 80% of the concentration of the radiolabeled analog in the brain tissue determined in the first component.

[0006] In some embodiments, the present disclosure relates to 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 nucleic acid base side chains; and (ii) a cell permeabilizing group attached to the series of peptide nucleic acid residues, and when the compound is subjected to an assay, the assay is: (a) A step of administering the compound to mice by intracerebroventricular injection at a dose of approximately 0.1 mg / kg to approximately 2 mg / kg; (b) A step in which mice are euthanized between approximately 1 hour and 28 days after intracerebroventricular administration; (c) A step of collecting brain tissue from mice after the euthanasia step; and (d) Steps to determine the concentration of mouse brain tissue using liquid chromatography-tandem mass spectrometry. In this case, the assay was observed in mice over a period of time from approximately 1 hour to approximately 50 hours after administration, and the average peak brain concentration in mice was observed to be approximately 3000 ng / mL to approximately 22000 ng / mL. Provides compounds.

[0007] In some embodiments, the present disclosure relates to 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 nucleic acid base side chains; and (ii) a cell permeabilizing group attached to the series of peptide nucleic acid residues, and when the compound is subjected to an assay, the assay is: (a) A step of administering the compound to mice by intracerebroventricular injection at a dose of approximately 0.1 mg / kg to approximately 1.5 mg / kg; (b) A step of collecting blood samples from the superior vena cava of mice at a time between approximately 1 hour and 28 days after intracerebroventricular administration; (c) After the step of collecting blood samples, the mice are euthanized approximately 1 hour to 28 days after intracerebroventricular administration; (d) After the euthanasia step, the step of collecting brain, intestine, liver, lung, kidney, or muscle tissue from the mouse; and (e) A step of 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) A step in which the concentration of compounds in plasma is determined from blood samples collected from mice using liquid chromatography-tandem mass spectrometry. In this case, the assay was observed to show that the compound accumulates in the mouse brain for up to approximately one month after the administration step, and that the compound is undetectable at detectable levels in the mouse plasma, intestines, liver, lungs, kidneys, or muscle tissue during that one month. Provides compounds.

[0008] In some embodiments, the present disclosure relates to 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 nucleic acid base side chains; and (ii) a cell permeabilizing group attached to the series of peptide nucleic acid residues, and when the compound is subjected to a plasma protein binding assay, the plasma protein binding assay is: (a) A step of carrying out the human component of a plasma protein binding assay, the human component of the plasma protein binding assay comprising: (1) spiking a first solution of the compound at 10 mg / mL into a single aliquot of human plasma to obtain at least a second solution of the compound at a concentration of approximately 1 μg / mL to approximately 50 μg / mL; (2) separating the mixture containing the compound bound to plasma proteins by ultracentrifugation of at least the second solution of the compound; and (3) determining the percentage of plasma protein binding in human plasma by liquid chromatography-tandem mass spectrometry; (b) A step of performing the mouse component of a plasma protein binding assay, wherein the mouse component of the plasma protein binding assay differs from the human component of the plasma protein binding assay in that mouse plasma is used instead of human plasma; (c) A step of performing the canine component of the plasma protein binding assay, wherein the canine component of the plasma protein binding assay differs from the human component of the plasma protein binding assay in that canine plasma is used instead of human plasma; (d) A step of performing a component of a plasma protein binding assay for miniature pigs, wherein the component of the plasma protein binding assay for miniature pigs differs from the component of the plasma protein binding assay for humans in that miniature pig plasma is used instead of human plasma; (e) A step of performing the sheep component of a plasma protein binding assay, wherein the sheep component of the plasma protein binding assay differs from the human component of the plasma protein binding assay in that sheep plasma is used instead of human plasma; and (f) A step of performing the monkey component of a plasma protein binding assay, wherein the monkey component of the plasma protein binding assay differs from the human component of the plasma protein binding assay in that monkey plasma is used instead of human plasma. The present invention provides a compound comprising, in this case, a plasma protein binding percentage of at least about 85% in a plasma protein binding assay in humans, mice, dogs, miniature pigs, sheep, or monkeys.

[0009] In some embodiments, the present disclosure relates to a compound having formula (I): [ka] During the ceremony: - Each B is an independent nucleic acid base; - Each R 1 These are independently the side chains of natural amino acids, guanidino (C1-C4) alkyl groups, or hydrogen atoms; - Each R 2 These are independently the side chains of natural amino acids, guanidino (C1-C4) alkyl groups, or hydrogen atoms; - R 5 is a sequence containing at least one alpha amino acid residue, beta amino acid residue, gamma amino acid residue, or a combination thereof; hydrogen; or a water-soluble group; - n is an integer between 3 and 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 containing at least one alpha amino acid residue, beta amino acid residue, gamma amino acid residue, or a combination thereof; or hydrogen; - m is either 0 or 1; Contains at least one guanine-cytosine-thymine sequence, Provides a compound or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, the Disclosure provides a method for treating a condition in a subject, comprising the step of administering a therapeutically effective dose of any compound of the Disclosure to the subject. [Brief explanation of the drawing]

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

[0012] [Figure 2] Figure 2 illustrates the individual blood and plasma profiles of total radioactivity after a single intravenous bolus administration of 5 mg / kg of [14C]-compound 1 to male cynomolgus monkeys in animal 101 (4 hours after administration, panel A), animal 102 (12 hours after administration, panel B), animal 103 (24 hours after administration, panel C), and animal 103 (168 hours after administration, panel D).

[0013] [Figure 3] Figure 3 illustrates the total radioactivity concentrations in representative organs and tissues at various time points after a single intravenous bolus administration of [14C]-compound 1 to male cynomolgus monkeys at a dose of 5 mg / kg.

[0014] [Figure 4] Figure 4 illustrates the total radioactivity concentrations in representative organs and tissues at various time points after a single intravenous bolus administration of [14C]-compound 1 to male cynomolgus monkeys at a dose of 5 mg / kg.

[0015] [Figure 5] Figure 5 illustrates the ratio of tissue to blood at various time points after a single intravenous bolus administration of [14C]-compound 1 to male cynomolgus monkeys at 5 mg / kg.

[0016] [Figure 6] Figure 6 illustrates the ratio of tissue to blood at various time points after a single intravenous bolus administration of [14C]-compound 1 to male cynomolgus monkeys at 5 mg / kg.

[0017] [Figure 7A] Figures 7A and 7B are autoradiographs showing the typical tissue distribution of total radioactivity in parasagittal sections of animal 101 after a single intravenous bolus administration of 5 mg / kg of [14C]-compound 1. Any gray signal beyond the background indicates the presence of the compound in the tissue. [Figure 7B] Same as above.

[0018] [Figure 8A] Figures 8A and 8B are autoradiographs showing the typical tissue distribution of total radioactivity in sagittal sections of animal 101 after a single intravenous bolus administration of 5 mg / kg of [14C]-compound 1. Any gray signal beyond the background indicates the presence of the compound in the tissue. [Figure 8B] Same as above.

[0019] [Figure 9A] Figures 9A and 9B are autoradiographs showing the typical tissue distribution of total radioactivity in sagittal sections of animal 101 after a single intravenous bolus administration of 5 mg / kg of [14C]-compound 1. Any gray signal beyond the background indicates the presence of the compound in the tissue. [Figure 9B] Same as above.

[0020] [Figure 10A]Figures 10A and 10B are autoradiographs showing the typical tissue distribution of total radioactivity in sagittal sections of animal 101 after a single intravenous bolus administration of 5 mg / kg of [14C]-compound 1. Any gray signal beyond the background indicates the presence of the compound in the tissue. [Figure 10B] Same as above.

[0021] [Figure 11] Figure 11 is an autoradiograph showing the typical tissue distribution of total radioactivity in median sagittal sections of animal 101 after a single intravenous bolus administration of 5 mg / kg of [14C]-compound 1. Any gray signal beyond the background indicates the presence of the compound in the tissue.

[0022] [Figure 12A] Figures 12A and 12B are autoradiographs showing the representative tissue distribution of total radioactivity in sagittal sections of animals 101 (4 hours after administration), 102 (12 hours after administration), and 103 (7 days after administration) following a single intravenous bolus of 5 mg / kg of [14C]-compound 1. Any gray signal beyond the background indicates the presence of the compound in the tissue. [Figure 12B] Same as above.

[0023] [Figure 13] Figure 13 is an autoradiograph showing the representative cranial tissue distribution of total radioactivity in selected sagittal sections of animals 101 (4 hours after administration), 102 (12 hours after administration), and 103 (7 days after administration) after a single intravenous bolus of 5 mg / kg of [14C]-compound 1. Any gray signal beyond the background indicates the presence of the compound in the tissue.

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

[0025] [Figure 15A] Figure 15A illustrates the mean brain concentration of compound 1 against the time profile in C57BL6J mice administered a dose of 0.3 mg / kg, Figure 15B illustrates the mean brain concentration of compound 1 against the time profile in mice administered a dose of 0.6 mg / kg, and Figure 15C illustrates the mean brain concentration of compound 1 against the time profile 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 of compound 1 against the time profile in C57BL6J mice administered a dose of 0.3 mg / kg, Figure 16B illustrates the mean spleen concentration of compound 1 against the time profile in mice administered a dose of 0.6 mg / kg, and Figure 16C illustrates the mean spleen concentration of compound 1 against the time profile in C57BL6J mice administered a dose of 1 mg / kg. [Figure 16B] Same as above. [Figure 16C] Same as above.

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

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

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

[0030] [Figure 19B] Figure 19B shows the relative expression of wtHTT (dark bars) and mHTT (light bars) in 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) in GM09197 cells after treatment with 1 or 5 μM of compound 4. The mHTT bars are not visible because mHTT levels were below the detection limit.

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

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

[0034] [Figure 20C] Figure 20C shows the results of a cytotoxicity assay evaluating the percentage of GM09197 dead 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] Figure 23 shows the structural formula of compound 3. [Modes for carrying out the invention]

[0038] Detailed explanation Huntington's disease (HD) is a genetic disorder associated with abnormally long CAG repeat elongations in the huntingtin gene (HTT), which codes for the huntingtin protein (HTT). HTT genes containing repeat lengths exceeding a certain threshold produce mutant huntingtin protein (mHTT), which can induce pathological changes in the central nervous system. The risk of disease onset, penetrance, and age may correlate with the length of the HTT repeat elongation. CAG triads with fewer than 27 repeats are associated with a normal phenotype, while 27–35 repeats generally confer a normal phenotype but increase the disease risk to offspring. 36–39 repeats are associated with incomplete or reduced penetrance, either resulting in disease symptoms appearing later in adulthood. Repeat lengths exceeding 40 confer full penetrance, and repeat lengths exceeding 60 result in disease that may appear in early childhood. Compounds of the Disclosure

[0039] This disclosure relates to compounds useful for the detection or modulation of target nucleic acids, including DNA and RNA. The disclosure further relates to a method for treating trinucleotide repeat disorders, which may include the administration of oligonucleotide analogs capable of binding to pathogenic nucleotide repeats in DNA or RNA. In some embodiments, the compounds of the disclosure bind to CAG repeats in mutant mHTT transcripts present in Huntington's disease, thereby modulating the expression of the mHTT protein.

[0040] In some embodiments, the disclosure provides compounds comprising a chain. The chain may comprise a series of atoms linked together to form a chain. Multiple atoms linked together to form a chain may be independently substituted by substituents having polar groups, such as guanidino groups. The chain may have a pattern consisting of one atom independently substituted by a substituent having a polar group, followed by five consecutive atoms not substituted by a substituent having a polar group, followed by a second atom independently substituted by a substituent having a polar group, followed by another five consecutive atoms not substituted by a substituent having a polar group, followed by a third atom independently substituted by 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 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 atoms not substituted with a substituent having a polar group. Eleven more consecutive atoms follow. In some embodiments, the first, second, and third atoms are each the gamma carbon of the peptide nucleic acid oligomer. In some embodiments, the first, second, and third atoms are each the 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 not substituted with a substituent having a polar group, then a second atom independently substituted with a substituent having a polar group, then another 11 consecutive atoms not substituted with a substituent having a polar group, and then 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 guanidino groups. In some embodiments, each substituent having a guanidino group is independently a guanidinoalkyl. In some embodiments, each substituent having a guanidino group is independently a guanidino(C1-C4)alkyl. In some embodiments, each substituent having a guanidino group is 2-guanidino-ethanol-1-yl. In some embodiments, each substituent having a guanidino group is 3-guanidinopropane-1-yl. In some embodiments, each substituent having a guanidino group is 4-guanidinobuta-1-yl.

[0044] The compounds of this disclosure may comprise nucleic acid bases or nucleic acid base analogs. In some embodiments, the pattern may comprise one atom independently substituted with a substituent having a first nucleic acid base, followed by five consecutive atoms not substituted with substituents having a nucleic acid base, followed by a second atom independently substituted with a substituent having a second nucleic acid base, followed by another five consecutive atoms not substituted with substituents having a nucleic acid base, followed by a third atom independently substituted with a substituent having a third nucleic acid base.

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

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

[0047] The peptide nucleic acid analogs of the present disclosure and pharmaceutically acceptable salts thereof. In some embodiments, the compounds include a peptide nucleic acid domain. Peptide nucleic acids are oligonucleotide analogs that include a chain of repeating N-(2-aminoethyl)-glycine units linked by peptide bonds, and the glycyl nitrogen of one or more units is functionalized by an alkylene or acyl group. Peptide nucleic acids may optionally include substitutions, for example, on the N-(2-aminoethyl)-glycine backbone: [[ID=十五]]

Chemical formula

[0048] The compounds of this disclosure (e.g., peptide nucleic acids) may comprise a chain of atoms having substituted or unsubstituted ends. For example, the first and second ends of the chain may each be independently unsubstituted or substituted by an amino acid. For example, the first and second ends of the chain may each be independently unsubstituted or substituted by a peptide. In some embodiments, the compound is a peptide nucleic acid oligomer, where the first end of the chain is the N-terminus of the peptide nucleic acid oligomer and the second end 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 bound by a peptide bond to a peptide, which may be a sequence containing, for example, 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 bound by a peptide bond to amidated lysine. In some embodiments, the C-terminus of the peptide nucleic acid oligomer is bound by a peptide bond to 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 be independently bound to the peptide nucleic acid chain. In some embodiments, the group containing the guanidino moiety is a 4-guanidinobuta-1-yl group, a 3-guanidinopropa-1-yl group, or a 2-guanidinoethanol-1-yl group. In some embodiments, the sequence of the peptide nucleic acid domain is (GCT) n The formula includes, where n is 1 to 10. In some embodiments, the sequence of the peptide nucleic acid domain is 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, the compounds of the Disclosure may include a portion that improves the cell permeability of the compound compared to a molecule that does not have a portion otherwise identical to the compound. For example, the compounds of the Disclosure The compound can reach intracellular targets in the cytoplasm or nucleus.

[0052] In some embodiments, the present disclosure relates to a compound comprising a pharmacophore region bonded to a plurality of positively charged regions: a) The pharmacophore region contains several peptide nucleic acid residues, and the number of peptide nucleic acid residues is at least 7, not a multiple of 3; b) Each peptide nucleic acid residue in the pharmacophore region independently comprises a skeletal portion and a side chain portion attached to the skeletal portion; c) None of the peptide nucleic acid residues in the pharmacophore region have a positive formal charge at neutral pH; d) Each side chain portion independently contains a nucleic acid base; e) The nucleic acid bases of each side chain collectively form a sequence; f) The sequence is complementary to the natural human nucleic acid sequence associated with Huntington's disease; g) The sequence includes a subsequence in which cytosine-thymine-guanine-cytosine-thymine-guanine; and h) Multiple positively charged regions comprising at least six consecutive construction blocks, each of which independently comprises a side chain having a positive formal charge at neutral pH. Provides compounds.

[0053] In some embodiments, the present disclosure relates to a compound represented by the structure of formula (I): [ka] During the ceremony, - Each B is an independent nucleic acid base; - Each R 1 These are independently the side chains of natural amino acids, guanidino (C1-C4) alkyl groups, or hydrogen atoms; - Each R 2 These are independently the side chains of natural amino acids, guanidino (C1-C4) alkyl groups, or hydrogen atoms; - R 5 is a sequence containing at least one alpha amino acid residue, beta amino acid residue, gamma amino acid residue, or a combination thereof; hydrogen; or a water-soluble group; - n is an integer between 3 and 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 containing at least one alpha amino acid residue, beta amino acid residue, gamma amino acid residue, or a combination thereof; or hydrogen; - m is either 0 or 1; Contains at least one guanine-cytosine-thymine sequence, The present invention provides a compound, a pharmaceutically acceptable salt thereof, or a radiolabeled derivative thereof.

[0054] In some embodiments, each nucleic acid base 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 nucleic acid base B is an analog of a naturally occurring nucleic acid base.

[0055] In some embodiments, at least one R 1 is a guanidino(C1-C4) alkyl. In some embodiments, one or more R 1 is a guanidino(C1-C4) alkyl. In some embodiments, at least one in two R 1 is a guanidino(C1-C4) alkyl. In some embodiments, at least one in three is a third R 1 is a guanidino(C1-C4) alkyl. In some embodiments, at least two or three R 1 is a guanidino (C1-C4) alkyl. In some embodiments, each R 1 is a guanidino(C1-C4) alkyl. In some embodiments, at least one R 1 is 4-guanidibut-1-yl. In some embodiments, at least one R 1 is 3-guanidinopropane-1-yl. In some embodiments, at least one R 1 is 2-guanidino-ethanol-1-yl. In some embodiments, at least one R 1 is hydrogen. In some embodiments, each R 1 It is hydrogen.

[0056] In some embodiments, at least one R 2 is a guanidino(C1-C4) alkyl. In some embodiments, one or more R 2is a guanidino(C1-C4) alkyl. In some embodiments, at least one in two R 2 is a guanidino(C1-C4) alkyl. In some embodiments, at least one in three R 2 is a guanidino(C1-C4) alkyl. In some embodiments, at least two or three R 2 is a guanidino (C1-C4) alkyl. In some embodiments, each R 2 is a guanidino(C1-C4) alkyl. In some embodiments, at least one R 2 is 4-guanidibut-1-yl. In some embodiments, at least one R 2 is 3-guanidinopropane-1-yl. In some embodiments, at least one R 2 is 2-guanidino-ethanol-1-yl. In some embodiments, at least one R 2 is hydrogen. In some embodiments, each R 2 It is hydrogen.

[0057] In some embodiments, G is [ka] That is the case.

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

[0059] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is an amino(C1-C4)alkyl. In some embodiments, R 3 is 4-aminobuta-1-yl. In some embodiments, R 3m is 3-aminopropane-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 containing at least one alpha-amino acid residue. In some embodiments, R 4 This is a sequence containing at least one beta-amino acid residue. In some embodiments, R 4 is a sequence containing at least one gamma amino acid residue. In some embodiments, R 4 teeth, [ka] And, During the ceremony, - p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; - Each R 6 These are independently hydrogen or amino(C1-C4)alkyl.

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

[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 It is hydrogen.

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

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

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

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

[0068] In some embodiments, the water-soluble group includes a structure having multiple formal charges at physiological pH. In some embodiments, R 5 These are multiple formal charges that are positive charges.

[0069] In some embodiments, if G is OH or NH2, then R 1 and R 2 At least one of them is a side chain of a natural amino acid or a guanidino (C1-C4) alkyl, R 5 It is not hydrogen.

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

[0071] In some embodiments, R 1 and R 2 If both are hydrogen, then G is [ka] And R 5 This 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-guanidibut-1-yl. In some embodiments, each R 1 is 4-guanidibut-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-aminobuta-1-yl. In some embodiments, R 3 is 3-aminopropane-1-yl. In some embodiments, R 4 is hydrogen. In some embodiments, R 5 is hydrogen. In some embodiments, R 5 teeth, [ka] That is the case.

[0074] In some embodiments, the compound is given the formula: [ka] It has, During the ceremony, - Each B 1a 、B 2a and B 3a is 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-guanidinobut-1-yl. In some embodiments, each R 1 is 4-guanidinobut-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:

Chemical formula

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

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

Chemical formula

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

Chemical formula

[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-guanidinobut-1-yl. In some embodiments, each R 1 is 4-guanidinobut-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:

Chemical formula

[0082] In some embodiments, n 2 is 2. In some embodiments, R 1 is 4-guanidinobut-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:

Chemical formula

[0084] In some embodiments, B 1bIt is cytosine, and B 2b is thymin, B 3b is guanine. In some embodiments, n 2 The answer is 2.

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

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

[0087] In some embodiments, the compound is given by formula: [ka] It has, During the ceremony, - p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; - Each R 6 These 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. Yes. In some embodiments, n is 19. In some embodiments, n is 20.

[0089] In some embodiments, at least one R 1 is hydrogen. In some embodiments, n is greater than 1 and one in two is R 1 is hydrogen. In some embodiments, at least one R 1is 4-guanidinobacter-1-yl. In some embodiments, n is greater than 1 and is one in two R 1 It is 4-guanidinobacter-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 It is 4-guanidibuta-1-yl. In some embodiments, one in two R 2 It is 4-guanidinobacter-1-yl.

[0091] In some embodiments, R 3 is 4-aminobuta-1-yl. In some embodiments, R 3 It is 3-aminopropane-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] That is the case.

[0095] In some embodiments, R 6 is 4-aminobuta-1-yl. In some embodiments, R 6 It is 3-aminopropane-1-yl.

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

[0097] In some embodiments, R 7 is 4-aminobuta-1-yl. In some embodiments, R 7 It is 3-aminopropane-1-yl.

[0098] In some embodiments, the compound has a structure [ka] It has, During the ceremony, - Each B 1c B 2c B 3c , and B 4c These are independently cytosine, guanine, or thymine; - n 3 It 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 It is guanine.

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

[0101] In some embodiments, p is 7.

[0102] In some embodiments, R 3 is 4-aminobuta-1-yl. In some embodiments, R 3 It is 3-aminopropane-1-yl.

[0103] In some embodiments, R 6 is 4-aminobuta-1-yl. In some embodiments, R 6 It is 3-aminopropane-1-yl.

[0104] In some embodiments, R 7 It is 4-aminobuta-1-yl. In some embodiments, , R 7 It is 3-aminopropane-1-yl.

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

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

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

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

[0109] In some embodiments, R 7 is 4-aminobuta-1-yl. In some embodiments, R 7 It is 3-aminopropane-1-yl.

[0110] In some embodiments, the compound has a structure [ka] It has, During the ceremony, - X is, [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 These are independently cytosine, guanine, or thymine; - n 4 is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; - n 5 It 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, B7d is guanine. In some embodiments, B 8d is cytosine. In some embodiments, B 9d is thymine. In some embodiments, B 10d It is guanine.

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

[0113] In some embodiments, R 3 is 4-aminobuta-1-yl. In some embodiments, at least one R 1 is 4-guanidibut-1-yl. In some embodiments, each R 1 It is 4-guanidinobacter-1-yl.

[0114] In some embodiments, R 3 It is 4-aminobuta-1-yl. In some embodiments, , R 3 is 3-aminopropane-1-yl. In some embodiments,

[0115] In some embodiments, R 7 is 4-aminobuta-1-yl. In some embodiments, R 7 It is 3-aminopropane-1-yl.

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

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

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

[0119] In some embodiments, B 1e 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 It is guanine.

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

[0121] In some embodiments, at least one R 2 It is 3-guanidinopropane-1-yl In some embodiments, each R 2 is 3-guanidinopropane-1-yl. In some embodiments, at least one R 2 is 4-guanidibut-1-yl. In some embodiments, each R 2 It is 4-guanidinobacter-1-yl.

[0122] In some embodiments, R 3 is 4-aminobuta-1-yl. In some embodiments, R 3 It is 3-aminopropane-1-yl.

[0123] In some embodiments, R 7 is 4-aminobuta-1-yl. In some embodiments, R 7 It is 3-aminopropane-1-yl.

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

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

[0126] Each chemical group disclosed herein may be unsubstituted or substituted. Non-limiting examples of substituents as needed include hydroxyl groups, sulfhydryl groups, halogens, amino groups, nitro groups, nitroso groups, cyano groups, azide groups, sulfoxide groups, sulfone groups, sulfonamide groups, carboxyl groups, carboxyaldehyde 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 linear, branched, 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 , C46 , C 47 , C 48 , C 49 , or C 50 It can be a group. (C1-C4) alkyl groups are alkyl groups that contain the space between 1 to 4 carbon atoms.

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

[0129] Examples of branched alkyl groups include any linear alkyl group substituted with any number of alkyl groups. Non-limiting examples of branched 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 condensed, crosslinked, and spirodicyclic groups, as well as higher-order condensed, crosslinked, and spiro systems. Cyclic alkyl groups can be substituted with any number of linear, branched, or cyclic alkyl groups.

[0131] Non-limiting examples of alkenyl and alkenylene groups include linear, branched, and cyclic alkenyl groups. Olefins of alkenyl groups or multiple olefins are, for example, The alkenyl or alkenylene group may be, for example, substituted or unsubstituted 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 could be the basis.

[0132] Non-limiting examples of alkynyl or alkynylene groups include linear, branched, or cyclic alkynyl groups. The triple bond of an alkynyl (alkylnyl) or alkynylene group can be internal or terminal. Alkynnyl or alkynylene groups can be, for example, substituted or unsubstituted 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 , C35 , 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 could be the basis.

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

[0135] The aryl group may be heterocyclic or nonheterocyclic. The aryl group may be monocyclic or polycyclic. The aryl group may 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] The aryloxy group can be, for example, an oxygen atom substituted with any aryl group, such as phenoxy.

[0137] The aralkyl group can be any alkyl group substituted with any aryl group, such as benzyl.

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

[0139] A heterocycle can be any ring containing a ring atom other than carbon, such as N, O, S, P, Si, B, or any other heteroatom. A heterocycle can be substituted with any number of substituents, such as alkyl groups and halogen atoms. A heterocycle can be aromatic (heteroaryl) or non-aromatic. Non-limiting examples of heterocycles include pyrrole, pyrrolidine, pyridine, piperidine, succinamide, maleimide, morpholin, 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 heterocyclic group. Non-limiting examples of acyls include acetyl, benzoyl, benzyloxycarbonyl, phenoxycarbonyl, methoxycarbonyl, and ethoxycarbonyl.

[0141] An acyloxy group can be an oxygen atom substituted by an acyl group. Esters or ester groups contain acyloxy groups. A non-restrictive example of an acyloxy or ester group is acetate.

[0142] A carbamate group can be an oxygen atom substituted by a carbamoyl group, and the nitrogen atom of the carbamoyl group is either unsubstituted or monosubstituted or disubstituted by one or more hydrocarbyl, alkyl, aryl, heterocyclyl, or aralkyl substituents. If the nitrogen atom is disubstituted, the two substituents can form a heterocycle with the nitrogen atom.

[0143] A hydrocarbyl group can be any group consisting of carbon and hydrogen atoms, and may include alkyl groups, alkenyl groups, alkynyl groups, and aryl groups. Examples of hydrocarbyl groups include 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 could be the basis.

[0144] A hydrocarbyl carbonyl group can be a carbonyl group substituted with a hydrocarbyl group, such as benzoyl, acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, heptanol, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridencanoyl, myristoyl, pentadecenoyl, palmitoyl, heptadecanoyl, stearoyl, nondecanoyl, arachidoyl, as well as acyl groups derived from saturated, monounsaturated, and polyunsaturated fatty acids, such as myristooleyl, palmitooleyl, sapienol, oleoyl, eridoyl, baxenoyl, linoleyl, linoleyl, α-linolenoyl, or arachidonoyl. Hydrocarbyl carbonyl groups can 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 could be the basis.

[0145] The aminoalkylene group is an alkyl group substituted with an amino group, for example, aminomethyl, 2-aminoethyl, 3-aminopropane-1-yl, 2-aminopropane-1-yl, 4-aminobuta-1-yl, 3-aminobuta-1-yl, 2-aminobuta-1-yl, 5-aminopenta-1-yl, 4-aminopenta-1-yl It may be 4-aminopenta-1-yl, 3-aminopenta-1-yl, 2-aminopenta-1-yl, a lysine side chain, or an ornithine side chain.

[0146] The guanidinoalkylene group is an alkyl group substituted with a guanidino group, for example, guanidinomethyl, 2-guanidinoethanol-1-yl, 3-guanidinopropane-1-yl, 2-guanidinopropane-1-yl, 4-guanidinobutane-1-yl, 3-guanidinobutane-1-yl, 2-guanidinobutane-1-yl, 5-guanidinopentane-1-yl, 4-guanidinomethyl It may be nidinopenta-1-yl, 4-guanidinopenta-1-yl, 3-guanidinopenta-1-yl, 2-guanidinopenta-1-yl, an arginine side chain, or a homoarginine side chain.

[0147] "Polypeptide," "peptide," and their grammatical equivalents, as used herein, refer to polymers of amino acid residues. Polypeptides and proteins disclosed herein (including their functional portions and functional variants) may contain synthetic amino acids instead of one or more naturally occurring amino acids. This disclosure intends both L- and D-forms of amino acid residues.

[0148] The compounds of the disclosed herein can be radiolabeled. One or more atoms of the compounds of the disclosed herein can be radiolabeled with radioactive or non-radioactive isotopes, for example. 2 H, 3 H, 11 C, 13 C, 14 C, 13N, 15 N, 15 O, 17 O,18 O may be substituted, or a combination thereof. In one embodiment, at least one carbon of the compound of the present disclosure is 14 It may also be replaced by C. Treatment method

[0149] This disclosure describes the use and methods of compounds for treating a condition or genetic disorder, including trinucleotide repeat disorders. The methods may include the step of administering a therapeutically effective dose of the compounds of this disclosure to a target. In some embodiments, the genetic disorder is a polyglutamine (polyQ) disease. Polyglutamine diseases include trinucleotide repeat disorders involving genes with 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 (spinal and bulbar 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 related to aging. In some embodiments, the condition is related to cognitive impairment. In some embodiments, the condition is related to memory loss. In some embodiments, the condition is related to deterioration of motor skills.

[0151] In some embodiments, the polyglutamine disease is Huntington's disease. Treatment may be administered based on the number of CAG repeats in the HTT gene of interest. For example, a subject to be administered the compounds of this disclosure may have an HTT gene containing more than 27 CAG repeats. In some embodiments, the HTT gene of interest may contain at least 36 repeats, at least 40 repeats, at least 50 repeats, or at least 60 repeats. In some embodiments, the target HTT gene 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, administration of the compounds of the Disclosure does not exhibit immunogenicity. In some embodiments, administration of the compounds of the Disclosure does not promote the production of neutralizing antibodies, cofactors, pro-inflammatory cytokines, or type 1 interferons at the time of or after administration of the compounds to a subject. In some embodiments, the compounds do not activate the TLR9 receptor and are not presented to the immune system in MHCI or MHCII complexes.

[0153] The compounds of this disclosure can be administered systemically to a subject in need as a therapeutically effective dose of the compound that binds to repeat codons. The subject may include the bloodstream, the brain, and the blood-brain barrier. Compounds that bind 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 this disclosure or compositions comprising the compounds of this disclosure (e.g., pharmaceutical compositions) can be administered to subjects in various forms and by various suitable routes of administration.

[0155] The compounds of this disclosure or compositions containing the compounds of this disclosure (e.g., pharmaceutical compositions) may be administered topically, for example, by direct injection of the compounds into organs, as required by depot, sustained-release formulations or implants. The compounds of this disclosure or compositions containing the compounds of this disclosure (e.g., pharmaceutical compositions) may be administered systemically.

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

[0157] In some embodiments, the compounds of the Disclosure or compositions containing the compounds of the Disclosure (e.g., pharmaceutical compositions) are administered orally. In some embodiments, the compounds of the Disclosure or compositions containing the compounds of the Disclosure (e.g., pharmaceutical compositions) are administered via intravenous, intratumoral, subcutaneous, intramuscular, intracerebral, intraventricular, intraarticular, intraperitoneal, intracranial, intrathecal, intranasal, oral, sublingual, oral, or rectal administration routes. In some embodiments, the compounds of the Disclosure or compositions containing the compounds of the Disclosure (e.g., pharmaceutical compositions) are administered intravenously. In some embodiments, the compounds of the Disclosure or compositions containing the compounds of the Disclosure (e.g., pharmaceutical compositions) are administered subcutaneously. In some embodiments, the compounds of the Disclosure or compositions containing the compounds of the Disclosure (e.g., pharmaceutical compositions) are administered intraventricularly. In some embodiments, the compounds of the Disclosure or compositions containing the compounds of the Disclosure (e.g., pharmaceutical compositions) are administered orally. In some embodiments, the compounds of the Disclosure or compositions containing the compounds of the Disclosure (e.g., pharmaceutical compositions) are administered by intrathecal administration.

[0158] Any of the above-described routes of administration can be combined with other routes of administration. For example, the compounds of the Disclosure may be delivered by a first route of administration, and one or more subsequent maintenance doses of the compounds may be delivered by the same or different routes of administration. In some embodiments, the compounds of the Disclosure or compositions containing the compounds of the Disclosure (e.g., pharmaceutical compositions) are administered by intrathecal administration, and one or more subsequent maintenance doses of the compounds or compositions containing the compounds are delivered by subcutaneous or intravenous administration.

[0159] Non-limiting examples of suitable modes and routes of administration include oral, topical, parenteral, intravenous injection, intravenous infusion, subcutaneous injection, subcutaneous infusion, intramuscular injection, intramuscular infusion, intradermal injection, intradermal infusion, intraperitoneal injection, intraperitoneal infusion, intracerebral injection, intracerebral infusion, subarachnoid injection, subarachnoid injection, intraocular injection, intrathecal injection, intraocular injection, intrathecal injection, administration to the eye, endothelial administration, topical administration, intranasal administration, intrapulmonary administration, rectal administration, intra-arterial administration, intrathecal administration, inhalation, intralesional administration, intradermal administration, epidural administration, absorption through the epithelium or mucocutaneous lining (e.g., oral mucosa, rectal and intestinal mucosa), intracapsular administration, subcapsular administration, intracardiac administration, transtracheal administration, subepidermal administration, subarachnoid administration, subcapsular administration, intrathecal administration, and intrasternal administration.

[0160] The compounds of this disclosure or compositions containing the compounds of this disclosure (e.g., pharmaceutical compositions) are non-invasive. It can be administered via non-invasive methods. Examples of non-invasive administration methods include needle-free injection devices and topical administration, such as eye drops. Multiple routes of administration can be used for efficient delivery.

[0161] Depending on the intended mode of administration, the composition may be in solid, semi-solid, or liquid dosage forms, such as tablets, suppositories, pills, capsules, powders, solutions, suspensions, lotions, creams, or gels, suitable for single doses of precise amounts. 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 subjects or patients.

[0162] Examples of solid compositions include powders, tablets, dispersible granules, capsules, and cachets. Examples of liquid compositions include solutions in which the compound is dissolved, emulsions containing the compound, or solutions containing liposomes, micelles, or nanoparticles containing the compound disclosed herein. Examples of semi-solid compositions include gels, suspensions, and creams. The compositions may be liquid solutions or suspensions, solid dosage forms suitable for being converted into solutions or suspensions in liquid before use, or emulsions. These compositions may also contain trace amounts of non-toxic auxiliaries, such as wetting agents or emulsifiers, pH buffers, and other pharmaceutically acceptable additives.

[0163] In some embodiments, the composition is formulated in solution (for example, for IV administration). In some examples, the pharmaceutical composition is formulated as an injectable preparation. In some examples, the pharmaceutical composition is formulated as an injectable preparation.

[0164] The compounds of this disclosure or compositions comprising the compounds of this disclosure (e.g., pharmaceutical compositions) may be administered in rapid-release formulations, sustained-release formulations, or intermediate-release formulations. Rapid-release formulations may provide immediate release. Sustained-release formulations may provide controlled release or sustained delayed release.

[0165] Compositions comprising the compounds of this disclosure may be, for example, immediate-release 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 may be pharmaceutical formulations in which the release rate and release profile of the activator are adapted to meet physiological and chronotherapeutic requirements, or are formulated to release the activator at a programmed rate. Non-limiting examples of controlled-release formulations include granules, delayed-release granules, hydrogels (e.g., synthetic or naturally occurring), other gelling agents (e.g., gel-forming dietary fiber), matrix-based formulations (e.g., formulations comprising a polymer material in which at least one active ingredient is dispersed), granules in a matrix, polymer mixtures, and granular masses.

[0166] In some embodiments, controlled-release formulations are delayed-release formulations. Delayed-release formulations can be formulated to delay the action of a compound over a long period of time. Delayed-release formulations can be formulated to delay the release of an effective dose of one or more compounds for, for example, about 4, about 8, about 12, about 16, or about 24 hours. Controlled-release formulations can also be sustained-release formulations. Sustained-release formulations can be formulated, for example, to maintain the action of a compound over a long period of time. Sustained-release formulations can be formulated to provide an effective dose of any compound described herein over 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 are intended to target any suitable tissue or cell type. This is possible. The forms, routes, and compositions of the Disclosure may be suitable for targeting the compounds of the Disclosure to specific tissues or subsets of tissues. Non-limiting examples of tissues that can be targeted include the kidneys (e.g., renal cortex), joints, cartilage, liver, salivary glands, bones (e.g., bone surface), skin, lungs, muscles, 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, choroidal plexus, and combinations thereof. dosage

[0168] The pharmaceutical compositions described herein may be in unit dosing form suitable for single-dose administration of precise dosages. In unit dosing form, the formulation is divided into unit doses containing appropriate amounts of one or more compounds. The dosage of the compounds described herein (e.g., therapeutically effective dose) may be any amount required.

[0169] The compounds described herein contain approximately 1 mg to approximately 2000 mg in a composition or unit dose; approximately 5 mg to approximately 1000 mg, approximately 10 mg to approximately 25 mg, approximately 50 mg to approximately 250 mg, approximately 100 mg to approximately 200 mg, approximately 1 mg to approximately 50 mg, approximately 50 mg to approximately 100 mg, approximately 100 mg to approximately 150 mg, approximately 150 mg to approximately 200 mg, approximately 200 mg to approximately 250 mg, approximately 250 mg to approximately 300 mg, approximately 300 mg to approximately 350 mg, and approximately 350 mg. It may exist in the range of mg to approximately 400 mg, approximately 400 mg to approximately 450 mg, approximately 450 mg to approximately 500 mg, approximately 500 mg to approximately 550 mg, approximately 550 mg to approximately 600 mg, approximately 600 mg to approximately 650 mg, approximately 650 mg to approximately 700 mg, approximately 700 mg to approximately 750 mg, approximately 750 mg to approximately 800 mg, approximately 800 mg to approximately 850 mg, approximately 850 mg to approximately 900 mg, approximately 900 mg to approximately 950 mg, or approximately 950 mg to approximately 1000 mg.

[0170] The compounds described herein are present in compositions or unit doses of approximately 1 μg to 2000 μg; approximately 5 μg to 1000 μg, approximately 10 μg to 25 μg, approximately 50 μg to 250 μg, approximately 100 μg to 200 μg, approximately 1 μg to 50 μg, approximately 50 μg to 100 μg, approximately 100 μg to 150 μg, approximately 150 μg to 200 μg, approximately 200 μg to 250 μg, approximately 250 μg to 300 μg, approximately 300 μg to 350 μg, and approximately 350 μg. It may exist in the range of μg to approximately 400 μg, approximately 400 μg to approximately 450 μg, approximately 450 μg to approximately 500 μg, approximately 500 μg to approximately 550 μg, approximately 550 μg to approximately 600 μg, approximately 600 μg to approximately 650 μg, approximately 650 μg to approximately 700 μg, approximately 700 μg to approximately 750 μg, approximately 750 μg to approximately 800 μg, approximately 800 μg to approximately 850 μg, approximately 850 μg to approximately 900 μg, approximately 900 μg to approximately 950 μg, or approximately 950 μg to approximately 1000 μg.

[0171] The compounds described herein contain approximately 0.001 mg, approximately 0.002 mg, approximately 0.003 mg, approximately 0.004 mg, approximately 0.005 mg, approximately 0.006 mg, approximately 0.007 mg, approximately 0.008 mg, approximately 0.009 mg, approximately 0.01 mg, approximately 0.02 mg, approximately 0.03 mg, approximately 0.04 mg, approximately 0.05 mg in a composition or unit dose. Approximately 0.06mg, approximately 0.07mg, approximately 0.08mg, approximately 0.09mg, approximately 0.1mg, approximately 0.2mg, approximately 0.3mg, approximately 0.4mg, approximately 0.5mg, approximately 0.6mg, approximately 0.7mg, about 0.8mg, about 0.9mg, about 1mg, about 2mg, about 3mg, about 4mg, about 5mg, about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, About 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95 mg, about 100mg, about 125mg, about 150mg, about 175mg, about 200mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg, about 5 00mg, about 550mg, about 600mg, about 650mg, about 700mg, about 750mg, about 800mg, about 850mg, about 900mg, about 950mg, about 1000mg , about 1050mg, about 1100mg, about 1150mg, about 1200mg, about 1250mg, about 1300mg, about 1350mg, about 1400mg, about 1450mg, about 1 It may be present in amounts of 500 mg, approximately 1550 mg, approximately 1600 mg, approximately 1650 mg, approximately 1700 mg, approximately 1750 mg, approximately 1800 mg, approximately 1850 mg, approximately 1900 mg, approximately 1950 mg, or approximately 2000 mg.

[0172] In some embodiments, the composition contains 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, and at least about 0.9mg, at least about 1mg, at least about 2mg, at least about 3mg, at least about 4mg, at least about 5mg, at least about 10mg, at least about 15mg, at least about 20mg, at least about 25mg, at least about 30mg, at least about 35mg, at least about 40mg, at least about 45mg, at least about 50mg, at least about 55mg, at least about 60mg, at least about 65mg, at least about 70mg, at least about 75mg, at least about 80mg, at least about 85mg, at least about 90mg, at least about 95mg, at least about 100mg, at least about 125mg, at least about 150mg, at least about 175mg, at least about 200mg, at least about 250mg, at least about 300mg, at least about 350mg, at least about 400mg, at least about 450mg, at least about 500mg, less Each is present in amounts of approximately 550 mg, at least approximately 600 mg, at least approximately 650 mg, at least approximately 700 mg, at least approximately 750 mg, at least approximately 800 mg, at least approximately 850 mg, at least approximately 900 mg, at least approximately 950 mg, at least approximately 1000 mg, at least approximately 1050 mg, at least approximately 1100 mg, at least approximately 1150 mg, at least approximately 1200 mg, at least approximately 1250 mg, at least approximately 1300 mg, at least approximately 1350 mg, at least approximately 1400 mg, at least approximately 1450 mg, at least approximately 1500 mg, at least approximately 1550 mg, at least approximately 1600 mg, at least approximately 1650 mg, at least approximately 1700 mg, at least approximately 1750 mg, at least approximately 1800 mg, at least approximately 1850 mg, at least approximately 1900 mg, at least approximately 1950 mg, or at least approximately 2000 mg.

[0173] In some embodiments, the composition contains, in the composition or unit dose, up to about 0.001 mg, up to about 0.002 mg, up to about 0.003 mg, up to about 0.004 mg, up to about 0.005 mg, up to about 0.006 mg, up to about 0.007 mg, up to about 0.008 mg, up to about 0.009 mg, up to about 0.01 mg, up to about 0.02 mg, and more. Large: approximately 0.03 mg, Maximum: approximately 0.04 mg, Maximum: approximately 0.05 mg, Maximum: approximately 0.06 mg, Maximum: approximately 0.07 mg, Maximum: approximately 0.08 mg, Maximum: approximately 0.09 mg, Maximum: approximately 0.1 mg, Maximum: approximately 0.2 mg, Maximum: approximately 0.3 mg, Maximum: approximately 0.4 mg, Maximum: approximately 0.5 mg, Maximum: approximately 0.6 mg, Maximum: approximately 0.7 mg, Maximum: approximately 0.8 mg, 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 70 mg, up to approximately 75 mg, up to approximately 80 mg, up to approximately 85 mg, up to approximately 90 mg, up to approximately 95 mg, up to approximately 100 mg, up to approximately 125 mg, up to approximately 150 mg, up to approximately 175 mg, up to approximately 200 mg, up to approximately 250 mg, up to approximately 300 mg, up to approximately 350 mg, up to approximately 400 mg, up to approximately 450 mg, up to approximately 500 mg, maximum Approximately 550mg, up to approximately 600mg, up to approximately 650mg, up to approximately 700mg, up to approximately 750mg, up to approximately 800mg, up to approximately 850mg, up to approximately 900mg, up to approximately 950mg, up to approximately 1000mg, up to approximately 1050mg, up to approximately 1100mg, up to approximately 1150mg, up to approximately 1200mg, up to approximately 1250mg, up to approximately 1300mg It is present in amounts of up to approximately 1350 mg, up to approximately 1400 mg, up to approximately 1450 mg, up to approximately 1500 mg, up to approximately 1550 mg, up to approximately 1600 mg, up to approximately 1650 mg, up to approximately 1700 mg, up to approximately 1750 mg, up to approximately 1800 mg, up to approximately 1850 mg, up to approximately 1900 mg, up to approximately 1950 mg, or up to approximately 2000 mg.

[0174] In some embodiments, the dose (e.g., unit dose) is approximately 0.001 mg / kg, approximately 0.002 mg / kg, approximately 0.003 mg / kg, approximately 0.004 mg / kg, approximately 0.005 mg / kg, approximately 0.006 mg / kg, approximately 0.007 mg / kg, approximately 0.008 mg / kg, approximately 0.009 mg / kg, approximately 0.01 mg / kg, approximately 0.02 mg / kg, approximately 0.03 mg / kg, approximately 0.04 mg / kg, approximately 0.05 mg / kg, approximately 0.06 mg / kg, approximately 0.07 mg / kg, approximately 0.08 mg / kg, approximately 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 The dosages are approximately 50 mg / kg, 1000 mg / kg, 1050 mg / kg, 1100 mg / kg, 1150 mg / kg, 1200 mg / kg, 1250 mg / kg, 1300 mg / kg, 1350 mg / kg, 1400 mg / kg, 1450 mg / kg, 1500 mg / kg, 1550 mg / kg, 1600 mg / kg, 1650 mg / kg, 1700 mg / kg, 1750 mg / kg, 1800 mg / kg, 1850 mg / kg, 1900 mg / kg, 1950 mg / kg, or 2000 mg / kg.

[0175] In some embodiments, the dose (e.g., unit dose) is based on the body mass of the subject or patient and 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 0.03 mg / kg, at least about 0.04 mg / kg, at least about 0.05 mg / kg, and Approximately 0.06 mg / kg, at least approximately 0.07 mg / kg, at least approximately 0.08 mg / kg, at least approximately 0.09 mg / kg, at least approximately 0.1 mg / kg, at least approximately 0.2 mg / kg, at least approximately 0.3 mg / kg, at least approximately 0.4 mg / kg, at least approximately 0.5 mg / kg, at least approximately 0.6 mg / kg, at least approximately 0.7 mg / kg, at least approximately 0.8 mg / kg, at least approximately 0.9 mg / kg, at least approximately 1 mg / kg, at least approximately 2 mg / kg, at least approximately 3 mg / kg, at least approximately 4 mg / kg, at least approximately 5 mg / kg, at least approximately 10 mg / kg, at least approximately 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 approximately 95 mg / kg, at least approximately 100 mg / kg, at least approximately 125 mg / kg, at least approximately 150 mg / kg, at least approximately 175 mg / kg, at least approximately 200 mg / kg, at least approximately 250 mg / kg, at least approximately 300 mg / kg, at least approximately 350 mg / kg, at least approximately 400 mg / kg, at least approximately 450 mg / kg, at least approximately 500 mg / kg, at least approximately 550 mg / kg, at least approximately 600 mg / kg, at least approximately 650 mg g / 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, at least about 1300 mg / kg, at least about 1350 mg g / 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 mg / kg, based on the body mass of the subject or patient. Large: approximately 0.03 mg / kg, Maximum: approximately 0.04 mg / kg, Maximum: approximately 0.05 mg / kg, Maximum: approximately 0.06 mg / kg, Maximum: approximately 0.07 mg / kg, Maximum: approximately 0.08 mg / kg, Maximum: approximately 0.09 mg / kg, Maximum: approximately 0.1 mg / kg, Maximum: approximately 0.2 mg / kg, Maximum: approximately 0.3 mg / kg, Maximum: approximately 0.4 mg / kg, Maximum: approximately 0.5 mg / kg, Maximum: approximately 0.6 mg / kg, Maximum: approximately 0.7 mg / kg, Maximum: approximately 0.8 mg / kg, Maximum: approximately 0.9 mg / kg, maximum approximately 1 mg / kg, maximum approximately 2 mg / kg, maximum approximately 3 mg / kg, maximum approximately 4 mg / kg, maximum approximately 5 mg / kg, maximum approximately 10 mg / kg, maximum approximately 15 mg / kg, maximum approximately 20 mg / kg, maximum approximately 25 mg / kg, maximum approximately 30 mg / kg, maximum approximately 35 mg / kg, maximum approximately 40 mg / kg, maximum approximately 45 mg / kg, maximum approximately 50 mg / kg, maximum approximately 55mg / kg, maximum approximately 60mg / kg, maximum approximately 65mg / kg, maximum approximately 70mg / kg, maximum approximately 75mg / kg, maximum approximately 80mg / kg, maximum approximately 85mg / kg, maximum approximately 90mg / kg, maximum approximately 95mg / kg, maximum approximately 100mg / kg, maximum approximately 125mg / kg, maximum approximately 150mg / kg, maximum approximately 175mg / kg, maximum Approximately 200 mg / kg, maximum approximately 250 mg / kg, maximum approximately 300 mg / kg, maximum approximately 350 mg / kg, maximum approximately 400 mg / kg, maximum approximately 450 mg / kg, maximum approximately 500 mg / kg, maximum approximately 550 mg / kg, maximum approximately 600 mg / kg, maximum approximately 650 mg / kg, maximum approximately 700 mg / kg, maximum approximately 750 mg / kg, maximum approximately 800 mg / kg, maximum Large: approximately 850 mg / kg, Maximum: approximately 900 mg / kg, Maximum: approximately 950 mg / kg, Maximum: approximately 1000 mg / kg, Maximum: approximately 1050 mg / kg, Maximum: approximately 1100 mg / kg, Maximum: approximately 1150 mg / kg, Maximum: approximately 1200 mg / kg, Maximum: approximately 1250 mg / kg, Maximum: approximately 1300 mg / kg, Maximum: approximately 1350 mg / kg, Maximum: approximately 1400 mg / kg, Maximum: approximately 130350 mg / kg, Maximum: approximately 1400 mg / kg, Maximum: approximately 1300 mg / kg. The levels are approximately 1450 mg / kg, with a maximum of approximately 1500 mg / kg, 1550 mg / kg, 1600 mg / kg, 1650 mg / kg, 1700 mg / kg, 1750 mg / kg, 1800 mg / kg, 1850 mg / kg, 1900 mg / kg, 1950 mg / kg, or 2000 mg / kg.

[0177] In some embodiments, the dose (e.g., unit dose) is based on the body mass of the subject or patient and ranges from approximately 1 mg / kg to approximately 2000 mg / kg; approximately 5 mg / kg to approximately 1000 mg / kg, approximately 10 mg / kg to approximately 25 mg / kg, approximately 50 mg / kg to approximately 250 mg / kg, approximately 100 mg / kg to approximately 200 mg / kg, approximately 1 mg / kg to approximately 50 mg / kg, approximately 50 mg / kg to approximately 100 mg / kg, approximately 100 mg / kg to approximately 150 mg / kg, approximately 150 mg / kg to approximately 200 mg / kg, approximately 200 mg / kg to approximately 250 mg / kg, approximately 250 mg / kg to approximately 300 mg / kg, approximately 300 mg / kg to approximately 350 mg / kg, and approximately 35 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. The concentrations are approximately 450 μg / kg, 500 μg / kg, 550 μg / kg, 600 μg / kg, 700 μg / kg, 800 μg / kg, 850 μg / kg, 900 μg / kg, 950 μg / kg, or 1000 μg / kg.

[0178] Pharmaceutical compositions and formulations described herein may, for example, contain the compounds disclosed herein at 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, and about 0.04 mg / mL. L, approx. 0.05 mg / mL, approx. 0.06 mg / mL, approx. 0.07 mg / mL, approx. 0.08 mg / mL, approx. 0.09 mg / mL, approx. 0.1 mg / mL, approx. 0.2 mg / mL, approx. 0 .3mg / mL, approx. 0.4mg / mL, approx. 0.5mg / mL, approx. 0.6mg / mL, approx. 0.7mg / mL, approx. 0.8mg / mL, approx. 0.9mg / mL, approx. 1mg / mL, approx. 2m g / mL, approx. 3 mg / mL, approx. 4 mg / mL, approx. 5 mg / mL, approx. 10 mg / mL, approx. 15 mg / mL, approx. 20 mg / mL, approx. 25 mg / mL, approx. 30 mg / mL, approx. 35 mg / 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 80 mg / mL, approx. 85 mg / mL, approx. 90 mg / mL, approx. 95 mg / mL, approx. 100 mg / mL, approx. 125 mg / mL, approx. 150 mg / mL, approx. 175 mg / mL, approx. 200 mg / mL, approx. 250mg / mL, approx. 300mg / mL, approx. 350mg / mL, approx. 400mg / mL, approx. 450mg / mL, approx. 500mg / mL, approx. 550mg / mL, approx. 600m g / mL, approximately 650 mg / mL, approximately 700 mg / mL, approximately 750 mg / mL, approximately 800 mg / mL, approximately 850 mg / mL, approximately 900 mg / mL, approximately 950 mg / mL, approximately 1000 m g / mL, approx. 1050 mg / mL, approx. 1100 mg / mL, approx. 1150 mg / mL, approx. 1200 mg / mL, approx. 1250 mg / mL, approx. 1300 mg / mL, approx. 1350 mg / mL The compositions of this disclosure may comprise concentrations of approximately 1400 mg / mL, approximately 1450 mg / mL, approximately 1500 mg / mL, approximately 1550 mg / mL, approximately 1600 mg / mL, approximately 1650 mg / mL, approximately 1700 mg / mL, approximately 1750 mg / mL, approximately 1800 mg / mL, approximately 1850 mg / mL, approximately 1900 mg / mL, approximately 1950 mg / mL, or approximately 2000 mg / mL.

[0179] In some embodiments, the formulations of this disclosure contain 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, and less At least approximately 0.04 mg / mL, at least approximately 0.05 mg / mL, at least approximately 0.06 mg / mL, at least approximately 0.07 mg / mL, at least approximately 0.08 mg / mL, at least approximately 0.09 mg / mL, at least approximately 0.1 mg / mL, at least approximately 0.2 mg / mL, at least approximately 0.3 mg / mL, at least approximately 0.4 mg / mL, at least approximately 0.5 mg / mL, at least approximately 0.6 mg / mL, at least approximately 0.7 mg / mL, at least approximately 0.8 mg / mL, at least approximately 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 Approximately 70 mg / mL, at least approximately 75 mg / mL, at least approximately 80 mg / mL, at least approximately 85 mg / mL, at least approximately 90 mg / mL, at least approximately 95 mg / mL, at least approximately 100 mg / mL, at least approximately 125 mg / mL, at least approximately 150 mg / mL, at least approximately 175 mg / mL, at least approximately 200 mg / mL, at least approximately 250 mg / mL, at least approximately 300 mg / mL, at least approximately 350 mg / mL, at least approximately 400 mg / mL, at least approximately 450 mg / mL, at least approximately 500 mg / mL , at least approximately 550 mg / mL, at least approximately 600 mg / mL, at least approximately 650 mg / mL, at least approximately 700 mg / mL, at least approximately 750 mg / mL, at least approximately 800 mg / mL, at least approximately 850 mg / mL, at least approximately 900 mg / mL, at least approximately 950 mg / mL, at least approximately 1000 mg / mL, at least approximately 1050 mg / mL, at least approximately 1100 mg / mL, at least approximately 1150 mg / mL, at least approximately 1200 mg / mL, at least approximately 1250 mg / mL, at least approximately 1300 mg The compounds of this disclosure are contained in concentrations of at least approximately 1350 mg / mL, at least approximately 1400 mg / mL, at least approximately 1450 mg / mL, at least approximately 1500 mg / mL, at least approximately 1550 mg / mL, at least approximately 1600 mg / mL, at least approximately 1650 mg / mL, at least approximately 1700 mg / mL, at least approximately 1750 mg / mL, at least approximately 1800 mg / mL, at least approximately 1850 mg / mL, at least approximately 1900 mg / mL, at least approximately 1950 mg / mL, or at least approximately 2000 mg / mL.

[0180] In some embodiments, the formulations of the Disclosure have a maximum concentration of approximately 0.002 mg / mL, 0.003 mg / mL, 0.004 mg / mL, 0.005 mg / mL, 0.006 mg / mL, 0.007 mg / mL, and 0.008 mg / mL, maximum approximately 0.009 mg / mL, maximum approximately 0.01 mg / mL, maximum approximately 0.02 mg / mL, maximum approximately 0.03 mg / mL, maximum approximately 0.04 mg / mL, maximum approximately 0.05 mg / mL, maximum approximately 0.06 mg / mL, maximum approximately 0.07 mg / mL, maximum approximately 0.08 mg / mL, maximum approximately 0.09 mg / mL, maximum approximately 0.1 mg / mL, maximum approximately 0.2 mg / mL, maximum approximately 0.3 mg / mL, maximum approximately 0.4 mg / mL, maximum approximately 0.5 mg / mL, maximum approximately 0.6 mg / mL, maximum approximately 0.7 mg / mL, maximum approximately 0.8 mg / mL, maximum approximately 0.9 mg / mL, maximum approximately 1 mg / mL, maximum approximately 2 mg / mL, maximum approximately 3 mg / mL, maximum approximately 4 mg / mL, maximum approximately 5 mg / mL, maximum approximately 10 mg / mL, maximum approximately 15 mg / mL, maximum approximately 20 mg / mL, maximum approximately 25 mg / mL, maximum approximately 30 mg / mL, maximum approximately 35 mg / mL, maximum approximately 40 mg / mL, maximum approximately 45 mg / mL, maximum approximately 50 mg / mL, maximum approximately 55 mg / mL, maximum approximately 60 mg / mL, maximum approximately 65 mg / mL, maximum approximately 70 mg / mL, maximum of approximately 75 mg / mL, maximum of approximately 80 mg / mL, maximum of approximately 85 mg / mL, maximum of approximately 90 mg / mL, maximum of approximately 95 mg / mL, maximum of approximately 100 mg / mL, maximum of approximately 125 mg / mL, maximum of approximately 150 mg / mL, maximum of approximately 175 mg / mL, maximum of approximately 200 mg / mL, maximum of approximately 250 mg / mL, maximum of approximately 300 mg / mL, maximum of approximately 350 mg / mL, maximum of approximately 400 mg / mL, maximum of approximately 450 mg / mL, maximum of approximately 500 mg / mL, maximum Approximately 550 mg / mL, up to approximately 600 mg / mL, up to approximately 650 mg / mL, up to approximately 700 mg / mL, up to approximately 750 mg / mL, up to approximately 800 mg / mL, up to approximately 850 mg / mL, up to approximately 900 mg / mL, up to approximately 950 mg / mL, up to approximately 1000 mg / mL, up to approximately 1050 mg / mL, up to approximately 1100 mg / mL, up to approximately 1150 mg / mL, up to approximately 1200 mg / mL, up to approximately 1250 mg / mL, up to approximately 1300 mg / mL, The compounds disclosed herein are contained in concentrations of up to approximately 1350 mg / mL, up to approximately 1400 mg / mL, up to approximately 1450 mg / mL, up to approximately 1500 mg / mL, up to approximately 1550 mg / mL, up to approximately 1600 mg / mL, up to approximately 1650 mg / mL, up to approximately 1700 mg / mL, up to approximately 1750 mg / mL, up to approximately 1800 mg / mL, up to approximately 1850 mg / mL, up to approximately 1900 mg / mL, up to approximately 1950 mg / mL, or up to approximately 2000 mg / mL.

[0181] In some embodiments, the formulations of the present disclosure are approximately 1 mg / mL to approximately 2000 mg / mL; approximately 5 mg / mL to approximately 1000 mg / mL, approximately 10 mg / mL to approximately 25 mg / mL, approximately 50 mg / mL to approximately 250 mg / mL, approximately 100 mg / mL to approximately 200 mg / mL, approximately 1 mg / mL to approximately 50 mg / mL, approximately 50 mg / mL to approximately 100 mg / mL, approximately 100 mg / mL to approximately 150 mg / mL, approximately 150 mg / mL to approximately 200 mg / mL, approximately 200 mg / mL to approximately 250 mg / mL, Approximately 250mg / mL to approximately 300mg / mL, approximately 300mg / mL to approximately 350mg / mL, approximately 350mg / mL to approximately 400mg / mL, approximately 400mg / mL to approximately 450mg / mL, approximately 450mg / mL to approximately 500mg / mL, approximately 500m g / mL~about 550mg / mL, about 550mg / mL~about 600mg / mL, about 600mg / mL~about 650mg / mL, about 650mg / mL~about 700mg / mL, about 700mg / mL~about 750mg / mL, about 750mg / mL~ Approximately 800mg / mL, approximately 800mg / mL to approximately 850mg / mL, approximately 850mg / mL to approximately 900mg / mL, approximately 900mg / mL to approximately 950mg / mL, approximately 950mg / mL to approximately 1000mg / mL, approximately 1μg / mL to approximately 2000μ g / mL; about 5μg / mL to about 1000μg / mL, about 10μg / mL to about 25μg / mL, about 50μg / mL to about 250μg / mL, about 100μg / mL to about 200μg / mL, about 1μg / mL to about 50μg / mL, about 50μg / m L ~ about 100μg / mL, about 100μg / mL to about 150μg / mL, about 150μg / mL to about 200μg / mL, about 200μg / mL to about 250μg / mL, about 250μg / mL to about 300μg / mL, about 300μg / mL to about 35 0μg / mL, approximately 350μg / mL to approximately 400μg / mL, approximately 400μg / mL to approximately 450μg / mL, approximately 450μg / mL to approximately 500μg / mL, approximately 500μg / mL to approximately 550μg / mL, approximately 550μg / mL to approximately 600μg / m L contains the compound of the present disclosure at concentrations of approximately 600 μg / mL to 650 μg / mL, approximately 650 μg / mL to 700 μg / mL, approximately 700 μg / mL to 750 μg / mL, approximately 750 μg / mL to 800 μg / mL, approximately 800 μg / mL to 850 μg / mL, approximately 850 μg / mL to 900 μg / mL, approximately 900 μg / mL to 950 μg / mL, or approximately 950 μg / mL to 1000 μg / mL. Therapeutic effect Tissue distribution and pharmacokinetics

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

[0183] In some embodiments, if a study or assay (e.g., a tissue distribution study) is conducted, the study or assay includes the step of administering the compound of the Disclosure (e.g., compound 1) to a study patient or subject in a dose of about 0.1 mg / kg to about 1.5 mg / kg (e.g., intracerebroventricular administration), in which case 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, intestines, liver, lungs, kidneys, and / or muscles of the study patient for that one month.

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

[0185] Various analytical techniques can be used to determine the concentration of compounds in tissues and / or other samples (e.g., blood, plasma, urine, feces, etc.) collected from research patients. Non-limiting examples of techniques that can be used to determine the concentration of a compound include mass spectrometry, e.g., 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, fast or ultrafast liquid chromatography (HPLC or UHPLC, e.g., with MS or ultraviolet detection), time-of-flight (TOF) MS, monitoring of selected reactions (SRM), monitoring of multiple reactions (MRM), nuclear magnetic resonance (NMR, e.g., continuous wave (cw), pulse 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 may involve administering the compound of the Disclosure (e.g., compound 1) to a study patient (e.g., a mouse) or subject at doses of approximately 0.01 mg / kg to approximately 5 mg / kg (e.g., approximately 0.1 to approximately 2 mg / kg, approximately 0.2 to approximately 1.5 mg / kg, approximately 0.3 to approximately 1.2 mg / kg, approximately 0.3 to approximately 1 mg / kg, approximately 0.3 to approximately 1 mg / kg). The procedure includes a step of administering a dose of approximately 0.6 mg / kg (or approximately 0.6 to approximately 1 mg / kg) (e.g., via intracerebroventricular administration), in which case the compound accumulates in the brain of the study patient or subject for a period of up to approximately one month after administration (e.g., up to approximately 3 days, up to approximately 7 days, up to approximately 14 days, up to approximately 21 days, up to approximately 27 days, or up to approximately 28 days). In some embodiments, the compound is not observed at detectable levels or is barely observed in the plasma, intestines, liver, lungs, kidneys, and / or muscles 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 the step of administering a compound of the Disclosure (e.g., compound 1) to a study patient or subject in doses 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) (e.g., via intracerebroventricular administration), in which case the compound accumulates in the brain of the study patient or subject for a period of at least about 1 day after administration (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). In some embodiments, the compound is not detected or barely detected in the plasma, intestines, liver, lungs, kidneys, and / or muscles of the research patient or subject during this period.

[0188] In some embodiments, if an assay or study is performed, the study or assay includes the step of administering the compound of the Disclosure (e.g., compound 1) to a study patient or subject in doses 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) (e.g., via intracerebroventricular administration), in which case the compound accumulates in the spleen of the study patient or subject for a period of up to about 1 month after administration (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). In some embodiments, the compound is not observed at detectable levels or is barely observed in the plasma, intestines, liver, lungs, kidneys, and / or muscles 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 the step of administering a compound of the Disclosure (e.g., compound 1) to a study patient or subject in 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) (e.g., via intracerebroventricular administration), in which case the compound accumulates in the spleen of the study patient or subject for a period of at least about 1 day after administration (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). In some embodiments, the compound is not detected or barely detected in the plasma, intestines, liver, lungs, kidneys, and / or muscles of the research patient or subject during this period.

[0190] In some embodiments, if an assay or study is performed, the study or assay includes the step of administering the compound of the Disclosure (e.g., compound 1) to a study patient or subject in doses 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) (e.g., via intracerebroventricular administration), in which case the compound is present for up to about 1 month after administration (e.g., up to about 3 days) The compound accumulates in the heart of the study patient or subject for a timer period of up to approximately 7 days, up to approximately 14 days, up to approximately 21 days, up to approximately 27 days, or up to approximately 28 days. In some embodiments, the compound is not observed at detectable levels, or barely observed, in the plasma, intestines, liver, lungs, kidneys, and / or muscles 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 the step of administering a compound of the Disclosure (e.g., Compound 1) to a study patient or subject in doses 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) (e.g., via intracerebroventricular administration), in which case the compound accumulates in the heart of the study patient or subject for a period of at least about 1 day after administration (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). In some embodiments, the compound is not detected or barely detected in the plasma, intestines, liver, lungs, kidneys, and / or muscles of the research patient or subject during this period.

[0192] In some embodiments, if an assay or study is performed, the study or assay includes the step of administering a compound of the Disclosure (e.g., Compound 1) to a study patient or subject in 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) (e.g., via intracerebroventricular administration), in which case the compound accumulates in the brain of the study patient or subject for a period of up to about 1 month after administration (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). In some embodiments, the compound is not detected or barely detected in the plasma, intestines, liver, lungs, kidneys, and / or muscles of the research patient or subject during this period.

[0193] In some embodiments, if an assay or study is performed, the study or assay includes the step of administering a compound of the Disclosure (e.g., Compound 1) to a study patient or subject in 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) (e.g., via intracerebroventricular administration), in which case the compound accumulates in the brain of the study patient or subject for a period of at least about 1 day after administration (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). In some embodiments, the compound is not detected or barely detected in the plasma, intestines, liver, lungs, kidneys, and / or muscles of the research patient or subject during this period.

[0194] In some embodiments, if an assay or study is performed, the study or assay includes the step of administering the compound of the Disclosure (e.g., compound 1) to a study patient or subject in doses 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) (e.g., via intracerebroventricular administration), in which case the compound is absorbed for up to about 1 month after administration (e.g., up to about 3 days, up to about 7 days, up to about 1 The compound accumulates in the spleen of the study patient or subject for a period of 4 days, up to approximately 21 days, up to approximately 27 days, or up to approximately 28 days. In some embodiments, the compound is not detected or barely detected in the plasma, intestines, liver, lungs, kidneys, and / or muscles 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 the step of administering a compound of the Disclosure (e.g., Compound 1) to a study patient or subject in 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) (e.g., via intracerebroventricular administration), in which case the compound accumulates in the spleen of the study patient or subject for a period of at least about 1 day after administration (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). In some embodiments, the compound is not detected or barely detected in the plasma, intestines, liver, lungs, kidneys, and / or muscles of the research patient or subject during this period.

[0196] In some embodiments, if an assay or study is performed, the study or assay includes the step of administering a compound of the Disclosure (e.g., Compound 1) to a study patient or subject in 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) (e.g., via intracerebroventricular administration), in which case the compound accumulates in the heart of the study patient or subject for a period of up to about 1 month after administration (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). In some embodiments, the compound is not detected or barely detected in the plasma, intestines, liver, lungs, kidneys, and / or muscles of the research patient or subject during this period.

[0197] In some embodiments, if an assay or study is performed, the study or assay includes the step of administering a compound of the Disclosure (e.g., Compound 1) to a study patient or subject in 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) (e.g., via intracerebroventricular administration), in which case the compound accumulates in the heart of the study patient or subject for a period of at least about 1 day after administration (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). In some embodiments, the compound is not detected or barely detected in the plasma, intestines, liver, lungs, kidneys, and / or muscles of the research patient or subject during this period.

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

[0199] Pharmacokinetic and pharmacodynamic data can be obtained through various experimental techniques. The appropriate pharmacokinetic and pharmacodynamic profile components describing a particular composition may vary due to variability in drug metabolism in human subjects. Pharmacokinetic and pharmacodynamic profiles are relevant to the subject. The mean parameter can be determined based on the determination of the mean parameter of the group. The group of subjects includes any reasonable number of subjects suitable for determining a representative mean, e.g., 5 subjects, 10 subjects, 15 subjects, 20 subjects, 25 subjects, 30 subjects, 35 subjects, or more subjects. The mean is determined, for example, by calculating the average of the measurements of all subjects with respect to each parameter being measured. The dose can be modulated to achieve a desired pharmacokinetic or pharmacodynamic profile, e.g., 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, cattle, pig, miniature pig, dog, cat, goat, camel, rodent, rabbit, mouse, rat, hamster, gerbil, chinchilla, fancy rat, guinea pig, C57BL6J mouse, beagle, Göttingen miniature pig, or crab-eating macaque. 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, cattle, pig, miniature pig, dog, cat, goat, camel, rodent, rabbit, mouse, rat, hamster, gerbil, chinchilla, fancy rat, guinea pig, C57BL6J mouse, beagle, Göttingen miniature pig, or crab-eating macaque. 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 the subject are of the same species. In some embodiments, the subject and the patient are human.

[0203] In some embodiments, the patient and subject are of different species. In some embodiments, the subject is human, and the patient is non-human, for example, non-human vertebrates, non-human mammals, non-human primates, apes, monkeys, sheep, horses, cattle, pigs, miniature pigs, dogs, cats, goats, camels, rodents, rabbits, mice, rats, hamsters, gerbils, chinchillas, fancy rats, or guinea pigs. In some embodiments, the patient is human, and the subject is non-human, for example, non-human vertebrates, non-human mammals, non-human primates, apes, monkeys, sheep, horses, cattle, pigs, miniature pigs, dogs, cats, goats, camels, rodents, rabbits, mice, rats, hamsters, gerbils, chinchillas, fancy rats, or guinea pigs.

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

number

number

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[0205] In some embodiments, when a compound is subjected to research or assays (e.g., pharmacokinetic studies), the mean peak brain concentration (e.g., 3000 ng / mL to about 22000 ng / mL) may be observed in research patients (e.g., mice) at a time to peak brain concentration (e.g., about 1 hour to about 50 hours after administration). In some embodiments, the assay may include the step of administering the compound to research patients (e.g., mice) by administering a dose of about 0.1 mg / kg to about 2 mg / kg (e.g., intracerebroventricular administration). The mice can be euthanized at some point after administration (e.g., between about 1 hour and 28 days). Various tissues (e.g., brain tissue) can be collected from the research patients after the euthanasia step. The concentration in the research patient's tissues can be determined using various techniques disclosed herein, such as liquid chromatography-tandem mass spectrometry. Pharmacokinetics of the brain

[0206] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean T of the compound in the brain 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, and at least It is 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 conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean T of the compound in the brain max The maximum duration is 6, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 72, 96, or 120 hours.

[0208] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean T of the compound in the brain max These ranges from approximately 0.5 to 120, 1 to 24, 1 to 36, 1 to 48, 2 to 36, 6 to 24, 1 to 6, 6 to 12, 12 to 24, 12 to 18, 18 to 48, 18 to 36, or 24 to 48 hours.

[0209] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of this 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) (e.g., via intracerebroventricular administration), in which case the mean C of the compound in the brain max This 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 conducted, the pharmacokinetic study includes the step of administering the compound of this 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) (e.g., via intracerebroventricular administration), in which case the mean C of the compound in the brain max The maximum values ​​are approximately 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 12000, 14000, 16000, 18000, 20000, 22000, 25000, 30000, or 50000 ng / mL.

[0211] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case to the brain The average C of the compound in the given location max These ranges are approximately 1,000 to 50,000 ng / mL, 2,000 to 25,000 ng / mL, 3,000 to 22,000 ng / mL, 2,000 to 5,000 ng / mL, 5,000 to 15,000 ng / mL, or 10,000 to 25,000 ng / mL.

[0212] In some embodiments, at a dose of 0.3 mg / kg, the average peak brain concentration is approximately 3000 ng / mL to approximately 4000 ng / mL. In some embodiments, at a dose of 0.6 mg / kg, the average peak brain concentration is approximately 6000 ng / mL to approximately 12000 ng / mL. In some embodiments, at a dose of 1 mg / kg, the average peak brain concentration is approximately 15000 ng / mL to approximately 22000 ng / mL.

[0213] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of this 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) (e.g., via intracerebroventricular administration), in which case the mean AUC of the compound in the brain. last It 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 conducted, the pharmacokinetic study includes the step of administering the compound of this 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) (e.g., via intracerebroventricular administration), in which case the mean AUC of the compound in the brain. last The maximum values ​​are approximately 1.5 × 10^6, 2 × 10^6, 2.5 × 10^6, 3 × 10^6, 4 × 10^6, 5 × 10^6, 6 × 10^6, 7 × 10^6, 8 × 10^6, 10 × 10^6, 15 × 10^6, or 20 × 10^6 ng·h / mL.

[0215] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of this 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) (e.g., via intracerebroventricular administration), in which case the mean AUC of the compound in the brain. last The AUC ranges from approximately 0.5 × 10^6 to approximately 20 × 10^6, approximately 1 × 10^6 to approximately 15 × 10^6, approximately 1 × 10^6 to approximately 10 × 10^6, approximately 1.5 × 10^6 to approximately 8 × 10^6, approximately 1 × 10^6 to approximately 5 × 10^6, approximately 5 × 10^6 to approximately 10 × 10^6, approximately 1 × 10^6 to approximately 3 × 10^6, or approximately 2 × 10^6 to approximately 5 × 10^6 ng·h / mL. In some embodiments, the AUC of the research patient or subject (e.g., mouse) is also present. last It is approximately 1,400,000 hours * ng / mL~about 7500000h * A value of ng / mL was observed.

[0216] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the Disclosure to a study patient or subject in doses 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) (e.g., via intracerebroventricular administration), in which case the brain average 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 conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean brain T last The maximum duration is approximately 1, 2, 3, 4, 5, 6, 7, 10, 12, 14, 21, 28, 35, 42, 49, 100, 200, or 300 days.

[0218] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean brain T last These ranges from approximately 1 to 300 days, 2 to 100 days, 5 to 50 days, 10 to 30 days, 1 to 20 days, 20 to 40 days, 40 to 60 days, 60 to 80 days, or 80 to 100 days.

[0219] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean brain T 1 / 2 This 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 conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean brain T 1 / 2The maximum duration is 24, 48, 100, 200, 500, 1000, 1500, 2000, 2500, 3000, 5000, 10000, or 20000 hours.

[0221] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean brain T 1 / 2 These ranges from approximately 24 to 20,000, approximately 100 to 15,000, approximately 500 to 10,000, approximately 500 to 5,000, approximately 100 to 1,000, approximately 1,000 to 2,000, or It is approximately 3000 to 5000 hours.

[0222] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean T of the compound in the brain 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 conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean T of the compound in the brain max The maximum duration is 6, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 72, 96, or 120 hours.

[0224] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean T of the compound in the brain max These ranges from approximately 0.5 to 120, 1 to 24, 1 to 36, 1 to 48, 2 to 36, 6 to 24, 1 to 6, 6 to 12, 12 to 24, 12 to 18, 18 to 48, 18 to 36, or 24 to 48 hours.

[0225] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean C of the compound in the brain max This 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.

[0226] In some embodiments, when pharmacokinetic studies are conducted, the pharmacokinetic studies involve administering the compounds of this disclosure at concentrations of approximately 0.001 mg / kg to approximately 0.5 mg / kg (e.g., approximately 0.008 to approximately 0.163 mg / kg, approximately 0.016 to approximately 0.125 mg / kg, approximately 0.025 to approximately 0.1 mg / kg, approximately 0.025 to approximately 0.08 mg / kg, approximately 0.025 to approximately 0.05 mg / kg, and This includes a step of administering the compound to a research patient or subject at a dose of approximately 0.05 to approximately 0.08 mg / kg (e.g., via intracerebroventricular administration), in which case the mean C of the compound in the brain. max The maximum values ​​are approximately 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 12000, 14000, 16000, 18000, 20000, 22000, 25000, 30000, or 50000 ng / mL.

[0227] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean C of the compound in the brain max These ranges are approximately 1,000 to 50,000 ng / mL, 2,000 to 25,000 ng / mL, 3,000 to 22,000 ng / mL, 2,000 to 5,000 ng / mL, 5,000 to 15,000 ng / mL, or 10,000 to 25,000 ng / mL.

[0228] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of this 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) (e.g., via intracerebroventricular administration), in which case the mean AUC of the compound in the brain. last It 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 conducted, the pharmacokinetic study includes the step of administering the compound of this 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) (e.g., via intracerebroventricular administration), in which case the mean AUC of the compound in the brain. last The maximum values ​​are approximately 1.5 × 10^6, 2 × 10^6, 2.5 × 10^6, 3 × 10^6, 4 × 10^6, 5 × 10^6, 6 × 10^6, 7 × 10^6, 8 × 10^6, 10 × 10^6, 15 × 10^6, or 20 × 10^6 ng·h / mL.

[0230] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of this 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) (e.g., via intracerebroventricular administration), in which case the mean AUC of the compound in the brain. last This is approximately 0.5 × 10^6 to approximately 20 × 10^6, approximately 1 × 10^6 to approximately 15 × 10^6, approximately 1 × 10^6 to approximately 10 × 10^6, approximately 1.5 × 10^6 to approximately 8 × 10^6, approximately 1 × 10^6 to approximately 5 × 10^6, approximately 5 × 10^6 to approximately 10 × 10^6, approximately 1 × 10^6 to approximately 3 × It is 10^6, or approximately 2 × 10^6 to approximately 5 × 10^6 ng·h / mL.

[0231] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean brain 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.

[0232] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean brain T last The maximum duration is approximately 1, 2, 3, 4, 5, 6, 7, 10, 12, 14, 21, 28, 35, 42, 49, 100, 200, or 300 days.

[0233] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean brain T last These ranges from approximately 1 to 300 days, 2 to 100 days, 5 to 50 days, 10 to 30 days, 1 to 20 days, 20 to 40 days, 40 to 60 days, 60 to 80 days, or 80 to 100 days.

[0234] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean brain T 1 / 2 This 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 conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean brain T1 / 2 The maximum values ​​are 24, 48, 100, 200, 500, 1000, and 1 The maximum duration is 500, 2000, 2500, 3000, 5000, 10000, or 20000 hours.

[0236] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean brain T 1 / 2 These ranges from approximately 24 to 20,000 hours, 100 to 15,000 hours, 500 to 10,000 hours, 500 to 5,000 hours, 100 to 1,000 hours, 1,000 to 2,000 hours, or 3,000 to 5,000 hours.

[0237] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average T of the compound max However, after administering a single dose to male subjects, a 1.5-hour T2 dose of 0.3 mg / kg was administered. max A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0238] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average T of the compound max However, after administering a single dose to female subjects, 0.3 mg / kg was used for 48 hours. max A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0239] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average T of the compoundmax However, after administering a single dose to male subjects, 0.6 mg / kg was used for 4 hours of T14. max A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0240] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average T of the compound max However, after a single dose administration to female subjects, 0.6 mg / kg was used for 1.5 hours of T max A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0241] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average T of the compound max However, after administering a single dose to male subjects, 1 mg / kg was used for 24 hours. max A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0242] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average T of the compound max However, after a single dose administration to female subjects, 1 mg / kg was administered for 8 hours. max A pharmaceutical composition is provided that is within 70% to 130% of the total.

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

[0244] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average C of the compound is max However, the single target of females After administering the dose, 0.3 mg / kg resulted in a C level of 3930 ng / mL. max A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0245] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average C of the compound is max However, after a single dose administration to male subjects, C levels were 6490 ng / mL at 0.6 mg / kg. max A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0246] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average C of the compound is max However, after a single dose administration to female subjects, C levels were 11400 ng / mL at 0.6 mg / kg. max A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0247] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average C of the compound is max However, after a single dose administration to male subjects, C levels of 15,500 ng / mL were observed at 1 mg / kg. max A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0248] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average C of the compound is max However, after a single dose administration to female subjects, C2 was 21,500 ng / mL at 1 mg / kg. max A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0249] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average AUC of the compound lastHowever, after a single dose administration to male subjects, the AUC was 1,440,000 ng·h / mL at 0.3 mg / kg. last A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0250] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average AUC of the compound last However, after a single dose administration to female subjects, the AUC was 1,800,000 ng·h / mL at 0.3 mg / kg. last A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0251] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average AUC of the compound last However, after a single dose administration to male subjects, the AUC was 2,470,000 ng·h / mL at 0.6 mg / kg. last A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0252] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average AUC of the compound last However, after a single dose administration to female subjects, the AUC was 2,360,000 ng·h / mL at 0.6 mg / kg. last A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0253] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average AUC of the compound last However, after a single dose administration to male subjects, the AUC was 5,530,000 ng·h / mL at 1 mg / kg. last A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0254] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average AUC of the compound last However, female target After a single dose administration, the AUC was 7,150,000 ng·h / mL at 1 mg / kg. last A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0255] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average T of the compound last However, after administering a single dose to the subject, the T648 hours later last A pharmaceutical composition is provided that is within 70% to 130% of the total. Pharmacokinetics of the spleen

[0256] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean T of the compound in the spleen 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 conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean T of the compound in the spleen max The maximum duration is 6, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 72, 96, or 120 hours.

[0258] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean T of the compound in the spleen max These ranges from approximately 0.5 to 120, 1 to 24, 1 to 36, 1 to 48, 2 to 36, 6 to 24, 1 to 6, 6 to 12, 12 to 24, 12 to 18, 18 to 48, 18 to 36, or 24 to 48 hours.

[0259] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean C of the compound in the spleen maxThis 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 pharmacokinetic studies are conducted, the pharmacokinetic studies will be conducted on the compounds of the disclosure. The step includes administering the compound to research patients or subjects in doses of approximately 0.01 mg / kg to approximately 5 mg / kg (e.g., approximately 0.1 to approximately 2 mg / kg, approximately 0.2 to approximately 1.5 mg / kg, approximately 0.3 to approximately 1.2 mg / kg, approximately 0.3 to approximately 1 mg / kg, approximately 0.3 to approximately 0.6 mg / kg, or approximately 0.6 to approximately 1 mg / kg) (e.g., via intracerebroventricular administration), in which case the mean C of the compound in the spleen max The maximum values ​​are approximately 1000, 1500, 2000, 2500, 3000, 4000, 5000, or 10000 ng / mL.

[0261] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean C of the compound in the spleen max These ranges are approximately 100-50000, 200-5000, 300-4000, 500-3000, 500-1000, 1000-2000, 1000-3000, or 2000-4000 ng / mL.

[0262] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean AUC of the compound in the spleen. last It 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 conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean AUC of the compound in the spleen. last The maximum values ​​are approximately 0.08 × 10^6, 0.1 × 10^6, 0.2 × 10^6, 0.3 × 10^6, 0.4 × 10^6, 0.5 × 10^6, 0.75 × 10^6, 1 × 10^6, 1.5 × 10^6, 2 × 10^6, or 5 × 10^6 ng·h / mL.

[0264] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean AUC of the compound in the spleen. last This is approximately 0.01 × 10^6 to approximately 5 × 10^6, approximately 0.05 × 10^6 to approximately 3 × 10^6, approximately 0.075 × 10^6 to approximately 2 × 10^6, approximately 0.09 × 10^6 to approximately 1.1 × 10^6, approximately 0.1 × 10^6 to approximately 0.8 × 10^6, approximately 0.1 × 10^6 to approximately 0.5 × 10^6, approximately 0.1 × 10^6 to approximately 0.3 × 10^6, approximately 0.3 × 10^6 to approximately 1 × 10^6, approximately 0.5 × 10^6 to approximately 1 × 10^6, approximately 0.1 × 1 The values ​​are approximately 0.6 to 0.2 × 10⁶, approximately 0.2 × 10⁶ to 0.3 × 10⁶, or approximately 0.3 × 10⁶ to 0.5 × 10⁶ ng·h / mL.

[0265] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the Disclosure to a study patient or subject in doses 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) (e.g., via intracerebroventricular administration), in which case the mean T2 of the spleen 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 conducted, the pharmacokinetic study includes the step of administering the compound of the Disclosure to a study patient or subject in doses 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) (e.g., via intracerebroventricular administration), in which case the mean T2 of the spleen last The maximum duration is approximately 1, 2, 3, 4, 5, 6, 7, 10, 12, 14, 21, 28, 35, 42, 49, 100, 200, or 300 days.

[0267] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the Disclosure to a study patient or subject in doses 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) (e.g., via intracerebroventricular administration), in which case the mean T2 of the spleen last These ranges from approximately 1 to 300 days, 2 to 100 days, 5 to 50 days, 10 to 30 days, 1 to 20 days, 20 to 40 days, 40 to 60 days, 60 to 80 days, or 80 to 100 days.

[0268] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the Disclosure to a study patient or subject in doses 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) (e.g., via intracerebroventricular administration), in which case the mean T2 of the spleen 1 / 2This 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 conducted, the pharmacokinetic study includes the step of administering the compound of the Disclosure to a study patient or subject in doses 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) (e.g., via intracerebroventricular administration), in which case the mean T2 of the spleen 1 / 2 The maximum duration is 24, 48, 100, 200, 300, 400, 500, 600, 750, 1000, or 5000 hours.

[0270] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the Disclosure to a study patient or subject in doses 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) (e.g., via intracerebroventricular administration), in which case the mean T2 of the spleen 1 / 2 These ranges from approximately 24 to 20,000 hours, 50 to 15,000 hours, 50 to 1,000 hours, 100 to 500 hours, 100 to 300 hours, 100 to 200 hours, 200 to 300 hours, 300 to 400 hours, 400 to 500 hours, or 3,000 to 5,000 hours.

[0271] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean T of the compound in the spleen 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 conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean T of the compound in the spleen max The maximum duration is 6, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 72, 96, or 120 hours.

[0273] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean T of the compound in the spleen max These ranges from approximately 0.5 to 120, 1 to 24, 1 to 36, 1 to 48, 2 to 36, 6 to 24, 1 to 6, 6 to 12, 12 to 24, 12 to 18, 18 to 48, 18 to 36, or 24 to 48 hours.

[0274] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean C of the compound in the spleen 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 It is approximately 5000, or at least about 10000 ng / mL.

[0275] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean C of the compound in the spleen max The maximum values ​​are approximately 1000, 1500, 2000, 2500, 3000, 4000, 5000, or 10000 ng / mL.

[0276] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean C of the compound in the spleen max These ranges are approximately 100-50000, 200-5000, 300-4000, 500-3000, 500-1000, 1000-2000, 1000-3000, or 2000-4000 ng / mL.

[0277] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of this 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) (e.g., via intracerebroventricular administration), in which case the mean AUC of the compound in the spleen. last It 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 conducted, the pharmacokinetic study includes the step of administering the compound of this 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) (e.g., via intracerebroventricular administration), in which case the mean AUC of the compound in the spleen. last The maximum values ​​are approximately 0.08 × 10^6, 0.1 × 10^6, 0.2 × 10^6, 0.3 × 10^6, 0.4 × 10^6, 0.5 × 10^6, 0.75 × 10^6, 1 × 10^6, 1.5 × 10^6, 2 × 10^6, or 5 × 10^6 ng·h / mL.

[0279] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study involves administering the compound of this disclosure to a study patient or subject at a dose of approximately 0.001 mg / kg to approximately 0.5 mg / kg (e.g., approximately 0.008 to approximately 0.163 mg / kg, approximately 0.016 to approximately 0.125 mg / kg, approximately 0.025 to approximately 0.1 mg / kg, approximately 0.025 to approximately 0.08 mg / kg, approximately 0.025 to approximately 0.05 mg / kg, or approximately 0.05 to approximately 0.08 mg / kg). This includes (for example, via intracerebroventricular administration), in which case the mean AUC of the compound in the spleen. last The values ​​are approximately 0.01 × 10^6 to approximately 5 × 10^6, approximately 0.05 × 10^6 to approximately 3 × 10^6, approximately 0.075 × 10^6 to approximately 2 × 10^6, approximately 0.09 × 10^6 to approximately 1.1 × 10^6, approximately 0.1 × 10^6 to approximately 0.8 × 10^6, approximately 0.1 × 10^6 to approximately 0.5 × 10^6, approximately 0.1 × 10^6 to approximately 0.3 × 10^6, approximately 0.3 × 10^6 to approximately 1 × 10^6, approximately 0.5 × 10^6 to approximately 1 × 10^6, approximately 0.1 × 10^6 to approximately 0.2 × 10^6, approximately 0.2 × 10^6 to approximately 0.3 × 10^6, or approximately 0.3 × 10^6 to approximately 0.5 × 10^6 ng·h / mL.

[0280] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean T2 of the spleen 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 conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean T2 of the spleen last The maximum duration is approximately 1, 2, 3, 4, 5, 6, 7, 10, 12, 14, 21, 28, 35, 42, 49, 100, 200, or 300 days.

[0282] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean T2 of the spleen last These ranges from approximately 1 to 300 days, 2 to 100 days, 5 to 50 days, 10 to 30 days, 1 to 20 days, 20 to 40 days, 40 to 60 days, 60 to 80 days, or 80 to 100 days.

[0283] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean T2 of the spleen 1 / 2 This 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 conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean T2 of the spleen 1 / 2 The maximum duration is 24, 48, 100, 200, 300, 400, 500, 600, 750, 1000, or 5000 hours.

[0285] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean T2 of the spleen 1 / 2These ranges from approximately 24 to 20,000 hours, 50 to 15,000 hours, 50 to 1,000 hours, 100 to 500 hours, 100 to 300 hours, 100 to 200 hours, 200 to 300 hours, 300 to 400 hours, 400 to 500 hours, or 3,000 to 5,000 hours.

[0286] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average T of the compound max However, after administering a single dose to male subjects, 0.3 mg / kg was used for 4 hours of T14. max A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0287] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average T of the compound max However, after a single dose administration to female subjects, 0.3 mg / kg was administered for 8 hours. max A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0288] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average T of the compound max However, after administering a single dose to male subjects, 0.6 mg / kg was used for 24 hours. max A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0289] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average T of the compound max However, after administering a single dose to female subjects, 0.6 mg / kg was administered for 24 hours. max A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0290] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average T of the compound maxHowever, after administering a single dose to male subjects, 1 mg / kg for 48 hours max A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0291] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average T of the compound max However, after a single dose administration to female subjects, 1 mg / kg was administered for 48 hours. max A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0292] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average C of the compound is max However, after a single dose administration to male subjects, C levels were 756 ng / mL at 0.3 mg / kg. max A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0293] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average C of the compound is max However, after a single dose administration to female subjects, C was 586 ng / mL at 0.3 mg / kg. max A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0294] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average C of the compound is max However, after administering a single dose to male subjects, C levels were 1530 ng / mL at 0.6 mg / kg. max A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0295] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average C of the compound is max However, after a single dose administration to female subjects, C levels were 984 ng / mL at 0.6 mg / kg.max A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0296] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average C of the compound is max However, after a single dose administration to male subjects, C2440 ng / mL was observed at 1 mg / kg. max A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0297] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average C of the compound is max However, after a single dose administration to female subjects, C270 ng / mL was observed at 1 mg / kg. max A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0298] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average AUC of the compound last However, after a single dose administration to male subjects, the AUC was 48,300 ng·h / mL at 0.3 mg / kg. last A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0299] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average AUC of the compound last However, after a single dose administration to female subjects, the AUC was 96,500 ng·h / mL at 0.3 mg / kg. last A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0300] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average AUC of the compound last However, after a single dose administration to male subjects, the AUC was 166,000 ng·h / mL at 0.6 mg / kg.last A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0301] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average AUC of the compound last However, after a single dose administration to female subjects, the AUC was 98,300 ng·h / mL at 0.6 mg / kg. last A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0302] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average AUC of the compound last However, after a single dose administration to male subjects, the AUC was 1,010,000 ng·h / mL at 1 mg / kg. last A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0303] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average AUC of the compound last However, after a single dose administration to female subjects, the AUC was 449,000 ng·h / mL at 1 mg / kg. last A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0304] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average T of the compound last However, after a single dose administration to male subjects, 0.3 mg / kg was used for 144 hours. last A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0305] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average T of the compound last However, after a single dose administration to female subjects, the T250 648-hour period was observed at 0.3 mg / kg. lastA pharmaceutical composition is provided that is within 70% to 130% of the total.

[0306] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average T of the compound last However, after a single dose was administered to male subjects, 0.6 mg / kg was used for 312 hours. last A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0307] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average T of the compound last However, after a single dose administration to female subjects, the T10 test was performed at 0.6 mg / kg for 648 hours. last A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0308] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average T of the compound last However, after a single dose administration to male subjects, the T125 648-hour period was observed at 1 mg / kg. last A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0309] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average T of the compound last However, after a single dose administration to female subjects, 1 mg / kg was administered for 312 hours. last A pharmaceutical composition is provided that is within 70% to 130% of the total. Cardiac pharmacokinetics

[0310] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the 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) (e.g., via intracerebroventricular administration), in which case the mean T of the compound in the heart 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 conducted, the pharmacokinetic study includes the step of administering the 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) (e.g., via intracerebroventricular administration), in which case the mean T of the compound in the heart max The maximum duration is 6, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 72, 96, or 120 hours.

[0312] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the 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) (e.g., via intracerebroventricular administration), in which case the mean T of the compound in the heart maxThese ranges from approximately 0.5 to 120, 1 to 24, 1 to 36, 1 to 48, 2 to 36, 6 to 24, 1 to 6, 6 to 12, 12 to 24, 12 to 18, 18 to 48, 18 to 36, or 24 to 48 hours.

[0313] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the 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) (e.g., via intracerebroventricular administration), in which case the mean C of the compound in the heart max This 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 conducted, the pharmacokinetic study includes the step of administering the 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) (e.g., via intracerebroventricular administration), in which case the mean C of the compound in the heart max The maximum values ​​are approximately 750, 1000, 1500, 2000, 2500, 3000, 4000, 5000, or 10000 ng / mL.

[0315] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the 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) (e.g., via intracerebroventricular administration), in which case the mean C of the compound in the heart max These ranges are approximately 100-50000, 200-5000, 300-4000, 300-3000, 300-1000, 100-2000, 1000-3000, or 2000-4000 ng / mL.

[0316] In some embodiments, if pharmacokinetic studies are conducted, the pharmacokinetic studies will be conducted on the compounds of the disclosure. The step includes administering the compound to a test patient or subject in doses of approximately 0.01 mg / kg to approximately 5 mg / kg (e.g., approximately 0.1 to approximately 2 mg / kg, approximately 0.2 to approximately 1.5 mg / kg, approximately 0.3 to approximately 1.2 mg / kg, approximately 0.3 to approximately 1 mg / kg, approximately 0.3 to approximately 0.6 mg / kg, or approximately 0.6 to approximately 1 mg / kg) (e.g., via intracerebroventricular administration), in which case the mean AUC of the compound in the heart. last It 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.

[0317] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the 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) (e.g., via intracerebroventricular administration), in which case the mean AUC of the compound in the heart. last The maximum values ​​are approximately 0.08 × 10^6, 0.1 × 10^6, 0.2 × 10^6, 0.3 × 10^6, 0.4 × 10^6, 0.5 × 10^6, 0.75 × 10^6, 1 × 10^6, 1.5 × 10^6, 2 × 10^6, or 5 × 10^6 ng·h / mL.

[0318] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the 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) (e.g., via intracerebroventricular administration), in which case the mean AUC of the compound in the heart. last The values ​​are approximately 0.01 × 10^6 to approximately 5 × 10^6, approximately 0.05 × 10^6 to approximately 3 × 10^6, approximately 0.075 × 10^6 to approximately 2 × 10^6, approximately 0.09 × 10^6 to approximately 1.1 × 10^6, approximately 0.1 × 10^6 to approximately 0.8 × 10^6, approximately 0.1 × 10^6 to approximately 0.5 × 10^6, approximately 0.1 × 10^6 to approximately 0.3 × 10^6, approximately 0.3 × 10^6 to approximately 1 × 10^6, approximately 0.5 × 10^6 to approximately 1 × 10^6, approximately 0.1 × 10^6 to approximately 0.2 × 10^6, approximately 0.2 × 10^6 to approximately 0.3 × 10^6, or approximately 0.3 × 10^6 to approximately 0.5 × 10^6 ng·h / mL.

[0319] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the Disclosure to a test patient or subject in doses 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) (e.g., via intraventricular administration), in which case the mean cardiac 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 conducted, the pharmacokinetic study includes the step of administering the compound of the Disclosure to a test patient or subject in doses 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) (e.g., via intraventricular administration), in which case the cardiac Average T last The maximum duration is approximately 1, 2, 3, 4, 5, 6, 7, 10, 12, 14, 21, 28, 35, 42, 49, 100, 200, or 300 days.

[0321] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the Disclosure to a test patient or subject in doses 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) (e.g., via intraventricular administration), in which case the mean cardiac T last These ranges from approximately 1 to 300 days, 2 to 100 days, 5 to 50 days, 10 to 30 days, 1 to 20 days, 20 to 40 days, 40 to 60 days, 60 to 80 days, or 80 to 100 days.

[0322] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the Disclosure to a test patient or subject in doses 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) (e.g., via intraventricular administration), in which case the mean cardiac T 1 / 2 This 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 conducted, the pharmacokinetic study includes the step of administering the compound of the Disclosure to a test patient or subject in doses 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) (e.g., via intraventricular administration), in which case the mean cardiac T 1 / 2 The maximum duration is 24, 48, 100, 200, 300, 400, 500, 600, 750, 1000, or 5000 hours.

[0324] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the Disclosure to a test patient or subject in doses 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) (e.g., via intraventricular administration), in which case the mean cardiac T 1 / 2 These ranges from approximately 24 to 20,000 hours, 50 to 15,000 hours, 50 to 1,000 hours, 100 to 500 hours, 100 to 300 hours, 100 to 200 hours, 200 to 300 hours, 300 to 400 hours, 400 to 500 hours, or 3,000 to 5,000 hours.

[0325] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the Disclosure to a test 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) (e.g., via intracerebroventricular administration), in which case the mean T of the compound in the heart max 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 conducted, the pharmacokinetic study includes the step of administering the compound of the Disclosure to a test 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) (e.g., via intracerebroventricular administration), in which case the mean T of the compound in the heart max The maximum duration is 6, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 72, 96, or 120 hours.

[0327] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the Disclosure to a test 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) (e.g., via intracerebroventricular administration), in which case the mean T of the compound in the heart max These ranges from approximately 0.5 to 120, 1 to 24, 1 to 36, 1 to 48, 2 to 36, 6 to 24, 1 to 6, 6 to 12, 12 to 24, 12 to 18, 18 to 48, 18 to 36, or 24 to 48 hours.

[0328] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the Disclosure to a test 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) (e.g., via intracerebroventricular administration), in which case the mean C of the compound in the heart max This 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 conducted, the pharmacokinetic study includes the step of administering the compound of the Disclosure to a test 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) (e.g., via intracerebroventricular administration), in which case the mean C of the compound in the heart max The maximum values ​​are approximately 1000, 1500, 2000, 2500, 3000, 4000, 5000, or 10000 ng / mL.

[0330] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the Disclosure to a test 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) (e.g., via intracerebroventricular administration), in which case the mean C of the compound in the heart ma x These ranges are approximately 100-50000, 200-5000, 300-4000, 500-3000, 500-1000, 1000-2000, 1000-3000, or 2000-4000 ng / mL.

[0331] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the Disclosure to a test 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) (e.g., via intracerebroventricular administration), in which case the mean AUC of the compound in the heart. last It 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 conducted, the pharmacokinetic study includes the step of administering the compound of the Disclosure to a test 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) (e.g., via intracerebroventricular administration), in which case the mean AUC of the compound in the heart. last The maximum values ​​are approximately 0.08 × 10^6, 0.1 × 10^6, 0.2 × 10^6, 0.3 × 10^6, 0.4 × 10^6, 0.5 × 10^6, 0.75 × 10^6, 1 × 10^6, 1.5 × 10^6, 2 × 10^6, or 5 × 10^6 ng·h / mL.

[0333] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the Disclosure to a test 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) (e.g., via intracerebroventricular administration), in which case the mean AUC of the compound in the heart. last The values ​​are approximately 0.01 × 10^6 to approximately 5 × 10^6, approximately 0.05 × 10^6 to approximately 3 × 10^6, approximately 0.075 × 10^6 to approximately 2 × 10^6, approximately 0.09 × 10^6 to approximately 1.1 × 10^6, approximately 0.1 × 10^6 to approximately 0.8 × 10^6, approximately 0.1 × 10^6 to approximately 0.5 × 10^6, approximately 0.1 × 10^6 to approximately 0.3 × 10^6, approximately 0.3 × 10^6 to approximately 1 × 10^6, approximately 0.5 × 10^6 to approximately 1 × 10^6, approximately 0.1 × 10^6 to approximately 0.2 × 10^6, approximately 0.2 × 10^6 to approximately 0.3 × 10^6, or approximately 0.3 × 10^6 to approximately 0.5 × 10^6 ng·h / mL.

[0334] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the Disclosure to a test 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) (e.g., via intracerebroventricular administration), in which case the mean cardiac 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, and at least It is also about 49, or at least about 100 days.

[0335] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the Disclosure to a test 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) (e.g., via intracerebroventricular administration), in which case the mean cardiac T last The maximum duration is approximately 1, 2, 3, 4, 5, 6, 7, 10, 12, 14, 21, 28, 35, 42, 49, 100, 200, or 300 days.

[0336] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the Disclosure to a test 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) (e.g., via intracerebroventricular administration), in which case the mean cardiac T last These ranges from approximately 1 to 300 days, 2 to 100 days, 5 to 50 days, 10 to 30 days, 1 to 20 days, 20 to 40 days, 40 to 60 days, 60 to 80 days, or 80 to 100 days.

[0337] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the Disclosure to a test 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) (e.g., via intracerebroventricular administration), in which case the mean cardiac T 1 / 2 This 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 conducted, the pharmacokinetic study includes the step of administering the compound of the Disclosure to a test 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) (e.g., via intracerebroventricular administration), in which case the mean cardiac T 1 / 2The maximum duration is 24, 48, 100, 200, 300, 400, 500, 600, 750, 1000, or 5000 hours.

[0339] In some embodiments, if a pharmacokinetic study is conducted, the pharmacokinetic study includes the step of administering the compound of the 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) (e.g., via intracerebroventricular administration), in which case the mean cardiac T 1 / 2 The ranges are approximately 24-20000, 50-15000, 50-1000, 100-500, 100-300, 100-200, 200-300, 300-400, and 4 This ranges from 0 to approximately 500 hours, or from approximately 3000 to approximately 5000 hours.

[0340] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average T of the compound max However, after a single dose administration to male subjects, 0.3 mg / kg was used for 48 hours. max A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0341] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average T of the compound max However, after administering a single dose to female subjects, 0.3 mg / kg was administered for 24 hours. max A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0342] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average C of the compound is maxHowever, after a single dose administration to male subjects, C416 ng / mL was observed at 0.3 mg / kg. max A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0343] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average C of the compound is max However, after a single dose administration to female subjects, C levels were 729 ng / mL at 0.3 mg / kg. max A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0344] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average AUC of the compound last However, after a single dose administration to male subjects, the AUC was 160,000 ng·h / mL at 0.3 mg / kg. last A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0345] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average AUC of the compound last However, after a single dose administration to female subjects, the AUC was 184,000 ng·h / mL at 0.3 mg / kg. last A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0346] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average T of the compound last However, after a single dose administration to male subjects, the T250 648-hour period was observed at 0.3 mg / kg. last A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0347] In some embodiments herein, a pharmaceutical composition in a unit dose form for intracerebral delivery of a compound comprising a peptide nucleic acid sequence, wherein the average T of the compound lastHowever, after a single dose administration to female subjects, the T250 648-hour period was observed at 0.3 mg / kg. last A pharmaceutical composition is provided that is within 70% to 130% of the total. Biological distribution

[0348] The biodistribution of the compounds of this disclosure can be assessed by methods that can directly or indirectly detect the presence of the compounds in tissues. For example, the tissue of a subject administered with the compounds of this disclosure can be assessed by mass spectrometry, such as tandem mass spectrometry, and the presence of the compounds in the tissue sample can be assessed based on the intensity of the signal corresponding to the mass of the ionized compound or compound fragments. Other methods suitable for determining biodistribution include administration of radiolabeled analogs of the compounds and imaging techniques, such as autoradiography, positron emission tomography, or single-photon emission computed tomography. One example is the evaluation of analog radiation signatures in this context.

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

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

[0351] When administered systemically, the compounds of this disclosure or their radiolabeled analogs may exhibit distribution to specific tissues, as determined, for example, by quantitative whole-body autoradiography (QWBA).

[0352] In some embodiments, when an assay (e.g., a tissue distribution study) is performed, the assay may use a radiolabeled analog of the compound of the Disclosure (e.g., [ 14The step of administering compound 1) to a research patient (e.g., a monkey) or subject at a dose of approximately 5 mg / kg (e.g., approximately 0.05 to approximately 500 mg / kg, approximately 0.5 to approximately 50 mg / kg, approximately 1 to approximately 10 mg / kg, approximately 2 to approximately 8 mg / kg, approximately 3 to approximately 7 mg / kg, or approximately 4 to approximately 6 mg / kg) (e.g., via a single intravenous dose), in which case the compound may be distributed to, for example, the renal cortex, joints, cartilage, liver, salivary glands, bone surface, pancreas, hair follicles, colonic mucosa, aortic wall, small intestinal mucosa, adrenal gland, gastric mucosa, spleen, bone marrow, lymph nodes, thymus, brain, cerebellum, olfactory bulb, thalamus, caudate nucleus, putamen, cerebral cortex, substantia nigra, lateral ventricle, choroidal plexus, or a combination 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 to the study patient or subject at a dose of approximately 5 mg / kg (e.g., approximately 0.05 to approximately 500 mg / kg, approximately 0.5 to approximately 50 mg / kg, approximately 1 to approximately 10 mg / kg, approximately 2 to approximately 8 mg / kg, approximately 3 to approximately 7 mg / kg, or approximately 4 to approximately 6 mg / kg) (e.g., via a single intravenous dose), in which case the compound is distributed to, for example, the adrenal cortex, adrenal medulla, aortic wall, intraosseous, bone surface, bone marrow, caudate nucleus, cerebellum, cerebral cortex, lateral ventricle, olfactory bulb, putamen, substantia nigra, etc., as determined by quantitative whole-body autoradiography (QWBA). The compound can be distributed to the brain thalamus, brown fat, ophthalmic duct (choroid plexus + RPE), hair follicles, heart 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, gastric contents, gastric mucosa, gastric 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, this disclosure provides compounds comprising a peptide nucleic acid sequence and a cell-permeable group bound to the peptide nucleic acid sequence. In assays concerning the retention of the compound in the brain of a subject after administration of the compound to the subject, the amount of the compound in the brain on day 7, 8, 9, or 10 after administration may be equivalent to at least 80% of the amount of the compound in the brain at 4 hours after administration. In some embodiments, the amount of the compound in the brain on day 7, 8, 9, or 10 after administration is equivalent to at least 100% of the amount of the compound in the brain at 4 hours after administration. In some embodiments, the amount of the compound in the brain on day 7, 8, 9, or 10 after administration is equivalent to at least 150% of the amount of the compound in the brain at 4 hours after administration. In some embodiments, the amount of the compound in the brain on day 7, 8, 9, or 10 after administration is equivalent to at least 200% of the amount of the compound in the brain at 4 hours after administration.

[0355] In some embodiments, the disclosure provides compounds comprising a peptide nucleic acid sequence and a cell-permeable group bound to the peptide nucleic acid sequence. In assays concerning the retention of compounds in the brain of a subject after administration of the compound to the subject, at least 80% of the compound present in the brain 4 hours after administration may remain in the brain for at least 7 days after administration. In some embodiments, the assay is a quantitative whole-body autoradiography assay.

[0356] In some embodiments, this disclosure provides compounds comprising a peptide nucleic acid sequence and a cell-permeable group bound to the peptide nucleic acid sequence. In assays concerning the retention of a compound in the skeletal muscle of a subject after administration of the compound to the subject, the amount of the compound in the skeletal muscle on day 7, 8, 9, or 10 after administration may be equivalent to at least 40% of the amount of the compound in the skeletal muscle at 4 hours after administration. In some embodiments, the amount of the compound in the skeletal muscle on day 7, 8, 9, or 10 after administration is equivalent to at least 60% of the amount of the compound in the skeletal muscle at 4 hours after administration. In some embodiments, the amount of the compound in the skeletal muscle on day 7, 8, 9, or 10 after administration is equivalent to at least 80% of the amount of the compound in the skeletal muscle at 4 hours after administration. In some embodiments, the amount of the compound in the skeletal muscle on day 7, 8, 9, or 10 after administration is equivalent to at least 90% of the amount of the compound in the skeletal muscle at 4 hours after administration. In some embodiments, the assay is quantitative whole-body autoradiography.

[0357] In some embodiments, the disclosure provides compounds comprising a peptide nucleic acid sequence and a cell-permeable group bound to the peptide nucleic acid sequence. In assays of the retention of a compound in the skeletal muscle of a subject after administration of the compound to the subject, at least 80% of the compound present in the skeletal muscle 4 hours after administration may remain in the skeletal muscle for at least 7 days after administration. In some embodiments, the assay is a quantitative whole-body autoradiography assay.

[0358] In some embodiments, the concentration of the compound in the target brain is at least about 100 nanograms of the compound per gram of moist brain tissue, 200 nanograms of the compound per gram of moist brain tissue, 300 nanograms of the compound per gram of moist brain tissue, 400 nanograms of the compound per gram of moist brain tissue, 500 nanograms of the compound per gram of moist brain tissue, 600 nanograms of the compound per gram of moist brain tissue, 700 nanograms of the compound per gram of moist brain tissue, 800 nanograms of the compound per gram of moist brain tissue, and 1 gram of moist brain tissue. This is 900 nanograms of the compound per gram, or 1000 nanograms of the compound per gram of moist brain tissue.

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

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

[0361] When administered systemically, the compounds of this disclosure or their radiolabeled analogs may exhibit a low excretion rate.

[0362] In some embodiments, when an assay (e.g., a tissue distribution study) is performed, the assay uses the compound of the Disclosure (e.g., Compound 1) or its radiolabeled analog (e.g., [ 14The procedure includes administering compound 1) to a research patient (e.g., a monkey) or subject in a dose of approximately 5 mg / kg (e.g., approximately 0.05 to approximately 500 mg / kg, approximately 0.5 to approximately 50 mg / kg, approximately 1 to approximately 10 mg / kg, approximately 2 to approximately 8 mg / kg, approximately 3 to approximately 7 mg / kg, or approximately 4 to approximately 6 mg / kg) (e.g., via a single intravenous dose), in which case less than approximately 20% of the dose, approximately Less than 15%, approximately less than 10%, approximately less than 9%, approximately less than 8%, approximately less than 7%, approximately less than 6%, approximately less than 5%, approximately less than 4%, approximately less than 3%, approximately less than 2.5%, approximately less than 2%, approximately less than 1.9%, approximately less than 1.8%, approximately less than 1.7%, approximately less than 1.6%, approximately less than 1.5%, approximately less than 1.4%, approximately less than 1.3%, approximately less than 1.2%, approximately less than 1.1%, or approximately less than 1%, may be recovered from urine during, for example, approximately 168.

[0363] In some embodiments, when an assay (e.g., a tissue distribution study) is performed, the assay uses the compound of the Disclosure (e.g., Compound 1) or its radiolabeled analog (e.g., [ 14 The step includes administering compound 1) to a research patient (e.g., a monkey) or subject in a dose of approximately 5 mg / kg (e.g., approximately 0.05 to approximately 500 mg / kg, approximately 0.5 to approximately 50 mg / kg, approximately 1 to approximately 10 mg / kg, approximately 2 to approximately 8 mg / kg, approximately 3 to approximately 7 mg / kg, or approximately 4 to approximately 6 mg / kg) (e.g., via a single intravenous dose), in which case less than approximately 20% of the dose, approximately 1 Less than 5%, approximately less than 10%, approximately less than 9%, approximately less than 8%, approximately less than 7%, approximately less than 6%, approximately less than 5%, approximately less than 4%, approximately less than 3%, approximately less than 2.5%, approximately less than 2%, approximately less than 1.9%, approximately less than 1.8%, approximately less than 1.7%, approximately less than 1.6%, approximately less than 1.5%, approximately less than 1.4%, approximately less than 1.3%, approximately less than 1.2%, approximately less than 1.1%, or approximately less than 1%, may be recovered from feces within, for example, approximately 168 hours.

[0364] In some embodiments, when an assay (e.g., a tissue distribution study) is performed, the assay uses the compound of the Disclosure (e.g., Compound 1) or its radiolabeled analog (e.g., [ 14 C The procedure includes a step of administering compound 1) to a research patient (e.g., a monkey) or subject in a dose of approximately 5 mg / kg (e.g., approximately 0.05 to approximately 500 mg / kg, approximately 0.5 to approximately 50 mg / kg, approximately 1 to approximately 10 mg / kg, approximately 2 to approximately 8 mg / kg, approximately 3 to approximately 7 mg / kg, or approximately 4 to approximately 6 mg / kg) (e.g., via a single intravenous dose), in which case less than approximately 20% of the dose, approximately Less than 15%, approximately less than 10%, approximately less than 9%, approximately less than 8%, approximately less than 7%, approximately less than 6%, approximately less than 5%, approximately less than 4%, approximately less than 3%, approximately less than 2.5%, approximately less than 2%, approximately less than 1.9%, approximately less than 1.8%, approximately less than 1.7%, approximately less than 1.6%, approximately less than 1.5%, approximately less than 1.4%, approximately less than 1.3%, approximately less than 1.2%, approximately less than 1.1%, or approximately less than 1%, may be excreted, for example, within approximately 168 hours.

[0365] In some embodiments, if a study or assay (e.g., a tissue distribution study) is performed, the assay may involve the compound of the Disclosure (e.g., Compound 1) or its radiolabeled analog (e.g., [ 14 The step of administering compound 1) to a research patient (e.g., a monkey) or subject at a dose of approximately 5 mg / kg (e.g., approximately 0.05 to approximately 500 mg / kg, approximately 0.5 to approximately 50 mg / kg, approximately 1 to approximately 10 mg / kg, approximately 2 to approximately 8 mg / kg, approximately 3 to approximately 7 mg / kg, or approximately 4 to approximately 6 mg / kg) (e.g., via a single intravenous dose), in which case the mean T12 of plasma 1 / 2 This 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, if a study or assay (e.g., a tissue distribution study) is performed, the assay may involve the compound of the Disclosure (e.g., Compound 1) or its radiolabeled analog (e.g., [ 14The step of administering compound 1) to a research patient (e.g., a monkey) or subject at a dose of approximately 5 mg / kg (e.g., approximately 0.05 to approximately 500 mg / kg, approximately 0.5 to approximately 50 mg / kg, approximately 1 to approximately 10 mg / kg, approximately 2 to approximately 8 mg / kg, approximately 3 to approximately 7 mg / kg, or approximately 4 to approximately 6 mg / kg) (e.g., via a single intravenous dose), in which case the mean T12 of plasma 1 / 2 The maximum duration is 24, 48, 100, 200, 300, 400, 500, 600, 750, 1000, or 5000 hours.

[0367] In some embodiments, if a study or assay (e.g., a tissue distribution study) is performed, the assay may involve the compound of the Disclosure (e.g., Compound 1) or its radiolabeled analog (e.g., [ 14 The step of administering compound 1) to a research patient (e.g., a monkey) or subject at a dose of approximately 5 mg / kg (e.g., approximately 0.05 to approximately 500 mg / kg, approximately 0.5 to approximately 50 mg / kg, approximately 1 to approximately 10 mg / kg, approximately 2 to approximately 8 mg / kg, approximately 3 to approximately 7 mg / kg, or approximately 4 to approximately 6 mg / kg) (e.g., via a single intravenous dose), in which case the mean T12 of plasma 1 / 2 These ranges from approximately 24 to 20,000 hours, 50 to 15,000 hours, 50 to 1,000 hours, 100 to 500 hours, 100 to 300 hours, 100 to 200 hours, 200 to 300 hours, 300 to 400 hours, 400 to 500 hours, or 3,000 to 5,000 hours.

[0368] In some embodiments, when a study or assay (e.g., a tissue distribution study) is performed, the assay may use a radiolabeled analog of the compound of the Disclosure (e.g., [ 14 The step of administering compound 1) to a research patient (e.g., a monkey) or subject at a dose of approximately 5 mg / kg (e.g., approximately 0.05 to approximately 500 mg / kg, approximately 0.5 to approximately 50 mg / kg, approximately 1 to approximately 10 mg / kg, approximately 2 to approximately 8 mg / kg, approximately 3 to approximately 7 mg / kg, or approximately 4 to approximately 6 mg / kg) (e.g., via a single intravenous dose), in which case the mean C of the compound in plasma 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, It is 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, if a study or assay (e.g., a tissue distribution study) is performed, the assay may involve the compound of the Disclosure (e.g., Compound 1) or its radiolabeled analog (e.g., [ 14 The step of administering compound 1) to a research patient (e.g., a monkey) or subject at a dose of approximately 5 mg / kg (e.g., approximately 0.05 to approximately 500 mg / kg, approximately 0.5 to approximately 50 mg / kg, approximately 1 to approximately 10 mg / kg, approximately 2 to approximately 8 mg / kg, approximately 3 to approximately 7 mg / kg, or approximately 4 to approximately 6 mg / kg) (e.g., via a single intravenous dose), in which case the mean C of the compound in plasma max The maximum values ​​are approximately 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 12000, 14000, 16000, 18000, 20000, 22000, 25000, 30000, or 50000 ng-equivalents / g.

[0370] In some embodiments, when a study or assay (e.g., a tissue distribution study) is performed, the assay may use a radiolabeled analog of the compound of the Disclosure (e.g., [ 14The step of administering compound 1) to a research patient (e.g., a monkey) or subject at a dose of approximately 5 mg / kg (e.g., approximately 0.05 to approximately 500 mg / kg, approximately 0.5 to approximately 50 mg / kg, approximately 1 to approximately 10 mg / kg, approximately 2 to approximately 8 mg / kg, approximately 3 to approximately 7 mg / kg, or approximately 4 to approximately 6 mg / kg) (e.g., via a single intravenous dose), in which case the mean C of the compound in plasma max These ranges from approximately 1,000 to 50,000 ng-equivalents / g, 2,000 to 25,000 ng-equivalents / g, 3,000 to 22,000 ng-equivalents / g, 2,000 to 5,000 ng-equivalents / g, 5,000 to 15,000 ng-equivalents / g, or 10,000 to 25,000 ng-equivalents / g.

[0371] In some embodiments, if a study or assay (e.g., a tissue distribution study) is performed, the assay may involve the compound of the Disclosure (e.g., Compound 1) or its radiolabeled analog (e.g., [ 14 The step includes administering compound 1) to a research patient (e.g., a monkey) or subject at a dose of approximately 1.6 mg / kg (e.g., approximately 0.015 to approximately 160 mg / kg, approximately 0.16 to approximately 16 mg / kg, approximately 0.3 to approximately 3.2 mg / kg, approximately 0.65 to approximately 2.6 mg / kg, approximately 1 to approximately 2.3 mg / kg, or approximately 1.3 to approximately 2 mg / kg) (e.g., via a single intravenous dose), in which case the mean T10 of plasma 1 / 2 This 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, if a study or assay (e.g., a tissue distribution study) is performed, the assay may involve the compound of the Disclosure (e.g., Compound 1) or its radiolabeled analog (e.g., [ 14The step includes administering compound 1) to a research patient (e.g., a monkey) or subject at a dose of approximately 1.6 mg / kg (e.g., approximately 0.015 to approximately 160 mg / kg, approximately 0.16 to approximately 16 mg / kg, approximately 0.3 to approximately 3.2 mg / kg, approximately 0.65 to approximately 2.6 mg / kg, approximately 1 to approximately 2.3 mg / kg, or approximately 1.3 to approximately 2 mg / kg) (e.g., via a single intravenous dose), in which case the mean T10 of plasma 1 / 2 The maximum duration is 24, 48, 100, 200, 300, 400, 500, 600, 750, 1000, or 5000 hours.

[0373] In some embodiments, if a study or assay (e.g., a tissue distribution study) is performed, the assay may use the compounds of the Disclosure (e.g., Compound 1) or its radiolabeled analog (e.g., [ 14 The step includes administering compound 1) to a research patient (e.g., a monkey) or subject at a dose of approximately 1.6 mg / kg (e.g., approximately 0.015 to approximately 160 mg / kg, approximately 0.16 to approximately 16 mg / kg, approximately 0.3 to approximately 3.2 mg / kg, approximately 0.65 to approximately 2.6 mg / kg, approximately 1 to approximately 2.3 mg / kg, or approximately 1.3 to approximately 2 mg / kg) (e.g., via a single intravenous dose), in which case the mean T10 of plasma 1 / 2 These ranges from approximately 24 to 20,000 hours, 50 to 15,000 hours, 50 to 1,000 hours, 100 to 500 hours, 100 to 300 hours, 100 to 200 hours, 200 to 300 hours, 300 to 400 hours, 400 to 500 hours, or 3,000 to 5,000 hours.

[0374] In some embodiments, when a study or assay (e.g., a tissue distribution study) is performed, the assay may use a radiolabeled analog of the compound of the Disclosure (e.g., [ 14The step of administering compound 1) to a research patient (e.g., a monkey) or subject at a dose of approximately 1.6 mg / kg (e.g., approximately 0.015 to approximately 160 mg / kg, approximately 0.16 to approximately 16 mg / kg, approximately 0.3 to approximately 3.2 mg / kg, approximately 0.65 to approximately 2.6 mg / kg, approximately 1 to approximately 2.3 mg / kg, or approximately 1.3 to approximately 2 mg / kg) (e.g., via a single intravenous dose), in which case the mean C of the compound in plasma max This 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, when a study or assay (e.g., a tissue distribution study) is performed, the assay may use a radiolabeled analog of the compound of the Disclosure (e.g., [ 14 The step of administering compound 1) to a research patient (e.g., a monkey) or subject at a dose of approximately 1.6 mg / kg (e.g., approximately 0.015 to approximately 160 mg / kg, approximately 0.16 to approximately 16 mg / kg, approximately 0.3 to approximately 3.2 mg / kg, approximately 0.65 to approximately 2.6 mg / kg, approximately 1 to approximately 2.3 mg / kg, or approximately 1.3 to approximately 2 mg / kg) (e.g., via a single intravenous dose), in which case the mean C of the compound in plasma max The maximum values ​​are approximately 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 12000, 14000, 16000, 18000, 20000, 22000, 25000, 30000, or 50000 ng-equivalents / g.

[0376] In some embodiments, when a study or assay (e.g., a tissue distribution study) is performed, the assay may use a radiolabeled analog of the compound of the Disclosure (e.g., [ 14 The step of administering compound 1) to a research patient (e.g., a monkey) or subject at a dose of approximately 1.6 mg / kg (e.g., approximately 0.015 to approximately 160 mg / kg, approximately 0.16 to approximately 16 mg / kg, approximately 0.3 to approximately 3.2 mg / kg, approximately 0.65 to approximately 2.6 mg / kg, approximately 1 to approximately 2.3 mg / kg, or approximately 1.3 to approximately 2 mg / kg) (e.g., via a single intravenous dose), in which case the mean C of the compound in plasma max These ranges from approximately 1,000 to 50,000 ng-equivalents / g, 2,000 to 25,000 ng-equivalents / g, 3,000 to 22,000 ng-equivalents / g, 2,000 to 5,000 ng-equivalents / g, 5,000 to 15,000 ng-equivalents / g, or 10,000 to 25,000 ng-equivalents / g.

[0377] In some embodiments herein, a pharmaceutical composition in a unit dose form for intravenous delivery of a compound comprising a peptide nucleic acid sequence or a radiolabeled analog thereof, wherein the average AUC of the compound 0-t However, after administration of a single dose to the target, the AUC in plasma was 205,000 h·ng-equivalents / g. 0-t A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0378] In some embodiments, as described herein, compounds comprising peptide nucleic acid sequences or their release A pharmaceutical composition in a unit dose form for intravenous delivery of an injection-labeled analog, wherein the average C of the compound max However, after a single dose was administered to the subject, 11,500 ng-equivalents / g of C was observed in the plasma. max A pharmaceutical composition is provided that is within 70% to 130% of the total.

[0379] In some embodiments herein, a pharmaceutical composition in a unit dose form for intravenous delivery of a compound comprising a peptide nucleic acid sequence, wherein the average t of the compound 1 / 2 However, after administration of a single dose to the target, t in plasma for 141 hours 1 / 2 A pharmaceutical composition is provided that is within 70% to 130% of the total.

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

[0381] In some embodiments, if a study or assay (e.g., a tissue distribution study) is performed, the assay may involve the compound of the Disclosure (e.g., Compound 1) or its radiolabeled analog (e.g., [ 14 The step includes administering compound 1) to a research patient (e.g., a monkey) or subject at a dose of approximately 5 mg / kg (e.g., approximately 0.05 to approximately 500 mg / kg, approximately 0.5 to approximately 50 mg / kg, approximately 1 to approximately 10 mg / kg, approximately 2 to approximately 8 mg / kg, approximately 3 to approximately 7 mg / kg, or approximately 4 to approximately 6 mg / kg) (e.g., via a single intravenous dose), in which case the mean T1 in the blood 1 / 2 This 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, if a study or assay (e.g., a tissue distribution study) is performed, the assay may involve the compound of the Disclosure (e.g., Compound 1) or its radiolabeled analog (e.g., [ 14 The step includes administering compound 1) to a research patient (e.g., a monkey) or subject at a dose of approximately 5 mg / kg (e.g., approximately 0.05 to approximately 500 mg / kg, approximately 0.5 to approximately 50 mg / kg, approximately 1 to approximately 10 mg / kg, approximately 2 to approximately 8 mg / kg, approximately 3 to approximately 7 mg / kg, or approximately 4 to approximately 6 mg / kg) (e.g., via a single intravenous dose), in which case the mean T1 in the blood 1 / 2 The maximum duration is 24, 48, 100, 200, 300, 400, 500, 600, 750, 1000, or 5000 hours.

[0383] In some embodiments, if a study or assay (e.g., a tissue distribution study) is performed, the assay may involve the compound of the Disclosure (e.g., Compound 1) or its radiolabeled analog (e.g., [14 The step includes administering compound 1) to a research patient (e.g., a monkey) or subject at a dose of approximately 5 mg / kg (e.g., approximately 0.05 to approximately 500 mg / kg, approximately 0.5 to approximately 50 mg / kg, approximately 1 to approximately 10 mg / kg, approximately 2 to approximately 8 mg / kg, approximately 3 to approximately 7 mg / kg, or approximately 4 to approximately 6 mg / kg) (e.g., via a single intravenous dose), in which case the mean T1 in the blood 1 / 2 These ranges from approximately 24 to 20,000 hours, 50 to 15,000 hours, 50 to 1,000 hours, 100 to 500 hours, 100 to 300 hours, 100 to 200 hours, 200 to 300 hours, 300 to 400 hours, 400 to 500 hours, or 3,000 to 5,000 hours.

[0384] In some embodiments, when a study or assay (e.g., a tissue distribution study) is performed, the assay may use a radiolabeled analog of the compound of the Disclosure (e.g., [ 14 The step of administering compound 1) to a research patient (e.g., a monkey) or subject at a dose of approximately 5 mg / kg (e.g., approximately 0.05 to approximately 500 mg / kg, approximately 0.5 to approximately 50 mg / kg, approximately 1 to approximately 10 mg / kg, approximately 2 to approximately 8 mg / kg, approximately 3 to approximately 7 mg / kg, or approximately 4 to approximately 6 mg / kg) (e.g., via a single intravenous dose), in which case the mean C of the compound in the blood max is at least about 1, at least about 1000, at least about 2000, and at least It is approximately 3000, at least 4000, at least 5000, at least 6000, at least 7000, at least 8000, at least 9000, at least 10000, at least 12000, at least 14000, at least 16000, at least 18000, at least 20000, at least 22000, or at least 25000 ng-equivalents / g.

[0385] In some embodiments, when a study or assay (e.g., a tissue distribution study) is performed, the assay may use a radiolabeled analog of the compound of the Disclosure (e.g., [ 14The step of administering compound 1) to a research patient (e.g., a monkey) or subject at a dose of approximately 5 mg / kg (e.g., approximately 0.05 to approximately 500 mg / kg, approximately 0.5 to approximately 50 mg / kg, approximately 1 to approximately 10 mg / kg, approximately 2 to approximately 8 mg / kg, approximately 3 to approximately 7 mg / kg, or approximately 4 to approximately 6 mg / kg) (e.g., via a single intravenous dose), in which case the mean C of the compound in the blood max The maximum values ​​are approximately 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 12000, 14000, 16000, 18000, 20000, 22000, 25000, 30000, or 50000 ng-equivalents / g.

[0386] In some embodiments, when a study or assay (e.g., a tissue distribution study) is performed, the assay may use a radiolabeled analog of the compound of the Disclosure (e.g., [ 14 The step of administering compound 1) to a research patient (e.g., a monkey) or subject at a dose of approximately 5 mg / kg (e.g., approximately 0.05 to approximately 500 mg / kg, approximately 0.5 to approximately 50 mg / kg, approximately 1 to approximately 10 mg / kg, approximately 2 to approximately 8 mg / kg, approximately 3 to approximately 7 mg / kg, or approximately 4 to approximately 6 mg / kg) (e.g., via a single intravenous dose), in which case the mean C of the compound in the blood max These ranges from approximately 1,000 to 50,000 ng-equivalents / g, 2,000 to 25,000 ng-equivalents / g, 3,000 to 22,000 ng-equivalents / g, 2,000 to 5,000 ng-equivalents / g, 5,000 to 15,000 ng-equivalents / g, or 10,000 to 25,000 ng-equivalents / g.

[0387] In some embodiments, if a study or assay (e.g., a tissue distribution study) is performed, the assay may involve the compound of the Disclosure (e.g., Compound 1) or its radiolabeled analog (e.g., [ 14The step includes administering compound 1) to research patients or subjects at a dose of approximately 1.6 mg / kg (e.g., approximately 0.015 to approximately 160 mg / kg, approximately 0.16 to approximately 16 mg / kg, approximately 0.3 to approximately 3.2 mg / kg, approximately 0.65 to approximately 2.6 mg / kg, approximately 1 to approximately 2.3 mg / kg, or approximately 1.3 to approximately 2 mg / kg) (e.g., via a single intravenous dose), in which case the mean T1 in the blood 1 / 2 This 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, if a study or assay (e.g., a tissue distribution study) is performed, the assay may involve the compound of the Disclosure (e.g., Compound 1) or its radiolabeled analog (e.g., [ 14 The step includes administering compound 1) to research patients or subjects at a dose of approximately 1.6 mg / kg (e.g., approximately 0.015 to approximately 160 mg / kg, approximately 0.16 to approximately 16 mg / kg, approximately 0.3 to approximately 3.2 mg / kg, approximately 0.65 to approximately 2.6 mg / kg, approximately 1 to approximately 2.3 mg / kg, or approximately 1.3 to approximately 2 mg / kg) (e.g., via a single intravenous dose), in which case the mean T1 in the blood 1 / 2 The maximum duration is 24, 48, 100, 200, 300, 400, 500, 600, 750, 1000, or 5000 hours.

[0389] In some embodiments, when a study or assay (e.g., a tissue distribution study) is performed, The assay involves a compound of the present disclosure (e.g., Compound 1) or its radiolabeled analog (e.g., [ 14The step includes administering compound 1) to research patients or subjects at a dose of approximately 1.6 mg / kg (e.g., approximately 0.015 to approximately 160 mg / kg, approximately 0.16 to approximately 16 mg / kg, approximately 0.3 to approximately 3.2 mg / kg, approximately 0.65 to approximately 2.6 mg / kg, approximately 1 to approximately 2.3 mg / kg, or approximately 1.3 to approximately 2 mg / kg) (e.g., via a single intravenous dose), in which case the mean T1 in the blood 1 / 2 These ranges from approximately 24 to 20,000 hours, 50 to 15,000 hours, 50 to 1,000 hours, 100 to 500 hours, 100 to 300 hours, 100 to 200 hours, 200 to 300 hours, 300 to 400 hours, 400 to 500 hours, or 3,000 to 5,000 hours.

[0390] In some embodiments, when a study or assay (e.g., a tissue distribution study) is performed, the assay may use a radiolabeled analog of the compound of the Disclosure (e.g., [ 14 The step of administering compound 1) to research patients or subjects at a dose of approximately 1.6 mg / kg (e.g., approximately 0.015 to approximately 160 mg / kg, approximately 0.16 to approximately 16 mg / kg, approximately 0.3 to approximately 3.2 mg / kg, approximately 0.65 to approximately 2.6 mg / kg, approximately 1 to approximately 2.3 mg / kg, or approximately 1.3 to approximately 2 mg / kg) (e.g., via a single intravenous dose), in which case the mean C of the compound in the blood max This 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, when a study or assay (e.g., a tissue distribution study) is performed, the assay may use a radiolabeled analog of the compound of the Disclosure (e.g., [ 14The step of administering compound 1) to research patients or subjects at a dose of approximately 1.6 mg / kg (e.g., approximately 0.015 to approximately 160 mg / kg, approximately 0.16 to approximately 16 mg / kg, approximately 0.3 to approximately 3.2 mg / kg, approximately 0.65 to approximately 2.6 mg / kg, approximately 1 to approximately 2.3 mg / kg, or approximately 1.3 to approximately 2 mg / kg) (e.g., via a single intravenous dose), in which case the mean C of the compound in the blood max The maximum values ​​are approximately 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 12000, 14000, 16000, 18000, 20000, 22000, 25000, 30000, or 50000 ng-equivalents / g.

[0392] In some embodiments, when a study or assay (e.g., a tissue distribution study) is performed, the assay may use a radiolabeled analog of the compound of the Disclosure (e.g., [ 14 The step of administering compound 1) to research patients or subjects at a dose of approximately 1.6 mg / kg (e.g., approximately 0.015 to approximately 160 mg / kg, approximately 0.16 to approximately 16 mg / kg, approximately 0.3 to approximately 3.2 mg / kg, approximately 0.65 to approximately 2.6 mg / kg, approximately 1 to approximately 2.3 mg / kg, or approximately 1.3 to approximately 2 mg / kg) (e.g., via a single intravenous dose), in which case the mean C of the compound in the blood max These ranges from approximately 1,000 to 50,000 ng-equivalents / g, 2,000 to 25,000 ng-equivalents / g, 3,000 to 22,000 ng-equivalents / g, 2,000 to 5,000 ng-equivalents / g, 5,000 to 15,000 ng-equivalents / g, or 10,000 to 25,000 ng-equivalents / g.

[0393] In some embodiments herein, a pharmaceutical composition in a unit dose form for intravenous delivery of a compound comprising a peptide nucleic acid sequence, wherein the average AUC of the radiolabeled analog of the compound is used. 0-t However, after a single dose was administered to the target, the AUC in the blood was 231,000 h·ng-equivalents / g. 0-t A pharmaceutical composition is provided that is within 70% to 130% of the total.

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

[0395] In some embodiments herein, a pharmaceutical composition in a unit dose form for intravenous delivery of a compound comprising a peptide nucleic acid sequence, wherein the average t of the compound 1 / 2 However, after a single dose was administered to the target, the t29 hours in the blood showed 1 / 2 A pharmaceutical composition is provided that is within 70% to 130% of the total.

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

[0397] In some embodiments, less than 2% of the therapeutically effective amount of the compound is excreted in the urine by the subject during the 7 days following the administration step. In some embodiments, less than 2% of the therapeutically effective amount of the compound is excreted in the feces by the subject during the 7 days following the administration step.

[0398] In some embodiments, the compounds of this disclosure can achieve complete biodistribution even without lipid nanoparticles. For example, the skeleton is modified by covalent bonding so that the compound exhibits cell permeability that is indistinguishable from cell type. For example, the skeleton can be modified by covalent bonding of functional groups (e.g., guanidino groups) so that the compound exhibits cell permeability that is indistinguishable from cell type.

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

[0400] In some embodiments, the plasma protein binding assay includes the step of spiking a first solution of the compound (e.g., a first solution of the compound at 10 mg / mL) into a single aliquot of the study patient's plasma to obtain at least a second solution of the compound (e.g., at a concentration of about 1 μg / mL to about 50 μg / mL). In some embodiments, a separation technique (e.g., ultracentrifugation) is used on at least the second solution of the compound to separate the mixture containing the compound bound to plasma proteins. In some embodiments, the percentage of plasma protein binding 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 the step of spiking a first solution of the compound (e.g., a first solution of the compound at 10 mg / mL) into a single aliquot of human plasma to obtain at least a second solution of the compound (e.g., at a concentration of about 1 μg / mL to about 50 μg / mL). In some embodiments, a separation technique (e.g., ultracentrifugation) is used on at least the second solution of the compound to separate the mixture containing the compound bound to plasma proteins. In some embodiments, The percentage of plasma proteins bound to human plasma can be determined using various techniques disclosed herein, such as liquid chromatography-tandem mass spectrometry. In some embodiments, a mouse component of the plasma protein binding assay is performed. In some embodiments, the mouse 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, a 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, a miniature pig component of the plasma protein binding assay is performed. In some embodiments, the miniature pig component of the plasma protein binding assay differs from the human component of the plasma protein binding assay only in that miniature pig plasma is used instead of human plasma. In some embodiments, a 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, a 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 evaluating a compound in plasma-bound protein assays (e.g., in vitro plasma-bound protein assays) using plasma from a host species (e.g., spiking pooled plasma at concentrations of approximately 0.01, 0.1, 0.5, 1, 5, 10, 50, 100, 500, or 1000 μg / mL), the percentage binding (PPB) of the compound to plasma proteins is approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, and 10%. %, approximately 11%, approximately 12%, approximately 13%, approximately 14%, approximately 15%, approximately 16%, approximately 17%, approximately 18%, approximately 19%, approximately 20%, approximately 21%, approximately 22%, approximately 23%, approximately 24%, approximately 25%, approximately 26%, approximately 27%, approximately 28%, approximately 29%, approximately 30%, approximately 31%, approximately 32%, approximately 33%, approximately 34%, approximately 35%, approximately 36%, approximately 37%, approximately 38%, approximately 39%, approximately 40%, approximately 41%, approximately 42%, approximately 43%, approximately 44%, approximately 45%, approximately 46%, approximately 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 The percentages are approximately 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5%, 99%, 99.1%, 99.1%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, 99.95%, or 99.99%. The host species may be, for example, a mouse (e.g., C57BL6), a dog (e.g., a beagle), a miniature pig (e.g., a Göttingen miniature pig), a sheep, a monkey (e.g., a cynomolgus macaque), a human, or any other suitable animal disclosed herein.

[0403] In some embodiments, when evaluating a compound in plasma-bound protein assays (e.g., in vitro plasma-bound protein assays) using plasma from a host species (e.g., by adding it to pooled plasma at concentrations of approximately 0.01, 0.1, 0.5, 1, 5, 10, 50, 100, 500, or 1000 μg / mL), the percentage binding (PPB) of the compound to plasma proteins is at least approximately 1%, at least approximately 2%, at least approximately 3%, at least approximately 4%, at least approximately 5%, at least approximately 6%, at least approximately 7%, and less than approximately 1%. 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%, and less 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%, and at least 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 approximately 83%, at least approximately 84%, at least approximately 85%, at least approximately 86%, at least approximately 87%, at least approximately 88%, at least approximately 89%, at least approximately 90%, at least approximately 91%, at least approximately 92%, at least approximately 93%, at least approximately 94%, at least approximately 95%, at least approximately 95.5%, at least approximately 96%, at least approximately 96.5%, at least approximately 97%, at least approximately 97.5%, at least approximately 98%, at least approximately 98.5%, at least approximately 99%, at least approximately 99.1%, at least approximately 99.The percentages are 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 may be, for example, mice (e.g., C57BL6), dogs (e.g., beagles), miniature pigs (e.g., Göttingen miniature pigs), sheep, monkeys (e.g., cynomolgus macaques), humans, or any suitable animal disclosed herein.

[0404] In some embodiments, when evaluating a compound in plasma-bound protein assays (e.g., in vitro plasma-bound protein assays) in plasma from a host species (e.g., spiking pooled plasma at concentrations of approximately 0.01, 0.1, 0.5, 1, 5, 10, 50, 100, 500, or 1000 μg / mL), the percentage binding (PPB) of the compound to plasma proteins is up to approximately 1%, 2%, 3%, and 4%. %, maximum approximately 5%, maximum approximately 6%, maximum approximately 7%, maximum approximately 8%, maximum approximately 9%, maximum approximately 10%, maximum approximately 11%, maximum approximately 12%, maximum approximately 13%, maximum approximately 14%, maximum approximately 15%, maximum approximately 16%, maximum approximately 17%, maximum approximately 18%, maximum approximately 19%, maximum approximately 20%, maximum approximately 21%, maximum approximately 22%, maximum approximately 23%, maximum approximately 24%, maximum approximately 25%, maximum approximately 26% , up to approximately 27%, up to approximately 28%, up to approximately 29%, up to approximately 30%, up to approximately 31%, up to approximately 32%, up to approximately 33%, up to approximately 34%, up to approximately 35%, up to approximately 36%, up to approximately 37%, up to approximately 38%, up to approximately 39%, up to approximately 40%, up to approximately 41%, up to approximately 42%, up to approximately 43%, up to approximately 44%, up to approximately 45%, up to approximately 46%, up to approximately 47%, up to Approximately 48%, up to approximately 49%, up to approximately 50%, up to approximately 51%, up to approximately 52%, up to approximately 53%, up to approximately 54%, up to approximately 55%, up to approximately 56%, up to approximately 57%, up to approximately 58%, up to approximately 59%, up to approximately 60%, up to approximately 61%, up to approximately 62%, up to approximately 63%, up to approximately 64%, up to approximately 65%, up to approximately 66%, up to approximately 67%, up to approximately 68%, up to approximately 69% Up to approximately 70%, up to approximately 71%, up to approximately 72%, up to approximately 73%, up to approximately 74%, up to approximately 75%, up to approximately 76%, up to approximately 77%, up to approximately 78%, up to approximately 79%, up to approximately 80%, up to approximately 81%, up to approximately 82%, up to approximately 83%, up to approximately 84%, up to approximately 85%, up to approximately 86%, up to approximately 87%, up to approximately 88%, up to approximately 89%, up to approximately 90%, up to approximately 91%, up to approximately 92%, up to approximately 93%, up to approximately 94% The percentages are approximately 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5%, 99%, 99.1%, 99.1%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, 99.95%, or 99.99%. The host species may be, for example, a mouse (e.g., C57BL6), a dog (e.g., a beagle), a miniature pig (e.g., a Göttingen miniature pig), a sheep, a monkey (e.g., a cynomolgus macaque), a human, or any suitable animal disclosed herein.

[0405] In some embodiments, when evaluating a compound in plasma-bound protein assays (e.g., in vitro plasma-bound protein assays) using plasma from a host species (e.g., spiking pooled plasma at concentrations of approximately 0.01, 0.1, 0.5, 1, 5, 10, 50, 100, 500, or 1000 μg / mL), the percentage binding (PPB) of the compound to plasma proteins is approximately 0% to 10%, 10% to 20%, 20% to 30%, 30% to 40%, 40% to 50%, 50% to 60%, 60% to 70%, 70% to 80%, 80% to 90%, and 90% to 1 00%, approximately 0% to approximately 20%, approximately 0% to approximately 30%, approximately 0% to approximately 40%, approximately 0% to approximately 50%, approximately 0% to approximately 60%, approximately 0% to approximately 70%, approximately 0% to approximately 80%, approximately 0% to approximately 90%, approximately 10% to approximately 30%, approximately 10% to approximately 40%, approximately 10% to approximately 50%, approximately 10% to approximately 60%, approximately 10% to approximately 70%, approximately 10% to approximately 80%, approximately 10% to approximately 90%, approximately 10% to approximately 100%, approximately 20% to approximately 40%, approximately 20% to approximately 50%, approximately 20% to approximately 60%, approximately 20% to approximately 70%, approximately 20% to approximately 80%, approximately 20% to approximately 90%, approximately 20% to approximately 100%, approximately 30% to approximately 50%, approximately 30% ~60%, 30%~70%, 30%~80%, 30%~90%, 30%~100%, 40%~60%, 40%~70%, 40%~80%, 40%~90%, 40%~100%, 50%~70%, 50%~80%, 50%~90%, 50%~100%, 60%~80%, 60%~90%, 60%~100%, 70%~90%, 70%~100%, or 80%~100%, 85%~99%, 87%~99%, 88%~99%, 89%~99% 9%, approximately 90%~99%, approximately 91%~99%, approximately 92%~99%, approximately 93%~99%, approximately 94%~99%, approximately 95%~99%, approximately 96%~99%, approximately 97%~99%, approximately 98%~99%, approximately 85%~98%, approximately 87%~98%, approximately 88%~98%, approximately 89%~98%, approximately 90%~98%, approximately 91%~98%, approximately 92%~98%, approximately 93%~98%, approximately 94%~98%, approximately 95%~98%, approximately 96%~98%, approximately 97%~98%, approximately 85%~97%, approximately 87%~97%, approximately 88%~97%Approximately 89% to 97%, approximately 90% to 97%, approximately 91% to 97%, approximately 92% to 97%, approximately 93% to 97%, approximately 94% to 97%, approximately 95% to 97%, approximately 96% to 97%, approximately 85% to 96%, approximately 87% to 96%, approximately 88% to 96%, approximately 89% to 96%, approximately 90% to 96%, approximately 91% to 96% The percentages are approximately 92%–96%, 93%–96%, 94%–96%, 95%–96%, 85%–95%, 87%–95%, 88%–95%, 89%–95%, 90%–95%, 91%–95%, 92%–95%, 93%–95%, or 94%–95%. The host species may be, for example, mice (e.g., C57BL6), dogs (e.g., beagles), miniature pigs (e.g., Göttingen miniature pigs), sheep, monkeys (e.g., cynomolgus macaques), humans, or any suitable animal disclosed herein. [Examples]

[0406] (Example 1) In vitro binding of compound 1 to plasma proteins in mice, dogs, miniature pigs, 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 miniature pigs, sheep, cynomolgus monkeys, and humans. Plasma protein binding (PPB) was evaluated in pooled male plasma at nominal concentrations of compound 1 of 1, 10, and 50 μg / mL. Assays were performed using ultrafiltration techniques, and the concentration of compound 1 was 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 PPB to become non-linear with increasing concentration of compound 1. This tendency was more pronounced in mice, dogs, miniature pigs, and humans. Table 1 summarizes the PPB results for compound 1 at various concentrations. [Table 1] Testing System

[0407] Plasma from male C57BL6J mice, male beagle dogs, male Göttingen miniature pigs, 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 an anticoagulant for all species. All plasma samples were 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 mouse, dog, miniature pig, sheep, monkey, and human was determined in triplicate at nominal concentrations of 1, 10, and 50 μg / mL using ultrafiltration techniques.

[0409] Unbound compound 1 was separated from plasma proteins 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] In male human plasma (n=3), warfarin at a single concentration of 4.1 μM was used as a control compound. During each ultrafiltration run, the control was tested in parallel with the test sample to confirm accurate experimental performance. Methods and Procedures Preparation of phosphate-buffered saline (PBS).

[0412] A phosphate-buffered saline (PBS) solution 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. A spike solution of compound 1.

[0413] A storage 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 working solution WS1, 100 μg / mL. Compound 1 SS and compound 1 WS were stored at -80°C. Preparation of warfarin solution.

[0414] A warfarin storage solution (SS_W) was prepared in water:acetonitrile (50:50, v / v) with 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 (for no more than 21 days, according to the methods sheet). Warfarin WS_W was prepared fresh after each ultrafiltration. Preparation of plasma samples.

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

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

[0418] To evaluate the suitability of the ultrafiltration technique, experiments were conducted to determine the possibility of nonspecific binding to the filtration membrane and the stability of the test material in plasma and PBS over incubation time. Evaluation of nonspecific binding of compound 1 to ultrafiltration equipment.

[0419] Appropriate amounts of PBS were spiked at three test substance concentrations (1, 10, and 50 μg / mL). The samples were mixed at room temperature for 1–2 minutes.

[0420] Triple aliquots of each spike sample were transferred to an ultrafiltration tube and spun at 1500 g in a Biofuge centrifuge with a fixed-angle rotor at room temperature until all the load passed through the filter.

[0421] Before centrifugation (t0), triple aliquots were collected from each sample, and the concentration of compound 1 (C0) was determined by LC-MS / MS analysis. After centrifugation, the ultrafiltrate at the bottom (C0) was analyzed. u The three aliquots of the sample were retained and then analyzed by LC-MS / MS. Stability evaluation of compound 1 in plasma and PBS.

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

[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 dried for at least 1 hour before use.

[0425] Triple aliquots of each spiked plasma sample were transferred to an ultrafiltration tube. The ultrafiltration tubes were spun at 1500 g in a Biofuge centrifuge with a fixed-angle rotor at room temperature for 20 minutes.

[0426] Before centrifugation, triple aliquots of spiked plasma were retained to obtain the concentration of compound 1 in the plasma (C0) after ultracentrifugation. Then, after centrifugation, the upper retaining solution (C0) was obtained. r ) and bottom ultrafiltrate (C u Appropriate aliquots were 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 (for the entire ultrafiltration device only), and at the end of centrifugation.

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

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

[0430] Calibration standard curves for bovine serum albumin were prepared at the following concentrations: 0, 50, 100, 200, 400, 600, 800, and 1000 μg / mL.

[0431] Calibration standard samples and ultrafiltrate samples were dispensed into 96-well plates (6 μL / well), and Coomassie Brilliant Blue G solution (300 μL) was added. After 1 minute at room temperature, the absorbance of each well was measured at λ = 595 nm using an absorbance microplate reader. Sample preparation and analysis.

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

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

[0434] All samples were collected in uniquely identifiable containers labeled with study number, sample type, nominal sample concentration, and incubation time. Samples of compound 1 and warfarin were stored at -80°C. Data handling and analysis Calculation of plasma protein binding Non-specific binding (NSB)

[0435] In the PBS sample before centrifugation (C0) and in the ultrafiltration sample collected after centrifugation (C0) u The NSB to the ultrafiltration tube was determined from the concentration of compound 1 in the sample.

number

[0436] During the ceremony,

[0437] C0 = Concentration of compound 1 before ultrafiltration, ng / mL

[0438] C u =Concentration of compound 1 after ultrafiltration, ng / mL Stability evaluation

[0439] In plasma (or PBS), at room temperature for the experimental period (t 4h The degree of any possible loss of compound 1 after incubation for the same length as ) was calculated as follows:

number

[0440] During the ceremony,

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

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

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

number

[0444] During the ceremony,

[0445] F=free fraction

[0446] R = Recovery Rate

[0447] The same calculations were performed for the warfarin control sample. Total recovery rate.

[0448] The concentrations of compound 1 in the ultrafiltrate and the retaining solution sample (after ultrafiltration) were compared with the concentration of compound 1 in the sample before ultrafiltration, and the recovery rate was obtained as shown in the following formula:

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, the positive control, should be 98.0% or higher. 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 represented 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 suitable for the purpose.

[0452] The results of the NSB evaluation are shown in Table 2.

Table 2

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

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

[0455] Table 3 shows the results of the stability of compound 1 in plasma and PBS samples. [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 medium to 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 fully reported in Table 4. [Table 4-1] [Table 4-2] [Table 4-3]

[0458] A slight concentration dependence was observed across the investigated concentration range. This observation suggests that the PPB tends to become nonlinear with increasing concentration of compound 1, and this is more pronounced in mice, dogs, miniature pigs, and humans.

[0459] The average PPB of warfarin was over 99.2% in all experiments, thus justifying the effectiveness of each ultrafiltration (see Table 5). [Table 5]

[0460] No protein contamination was detected in any of the ultrafiltration samples of compound 1. Results of biological analysis.

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

[0462] Carryover throughout the study phase was assessed by injecting one or more blank samples after high-concentration standard substances. Carryover was L for compound 1. The response rate exceeded 25% with the LLOQ and was less than 5% with the internal standard. Carryover was greater than 25% with the LLOQ for warfarin and less than 5% with the internal standard. To avoid potential influence on the final results, study samples were analyzed according to predicted concentrations.

[0463] The concentrations of compound 1 and warfarin in the study samples were determined from appropriate calibration plots within BioLims.

[0464] Samples with unexpected results were re-assayed in a double series. In some cases, the results were unreportable (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 at both 10 μg / mL and 50 μg / mL (85.0% ≤ PPB ≤ 98.0%). A slight concentration dependence was observed across the concentration range investigated, suggesting a tendency for PPB to become non-linear with increasing concentration of compound 1. This tendency was more pronounced in mice, dogs, miniature pigs, 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 evaluate the effects of a single intravenous (IV) administration of a target dose of 5 mg / kg to male cynomolgus monkeys (Macaca fascicularis) [ 14 The objective was to evaluate the tissue distribution, dynamics, and pharmacokinetics (PK) of compound 1 [C]-a drug-related substance. Cynomolgus monkeys are representative of human distribution and excretion. After administration, three animals were placed in metabolic cages and kept for 4, 12, and 168 hours after administration, respectively.

[0467] [ 14 The changes in [C]-compound 1 were investigated in only one animal (number 103, 168 hours). Total radioactivity was measured in urine, feces, and cage rinse fluid.

[0468] Pharmacokinetic profiles were obtained in blood and plasma collected from each animal from a selected point in time after administration to the end of the treatment period.

[0469] After euthanasia at 4, 12, and 168 hours after administration, quantitative whole-body autoradiography was used, 14 The tissue distribution of compound 1 [C] was investigated.

[0470] [ 14Following an IV bolus administration of compound 1 [C]-1, a very limited amount of the administered radioactivity (4.2% of the dose) was excreted over 168 hours post-administration. This observation indicates that most of the dose was retained in the tissues: 1.5% and 1.7% of the dose were recovered in urine and feces, respectively. Cage rinse fluid, associated with urinary excretion, accounted for a further 0.9% of the dose.

[0471] Total radioactivity in blood and plasma was quantifiable in all animals up to the end of the trial period. Over 168 hours after administration (animal 103), from the start of administration to the last quantifiable time (T last Total systemic exposure to radioactivity (AUC) is measured as the area under the plasma concentration-time curve (AUC) up to ) 0~t The concentrations in blood and plasma were 231,000 and 205,000 hours·ng-eq / g, respectively, while the maximum concentration (C) max The values ​​were 7510 ng-eq / g (C09 260 ng-eq / g) and 11500 ng-eq / g (C01 4000 ng-eq / g), respectively. The total radioactivity was observed at a ratio of 2.1 over 168 hours. Except in certain cases, the distribution was greater in plasma than in blood (the ratio of blood to plasma was 0.6-0.8).

[0472] The clearance (CL) was 6.69 mL / hour / kg (blood) and 14.0 mL / hour / kg (plasma), which was significantly lower than the blood flow rates in the liver and kidney (approximately 2616 and 1656 mL / hour / kg). Consistent with this, the mean volume of the distribution at steady state (V) ss This accounted for 2480 mL / kg (blood) and 2780 mL / kg (plasma), which is more than the total body water in cynomolgus monkeys (approximately 693 mL / kg), indicating a moderate distribution volume (0.6–5 L / kg).

[0473] in general,[ 14The [C]-compound 1 drug-related substance was widely distributed throughout the body and was quantifiable in all tissues up to the final sampling time. The distribution pattern in tissues was similar across selected time points over 168 hours post-administration. Very high concentrations were observed in the renal cortex, joints (mostly thought to be connected to cartilage), and liver, suggesting the possibility of accumulation in these tissues.

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

[0475] Moderate brain penetration was observed (brain-to-blood ratio <1): total radioactivity was distributed very uniformly across 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 in the choroid plexus.

[0476] Ultimately, radioactivity was also measured within melanin-containing tissues (e.g., hair follicles and, most importantly, the uveal tract of the eye), indicating its potential to bind to melanin. Radiation-labeled test specimen.

[0477] [ 14 C]-Compound 1( 14 (Radially labeled by conjugation to glycine double-labeled with 1C)

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

[0479] Radiochemical purity: 73.7%

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

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

[0482] pH 7.1~7.5

[0483] Osmotic pressure: 275-304 mOs / kg.

[0484] Storage conditions: Below 30°C (ambient temperature, AT), 2-8°C after opening. Test substance 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 suspended solids (SS) were thawed at ambient temperature, heated at approximately 65°C for 5 minutes, and then cooled to room temperature under magnetic stirring. Appropriate aliquots of the SS were diluted in the required volume of vehicle and kept at room temperature overnight under magnetic stirring. At the described specific activity, no further isotopic dilution with non-radiolabeled test material was required.

[0491] Stability of the final formulation: [ 14 To ensure that the stability of compound 1 [C]- was not affected, the heating step was evaluated beforehand. Stability at ambient temperature was assessed over 24 hours, enabling formulation preparation the day before administration.

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

[0493] Residual test preparation: The residual preparation was stored at -20°C. Testing System Characterization of the examination 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 acclimatization period: at least 21 days (before day 1)

[0498] The study guidance stipulated that monkeys were used as one of the non-rodent species required for toxicity testing. Crynomolgus 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] During the research phase, temperature and humidity were recorded daily. The actual average measurements (including ranges) were 21.3°C and 52.7%. The average temperature and relative humidity remained within acceptable limits throughout the living phase: 21–23°C (20–24°C acceptable for periods less than 24 hours) and 45–65% (40–70% acceptable for periods less than 24 hours), respectively. Diet, water, and environmental enrichment.

[0500] Except for approximately one hour before and one hour after administration, the subjects were given free rein to eat throughout the study. They were also given supplements of fruits, vegetables, and feed mixtures.

[0501] Throughout the study, participants were given free access to filtered water from regular household tap water.

[0502] The monkeys had access to special environmental enrichment devices within their respective cages. Social interaction between the animals and staff was provided for an appropriate amount of time, twice a day on working days and once a day on weekends. Experimental Design

[0503] Three naive male cynomolgus monkeys each received a target dose of 5 mg / kg [ 14 The animals received a single IV bolus dose of compound 1. After dose administration, the animals were placed in metabolic cages and the following matrix, outlined in Table 6, was collected. [Table 6]

[0504] The following matrix was used to determine the total radioactivity levels in blood, plasma, urine, feces, and cage rinse fluid using liquid scintillation count (LSC).

[0505] At the end of the study (4 hours, 12 hours, and 168 hours after administration, respectively), the animals were euthanized, and the tissue distribution of total radioactivity was assessed using QWBA.

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

[0507] Where possible, radioactivity data from blood, plasma, and tissues were subjected to non-compartmental analysis to evaluate appropriate pharmacokinetic parameters. Methods and Procedures Evaluation of the stability of the test sample.

[0508] Before commencing in-vivo experimental activities, the stability of the test material was evaluated by measuring its radiochemical purity under the following conditions.

[0509] The aliquots of SS are heated to approximately 65°C for 5 minutes, and this step is performed during formulation preparation. 14 We confirmed that it does not affect the stability of the C label.

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

[0511] In the blood of monkeys [ 14 A preliminary assessment of the stability of compound 1 was also performed: a certain volume of monkey blank blood was spiked with appropriate aliquots of radiolabeled SS and incubated at 37°C for 4 hours and 24 hours.

[0512] Because radioactivity could not be extracted using standard approaches, it was impossible to measure the radiochemical purity after incubation in blood and to evaluate its stability in biological matrices. Characterization of stock solutions and formulations.

[0513] The radioactivity concentrations of the stock solution and dose formulations were determined as follows: Three weighed aliquots were dispensed into glass vials and appropriately diluted with DPBS. Then, the three weighed aliquots were removed from each dilution, liquid scintillant was added, and radioassay was performed with LSC to determine the actual radioactivity concentration and homogeneity of the solution. Dosage administration.

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

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

[0516] After administration, urine and feces were quantitatively collected at selected post-administration points in time, and the samples were refrigerated on moist ice during collection.

[0517] Almost daily, and / or at the end of the collection period, the metabolic cages were rinsed with ethanol / water (50:50, v / v), and the washing solution was retained for quantitative determination of radioactivity.

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

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

[0520] Triple aliquots of liquid samples (e.g., dosage formulations, urine, plasma, and cage wash solution) were directly counted in a liquid scintillant.

[0521] Feces were homogenized in a suitable amount of ultrapure water using a Stomacher homogenizer (approximate ratio 1:2, w / v). Four aliquots (0.2-0.4 g) of the homogenate were weighed and solubilized by adding 1 mL of Solvable tissue solubilizer, and incubated at approximately 50°C until appropriate color change was achieved, with two replenishments of 200 μL of 30% hydrogen peroxide (H2O2), before adding scintillant.

[0522] Three aliquots (100 μL) of blood were weighed and processed as fecal homogenate.

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

[0524] Radioactivity was determined using 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 the sample counting efficiency from instrument-stored quench curves prepared from a sealed series of quench standards. Using the interpolated efficiency value, the counts per minute (cpm) of the LSC data were automatically corrected to obtain decays per minute (dpm). A suitable scintillation solution (Ultima Gold) was added to each sample, and then radioassay was performed by LSC for an appropriate time. Background counts were subtracted from the quench-corrected sample counts. The limit of quantification was calculated from the background value and count time. Tissue distribution.

[0525] At the final time points (4 hours, 12 hours, and 168 hours after administration, respectively), the animals were euthanized, and the tissue distribution of total radioactivity was assessed using whole-body quantitative autoradiography. 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] The frozen corpse was buried with its left side facing upwards in a block of sodium carboxymethylcellulose (approximately 2% w / v in water). Sectioning.

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

[0529] Freeze-dried sections, 14 The sample was placed on a suitable image plate (IP) for C for approximately 4 days. During the exposure period, the IP was placed in a copper-lead shielded box to minimize external background signal. After exposure, the sample was placed in a Fuji FLA5000 phosphor imager. Using a system, the IP was scanned with a laser beam to capture a latent image, which was then saved to an electronic data file.

[0530] For each set of whole-body images obtained, the system was calibrated using a known biological standard for radioactivity.

[0531] Selected tissues were identified on the images, fused using AIDA software, and values ​​for tissue density were obtained. For each selected organ / tissue, triplicate measurements were performed, where possible, by either multiple fusions from a single section or multiple fusions from several different sections.

[0532] The results obtained 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 quantification (LOQ) for tissue distribution was set at three times the average background level of radioactivity (the...

Claims

[Claim 1] The invention described in the specification.

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