Use of small molecule glutaminase inhibitors for treating age-related disorders

Abstract

The present disclosure provides methods of treating or preventing age-related diseases and disorders (e.g., age-related diseases or disorders associated with the glutamate pathway and / or glutaminase-1 (GLS1)) by administering to a subject in need thereof a provided compound (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. The present disclosure also provides methods of modulating mitochondrial function, reducing reactive oxygen species levels, reducing pro-inflammatory signaling, and / or preventing or inhibiting cellular senescence by contacting a cell, tissue, or biological sample with or administering to a subject in need thereof a provided compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

Description

USE OF SMALL MOLECULE GLUTAMINASE INHIBITORS FOR TREATING AGE-RELATED DISORDERSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority under 35 U. S. C. § 119(e) to U. S. Provisional Application Number 63 / 720,141, filed November 13, 2024, U. S. Provisional Application Number 63 / 797,010, filed April 29, 2025, U. S. Provisional Application Number 63 / 819,112, filed June 6, 2025, and U. S. Provisional Application Number 63 / 829,604, filed June 24, 2025, the contents of each of which are incorporated herewith by reference in their entireties.BACKGROUND OF THE INVENTION

[0002] Glutaminase is a mitochondrial enzyme that transforms glutamine into glutamate through glutaminolysis, which can be used as an alternative to glycolysis that provides a source of carbon for energy homeostasis and biosynthesis, is a source of energy in the brain and other organs. Excessive glutaminase promotes aging, for example by increasing oxidative stress, inflammation, cellular senescence, and hypermetabolism.SUMMARY OF THE INVENTION

[0003] Aspects of the disclosure relate to compositions and methods for treating an age-related disease or disorder associated with dysregulation of glutamine levels. In some embodiments, the dysregulation of glutamine is associated with activity or levels of glutaminase (GLS1) protein. The disclosure is based, in part, on compounds and / or compositions that reduce GLS1 activity or protein levels and, in turn, modulate levels of glutamate and / or glutamine in a cell or subject. In some embodiments, the subject has an age-related disease or disorder. In some embodiments, the age-related disease or disorder is a metabolic disorder associated with ageing (e.g., obesity, diabetes, a liver disease (e.g., non-alcoholic fatty liver disease)), adipose tissue dysfunction, muscular atrophy (e.g., muscle wasting, such as age-related muscular atrophy, frailty, etc.), organ dysfunction associated with ageing (e.g. lung fibrosis, etc.), or a cardiovascular disease (e.g., atherosclerosis). Aspects of the disclosure are based on peripheral delivery of compounds and / or compositions that reduce GLS1 activity or protein levels.

[0004] Accordingly, in one aspect, the present disclosure provides methods of treating an age-related disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof:a therapeutically effective amount of a compound of Formula (I):or a pharmaceutically acceptable salt thereof; ora pharmaceutical composition comprising a therapeutically effective amount of a compound ofL0907.70047WO00 1 / 150#14596547vlFormula (I), or a pharmaceutically acceptable salt thereof, and an excipient; wherein R1, R2, R3B, R3C, RY, Z, and n are as defined herein.

[0005] In some embodiments, the age-related disease or disorder is associated with the glutamate pathway. In some embodiments, the age-related disease or disorder is associated with glutaminase- 1 (GLS1). In some embodiments, the age-related disease or disorder is a metabolic disorder associated with ageing (e.g., obesity, diabetes, a liver disease (e.g., non-alcoholic fatty liver disease)), adipose tissue dysfunction, muscular atrophy (e.g., muscle wasting, such as age-related muscular atrophy, frailty, etc.), organ dysfunction associated with ageing (e.g. lung fibrosis, etc.), or a cardiovascular disease (e.g., atherosclerosis).

[0006] In some embodiments, the administration comprises peripheral administration. In some embodiments, the peripheral administration comprises intrathecal injection, subcutaneous injection, intramuscular injection or intravenous injection.

[0007] In some embodiments, the subject has or is suspected of having an age-related disease or disorder. In some embodiments, the subject has or is suspected of having a metabolic disorder associated with ageing (e.g., obesity, diabetes, a liver disease (e.g., non-alcoholic fatty liver disease)), adipose tissue dysfunction, muscular atrophy (e.g., muscle wasting, such as age-related muscular atrophy, frailty, etc.), organ dysfunction associated with ageing (e.g. lung fibrosis, etc.), or a cardiovascular disease (e.g., atherosclerosis). In some embodiment, the subject has or is suspected of having organ dysfunction associated with ageing (e.g. lung fibrosis, etc.).

[0008] In some embodiments, the subject is characterized as having decreased glutamine levels, increased glutamate levels, increased pro-inflammatory signaling, adipose tissue dysfunction, mitochondrial dysfunction, increased cellular senescence, and / or increased reactive oxygen species production. In some embodiment, a subject is characterized as having organ dysfunction associated with ageing (e.g. lung fibrosis, etc.). In some embodiments, the subject is a human subject.

[0009] In another aspect, the present disclosure provides methods of preventing an age-related disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof:a prophylactically effective amount of a compound of Formula (I):N(I),or a pharmaceutically acceptable salt thereof; ora pharmaceutical composition comprising a prophylactically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and an excipient; wherein R1, R2, R3B, R3C, RY, Z, and n are as defined herein.

[0010] In some embodiments, the age-related disease or disorder is associated with the glutamate pathway. In some embodiments, the age-related disease or disorder is associated with GLS1. In some embodiments, the age-related disease or disorder is a metabolic disorder associated with ageing (e.g.,L0907.70047WO00 2 / 150#14596547vlobesity, diabetes, a liver disease (e.g., non-alcoholic fatty liver disease)), adipose tissue dysfunction, muscular atrophy (e.g., muscle wasting, such as age-related muscular atrophy, frailty, etc.), organ dysfunction associated with ageing (e.g. lung fibrosis, etc.), or a cardiovascular disease (e.g., atherosclerosis).

[0011] In some embodiments, the administration comprises peripheral administration. In some embodiments, the peripheral administration comprises intrathecal injection, subcutaneous injection, intramuscular injection or intravenous injection.

[0012] In some embodiments, the subject has or is suspected of having an age-related disease or disorder. In some embodiments, the subject has or is suspected of having a metabolic disorder associated with ageing (e.g., obesity, diabetes, a liver disease (e.g., non-alcoholic fatty liver disease)), adipose tissue dysfunction, muscular atrophy (e.g., muscle wasting, such as age-related muscular atrophy, frailty, etc.), organ dysfunction associated with ageing (e.g. lung fibrosis, etc.), or a cardiovascular disease (e.g., atherosclerosis). In some embodiment, the subject has or is suspected of having organ dysfunction associated with ageing (e.g. lung fibrosis, etc.).

[0013] In some embodiments, the subject is characterized as having decreased glutamine levels, increased glutamate levels, increased pro-inflammatory signaling, adipose tissue dysfunction, mitochondrial dysfunction, increased cellular senescence, and / or increased reactive oxygen species production. In some embodiment, a subject is characterized as having organ dysfunction associated with ageing (e.g. lung fibrosis, etc.). In some embodiments, the subject is a human subject.

[0014] In another aspect, the present disclosure provides methods of modulating mitochondrial function in a cell, tissue, or biological sample, or in a subject in need thereof, comprising contacting the cell, tissue, or biological sample with or administering to the subject in need thereof:an effective amount of a compound of Formula (I):R- Z= / N(I),or a pharmaceutically acceptable salt thereof; ora pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and an excipient; wherein R1, R2, R3B, R3C, RY, Z, and n are as defined herein.

[0015] In some embodiments, the cell is a human cell. In some embodiments, the cell is in a subject. In some embodiments, the cell is a senescent cell. In some embodiments, the cell is an adipose cell (e.g., adipocyte). In some embodiments, the cell is a muscle cell. In some embodiments, the muscle cell is a skeletal muscle cell. In some embodiments, the cell is a liver cell. In some embodiments, the cell is a microglial cell. In some embodiments, the cell is a liver cell. In some embodiments, the cell is a pancreas cell. In some embodiments, the cell is a lung cell.

[0016] In some embodiments, the administration comprises peripheral administration. In someL0907.70047WO00 3 / 150#14596547vlembodiments, the peripheral administration comprises intrathecal injection, subcutaneous injection, intramuscular injection or intravenous injection.

[0017] In some embodiments, the subject has or is suspected of having an age-related disease or disorder. In some embodiments, the subject has or is suspected of having a metabolic disorder associated with ageing (e.g., obesity, diabetes, a liver disease (e.g., non-alcoholic fatty liver disease)), adipose tissue dysfunction, muscular atrophy (e.g., muscle wasting, such as age-related muscular atrophy, frailty, etc.), organ dysfunction associated with ageing (e.g. lung fibrosis, etc.), or a cardiovascular disease (e.g., atherosclerosis). In some embodiment, the subject has or is suspected of having organ dysfunction associated with ageing (e.g. lung fibrosis, etc.).

[0018] In some embodiments, the subject is characterized as having decreased glutamine levels, increased glutamate levels, increased pro-inflammatory signaling, adipose tissue dysfunction, mitochondrial dysfunction, increased cellular senescence, and / or increased reactive oxygen species production. In some embodiment, a subject is characterized as having organ dysfunction associated with ageing (e.g. lung fibrosis, etc.). In some embodiments, the subject is a human subject.

[0019] In another aspect, the present disclosure provides methods of reducing reactive oxygen species levels in a cell, tissue, or biological sample, or in a subject in need thereof, comprising contacting the cell, tissue, or biological sample with or administering to the subject in need thereof:an effective amount of a compound of Formula (I):or a pharmaceutically acceptable salt thereof; ora pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and an excipient; wherein R1, R2, R3B, R3C, RY, Z, and n are as defined herein.

[0020] In some embodiments, the cell is a human cell. In some embodiments, the cell is in a subject. In some embodiments, the cell is a senescent cell. In some embodiments, the cell is an adipose cell (e.g., adipocyte). In some embodiments, the cell is a muscle cell. In some embodiments, the muscle cell is a skeletal muscle cell. In some embodiments, the cell is a liver cell. In some embodiments, the cell is a microglial cell. In some embodiments, the cell is a liver cell. In some embodiments, the cell is a pancreas cell. In some embodiments, the cell is a lung cell.

[0021] In some embodiments, the administration comprises peripheral administration. In some embodiments, the peripheral administration comprises intrathecal injection, subcutaneous injection, intramuscular injection or intravenous injection.

[0022] In some embodiments, the subject has or is suspected of having an age-related disease or disorder. In some embodiments, the subject has or is suspected of having a metabolic disorder associated with ageing (e.g., obesity, diabetes, a liver disease (e.g., non-alcoholic fatty liver disease)), adipose tissueL0907.70047WO00 4 / 150#14596547vldysfunction, muscular atrophy (e.g., muscle wasting, such as age-related muscular atrophy, frailty, etc.), organ dysfunction associated with ageing (e.g. lung fibrosis, etc.), or a cardiovascular disease (e.g., atherosclerosis). In some embodiment, the subject has or is suspected of having organ dysfunction associated with ageing (e.g. lung fibrosis, etc.).

[0023] In some embodiments, the subject is characterized as having decreased glutamine levels, increased glutamate levels, increased pro-inflammatory signaling, adipose tissue dysfunction, mitochondrial dysfunction, increased cellular senescence, and / or increased reactive oxygen species production. In some embodiment, a subject is characterized as having organ dysfunction associated with ageing (e.g. lung fibrosis, etc.). In some embodiments, the subject is a human subject.

[0024] In another aspect, the present disclosure provides methods of reducing pro-inflammatory signaling in a cell, tissue, or biological sample, or in a subject in need thereof, comprising contacting the cell, tissue, or biological sample with or administering to the subject in need thereof:an effective amount of a compound of Formula (I):R- Z= / N(I),or a pharmaceutically acceptable salt thereof; ora pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and an excipient; wherein R1, R2, R3B, R3C, RY, Z, and n are as defined herein.

[0025] In some embodiments, the cell is a human cell. In some embodiments, the cell is in a subject. In some embodiments, the cell is a senescent cell. In some embodiments, the cell is an adipose cell (e.g., adipocyte). In some embodiments, the cell is a muscle cell. In some embodiments, the muscle cell is a skeletal muscle cell. In some embodiments, the cell is a liver cell. In some embodiments, the cell is a microglial cell. In some embodiments, the cell is a liver cell. In some embodiments, the cell is a pancreas cell. In some embodiments, the cell is a lung cell.

[0026] In some embodiments, the administration comprises peripheral administration. In some embodiments, the peripheral administration comprises intrathecal injection, subcutaneous injection, intramuscular injection or intravenous injection.

[0027] In some embodiments, the subject has or is suspected of having an age-related disease or disorder. In some embodiments, the subject has or is suspected of having a metabolic disorder associated with ageing (e.g., obesity, diabetes, a liver disease (e.g., non-alcoholic fatty liver disease)), adipose tissue dysfunction, muscular atrophy (e.g., muscle wasting, such as age-related muscular atrophy, frailty, etc.), organ dysfunction associated with ageing (e.g. lung fibrosis, etc.), or a cardiovascular disease (e.g., atherosclerosis). In some embodiment, the subject has or is suspected of having organ dysfunction associated with ageing (e.g. lung fibrosis, etc.).L0907.70047WO00 5 / 150#14596547vl

[0028] In some embodiments, the subject is characterized as having decreased glutamine levels, increased glutamate levels, increased pro-inflammatory signaling, adipose tissue dysfunction, mitochondrial dysfunction, increased cellular senescence, and / or increased reactive oxygen species production. In some embodiment, a subject is characterized as having organ dysfunction associated with ageing (e.g. lung fibrosis, etc.). In some embodiments, the subject is a human subject.

[0029] In another aspect, the present disclosure provides methods of preventing or inhibiting cellular senescence in a cell, tissue, or biological sample, or in a subject in need thereof, comprising contacting the cell, tissue, or biological sample with or administering to the subject in need thereof:an effective amount of a compound of Formula (I):R- Z= / N(I),or a pharmaceutically acceptable salt thereof; ora pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and an excipient; wherein R1, R2, R3B, R3C, RY, Z, and n are as defined herein.

[0030] In some embodiments, the cell is a human cell. In some embodiments, the cell is in a subject. In some embodiments, the cell is a senescent cell. In some embodiments, the cell is an adipose cell (e.g., adipocyte). In some embodiments, the cell is a muscle cell. In some embodiments, the muscle cell is a skeletal muscle cell. In some embodiments, the cell is a liver cell. In some embodiments, the cell is a microglial cell. In some embodiments, the cell is a liver cell. In some embodiments, the cell is a pancreas cell. In some embodiments, the cell is a lung cell.

[0031] In some embodiments, the administration comprises peripheral administration. In some embodiments, the peripheral administration comprises intrathecal injection, subcutaneous injection, intramuscular injection or intravenous injection.

[0032] In some embodiments, the subject has or is suspected of having an age-related disease or disorder. In some embodiments, the subject has or is suspected of having a metabolic disorder associated with ageing (e.g., obesity, diabetes, a liver disease (e.g., non-alcoholic fatty liver disease)), adipose tissue dysfunction, muscular atrophy (e.g., muscle wasting, such as age-related muscular atrophy, frailty, etc.), organ dysfunction associated with ageing (e.g. lung fibrosis, etc.), or a cardiovascular disease (e.g., atherosclerosis). In some embodiment, the subject has or is suspected of having organ dysfunction associated with ageing (e.g. lung fibrosis, etc.).

[0033] In some embodiments, the subject is characterized as having decreased glutamine levels, increased glutamate levels, increased pro-inflammatory signaling, adipose tissue dysfunction, mitochondrial dysfunction, increased cellular senescence, and / or increased reactive oxygen species production. In some embodiment, a subject is characterized as having organ dysfunction associated with ageing (e.g. lung fibrosis, etc.). In some embodiments, the subject is a human subject.L0907.70047WO00 6 / 150#14596547vl

[0034] It should be appreciated that the foregoing concepts, and the additional concepts discussed below, may be arranged in any suitable combination, as the present disclosure is not limited in this respect. Further, other advantages and novel features of the present disclosure will become apparent from the following detailed description of various non-limiting embodiments when considered in conjunction with the accompanying drawings.BRIEF DESCRIPTION OF THE DRAWINGS

[0035] FIGs. 1A-1B show % body weight reduction (BW) from baseline in DIO mice after treatment with a low dose and high dose of compound 24A compared to vehicle (FIG. 1A) and % body weight reduction from baseline after treatment with a low dose and high dose of compound 24A compared to vehicle and semaglutide (FIG. IB). There was a significant reduction in body weight of DIO mice after dosing with compound 24A after 21 days. Dosing regimen: IP, QD. Data represented as Mean + / - SEM. n=12. ANOVA followed by Dunnett multiple comparisons. * p<0.05; **** p<0.0001.

[0036] FIG. 2 shows a schematic of the experimental protocol used in FIGs. 3 and 4A-4D.

[0037] FIG. 3 shows % body weight reduction (BW) from baseline in DIO mice after treatment with a low dose and high dose of compound 24A compared to vehicle and semaglutide. There was a significant reduction in body weight of DIO mice after dosing with compound 24A after 31 days. Dosing regimen: PO, QD. Data represented as Mean + / - SEM. N=10-12. ANOVA followed by Dunnett’s test for Treatment vs. Vehicle. ****:p<0.0001, ***:p<0.001, **:p<0.01, *:p<0.05.

[0038] FIGs. 4A-4D show fasting serum glucose (FIG. 4A), non-fasting serum glucose (FIG. 4B), triglycerides (FIG. 4C), and plasma leptin (FIG. 4D) from the DIO mice of FIG. 3. Data represented as Mean + / - SEM. N=10-12. ANOVA followed by Dunnett’s test for Treatment vs. Vehicle.****:p<0.0001, ***:p<0.001, **:p<0.01, *:p<0.05. Fasting glucose was measured on day 29 post 16-hour fast. Serum glucose (non-fasting), triglycerides, and plasma leptin were measured on day 31.

[0039] FIG. 5 shows % body weight reduction (BW) from baseline in wild type mice (non-DIO mice) after treatment with a high dose of compound 24A compared to vehicle. Dosing regimen: PO, QD. Data represented as Mean + / - SEM. N=10-12. ANOVA followed by Dunnett’s test for Treatment vs. Vehicle. ****:p<0.0001, ***:p<0.001, **:p<0.01, *:p<0.05.DEFINITIONS

[0040] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this invention belongs. The following references provide one of skill with a general definition of many of the terms used in this invention: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them unless specified otherwise.L0907.70047WO00 7 / 150#14596547vl

[0041] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Michael B. Smith, March’s Advanced Organic Chemistry, 7thEdition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0042] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques etal., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The invention additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers. The term “isomers” is intended to include diastereoisomers, enantiomers, regioisomers, structural isomers, rotational isomers, tautomers, and the like. All such isomers of such compounds herein are expressly included in the present invention.

[0043] When a range of values (“range”) is listed, it encompasses each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided. For example “Ci-6 alkyl” encompasses, Ci, C2, C3, C4, C5, Ce, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.

[0044] The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0045] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1-20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“CHO alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”). In some embodiments, anL0907.70047WO00 8 / 150#14596547vlalkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of C1-6 alkyl groups include methyl (Ci), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertamyl), and hexyl (Ce) (e.g., / / -hexyl). Additional examples of alkyl groups include / / -heptyl (C7), n-octyl (Cs), n-dodecyl (C12), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In some embodiments, the alkyl group is an unsubstituted C1-12 alkyl (such as unsubstituted C1-6 alkyl, e.g., -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (z-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted / / -butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or / -Bu), unsubstituted.vec-butyl (sec-Bu or.v-Bu), unsubstituted isobutyl (z-Bu)). In some embodiments, the alkyl group is a substituted C1-12 alkyl (such as substituted C1-6 alkyl, e.g., -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, or benzyl (Bn)).

[0046] The term “haloalkyl” is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. “Perhaloalkyl” is a subset of haloalkyl and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 20 carbon atoms (“C1-20 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 10 carbon atoms (“Ci-10 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 9 carbon atoms (“C1-9 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“C1-8 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 7 carbon atoms (“C1-7 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C1-6 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 5 carbon atoms (“C1-5 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C1-4 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C1-3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1-2 haloalkyl”). In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with fluoro to provide a “perfluoroalkyl” group. In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with chloro to provide a “perchloroalkyl” group. Examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CCI3, -CFCI2, -CF2CI, and the like.

[0047] The term “heteroalkyl” refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In some embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-20 alkyl”). In some embodiments, a heteroalkyl group refers to a saturated group having from 1 to 12 carbon atoms and 1 or more heteroatoms within theL0907.70047WO00 9 / 150#14596547vlparent chain (“heteroCi-12 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 11 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCm alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCuo alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-9 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-s alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-7 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-6 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroCi-5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and lor 2 heteroatoms within the parent chain (“heteroCi-4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroCi-3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroCi-2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroCi alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In some embodiments, the heteroalkyl group is an unsubstituted heteroCi-12 alkyl. In some embodiments, the heteroalkyl group is a substituted heteroCi-12 alkyl.

[0048] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 2 to 20 carbon atoms (“C2-20 alkenyl”). In some embodiments, an alkenyl group has 2 to 12 carbon atoms (“C2-12 alkenyl”). In some embodiments, an alkenyl group has 2 to 11 carbon atoms (“C2-11 alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenylL0907.70047WO00 10 / 150#14596547vlgroups as well as pentenyl (Cs), pentadienyl (Cs), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In some embodiments, the alkenyl group is an unsubstituted C2-20 alkenyl. In some embodiments, the alkenyl group is a substituted C2-20 alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., -CH=CHCH3 or) may be in the (E)- or (Z) -configuration.

[0049] The term “heteroalkenyl” refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In some embodiments, a heteroalkenyl group refers to a group having from 2 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-2o alkenyl”). In some embodiments, a heteroalkenyl group refers to a group having from 2 to 12 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2 i2 alkenyl”). In some embodiments, a heteroalkenyl group refers to a group having from 2 to 11 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-n alkenyl”). In some embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2 io alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-9 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-8 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-7 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-5 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-4 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC2-3 alkenyl”). In some embodiments, a heteroalkenyl group has 2 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC2 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In some embodiments, the heteroalkenyl group is an unsubstituted heteroC2-2o alkenyl. In some embodiments, the heteroalkenyl group is a substituted heteroC2-2o alkenyl.

[0050] The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having L0907.70047WO00 11 / 150#14596547vlfrom 2 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“Ci-20 alkynyl”). In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (Ce), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (Cs), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In some embodiments, the alkynyl group is an unsubstituted C2-20 alkynyl. In some embodiments, the alkynyl group is a substituted C2-20 alkynyl.

[0051] The term “heteroalkynyl” refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In some embodiments, a heteroalkynyl group refers to a group having from 2 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-2o alkynyl”). In some embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2 io alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-9 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-8 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-7 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-5 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-4 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC2-3 alkynyl”). In some embodiments, a heteroalkynyl group has 2 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC2 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2L0907.70047WO00 12 / 150#14596547vlheteroatoms within the parent chain (“heteroC2-6 alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In some embodiments, the heteroalkynyl group is an unsubstituted heteroC2-2o alkynyl. In some embodiments, the heteroalkynyl group is a substituted heteroC2-2o alkynyl.

[0052] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 13 ring carbon atoms (“C3-13 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 11 ring carbon atoms (“C3-11 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. Exemplary C3-8 carbocyclyl groups include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), and the like. Exemplary C3-10 carbocyclyl groups include the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C$>), cyclononenyl (C$>), cyclodecyl (C10), cyclodecenyl (C10), octahydro- 1 H-indeny I (C$>), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. Exemplary C3-8 carbocyclyl groups include the aforementioned C3-10 carbocyclyl groups as well as cycloundecyl (Cn), spiro[5.5]undecanyl (Cn), cyclododecyl (C12), cyclododecenyl (C12), cyclotridecane (C13), cyclotetradecane (C14), and the like. As the foregoing examples illustrate, in some embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In some embodiments, the carbocyclyl group is an unsubstituted C3-14L0907.70047WO00 13 / 150#14596547vlcarbocyclyl. In some embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl.

[0053] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4).Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (Cs). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In some embodiments, the cycloalkyl group is an unsubstituted C3-14 cycloalkyl. In some embodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl. In some embodiments, the carbocyclyl includes 0, 1, or 2 C=C double bonds in the carbocyclic ring system, as valency permits.

[0054] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered nonaromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In some embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In some embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl. In some embodiments, the heterocyclyl is substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits.

[0055] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring systemL0907.70047WO00 14 / 150#14596547vlhaving ring carbon atoms and 1^1 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1^1 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1^1 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0056] Exemplary 3 -membered heterocyclyl groups containing 1 heteroatom include azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include azetidinyl, oxetanyl, and thietanyl. Exemplary 5 -membered heterocyclyl groups containing 1 heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5 -membered heterocyclyl groups containing 3 heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include triazinyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro- 1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, lH-benzo[e][l,4]diazepinyl, 1,4,5,7-tetrahydro-pyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-lH-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-lH-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, l,2,3,4-tetrahydro-l,6-naphthyridinyl, and the like.

[0057] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 % electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce-i4 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In L0907.70047WO00 15 / 150#14596547vlsome embodiments, an aryl group has 14 ring carbon atoms (“C14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In some embodiments, the aryl group is an unsubstituted Ce-i4 aryl. In some embodiments, the aryl group is a substituted Ce-i4 aryl.

[0058] “Aralkyl” is a subset of “alkyl” and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety.

[0059] The term “heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 147t electrons shared in a cyclic array) having ring carbon atoms and 1^1 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, e.g., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). In some embodiments, the heteroaryl is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In some embodiments, the heteroaryl is substituted or unsubstituted, 9- or 10-membered, bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.

[0060] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1^1 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1^1 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1^1 ring L0907.70047WO00 16 / 150#14596547vlheteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In some embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In some embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0061] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5 -membered heteroaryl groups containing 4 heteroatoms include tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0062] “Heteroaralkyl” is a subset of “alkyl” and refers to an alkyl group substituted by a heteroaryl group, wherein the point of attachment is on the alkyl moiety.

[0063] The term “unsaturated bond” refers to a double or triple bond.

[0064] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.

[0065] The term “saturated” or “fully saturated” refers to a moiety that does not contain a double or triple bond, e.g., the moiety only contains single bonds.

[0066] Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl.L0907.70047WO00 17 / 150#14596547vl

[0067] A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In some embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. “Optionally substituted” refers to a group which is substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds and includes any of the substituents described herein that results in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The invention is not limited in any manner by the exemplary substituents described herein.

[0068] Exemplary carbon atom substituents include halogen, -CN, -NCh, -N3, -SO2H, -SO3H, -OH, -ORaa, -ON(Rbb)2, -N(Rbb)2, -N(Rbb)3+X“, -N(ORcc)Rbb, -SH, -SRaa, -SSRCC, -C(=O)Raa, -CO2H, -CHO, -C(ORCC)2, -CO2Raa, -OC(=O)Raa, -OCO2Raa, -C(=O)N(Rbb)2, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, -NRbbC(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -OC(=NRbb)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -C(=O)NRbbSO2Raa, -NRbbSO2Raa, -SO2N(Rbb)2, -SO2Raa, -SO2ORaa, -OSO2Raa, -S(=O)Raa, -OS(=O)Raa, -Si(Raa)3, -OSi(Raa)3-C(=S)N(Rbb)2, -C(=O)SRaa, -C(=S)SRaa, -SC(=S)SRaa, -SC(=O)SRaa, -OC(=O)SRaa, -SC(=O)ORaa, -SC(=O)Raa, -P(=O)(Raa)2, -P(=O)(ORCC)2, -OP(=O)(Raa)2, -OP(=O)(ORCC)2, -P(=O)(N(Rbb)2)2, -OP(=O)(N(Rbb)2)2, -NRbbP(=O)(Raa)2, -NRbbP(=O)(ORcc)2, -NRbbP(=O)(N(Rbb)2)2, -P(RCC)2, -P(ORCC)2, -P(RCC)3+X“, -P(ORCC)3+X-, -P(RCC)4, -P(ORCC)4, -OP(RCC)2, -OP(RCC)3+X-, -OP(ORCC)2, -OP(ORCC)3+X-, -OP(RCC)4, -OP(ORCC)4, -B(Raa)2, -B(ORCC)2, -BRaa(ORcc), Ci-2o alkyl, C1-20 perhaloalkyl, C1-20 alkenyl, C1-20 alkynyl, heteroCi-2o alkyl, heteroCi-2o alkenyl, heteroCi-2o alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; wherein X" is a counterion;or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(Rbb)2,L0907.70047WO00 18 / 150#14596547vl=NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORCC;wherein:each instance of Raais, independently, selected from C1-20 alkyl, C1-20 perhaloalkyl, C1-20 alkenyl, C1-20 alkynyl, heteroCi-20 alkyl, heteroCi-2oalkenyl, heteroCi-2oalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups;each instance of Rbbis, independently, selected from hydrogen, -OH, -ORaa, -N(RCC)2, -CN, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, -P(=O)(Raa)2, -P(=O)(ORCC)2, -P(=O)(N(RCC)2)2, Ci-20 alkyl, Ci-20 perhaloalkyl, C1-20 alkenyl, C1-20 alkynyl, heteroCi-2oalkyl, heteroCi- 2oalkenyl, heteroCi-2oalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups;each instance of Rccis, independently, selected from hydrogen, C1-20 alkyl, C1-20 perhaloalkyl, C1-20 alkenyl, C1-20 alkynyl, heteroCi-20 alkyl, heteroCi-20 alkenyl, heteroCi-20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups;each instance of Rddis, independently, selected from halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORee, -ON(Rff)2, -N(Rff)2, -N(Rff)3+X“, -N(ORee)Rff, -SH, -SRee, -SSRee, -C(=O)Ree, -CO2H, -CO2Ree, -OC(=O)Ree, -OCO2Ree, -C(=O)N(Rff)2, -OC(=O)N(Rff)2, -NRffC(=O)Ree, -NRffCO2Ree, -NRffC(=O)N(Rff)2, -C(=NRff)ORee, -OC(=NRff)Ree, -OC(=NRff)ORee, -C(=NRff)N(Rff)2, -OC(=NRff)N(Rff)2, -NRffC(=NRff)N(Rff)2, -NRffSO2Ree, -SO2N(Rff)2, -SO2Ree, -SO2ORee, -OSO2Ree, -S(=O)Ree, — Si(Ree)3, -OSi(Ree)3, -C(=S)N(Rff)2, -C(=O)SRee, -C(=S)SRee, -SC(=S)SRee, -P(=O)(ORee)2, -P(=O)(Ree)2, -OP(=O)(Ree)2, -OP(=O)(ORee)2, C1-10 alkyl, C1-10 perhaloalkyl, C1-10 alkenyl, Cue alkynyl, heteroCnoalkyl, heteroCnoalkenyl, heteroCnoalkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce-io aryl, and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents are joined to form =0 or =S; wherein X" is a counterion;each instance of Reeis, independently, selected from C1-10 alkyl, Cue perhaloalkyl, Cue alkenyl, Cue alkynyl, heteroCuo alkyl, heteroCuo alkenyl, heteroCuo alkynyl, C3-10 carbocyclyl, Ce-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl,L0907.70047WO00 19 / 150#14596547vlalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups;each instance of Rffis, independently, selected from hydrogen, Cue alkyl, Cue perhaloalkyl, Ci- io alkenyl, Cue alkynyl, heteroCuo alkyl, heteroCuo alkenyl, heteroCuo alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce-io aryl, and 5-10 membered heteroaryl, or two Rffgroups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups;each instance of Rggis, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC1-6 alkyl, -ON(CI-6 alkyfh, -N(CI-6 alkyl)2, -N(CI-6 alkyl)3+X“, -NH(CI-6 alkyl)2+X“, -NH2(CI-6 alkyl)+X“, -NH3+X-, -N(OCI-6 alkyl)(Ci-6 alkyl), -N(OH)(CI-6alkyl), -NH(OH), -SH, -SC1-6 alkyl, -SS(Ci-6alkyl), -C(=O)(Ci-6alkyl), -CO2H, -CO2(Ci-6 alkyl), -OC(=O)(Ci-6alkyl), -OCO2(Ci 6 alkyl), -C(=O)NH2, -C(=O)N(CI-6 alkyl)2, -OC(=O)NH(CI-6 alkyl), -NHC(=O)( C1-6 alkyl), -N(CI-6alkyI)C(=O)( C1-6 alkyl), -NHCO2(CI 6 alkyl), -NHC(=O)N(CI-6alkyl)2, -NHC(=O)NH(Ci6alkyl), -NHC(=O)NH2, -C(=NH)O(CI-6alkyl), -OC(=NH)(CI-6alkyl), -OC(=NH)OCi6alkyl, -C(=NH)N(Ci- 6 alkyl)2, -C(=NH)NH(CI-6alkyl), -C(=NH)NH2, -OC(=NH)N(CI-6alkyl)2, -OC(NH)NH(Ci6alkyl), -OC(NH)NH2, -NHC(NH)N(CI-6alkyl)2, -NHC(=NH)NH2, -NHSO2(CI 6 alkyl), -SO2N(CI-6alkyl)2, -SO2NH(CI-6alkyl), -SO2NH2, -SO2C16alkyl, -SO2OC16alkyl, -OSO2C1 6 alkyl, -SOCi6alkyl, -Si(Ci-6 alkyl)3, -OSi(Ci-6alkyl)3-C(=S)N(CI-6alkyl)2, C(=S)NH(CI-6alkyl), C(=S)NH2, -C(=O)S(Ci- 6 alkyl), -C(=S)SCi-6 alkyl, -SC(=S)SCi-6alkyl, -P(=O)(OCi-6 alkyl)2, -P(=O)(Ci-6alkyl)2, -OP(=O)(Ci-6 alkyl)2, -OP(=O)(OCi-6 alkyfh, Cue alkyl, Cue perhaloalkyl, Cue alkenyl, Cue alkynyl, heteroCuo alkyl, heteroCuo alkenyl, heteroCuo alkynyl, C3-10 carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =0 or =S; andeach X" is a counterion.

[0069] In some embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -SCN, -NO2, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -OC(=O)Raa, -OCO2Raa, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, or -NRbbC(=O)N(Rbb)2. In some embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -SCN, -NO2, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -OC(=O)Raa, -OCO2Raa, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, or -NRbbC(=O)N(Rbb)2, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Cue alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Cue alkyl, or a nitrogen protecting groupL0907.70047WO00 20 / 150#14596547vl(e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In some embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -SCN, or -NO2. In some embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen moieties) or unsubstituted CMO alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -SCN, or -NO2, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-10 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Cue alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0070] In some embodiments, the molecular weight of a carbon atom substituent is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g / mol. In some embodiments, a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In some embodiments, a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen atoms. In some embodiments, a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In some embodiments, a carbon atom substituent consists of carbon, hydrogen, fluorine, and / or chlorine atoms.

[0071] The term “halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0072] The term “hydroxyl” or “hydroxy” refers to the group -OH. The term “substituted hydroxyl” or “substituted hydroxyl,” by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from -ORaa, -ON(Rbb)2, -OC(=O)SRaa, -OC(=O)Raa, -OCO2Raa, -OC(=O)N(Rbb)2, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -OC(=NRbb)N(Rbb)2, -OS(=O)Raa, -OSO2Raa, -OSi(Raa)3, -OP(RCC)2, -OP(RCC)3+X-, -OP(ORCC)2, -OP(ORCC)3+X’, -OP(=O)(Raa)2, -OP(=O)(ORCC)2, and -OP(=O)(N(Rbb))2, wherein X“, Raa, Rbb, and Rccare as defined herein.

[0073] The term “thiol” or “thio” refers to the group -SH. The term “substituted thiol” or “substituted thio,” by extension, refers to a thiol group wherein the sulfur atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from -SRaa, -S=SRCC, -SC(=S)SRaa, -SC(=S)ORaa, -SC(=S) N(Rbb)2, -SC(=O)SRaa, -SC(=O)ORaa, -SC(=O)N(Rbb)2, and -SC(=O)Raa, wherein Raaand Rccare as defined herein.

[0074] The term “amino” refers to the group -NH2. The term “substituted amino,” by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In some embodiments, the “substituted amino” is a monosubstituted amino or a disubstituted amino group.

[0075] The term “monosubstituted amino” refers to an amino group wherein the nitrogen atom directlyL0907.70047WO00 21 / 150#14596547vlattached to the parent molecule is substituted with one hydrogen and one group other than hydrogen, and includes groups selected from -NH(Rbb), -NHC(=O)Raa, -NHCO2Raa, -NHC(=O)N(Rbb)2, -NHC(=NRbb)N(Rbb)2, -NHSO2Raa, -NHP(=O)(ORCC)2, and -NHP(=O)(N(Rbb)2)2, wherein Raa, Rbband Rccare as defined herein, and wherein Rbbof the group -NH(Rbb) is not hydrogen.

[0076] The term “disubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with two groups other than hydrogen, and includes groups selected from -N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, -NRbbC(=O)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -NRbbSO2Raa, -NRbbP(=O)(ORcc)2, and -NRbbP(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.

[0077] The term “trisubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from -N(Rbb)3 and -N(Rbb)3+X“, wherein Rbband X“ are as defined herein.

[0078] The term “sulfonyl” refers to a group selected from -SO2N(Rbb)2, -SO2Raa, and -SO2ORaa, wherein Raaand Rbbare as defined herein.

[0079] The term “sulfinyl” refers to the group -S(=O)Raa, wherein Raais as defined herein.

[0080] The term “acyl” refers to a group having the general formula -C(=O)RX1, -C(=O)ORX1, -C(=O)-O-C(=O)RX1, -C(=O)SRX1, -C(=O)N(RX1)2, -C(=S)RX1, -C(=S)N(RX1)2, and -C(=S)S(RX1), -C(=NRX1)RX1, -C(=NRX1)ORX1, -C(=NRX1)SRX1, and -C(=NRX1)N(RX1)2, wherein RX1is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di-aliphaticamino, mono- or di- heteroaliphaticamino, mono- or di- alkylamino, mono- or diheteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two RX1groups taken together form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).L0907.70047WO00 22 / 150#14596547vl

[0081] The term “carbonyl” refers to a group wherein the carbon directly attached to the parent molecule is sp2hybridized, and is substituted with an oxygen, nitrogen or sulfur atom, e.g., a group selected from ketones (-C(=O)Raa), carboxylic acids (-CO2H), aldehydes (-CHO), esters (-CO2Raa, -C(=O)SRaa, -C(=S)SRaa), amides (-C(=O)N(Rbb)2, -C(=O)NRbbSO2Raa, -C(=S)N(Rbb)2), and imines (-C(=NRbb)Raa, -C(=NRbb)ORaa), -C(=NRbb)N(Rbb)2), wherein Raaand Rbbare as defined herein.

[0082] The term “silyl” refers to the group -Si(Raa)3, wherein Raais as defined herein.

[0083] The term “phosphino” refers to the group -P(RCC)2, wherein Rccis as defined herein.

[0084] The term “phosphono” refers to the group - (P=O)(ORCC)2, wherein Raaand Rccare as defined herein.

[0085] The term “phosphoramido” refers to the group -O(P=O)(N(Rbb)2)2, wherein each Rbbis as defined herein.

[0086] The term “oxo” refers to the group =0, and the term “thiooxo” refers to the group =S.

[0087] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, -OH, -ORaa, -N(RCC)2, -CN, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRbb)Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, -P(=O)(ORCC)2, -P(=O)(Raa)2, -P(=O)(N(RCC)2)2, C1-20 alkyl, C1-20 perhaloalkyl, C1-20 alkenyl, C1-20 alkynyl, hetero C1-20 alkyl, hetero C1-20 alkenyl, hetero C1-20 alkynyl, C3 10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, or two Rccgroups attached to an N atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined above.

[0088] In some embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -C(=O)Raa, -COoR", -C(=O)N(Rbb)2, or a nitrogen protecting group. In some embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, -C(=O)Raa, -COoR", -C(=O)N(Rbb)2, or a nitrogen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or a nitrogen protecting group. In some embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl or a nitrogen protecting group.

[0089] In some embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include -OH, -ORaa, -N(RCC)2, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRcc)Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, C no alkyl (e.g., aralkyl, heteroaralkyl), C1-20 alkenyl, C1-20 alkynyl, hetero C1-20 alkyl,L0907.70047WO00 23 / 150#14596547vlhetero C1-20 alkenyl, hetero C1-20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0090] For example, in some embodiments, at least one nitrogen protecting group is an amide group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., -C(=O)Raa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N’-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acety 1 methionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0091] In some embodiments, at least one nitrogen protecting group is a carbamate group (e.g., a moiety that includes the nitrogen atom to which the nitrogen protecting groups (e.g., -C(=O)ORaa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fhioroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), l-(l-adamantyl)-l -methylethyl carbamate (Adpoc), l,l-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), l,l-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-l-(4-biphenylyl)ethyl carbamate (Bpoc), l-(3,5-di-t-butylphenyl)-l-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4z-pyridyl)ethyl carbamate (Pyoc), 2-(N, N-dicyclohexylcarboxamido)ethyl carbamate, / -butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1 -isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9 -anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(l,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2- L0907.70047WO00 24 / 150#14596547vlphosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), l,l-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3, 5 -dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, / -amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(A, A-dimethylcarboxamido)benzyl carbamate, 1, 1 -diinethyl-3-(' / V, / V-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p’-methoxyphenylazo)benzyl carbamate, 1 -methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1 -methyl- 1 -cyclopropylmethyl carbamate, 1 -methyl- 1 -(3,5-dimethoxyphenyl)ethyl carbamate, 1 -methyl- l-(p-phenylazophenyl)ethyl carbamate, 1 -methyl- 1-phenylethyl carbamate, 1 -methyl- l-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0092] In some embodiments, at least one nitrogen protecting group is a sulfonamide group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., -S(=O)2Raa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of -toliienesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), P-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 444', 8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0093] In some embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of phenothiazinyl-(10)-acyl derivatives, A’-p-toluenesulfonylaminoacyl derivatives, N’-phenylaminothioacyl derivatives, A-benzoylphenylalanyl derivatives, acety 1 methionine derivatives, 4.5-diphenyl-3-oxazolin-2-one, ^-phthalimide, A-dithiasuccinimide (Dts), A-2,3-diphenylmaleimide, N- 2.5 -dimethylpyrrole, AM,l,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-l,3,5-triazacyclohexan-2-one, 5-substituted l,3-dibenzyl-l,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, A-methylamine, A-allylamine, A-[2-(trimethylsilyl)ethoxy]methylamine (SEM), A-3-acetoxypropylamine, A-(l-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, A-benzylamine, A-di(4-methoxyphenyl)methylamine, L0907.70047WO00 25 / 150#14596547vlX-5-dibenzosuberylamine, X-triphenylmethylamine (Tr), W[(4-methoxyphenyl)diphenylmethyl ]amine (MMTr), W9-phenylfluorenylamine (PhF), W2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fem), X-2-picolylamino X'-oxide, N- 1,1 -dimethylthiomethyleneamine, N-benzylideneamine, / V-p-methoxybenzylideneamine, / V-diphenylmethyleneamine, W[(2-pyridyl)mesityl]methyleneamine, W(W, -dimethylaminomethylene)amine, IV-p-nitrobenzylideneamine, IV-salicylideneamine, N-5 -chlorosalicylideneamine, iV-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, X-cycl ohexy 1 ide neami ne, N-(5,5 -dimethyl-3-oxo- 1 -cyclohexenyl)amine, X-borane derivatives, AMiphenylborinic acid derivatives, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, IV-copper chelate, X-zinc chelate, X-nitroamine, N-nitrosoamine, amine X-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys). In some embodiments, two instances of a nitrogen protecting group together with the nitrogen atoms to which the nitrogen protecting groups are attached are N, N’ -isopropyl idenediamine.

[0094] In some embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0095] In some embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or an oxygen protecting group. In some embodiments, each oxygen atom substituents is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or an oxygen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, or a nitrogen protecting group. In some embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl or an oxygen protecting group.

[0096] In some embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”). Oxygen protecting groups include -Raa, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=O)Raa, -SO2Raa, -Si(Raa)3, -P(RCC)2, -P(RCC)3+X-, -P(ORCC)2, -P(ORCC)3+X’, -P(=O)(Raa)2, -P(=O)(ORCC)2, and -P(=O)(N(Rbb) 2)2, wherein X", Raa, Rbb, and Rccare as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0097] In some embodiments, each oxygen protecting group, together with the oxygen atom to which the oxygen protecting group is attached, is selected from the group consisting of methyl, methoxymethylL0907.70047WO00 26 / 150#14596547vl(MOM), methylthiomethyl (MTM), / -butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM),p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), / -butoxy methyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3 -bromotetrahydropyranyl, tetrahydrothiopyranyl, 1 -methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S, S-dioxide, l-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), l,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, l-(2-chloroethoxy)ethyl, 1 -methyl- 1 -methoxyethyl, 1 -methyl- 1 -benzyloxyethyl, 1 -methyl- 1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, / -butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl A-oxido, diphenylmethyl, p,p’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, a-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4’-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4', 4"-tris(levulinoyloxyphenyl)methyl, 4,4',4"-tris(benzoyloxyphenyl)methyl, 4,4’-Dimethoxy-3"’-[N-(imidazolylmethyl) Jtrityl Ether (IDTr-OR), 4,4’-Dimethoxy-3"’-[N-(imidazolylethyl)carbamoyl]trityl Ether (lETr-OR), l,l-bis(4-methoxyphenyl)-l'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, l,3-benzodithiolan-2-yl, benzisothiazolyl S, S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, / -butyldimethylsilyl (TBDMS), / -butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), / -butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, / -butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-l-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate (MTMEC-OR), 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-( 1, 1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(l, 1 -L0907.70047WO00 27 / 150#14596547vldimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, a-naphthoate, nitrate, alkyl N, N, N’, N’-tetramethylphosphorodiamidate, alkyl A-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0098] In some embodiments, at least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, / -Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.

[0099] In some embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a sulfur protecting group. In some embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a sulfur protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, or a nitrogen protecting group. In some embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl or a sulfur protecting group.

[0100] In some embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). In some embodiments, each sulfur protecting group is selected from the group consisting of -Raa, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=O)Raa, -SO2Raa, -Si(Raa)3, -P(RCC)2, -P(RCC)3+X-, -P(ORCC)2, -P(ORCC)3+X“, -P(=O)(Raa)2, -P(=O)(ORCC)2, and -P(=O)(N(Rbb) 2)2, wherein R", Rbb, and Rccare as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0101] In some embodiments, the molecular weight of a substituent is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g / mol. In some embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In some embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen atoms. In some embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In some embodiments, a substituent consists of carbon, hydrogen, fluorine, and / or chlorine atoms. In some embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond donors. In some embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond acceptors.

[0102] A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be monovalent (e.g., including one formal negative charge). An anionic counterion may also be multi valent (e.g., including more than one formal negative charge), such as divalent or tri valent. Exemplary counterions include halide ions (e.g., F“, CP, Br, I"), NO3", CIO4, OH", H2PO4, HCO3“, HSO4,L0907.70047WO00 28 / 150#14596547vlsulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-l-sulfonic acid-5-sulfonate, ethan-1-sulfonic acid-2-sulfonate, and the like), carboxylate ions e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF, PF4, PFe, AsFe", SbFe", BU. S-iCFshCLHs hl, B(C6FS)4~, BPlu, A1(OC(CF3)3)4", and carborane anions (e.g., CB11H12" or (HCBi iMesBre) ). Exemplary counterions which may be multivalent include CO32", HPCL2", PCL3", B4O72", SCL2", S2O32", carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.

[0103] A “leaving group” (LG) is an art-understood term referring to an atomic or molecular fragment that departs with a pair of electrons in heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule. As used herein, a leaving group can be an atom or a group capable of being displaced by a nucleophile. See e.g., Smith, March Advanced Organic Chemistry 6th ed. (501-502). Exemplary leaving groups include, but are not limited to, halo (e.g., fluoro, chloro, bromo, iodo) and activated substituted hydroxyl groups (e.g., -OC(=O)SRaa, -OC(=O)Raa, -OCO2Raa, -OC(=O)N(Rbb)2, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -OC(=NRbb)N(Rbb)2, -OS(=O)Raa, -OSO2Raa, -OP(RCC)2, -OP(RCC)3, -OP(=O)2Raa, -OP(=O)(Raa)2, -OP(=O)(ORCC)2, -OP(=O)2N(Rbb)2, and -OP(=O)(NRbb)2, wherein Raa, Rbb, and Rccare as defined herein). Additional examples of suitable leaving groups include, but are not limited to, halogen alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, A,( -dimethylhydroxylamino, pixyl, and haloformates. In some embodiments, the leaving group is a sulfonic acid ester, such as toluenesulfonate (tosylate, -OTs), methanesulfonate (mesylate, -OMs), p-bromobenzenesulfonyloxy (brosylate, -OBs), -OS(=O)2(CF2)3CF3(nonaflate, -ONf), or trifluoromethanesulfonate (triflate, -OTf). In some embodiments, the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy. In some embodiments, the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy. In some embodiments, the leaving group is a sulfonate-containing group. In some embodiments, the leaving group is a tosylate group. In some embodiments, the leaving group is a phosphineoxide (e.g., formed during a Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate. Other non-limiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties.

[0104] Use of the phrase “at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.

[0105] A “non-hydrogen group” refers to any group that is defined for a particular variable that is not hydrogen.

[0106] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The invention is not limited in any manner by the above exemplary listing of substituents.L0907.70047WO00 29 / 150#14596547vl

[0107] As used herein, the term “salt” refers to any and all salts and encompasses pharmaceutically acceptable salts. The term “salt” refers to ionic compounds that result from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge). Salts of the compounds of this disclosure include those derived from inorganic and organic acids and bases.Examples of acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-tol uenesulfonate, undecanoate, valerate, hippurate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and NTCi 4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0108] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate,L0907.70047WO00 30 / 150#14596547vlpropionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and NTCi 4 al ky 1)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0109] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.”

[0110] Stereoisomers that are not mirror images of one another are termed “diastereomers,” and those that are non-superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture.”

[0111] The terms “pharmaceutical composition,” “composition,” and “formulation” are used interchangeably.

[0112] A “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In some embodiments, the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In some embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be a male or female at any stage of development. The non-human animal may be a transgenic animal or genetically engineered animal. The term “patient” refers to a human subject in need of treatment of a disease.

[0113] The term “biological sample” refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise). Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.L0907.70047WO00 31 / 150#14596547vl

[0114] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a pharmaceutical composition thereof, in or on a subject.

[0115] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0116] The term “prevent,” “preventing,” or “prevention” refers to a prophylactic treatment of a subject who is not and was not with a disease but is at risk of developing the disease or who was with a disease, is not with the disease, but is at risk of regression of the disease. In some embodiments, the subject is at a higher risk of developing the disease or at a higher risk of regression of the disease than an average healthy member of a population. In some embodiments, the subject is at risk of developing a disease or condition due to environmental factors (e.g., exposure to the sun).

[0117] An “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, severity of side effects, disease, or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular compound, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age and health or general condition of the subject. In some embodiments, an effective amount is a therapeutically effective amount. In some embodiments, an effective amount is a prophylactic treatment. In some embodiments, an effective amount is the amount of a compound described herein in a single dose. In some embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses. In some embodiments, the desired dosage is delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In some embodiments, the desired dosage is delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations). In some embodiments, an effective amount is an amount sufficient for modulating mitochondrial function in a subject in need thereof or in a cell, tissue, or biological sample. In some embodiments, an effective amount is an amount sufficient for reducing reactive oxygen species levels in a subject in need thereof or in a cell, tissue, or biological sample. In some embodiments, an effective amount is an amount sufficient for reducing pro-inflammatory signaling in a subject in need thereof or in a cell, tissue, or biological sample. In some embodiments, an effective amount is an amount sufficient for preventing or inhibiting cellular senescence in a subject in need thereof or in a cell, tissue, or biological sample.

[0118] In some embodiments, an effective amount of a compound for administration one or more timesL0907.70047WO00 32 / 150#14596547vla day to a 70 kg adult human comprises about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.

[0119] It will be appreciated that dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

[0120] A “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and / or enhances the therapeutic efficacy of another therapeutic agent. In some embodiments, a therapeutically effective amount is an amount sufficient for treating an age-related disease or disorder associated with glutaminase-1 (GLS1) (e.g., a metabolic disorder associated with ageing (e.g., obesity, diabetes, a liver disease (e.g., non-alcoholic fatty liver disease)), adipose tissue dysfunction, muscular atrophy (e.g., muscle wasting, such as age-related muscular atrophy, frailty, etc.), organ dysfunction associated with ageing (e.g. lung fibrosis, etc.), a cardiovascular disease (e.g., atherosclerosis)) in a subject in need thereof. In some embodiments, a therapeutically effective amount is an amount sufficient for modulating mitochondrial function in a subject in need thereof. In some embodiments, a therapeutically effective amount is an amount sufficient for reducing reactive oxygen species levels in a subject in need thereof. In some embodiments, a therapeutically effective amount is an amount sufficient for reducing pro-inflammatory signaling in a subject in need thereof. In some embodiments, a therapeutically effective amount is an amount sufficient for preventing or inhibiting cellular senescence in a subject in need thereof.

[0121] A “prophylactically effective amount” of a compound is an amount sufficient to prevent a condition, or one or more signs and / or symptoms associated with the condition or prevent its recurrence. In some embodiments, the prophylactically effective amount is an amount that improves overall prophylaxis and / or enhances the prophylactic efficacy of another prophylactic agent. In some embodiments, a prophylactically effective amount is an amount sufficient for preventing an age-related disease or disorder associated with glutaminase-1 (GLS1) (e.g., a metabolic disorder associated with ageing (e.g., obesity, diabetes, a liver disease (e.g., non-alcoholic fatty liver disease)), adipose tissue dysfunction, muscular atrophy (e.g., muscle wasting, such as age-related muscular atrophy, frailty, etc.), organ dysfunction associated with ageing (e.g. lung fibrosis, etc.), a cardiovascular disease (e.g., atherosclerosis)) in a subject in need thereof. In some embodiments, a prophylactically effective amount is an amount effective for reducing the risk of developing an age-related disease or disorder associatedL0907.70047WO00 33 / 150#14596547vlwith GLS1 (e.g., a metabolic disorder associated with ageing (e.g., obesity, diabetes, a liver disease (e.g., non-alcoholic fatty liver disease)), adipose tissue dysfunction, muscular atrophy (e.g., muscle wasting, such as age-related muscular atrophy, frailty, etc.), organ dysfunction associated with ageing (e.g. lung fibrosis, etc.), a cardiovascular disease (e.g., atherosclerosis)) in a subject in need thereof. In some embodiments, a prophylactically effective amount is an amount sufficient for modulating mitochondrial function in a subject in need thereof. In some embodiments, a prophylactically effective amount is an amount sufficient for reducing reactive oxygen species levels in a subject in need thereof. In some embodiments, a prophylactically effective amount is an amount sufficient for reducing pro-inflammatory signaling in a subject in need thereof. In some embodiments, a prophylactically effective amount is an amount sufficient for preventing or inhibiting cellular senescence in a subject in need thereof.DETAILED DESCRIPTION OF SOME EMBODIMENTS

[0122] Aspects of the disclosure are based on compositions and methods for treating age-related diseases or disorders associated with dysregulated glutamine levels associated with a glutaminase (GLS1) protein. In some embodiments, the age-related disease or disorder is obesity, diabetes, a liver disease (e.g., non-alcoholic fatty liver disease), adipose tissue dysfunction, muscular atrophy (e.g., muscle wasting, such as age-related muscular atrophy, frailty, etc.), or a cardiovascular disease (e.g., atherosclerosis). Further aspects of the disclosure are based on peripheral delivery of compounds and / or compositions that reduce GLS1 activity or protein levels.

[0123] Glutaminase is a mitochondrial enzyme that transforms glutamine into glutamate through glutaminolysis. There are two different types of glutaminase: “kidney-type” (also referred to as “GLS1”), and “liver-type” (also referred to as GLS2), although both types are expressed in CNS (e.g., brain) tissue. In some embodiments, a glutaminase protein is a GLS1 glutaminase protein.

[0124] Excessive glutaminolysis is associated with accelerated aging. For example, ammonia, a byproduct of glutaminolysis, generates reactive oxygen species (ROS), causing nitrosative / oxidative stress. Excessive glutamate can also cause toxicity intracellularly (oxidative stress) or through signaling receptors. Further, excessive glutaminolysis can contribute to aging by, for example: leading to a hypermetabolic state which can lead to mitochondrial defects and dysfunction; generating ammonia which causes toxic oxidative / nitrosative stress; allowing senescent cells to accumulate; and activating immune cells to a pro-inflammatory phenotype, which leads to systemic inflammation. Excessive glutaminolysis may also contribute to organ dysfunction associated with ageing (e.g., lung fibrosis).

[0125] Aspects of the disclosure relate to the inventors’ recognition that certain small molecule glutaminase inhibitors can be administered to decrease glutamate levels, increase glutamine levels, modulate dysregulated mitochondrial function (e.g., metabolic dysfunction, such as by improving mitochondrial respiration), reduce oxidative stress (e.g., by reducing levels of reactive oxygen species (ROS)), reduce the number of senescent cells in a target tissue, and / or reduce pro-inflammatory signaling (e.g., by reducing cytokine production) in a subject.

[0126] The aspects described herein are not limited to specific embodiments, systems, compositions,L0907.70047WO00 34 / 150#14596547vlmethods, or configurations, and as such can, of course, vary. The terminology used herein is for the purpose of describing particular aspects only and, unless specifically defined herein, is not intended to be limiting.Methods of Treatment and Prevention

[0127] In one aspect, the present disclosure provides a method of treating an age-related disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof:a therapeutically effective amount of a compound of Formula (I):R- Z= / N(I),or a pharmaceutically acceptable salt thereof; ora pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and an excipient; wherein:R1is optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;R2is hydrogen, optionally substituted alkyl, -ORA, or -N(RA)2;Z is CR3AorN;each occurrence of RYis independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, =0, =S, -CN, -0RA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -N02, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=0)N(RA)2, -C(=NRA)RA, -C(=NRA)0RA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -0C(=0)N(RA)2, -0C(=NRA)RA, -0C(=NRA)0RA, -OC(=NRA)SRA, -0C(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -0N(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=0)RA, -NRAC(=0)0RA, -NRAC(=O)SRA, -NRAC(=0)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)0RA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=0)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, — Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORa)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(0RA)2; each of R3A, R3Band R3Cis independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted L0907.70047WO00 35 / 150#14596547vlheteroaryl, -CN, -ORA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, — Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORa)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(ORA)2; each occurrence of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; andn is 0, 1, 2, 3, 4, 5, 6, or 7.

[0128] In some embodiments, the method comprises administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0129] In some embodiments, the method comprises administering to the subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and an excipient.

[0130] In another aspect, the present disclosure provides a method of treating an age-related disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I):R- Z= / N(I),or a pharmaceutically acceptable salt thereof, wherein:R1is optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;R2is hydrogen, optionally substituted alkyl, -ORA, or -N(RA)2;L0907.70047WQ00 36 / 150#14596547vlZ is CR3AorN;each occurrence of RYis independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, =0, =S, -CN, -ORA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=0)RA, -C(=0)0RA, -C(=O)SRA, -C(=0)N(RA)2, -C(=NRA)RA, -C(=NRA)0RA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -0C(=0)RA, -0C(=0)0RA, -OC(=O)SRA, -0C(=0)N(RA)2, -0C(=NRA)RA, -0C(=NRA)0RA, -OC(=NRA)SRA, -0C(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -0N(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=0)RA, -NRAC(=0)0RA, -NRAC(=O)SRA, -NRAC(=0)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)0RA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=0)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORa)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(0RA)2; each of R3A, R3Band R3Cis independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -ORA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=0)RA, -C(=0)0RA, -C(=O)SRA, -C(=0)N(RA)2, -C(=NRA)RA, -C(=NRA)0RA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -0C(=0)RA, -0C(=0)0RA, -OC(=O)SRA, -0C(=0)N(RA)2, -0C(=NRA)RA, -0C(=NRA)0RA, -OC(=NRA)SRA, -0C(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -0N(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=0)RA, -NRAC(=0)0RA, -NRAC(=O)SRA, -NRAC(=0)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)0RA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=0)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORa)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(0RA)2; each occurrence of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygenL0907.70047WO00 37 / 150#14596547vlprotecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; andn is 0, 1, 2, 3, 4, 5, 6, or 7.

[0131] In another aspect, the present disclosure provides a method of treating an age-related disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I):R- Z= / N(I),or a pharmaceutically acceptable salt thereof, and an excipient, wherein:R1is optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;R2is hydrogen, optionally substituted alkyl, -ORA, or -N(RA)2;Z is CR3AorN;each occurrence of RYis independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, =0, =S, -CN, -0RA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=0)N(RA)2, -C(=NRA)RA, -C(=NRA)0RA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=0)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -0C(=0)RA, -0C(=0)0RA, -OC(=O)SRA, -0C(=0)N(RA)2, -0C(=NRA)RA, -0C(=NRA)0RA, -0C(=NRA)SRA, -0C(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -0S(=0)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -0N(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)0RA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=0)RA, -NRAC(=0)0RA, -NRAC(=0)SRA, -NRAC(=0)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)0RA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=0)RA, -NRAS(=0)0RA, -NRAS(=O)SRA, -NRAS(=0)N(RA)2, -NRAS(=0)2RA, -NRAS(=0)20RA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, — Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORa)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(0RA)2; each of R3A, R3Band R3Cis independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -0RA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA,L0907.70047WO00 38 / 150#14596547vl-C(=O)SRA, -C(=0)N(RA)2, -C(=NRA)RA, -C(=NRA)0RA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -0C(=0)N(RA)2, -0C(=NRA)RA, -0C(=NRA)0RA, -OC(=NRA)SRA, -0C(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -0N(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=0)RA, -NRAC(=0)0RA, -NRAC(=O)SRA, -NRAC(=0)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)0RA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, — Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORa)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(ORA)2; each occurrence of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; andn is 0, 1, 2, 3, 4, 5, 6, or 7.

[0132] In another aspect, the present disclosure provides a method of preventing an age-related disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof:a prophylactically effective amount of a compound of Formula (I):N(I),or a pharmaceutically acceptable salt thereof; ora pharmaceutical composition comprising a prophylactically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and an excipient; wherein:R1is optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;R2is hydrogen, optionally substituted alkyl, -ORA, or -N(RA)2;Z is CR3AorN;each occurrence of RYis independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, =0, =S,L0907.70047WO00 39 / 150#14596547vl-CN, -ORA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, — Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORa)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(ORA)2; each of R3A, R3Band R3Cis independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -ORA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, — Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORa)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(ORA)2; each occurrence of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; andn is 0, 1, 2, 3, 4, 5, 6, or 7.

[0133] In some embodiments, the method comprises administering to the subject in need thereof aL0907.70047WO00 40 / 150#14596547vlprophylactically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0134] In some embodiments, the method comprises administering to the subject in need thereof a pharmaceutical composition comprising a prophylactically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and an excipient.

[0135] In another aspect, the present disclosure provides a method of preventing an age-related disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof a prophylactically effective amount of a compound of Formula (I):N(I),or a pharmaceutically acceptable salt thereof, wherein:R1is optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;R2is hydrogen, optionally substituted alkyl, -ORA, or -N(RA)2;Z is CR3AorN;each occurrence of RYis independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, =0, =S, -CN, -0RA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=0)N(RA)2, -C(=NRA)RA, -C(=NRA)0RA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=0)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -0C(=0)RA, -0C(=0)0RA, -OC(=O)SRA, -0C(=0)N(RA)2, -0C(=NRA)RA, -0C(=NRA)0RA, -0C(=NRA)SRA, -0C(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -0S(=0)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -0N(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)0RA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=0)RA, -NRAC(=0)0RA, -NRAC(=0)SRA, -NRAC(=0)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)0RA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=0)RA, -NRAS(=0)0RA, -NRAS(=O)SRA, -NRAS(=0)N(RA)2, -NRAS(=0)2RA, -NRAS(=0)20RA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, — Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORa)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(0RA)2; each of R3A, R3Band R3Cis independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -0RA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA,L0907.70047WO00 41 / 150#14596547vl-C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORa)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(ORA)2; each occurrence of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; andn is 0, 1, 2, 3, 4, 5, 6, or 7.

[0136] In another aspect, the present disclosure provides a method of preventing an age-related disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof a pharmaceutical composition comprising a prophylactically effective amount of a compound of Formula (I): HEIGHT="76" WIDTH="246" SRC="imgf000042_0001.tif" / >or a pharmaceutically acceptable salt thereof, and an excipient, wherein:R1is optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;R2is hydrogen, optionally substituted alkyl, -ORA, or -N(RA)2;Z is CR3AorN;each occurrence of RYis independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, =0, =S, -CN, -ORA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA,L0907.70047WO00 42 / 150#14596547vl-C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORa)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(ORA)2; each of R3A, R3Band R3Cis independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -ORA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, — Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORa)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(ORA)2; each occurrence of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; andn is 0, 1, 2, 3, 4, 5, 6, or 7.

[0137] In some embodiments, the compound of Formula (I) is of Formula (I-a):L0907.70047WO00 43 / 150#14596547vlor a pharmaceutically acceptable salt thereof.

[0138] In another aspect, the present disclosure provides a method of treating an age-related disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula:or a pharmaceutically acceptable salt thereof.

[0139] In another aspect, the present disclosure provides a method of preventing an age-related disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof a prophylactically effective amount of a compound of formula:or a pharmaceutically acceptable salt thereof.

[0140] In another aspect, the present disclosure provides a method of treating an age-related disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula:or a pharmaceutically acceptable salt thereof.

[0141] In another aspect, the present disclosure provides a method of preventing an age-related disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof aL0907.70047WO00 44 / 150#14596547vlpharmaceutical composition comprising a prophylactically effective amount of a compound of formula:or a pharmaceutically acceptable salt thereof.

[0142] In another aspect, the present disclosure provides a method of treating an age-related disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula:or a pharmaceutically acceptable salt thereof.

[0143] In another aspect, the present disclosure provides a method of preventing an age-related disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof a prophylactically effective amount of a compound of formula:or a pharmaceutically acceptable salt thereof.

[0144] In another aspect, the present disclosure provides a method of treating an age-related disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula:or a pharmaceutically acceptable salt thereof.

[0145] In another aspect, the present disclosure provides a method of preventing an age-related disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof aL0907.70047WO00 45 / 150#14596547vlpharmaceutical composition comprising a prophylactically effective amount of a compound of formula:or a pharmaceutically acceptable salt thereof.

[0146] In another aspect, the present disclosure provides a method of treating an age-related disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula:or a pharmaceutically acceptable salt thereof.

[0147] In another aspect, the present disclosure provides a method of preventing an age-related disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof a prophylactically effective amount of a compound of formula:or a pharmaceutically acceptable salt thereof.

[0148] In another aspect, the present disclosure provides a method of treating an age-related disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula:or a pharmaceutically acceptable salt thereof.

[0149] In another aspect, the present disclosure provides a method of preventing an age-related disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof aL0907.70047WO00 46 / 150#14596547vlpharmaceutical composition comprising a prophylactically effective amount of a compound of formula:or a pharmaceutically acceptable salt thereof.

[0150] In another aspect, the present disclosure provides a method of treating an age-related disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula:or a pharmaceutically acceptable salt thereof.

[0151] In another aspect, the present disclosure provides a method of preventing an age-related disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof a prophylactically effective amount of a compound of formula:or a pharmaceutically acceptable salt thereof.

[0152] In another aspect, the present disclosure provides a method of treating an age-related disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula:or a pharmaceutically acceptable salt thereof.

[0153] In another aspect, the present disclosure provides a method of preventing an age-related disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof aL0907.70047WO00 47 / 150#14596547vlpharmaceutical composition comprising a prophylactically effective amount of a compound of formula:N-Nor a pharmaceutically acceptable salt thereof.

[0154] In some embodiments, the method comprises administering to the subject an additional pharmaceutical agent. In some embodiments, the additional pharmaceutical agent is an antiepileptic agent (e.g., a benzodiazepine; a barbiturate; a GABAergic agent (e.g., valproate, vigabatrin); an ion channel modulator (e.g., phenytoin, carbamazepine, topiramate, gabapentin, ethosuximide, lamotrigine, lacosamide, zonisamide); a neurotransmitter release modulator (e.g., levetiracetam); a glutamate receptor modulator (e.g., perampanel)); an mTOR inhibitor (e.g., everolimus); an antipsychotic agent (e.g., a typical antipsychotic agent (e.g., chlorpromazine, haloperidol, fluphenazine); an atypical antipsychotic agent (e.g., risperidone, olanzapine, aripiprazole, quetiapine, lurasidone, lumateperone); a non-dopaminergic antipsychotic agent (e.g., pimavanserin)); a primary antidepressant agent (e.g., a tricyclic antidepressant (e.g., amitriptyline, imipramine); a selective serotonin reuptake inhibitor (SSRI) (e.g., fluoxetine, citalopram), a serotonin and norepinephrine reuptake inhibitor (SNRI) (e.g., venlafaxine, duloxetine, milnacipran); a monoamine oxidase inhibitor (MAOI) (e.g., phenylzine, selegiline); an other antidepressant agent (e.g., vortioxetine, trazodone, vilazodone, mirtazapine); an N-methyl-D-aspartate receptor antagonist (NMD AR antagonist) (e.g., esketamine)); an adjunctive antidepressant agent (e.g., a typical antipsychotic agent (e.g., chlorpromazine, haloperidol, fluphenazine); an atypical antipsychotic¬ agent (e.g., risperidone, olanzapine, aripiprazole, quetiapine, lurasidone, lumateperone); a non-dopaminergic antipsychotic agent (e.g., pimavanserin)); or a mood stabilizer (e.g., lithium; an antiepileptic mood stabilizer (AED) (e.g., lamotrigine, topiramate, valproate)).

[0155] In some embodiments, the age-related disease or disorder is associated with the glutamate pathway. In some embodiments, the age-related disease or disorder is associated with glutaminase- 1 (GLS1).

[0156] In some embodiments, the age-related disease or disorder is a metabolic disorder associated with ageing (e.g., obesity, diabetes, a liver disease (e.g., non-alcoholic fatty liver disease)), adipose tissue dysfunction, muscular atrophy (e.g., muscle wasting, such as age-related muscular atrophy, frailty, etc.), organ dysfunction associated with ageing (e.g. lung fibrosis, etc.), or a cardiovascular disease (e.g., atherosclerosis).

[0157] In some embodiments, the age-related disease or disorder is a metabolic disorder associated with ageing (e.g., obesity, diabetes, a liver disease (e.g., non-alcoholic fatty liver disease)). In some embodiments, the age-related disease or disorder is obesity, diabetes, or a liver disease (e.g., nonalcoholic fatty liver disease). In some embodiments, the age-related disease or disorder is obesity. In some embodiments, the age-related disease or disorder is diabetes. In some embodiments, the age-related L0907.70047WO00 48 / 150#14596547vldisease or disorder is a liver disease (e.g., non-alcoholic fatty liver disease). In some embodiments, the age-related disease or disorder is non-alcoholic fatty liver disease.

[0158] In some embodiments, the age-related disease or disorder is adipose tissue dysfunction.

[0159] In some embodiments, the age-related disease or disorder is muscular atrophy (e.g., muscle wasting, age-related muscular atrophy, or frailty). In some embodiments, the age-related disease or disorder is muscle wasting, age-related muscular atrophy, or frailty. In some embodiments, the age-related disease or disorder is muscle wasting. In some embodiments, the age-related disease or disorder is age-related muscular atrophy. In some embodiments, the age-related disease or disorder is frailty.

[0160] In some embodiments, the age-related disease or disorder is organ dysfunction associated with ageing (e.g. lung fibrosis, etc.). In some embodiments, the age-related disease or disorder is lung fibrosis.

[0161] In some embodiments, the age-related disease or disorder is a cardiovascular disease (e.g., atherosclerosis). In some embodiments, the age-related disease or disorder is atherosclerosis.

[0162] In some embodiments, the subject does not comprise one or more mutations in a gene associated with glutamate signaling. In some embodiments, a subject does not have a mutation in a GLS1 gene (i.e., the subject has wild type GLS1 protein). In some embodiments, the subject comprises one or more mutations in a gene that is associated with glutamate signaling. In some embodiments, the subject has a mutation in a GLS1 gene, in some embodiments, a GLS1 gene (or an mRNA encoded by a GLS1 gene) comprises one or more nucleotide substitutions, one or more nucleotide insertions, and / or one or more nucleotide deletions relative to a wild type GLS1 gene (or mRNA encoded by a wild type GLS1 gene), and may be referred to as a “mutant” GLS1 gene or a GLS1 variant. The number of nucleotide substitutions, nucleotide insertions, and / or nucleotide deletions in a GLS1 variant may vary. In some embodiments, a GLS1 variant comprises between 1 and 20, 5 and 10, 2 and 15, 10 and 30, or 20 and 100 nucleotide substitutions, nucleotide insertions, and / or nucleotide deletions relative to a wild type GLS1 gene (or mRNA encoded by a wild type GLS1 gene). In some embodiments, the one or more nucleotide substitutions, one or more nucleotide insertions, and / or one or more nucleotide deletions results in an amino acid substitution in the protein encoded by the GLS1 variant. In some embodiments, the subject is a human subject.

[0163] In some embodiments, the subject has or is suspected of having an age-related disease or disorder.

[0164] In some embodiments, the subject has or is suspected of having a metabolic disorder associated with ageing (e.g., obesity, diabetes, a liver disease (e.g., non-alcoholic fatty liver disease)), adipose tissue dysfunction, muscular atrophy (e.g., muscle wasting, such as age-related muscular atrophy, frailty, etc.), organ dysfunction associated with ageing (e.g. lung fibrosis, etc.), or a cardiovascular disease (e.g., atherosclerosis).

[0165] In some embodiments, the subject has or is suspected of having a metabolic disorder associated with ageing (e.g., obesity, diabetes, a liver disease (e.g., non-alcoholic fatty liver disease)). In some embodiments, the subject has or is suspected of having obesity, diabetes, or a liver disease (e.g., nonalcoholic fatty liver disease). In some embodiments, the subject has or is suspected of having obesity. InL0907.70047WO00 49 / 150#14596547vlsome embodiments, the subject has or is suspected of having diabetes. In some embodiments, the subject has or is suspected of having a liver disease (e.g., non-alcoholic fatty liver disease). In some embodiments, the subject has or is suspected of having non-alcoholic fatty liver disease.

[0166] In some embodiments, the subject has or is suspected of having adipose tissue dysfunction.

[0167] In some embodiments, the subject has or is suspected of having muscular atrophy (e.g., muscle wasting, age-related muscular atrophy, or frailty). In some embodiments, the subject has or is suspected of having muscle wasting, age-related muscular atrophy, or frailty. In some embodiments, the subject has or is suspected of having muscle wasting. In some embodiments, the subject has or is suspected of having age-related muscular atrophy. In some embodiments, the subject has or is suspected of having frailty.

[0168] In some embodiments, the subject has or is suspected of having organ dysfunction associated with ageing (e.g. lung fibrosis, etc.). In some embodiments, the subject has or is suspected of having lung fibrosis.

[0169] In some embodiments, the subject has or is suspected of having a cardiovascular disease (e.g., atherosclerosis). In some embodiments, the subject has or is suspected of having atherosclerosis.

[0170] In some embodiments, the subject is at risk for or is suspected of being at risk for an age-related disease or disorder.

[0171] In some embodiments, the subject is at risk for or is suspected of being at risk for a metabolic disorder associated with ageing (e.g., obesity, diabetes, a liver disease (e.g., non-alcoholic fatty liver disease)), adipose tissue dysfunction, muscular atrophy (e.g., muscle wasting, such as age-related muscular atrophy, frailty, etc.), organ dysfunction associated with ageing (e.g. lung fibrosis, etc.), or a cardiovascular disease (e.g., atherosclerosis).

[0172] In some embodiments, the subject is at risk for or is suspected of being at risk for a metabolic disorder associated with ageing (e.g., obesity, diabetes, a liver disease (e.g., non-alcoholic fatty liver disease)). In some embodiments, the subject is at risk for or is suspected of being at risk for obesity, diabetes, or a liver disease (e.g., non-alcoholic fatty liver disease). In some embodiments, the subject is at risk for or is suspected of being at risk for obesity. In some embodiments, the subject is at risk for or is suspected of being at risk for diabetes. In some embodiments, the subject is at risk for or is suspected of being at risk for a liver disease (e.g., non-alcoholic fatty liver disease). In some embodiments, the subject is at risk for or is suspected of being at risk for non-alcoholic fatty liver disease.

[0173] In some embodiments, the subject is at risk for or is suspected of being at risk for adipose tissue dysfunction.

[0174] In some embodiments, the subject is at risk for or is suspected of being at risk for muscular atrophy (e.g., muscle wasting, age-related muscular atrophy, or frailty). In some embodiments, the subject is at risk for or is suspected of being at risk for muscle wasting, age-related muscular atrophy, or frailty. In some embodiments, the subject is at risk for or is suspected of being at risk for muscle wasting. In some embodiments, the subject is at risk for or is suspected of being at risk for age-related muscular atrophy. In some embodiments, the subject is at risk for or is suspected of being at risk for frailty.L0907.70047WO00 50 / 150#14596547vl

[0175] In some embodiments, the subject is at risk for or is suspected of being at risk for organ dysfunction associated with ageing (e.g. lung fibrosis, etc.). In some embodiments, the subject is at risk for or is suspected of being at risk for lung fibrosis.

[0176] In some embodiments, the subject is at risk for or is suspected of being at risk for a cardiovascular disease (e.g., atherosclerosis). In some embodiments, the subject is at risk for or is suspected of being at risk for atherosclerosis.

[0177] In some embodiments, the administration comprises peripheral administration. In some embodiments, the peripheral administration comprises intrathecal injection, subcutaneous injection, intramuscular injection or intravenous injection. In some embodiments, the peripheral administration comprises intrathecal injection. In some embodiments, the peripheral administration comprises subcutaneous injection. In some embodiments, the peripheral administration comprises intramuscular injection. In some embodiments, the peripheral administration comprises intravenous injection.

[0178] In some embodiments, the peripheral administration comprises direct administration to a target tissue, e.g., heart tissue, liver tissue, muscle tissue, or brain tissue. In some embodiments, the peripheral administration comprises direct administration to heart tissue, liver tissue, muscle tissue, or brain tissue. In some embodiments, the peripheral administration comprises direct administration to heart tissue. In some embodiments, the peripheral administration comprises direct administration to liver tissue. In some embodiments, the peripheral administration comprises direct administration to muscle tissue. In some embodiments, the peripheral administration comprises direct administration to brain tissue.Compounds of Formula (I)

[0179] In some embodiments, R1is optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R1is optionally substituted carbocyclyl or optionally substituted aryl. In some embodiments, R1is optionally substituted carbocyclyl or optionally substituted heteroaryl. In some embodiments, R1is optionally substituted aryl or optionally substituted heteroaryl.

[0180] In some embodiments, R1is optionally substituted carbocyclyl. In some embodiments, R1is optionally substituted, monocyclic carbocyclyl (e.g., optionally substituted, monocyclic, 3- to 10-membered carbocyclyl). In some embodiments, R1is optionally substituted, polycyclic carbocyclyl (e.g., optionally substituted, bicyclic or tricyclic, 3- to 14-membered carbocyclyl). In some embodiments, R1is optionally substituted saturated carbocyclyl. In some embodiments, R1is optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, optionally substituted cycloheptyl, optionally substituted cyclooctyl, optionally substituted cyclononyl, or optionally substituted cyclodecyl. In some embodiments, R1is optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl. In some embodiments, R1is optionally substituted cyclopropyl. In some embodiments, R1is optionally substituted cyclohexyl. In some embodiments, R1is substituted carbocyclyl. In some embodiments, R1is substituted saturated carbocyclyl. In some embodiments, R1is unsubstituted carbocyclyl. In some embodiments, R1is unsubstituted saturated carbocyclyl. In some L0907.70047WO00 51 / 150#14596547vlembodiments, R1is substituted cyclopropyl. In some embodiments, R1is substituted cyclohexyl. In some embodiments, R1is unsubstituted cyclopropyl. In some embodiments, R1is unsubstituted cyclohexyl.

[0181] In some embodiments, R1is optionally substituted aryl. In some embodiments, R1is optionally substituted C6-14 aryl. In some embodiments, R1is optionally substituted phenyl. In some embodiments, R1is unsubstituted phenyl. In some embodiments, R1is substituted phenyl. In some embodiments, R1is phenyl substituted with one or more of halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -ORA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORA)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, and / or -B(ORA)2groups. In some embodiments, R1is phenyl.

[0182] In some embodiments, R1is phenyl substituted with one or more of halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2. In some embodiments, R1is phenyl substituted with halogen. In some embodiments, R1is phenyl substituted with -F, -Cl, -Br, and / or -I. In some embodiments, R1is phenyl substituted with -F. In some embodiments, R1is phenyl substituted with -Cl.

[0183] In some embodiments, R1is phenyl substituted with optionally substituted alkyl. In some embodiments, R1is phenyl substituted with optionally substituted C1-12 alkyl. In some embodiments, R1is phenyl substituted with optionally substituted Ci-6 alkyl. In some embodiments, R1is phenyl substituted with unsubstituted Ci-6 alkyl. In some embodiments, R1is phenyl substituted with substituted Ci-6 alkyl. In some embodiments, R1is phenyl substituted with optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, optionally substituted isopropyl, optionally substituted n-butyl, optionally substituted tert-butyl, optionally substituted sec-butyl, optionally substituted isobutyl, optionally substituted n-pentyl, optionally substituted 3-pentanyl, optionally substituted amyl, optionally substituted neopentyl, optionally substituted 3-methyl-2-butanyl, optionally substituted tert-amyl, or optionally substituted n-hexyl. In some embodiments, R1is phenyl substituted with optionally substituted methyl. In some embodiments, R1is phenyl substituted with substituted methyl. In some embodiments, R1is phenyl substituted with unsubstituted methyl. In some embodiments, R1is phenyl substituted withL0907.70047WO00 52 / 150#14596547vloptionally substituted ethyl. In some embodiments, R1is phenyl substituted with substituted ethyl. In some embodiments, R1is phenyl substituted with unsubstituted ethyl. In some embodiments, R1is phenyl substituted with optionally substituted isopropyl. In some embodiments, R1is phenyl substituted with substituted isopropyl. In some embodiments, R1is phenyl substituted with unsubstituted isopropyl. In some embodiments, R1is phenyl substituted with optionally substituted tert-butyl. In some embodiments, R1is phenyl substituted with substituted tert-butyl. In some embodiments, R1is phenyl substituted with unsubstituted tert-butyl. In some embodiments, R1is phenyl substituted with methyl, ethyl, isopropyl, or tert-butyl.

[0184] In some embodiments, R1is phenyl substituted with optionally substituted alkyl substituted with at least one halogen. In some embodiments, R1is phenyl substituted with optionally substituted C1-12 alkyl substituted with at least one halogen. In some embodiments, R1is phenyl substituted with optionally substituted C1-6 alkyl substituted with at least one halogen. In some embodiments, R1is phenyl substituted with substituted C1-6 alkyl substituted with at least one halogen. In some embodiments, R1is phenyl substituted with optionally substituted methyl substituted with at least one halogen, optionally substituted ethyl substituted with at least one halogen, optionally substituted n-propyl substituted with at least one halogen, optionally substituted isopropyl substituted with at least one halogen, optionally substituted n-butyl substituted with at least one halogen, optionally substituted tert-butyl substituted with at least one halogen, optionally substituted sec-butyl substituted with at least one halogen, optionally substituted isobutyl substituted with at least one halogen, optionally substituted n-pentyl substituted with at least one halogen, optionally substituted 3-pentanyl substituted with at least one halogen, optionally substituted amyl substituted with at least one halogen, optionally substituted neopentyl substituted with at least one halogen, optionally substituted 3-methyl-2-butanyl substituted with at least one halogen, optionally substituted tert-amyl substituted with at least one halogen, or optionally substituted n-hexyl substituted with at least one halogen.

[0185] In some embodiments, R1is phenyl substituted with optionally substituted carbocyclyl. In some embodiments, R1is phenyl substituted with optionally substituted, monocyclic carbocyclyl (e.g., optionally substituted, monocyclic, 3- to 10-membered carbocyclyl). In some embodiments, R1is phenyl substituted with optionally substituted, polycyclic carbocyclyl (e.g., optionally substituted, bicyclic or tricyclic, 3- to 14-membered carbocyclyl). In some embodiments, R1is phenyl substituted with optionally substituted saturated carbocyclyl. In some embodiments, R1is phenyl substituted with optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, optionally substituted cycloheptyl, optionally substituted cyclooctyl, optionally substituted cyclononyl, or optionally substituted cyclodecyl. In some embodiments, R1is phenyl substituted with optionally substituted cyclopropyl, optionally substitituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl. In some embodiments, R1is phenyl substituted with optionally substituted cyclopropyl. In some embodiments, R1is phenyl substituted with substituted carbocyclyl. In some embodiments, R1is phenyl substituted with substituted saturated carbocyclyl. In some embodiments, R1is phenyl substituted with unsubstituted carbocyclyl. In someL0907.70047WO00 53 / 150#14596547vlembodiments, R1is phenyl substituted with unsubstituted saturated carbocyclyl. In some embodiments, R1is phenyl substituted with substituted cyclopropyl. In some embodiments, R1is phenyl substituted with unsubstituted cyclopropyl.

[0186] In some embodiments, R1is phenyl substituted with optionally substituted aryl. In some embodiments, R1is phenyl substituted with optionally substituted C6-14 aryl. In some embodiments, R1is phenyl substituted with optionally substituted phenyl. In some embodiments, R1is phenyl substituted with unsubstituted phenyl. In some embodiments, R1is phenyl substituted with substituted phenyl. In some embodiments, R1is phenyl substituted with phenyl substituted with one or more of halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -ORA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORA)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, and / or -B(ORA)2groups. In some embodiments, R1is phenyl substituted with phenyl. In some embodiments, R1is phenyl substituted with phenyl substituted with -OCF3.

[0187] In some embodiments, R1is phenyl substituted with -ORA. In some embodiments, R1is phenyl substituted with -O(optionally substituted alkyl). In some embodiments, R1is phenyl substituted with -O(optionally substituted C1-12 alkyl). In some embodiments, R1is phenyl substituted with -O(optionally substituted C1-6 alkyl). In some embodiments, R1is phenyl substituted with -O(unsubstituted C1-6 alkyl). In some embodiments, R1is phenyl substituted with -O(substituted C1-6 alkyl). In some embodiments, R1is phenyl substituted with -O(optionally substituted methyl), -O(optionally substituted ethyl), -O(optionally substituted n-propyl), -O(optionally substituted isopropyl), -O(optionally substituted n-butyl), -O(optionally substituted tert-butyl), -O(optionally substituted sec-butyl), -O(optionally substituted isobutyl), -O(optionally substituted n-pentyl), -O(optionally substituted 3-pentanyl), -O(optionally substituted amyl), -O(optionally substituted neopentyl), -O(optionally substituted 3-methyl-2-butanyl), -O(optionally substituted tert-amyl), or -O(optionally substituted n-hexyl). In some embodiments, R1is phenyl substituted with -OCH3. In some embodiments, R1is phenyl substituted with -OCH(CH3)2.L0907.70047WO00 54 / 150#14596547vl

[0188] In some embodiments, R1is phenyl substituted with -ORAsubstituted with at least one halogen. In some embodiments, R1is phenyl substituted with -O(optionally substituted alkyl substituted with at least one halogen). In some embodiments, R1is phenyl substituted with -O(optionally substituted C1-12 alkyl substituted with at least one halogen). In some embodiments, R1is phenyl substituted with -O(optionally substituted C1-6 alkyl substituted with at least one halogen). In some embodiments, R1is phenyl substituted with -O(substituted C1-6 alkyl substituted with at least one halogen). In some embodiments, R1is phenyl substituted with -O(optionally substituted methyl substituted with at least one halogen), -O(optionally substituted ethyl substituted with at least one halogen), -O(optionally substituted n-propyl substituted with at least one halogen), -O(optionally substituted isopropyl substituted with at least one halogen), -O(optionally substituted n-butyl substituted with at least one halogen), -O(optionally substituted tert-butyl substituted with at least one halogen), -O(optionally substituted sec-butyl substituted with at least one halogen), -O(optionally substituted isobutyl substituted with at least one halogen), -O(optionally substituted n-pentyl substituted with at least one halogen), -O(optionally substituted 3-pentanyl substituted with at least one halogen), -O(optionally substituted amyl substituted with at least one halogen), -O(optionally substituted neopentyl substituted with at least one halogen), -O(optionally substituted 3-methyl-2-butanyl substituted with at least one halogen), -O(optionally substituted tert-amyl substituted with at least one halogen), or -O(optionally substituted n-hexyl substituted with at least one halogen).

[0189] In some embodiments, R1is phenyl substituted with -ORAsubstituted with at least one -F. In some embodiments, R1is phenyl substituted with -O(optionally substituted alkyl substituted with at least one -F). In some embodiments, R1is phenyl substituted with -O(optionally substituted C1-12 alkyl substituted with at least one -F). In some embodiments, R1is phenyl substituted with -O(optionally substituted C1-6 alkyl substituted with at least one -F). In some embodiments, R1is phenyl substituted with -O(substituted C1-6 alkyl substituted with at least one -F). In some embodiments, R1is phenyl substituted with -O(optionally substituted methyl substituted with at least one -F), -O(optionally substituted ethyl substituted with at least one -F), -O(optionally substituted n-propyl substituted with at least one -F), -O(optionally substituted isopropyl substituted with at least one -F), -O(optionally substituted n-butyl substituted with at least one -F), -O(optionally substituted tert-butyl substituted with at least one -F), -O(optionally substituted sec-butyl substituted with at least one -F), -O(optionally substituted isobutyl substituted with at least one -F), -O(optionally substituted n-pentyl substituted with at least one -F), -O(optionally substituted 3-pentanyl substituted with at least one -F), -O(optionally substituted amyl substituted with at least one -F), -O(optionally substituted neopentyl substituted with at least one -F), -O(optionally substituted 3-methyl-2-butanyl substituted with at least one -F), -O(optionally substituted tert-amyl substituted with at least one -F), or -O(optionally substituted n-hexyl substituted with at least one -F). In some embodiments, R1is phenyl substituted with -OCF3. In some embodiments, R1is phenyl substituted with -OCHF2.

[0190] In some embodiments, R1is phenyl substituted with -O(optionally substituted carbocyclyl). In some embodiments, R1is phenyl substituted with -O(optionally substituted, monocyclic carbocyclylL0907.70047WO00 55 / 150#14596547vl(e.g., optionally substituted, monocyclic, 3- to 10-membered carbocyclyl)). In some embodiments, R1is phenyl substituted with -O(optionally substituted, polycyclic carbocyclyl (e.g., optionally substituted, bicyclic or tricyclic, 3- to 14-membered carbocyclyl)). In some embodiments, R1is phenyl substituted with -O(optionally substituted saturated carbocyclyl). In some embodiments, R1is phenyl substituted with -O(optionally substituted cyclopropyl), -O(optionally substituted cyclobutyl), -O(optionally substituted cyclopentyl), -O(optionally substituted cyclohexyl), -O(optionally substituted cycloheptyl), -O(optionally substituted cyclooctyl), -O(optionally substituted cyclononyl), or -O(optionally substituted cyclodecyl). In some embodiments, R1is phenyl substituted with -O(optionally substituted cyclopropyl), -O(optionally substituted cyclobutyl), -O(optionally substituted cyclopentyl), or -O(optionally substituted cyclohexyl). In some embodiments, R1is phenyl substituted with -O(optionally substituted cyclopropyl). In some embodiments, R1is phenyl substituted with -O(optionally substituted cyclohexyl). In some embodiments, R1is phenyl substituted with -O(substituted carbocyclyl). In some embodiments, R1is phenyl substituted with -O(substituted saturated carbocyclyl). In some embodiments, R1is phenyl substituted with -O(unsubstituted carbocyclyl). In some embodiments, R1is phenyl substituted with -O(unsubstituted saturated carbocyclyl). In some embodiments, R1is phenyl substituted with -O(substituted cyclopropyl). In some embodiments, R1is phenyl substituted with -O(substituted cyclohexyl). In some embodiments, R1is phenyl substituted with -O(unsubstituted cyclopropyl). In some embodiments, R1is phenyl substituted with -O(unsubstituted cyclobutyl).

[0191] In some embodiments, R1is phenyl substituted with -N(RA)2. In some embodiments, at least one occurrence of RAis hydrogen. In some embodiments, at least one occurrence of RAis -CH3. In some embodiments, R1is phenyl substituted with -N(RA) (optionally substituted alkyl). In some embodiments, R1is phenyl substituted with -N(RA)(optionally substituted C1-12 alkyl). In some embodiments, R1is phenyl substituted with -N(RA)(optionally substituted C1-6 alkyl). In some embodiments, R1is phenyl substituted with -N(RA)(unsubstituted C1-6 alkyl). In some embodiments, R1is phenyl substituted with -N(RA)(substituted C1-6 alkyl). In some embodiments, R1is phenyl substituted with -N(RA)(optionally substituted methyl), -N(RA) (optionally substituted ethyl), -N( RA) (optionally substituted n-propyl), -N(RA)(optionally substituted isopropyl), -N(RA)(optionally substituted n-butyl), -N(RA) (optionally substituted tert-butyl), -N(RA)(optionally substituted sec-butyl), -N( RA) (optionally substituted isobutyl), -N(RA)(optionally substituted n-pentyl), -N(RA)(optionally substituted 3-pentanyl), -N(RA)(optionally substituted amyl), -N(RA)(optionally substituted neopentyl), -N(RA)(optionally substituted 3-methyl-2-butanyl), -N(RA)(optionally substituted tert-amyl), or -N(RA)(optionally substituted n-hexyl). In some embodiments, R1is phenyl substituted with -N(RA)CH3. In some embodiments, R1is phenyl substituted with -N(CH3)2.

[0192] In some embodiments, R1is of formula:— (a-1), wherein each occurrence of Rlais independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted L0907.70047WO00 56 / 150#14596547vlalkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -ORA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORA)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(ORA)2; and R1aml is 0, 1, 2, 3, 4, or 5. In some embodiments, the R1of formula (a-1) is of formula:(a-l-i), X^Rlaf j r l(a-l-ii), or — *"* (a-l-iii). In some embodiments, the R1of formula (a-1) is of formula (a-l-i) or (a-l-ii).

[0193] In some embodiments, at least one occurrence of Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2. In some embodiments, at least one occurrence of Rlais halogen. In some embodiments, at least one occurrence of Rlais -F, -Cl, -Br, and / or -I. In some embodiments, at least one occurrence of Rlais -F. In some embodiments, at least one occurrence of Rlais -Cl.

[0194] In some embodiments, at least one occurrence of Rlais optionally substituted alkyl. In some embodiments, at least one occurrence of Rlais optionally substituted C1-12 alkyl. In some embodiments, at least one occurrence of Rlais optionally substituted C1-6 alkyl. In some embodiments, at least one occurrence of Rlais unsubstituted C1-6 alkyl. In some embodiments, at least one occurrence of Rlais substituted C1-6 alkyl. In some embodiments, at least one occurrence of Rlais optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, optionally substituted isopropyl, optionally substituted n-butyl, optionally substituted tert-butyl, optionally substituted sec-butyl, optionally substituted isobutyl, optionally substituted n-pentyl, optionally substituted 3-pentanyl, optionally substituted amyl, optionally substituted neopentyl, optionally substituted 3-methyl-2-butanyl, optionally substituted tert-amyl, or optionally substituted n-hexyl. In some embodiments, at least one L0907.70047WO00 57 / 150#14596547vloccurrence of Rlais optionally substituted methyl. In some embodiments, at least one occurrence of Rlais substituted methyl. In some embodiments, at least one occurrence of Rlais unsubstituted methyl. In some embodiments, at least one occurrence of Rlais optionally substituted ethyl. In some embodiments, at least one occurrence of Rlais substituted ethyl. In some embodiments, at least one occurrence of Rlais unsubstituted ethyl. In some embodiments, at least one occurrence of Rlais optionally substituted isopropyl. In some embodiments, at least one occurrence of Rlais substituted isopropyl. In some embodiments, at least one occurrence of Rlais unsubstituted isopropyl. In some embodiments, at least one occurrence of Rlais optionally substituted tert-butyl. In some embodiments, at least one occurrence of Rlais substituted tert-butyl. In some embodiments, at least one occurrence of Rlais unsubstituted tertbutyl. In some embodiments, at least one occurrence of Rlais methyl, ethyl, isopropyl, or tert-butyl.

[0195] In some embodiments, at least one occurrence of Rlais optionally substituted alkyl substituted with at least one halogen. In some embodiments, at least one occurrence of Rlais optionally substituted Ci-6 alkyl substituted with at least one halogen. In some embodiments, at least one occurrence of Rlais optionally substituted methyl substituted with at least one halogen, optionally substituted ethyl substituted with at least one halogen, optionally substituted n-propyl substituted with at least one halogen, optionally substituted isopropyl substituted with at least one halogen, optionally substituted n-butyl substituted with at least one halogen, optionally substituted tert-butyl substituted with at least one halogen, optionally substituted.vcc-butyl substituted with at least one halogen, optionally substituted isobutyl substituted with at least one halogen, optionally substituted n-pentyl substituted with at least one halogen, optionally substituted 3-pentanyl substituted with at least one halogen, optionally substituted amyl substituted with at least one halogen, optionally substituted neopentyl substituted with at least one halogen, optionally substituted 3-methyl-2-butanyl substituted with at least one halogen, optionally substituted tert-amyl substituted with at least one halogen, or optionally substituted n-hexyl substituted with at least one halogen.

[0196] In some embodiments, at least one occurrence of Rlais optionally substituted carbocyclyl. In some embodiments, at least one occurrence of Rlais optionally substituted saturated carbocyclyl. In some embodiments, at least one occurrence of Rlais optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, optionally substituted cycloheptyl, optionally substituted cyclooctyl, optionally substituted cyclononyl, or optionally substituted cyclodecyl. In some embodiments, at least one occurrence of Rlais optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl. In some embodiments, at least one occurrence of Rlais optionally substituted cyclopropyl. In some embodiments, at least one occurrence of Rlais substituted carbocyclyl. In some embodiments, at least one occurrence of Rlais substituted saturated carbocyclyl. In some embodiments, at least one occurrence of Rlais unsubstituted carbocyclyl. In some embodiments, at least one occurrence of Rlais unsubstituted saturated carbocyclyl. In some embodiments, at least one occurrence of Rlais substituted cyclopropyl. In some embodiments, at least one occurrence of Rlais unsubstituted cyclopropyl.

[0197] In some embodiments, at least one occurrence of Rlais optionally substituted aryl. In someL0907.70047WO00 58 / 150#14596547vlembodiments, at least one occurrence of Rlais optionally substituted C6-14 aryl. In some embodiments, at least one occurrence of Rlais optionally substituted phenyl. In some embodiments, at least one occurrence of Rlais unsubstituted phenyl. In some embodiments, at least one occurrence of Rlais substituted phenyl. In some embodiments, at least one occurrence of Rlais phenyl substituted with one or more of halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -ORA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORA)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, and / or -B(ORA)2groups. In some embodiments, at least one occurrence of Rlais phenyl. In some embodiments, at least one occurrence of Rlais phenyl substituted with -OCF3.

[0198] In some embodiments, at least one occurrence of Rlais -ORA. In some embodiments, at least one occurrence of Rlais -O(optionally substituted alkyl). In some embodiments, at least one occurrence of Rlais -O(optionally substituted C1-6 alkyl). In some embodiments, at least one occurrence of Rlais -O(unsubstituted C1-6 alkyl). In some embodiments, at least one occurrence of Rlais -O(substituted C1-6 alkyl). In some embodiments, at least one occurrence of Rlais -O(optionally substituted methyl), -O(optionally substituted ethyl), -O(optionally substituted n-propyl), -O(optionally substituted isopropyl), -O(optionally substituted n-butyl), -O(optionally substituted tert-butyl), -O(optionally substituted sec-butyl), -O(optionally substituted isobutyl), -O(optionally substituted n-pentyl), -O(optionally substituted 3-pentanyl), -O(optionally substituted amyl), -O(optionally substituted neopentyl), -O(optionally substituted 3-methyl-2-butanyl), -O(optionally substituted tert-amyl), or -O(optionally substituted n-hexyl). In some embodiments, at least one occurrence of Rlais -OCH3. In some embodiments, at least one occurrence of Rlais -OCH(CH3)2.

[0199] In some embodiments, at least one occurrence of Rlais -ORAsubstituted with at least one halogen. In some embodiments, at least one occurrence of Rlais -O(optionally substituted alkyl substituted with at least one halogen). In some embodiments, at least one occurrence of Rlais -O(optionally substituted C1-12 alkyl substituted with at least one halogen). In some embodiments, at least one occurrence of Rlais -O(optionally substituted C1-6 alkyl substituted with at least one halogen). InL0907.70047WO00 59 / 150#14596547vlsome embodiments, at least one occurrence of Rlais -O(substituted Ci-6 alkyl substituted with at least one halogen). In some embodiments, at least one occurrence of Rlais -O(optionally substituted methyl substituted with at least one halogen), -O(optionally substituted ethyl substituted with at least one halogen), -O(optionally substituted n-propyl substituted with at least one halogen), -O(optionally substituted isopropyl substituted with at least one halogen), -O(optionally substituted n-butyl substituted with at least one halogen), -O(optionally substituted tert-butyl substituted with at least one halogen), -O(optionally substituted sec-butyl substituted with at least one halogen), -O(optionally substituted isobutyl substituted with at least one halogen), -O(optionally substituted n-pentyl substituted with at least one halogen), -O(optionally substituted 3-pentanyl substituted with at least one halogen), -O(optionally substituted amyl substituted with at least one halogen), -O(optionally substituted neopentyl substituted with at least one halogen), -O(optionally substituted 3-methyl-2-butanyl substituted with at least one halogen), -O(optionally substituted tert-amyl substituted with at least one halogen), or -O(optionally substituted n-hexyl substituted with at least one halogen).

[0200] In some embodiments, at least one occurrence of Rlais -ORAsubstituted with at least one -F. In some embodiments, at least one occurrence of Rlais -O(optionally substituted alkyl substituted with at least one -F). In some embodiments, at least one occurrence of Rlais -O(optionally substituted Ci-6 alkyl substituted with at least one -F). In some embodiments, at least one occurrence of Rlais -O(optionally substituted methyl substituted with at least one -F, -O(optionally substituted ethyl substituted with at least one -F), -O(optionally substituted n-propyl substituted with at least one -F), -O(optionally substituted isopropyl substituted with at least one -F), -O(optionally substituted n-butyl substituted with at least one -F), -O(optionally substituted tert-butyl substituted with at least one -F), -O(optionally substituted sec-butyl substituted with at least one -F), -O(optionally substituted isobutyl substituted with at least one -F), -O(optionally substituted n-pentyl substituted with at least one -F), -O(optionally substituted 3-pentanyl substituted with at least one -F), -O(optionally substituted amyl substituted with at least one -F), -O(optionally substituted neopentyl substituted with at least one -F), -O(optionally substituted 3-methyl-2-butanyl substituted with at least one -F), -O(optionally substituted tert-amyl substituted with at least one -F), or -O(optionally substituted n-hexyl substituted with at least one -F). In some embodiments, at least one occurrence of Rlais -OCF3. In some embodiments, at least one occurrence of Rlais -OCHF2.

[0201] In some embodiments, at least one occurrence of Rlais -Ofoptionally substituted carbocyclyl). In some embodiments, at least one occurrence of Rlais -©(optionally substituted saturated carbocyclyl). In some embodiments, at least one occurrence of Rlais -©(optionally substituted cyclopropyl), -©(optionally substituted cyclobutyl), -©(optionally substituted cyclopentyl), -Ofoptionally substituted cyclohexyl), -©(optionally substituted cycloheptyl), -©(optionally substituted cyclooctyl), -©(optionally substituted cyclononyl), or -©(optionally substituted cyclodecyl). In some embodiments, at least one occurrence of Rlais -Ofoptionally substituted cyclopropyl), -©(optionally substituted cyclobutyl), -©(optionally substituted cyclopentyl), or -©(optionally substituted cyclohexyl). In some embodiments, at least one occurrence of Rlais -O(optionally substituted cyclopropyl). In some embodiments, at leastL0907.70047WO00 60 / 150#14596547vlone occurrence of Rlais -O(optionally substituted cyclohexyl). In some embodiments, at least one occurrence of Rlais -O(substituted carbocyclyl). In some embodiments, at least one occurrence of Rlais -O(substituted saturated carbocyclyl). In some embodiments, at least one occurrence of Rlais -O(unsubstituted carbocyclyl). In some embodiments, at least one occurrence of Rlais -O(unsubstituted saturated carbocyclyl). In some embodiments, at least one occurrence of Rlais -O( substituted cyclopropyl). In some embodiments, at least one occurrence of Rlais -O( substituted cyclohexyl). In some embodiments, at least one occurrence of Rlais -O(unsubstituted cyclopropyl). In some embodiments, at least one occurrence of Rlais -O(unsubstituted cyclobutyl).

[0202] In some embodiments, at least one occurrence of Rlais -N(RA)2. In some embodiments, at least one occurrence of RAis hydrogen. In some embodiments, at least one occurrence of RAis -CH3. In some embodiments, at least one occurrence of Rlais -N(RA)(optionally substituted alkyl). In some embodiments, at least one occurrence of Rlais -N(RA)(optionally substituted C1-6 alkyl). In some embodiments, at least one occurrence of Rlais -N(RA)(optionally substituted methyl), -N(RA)(optionally substituted ethyl), -N(RA)(optionally substituted n-propyl), -N(RA)(optionally substituted isopropyl), -N(RA)(optionally substituted n-butyl), -N(RA) (optionally substituted tert-butyl), -N(RA) (optionally substituted sec-butyl), -N(RA)(optionally substituted isobutyl), -N(RA)(optionally substituted n-pentyl), -N(RA)(optionally substituted 3-pentanyl), -N(RA)(optionally substituted amyl), -N(RA) (optionally substituted neopentyl), -N(RA)(optionally substituted 3-methyl-2-butanyl), -N(RA) (optionally substituted tert-amyl), or -N(RA) (optionally substituted n-hexyl). In some embodiments, at least one occurrence of Rlais -N(RA)CH3. In some embodiments, at least one occurrence of Rlais -N(CH3)2.

[0203] In some embodiments, R1is of formula (a-1), and at least one occurrence of Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and ml is 0, 1, or 2. In some embodiments, R1is of formula (a-l-i) or (a-l-ii), and Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2. In some embodiments, R1is of formula (a-1), and at least one occurrence of Rlais halogen, optionally substituted alkyl, or -ORA. In some embodiments, R1is of formula (a-l-i) or (a-l-ii), and Rlais halogen, optionally substituted alkyl, or -ORA.F

[0204] In some embodiments, R1isL0907.70047WQ00 61 / 150#14596547vlembodiments, R1is

[0205] In some embodiments, the compound of Formula (I) is of Formula (I-b):or a pharmaceutically acceptable salt thereof, wherein:each occurrence of Rlais independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -ORA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA,L0907.70047WQ00 62 / 150#14596547vl-SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORA)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(ORA)2; andml is 0, 1, 2, 3, 4, or 5.

[0206] In some embodiments, the compound of Formula (I-b) is of Formulae (I-b-1) or (I-b-2):or a pharmaceutically acceptable salt thereof.

[0207] In some embodiments, R1is optionally substituted heteroaryl. In some embodiments, R1is optionally substituted 5-14 membered heteroaryl. In some embodiments, R1is optionally substituted monocyclic heteroaryl. In some embodiments, R1is optionally substituted 5- to 6-membered, monocyclic heteroaryl. In some embodiments, R1is optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted thiophenyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted thiazolyl, optionally substituted isothiazolyl, optionally substituted triazolyl, optionally substituted oxadiazolyl, optionally substituted thiadiazolyl, or optionally substituted tetrazolyl. In some embodiments, R1is optionally substituted pyridinyl, optionally substituted pyridazinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted triazinyl, optionally substituted tetrazinyl, optionally substituted oxepinyl, or optionally substituted thiepinyl. In some embodiments, R1is optionally substituted bicyclic heteroaryl (e.g. optionally substituted bicyclic, 9- or 10-membered heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur). In some embodiments, R1is optionally substituted indolyl, optionally substituted isoindolyl, optionally substituted indazolyl, optionally substituted benzotriazolyl, optionally substituted benzothiophenyl, optionally substituted isobenzothiophenyl, optionally substituted benzofuranyl, optionally substituted benzoisofuranyl, optionally substituted benzimidazolyl, optionally substitutedL0907.70047WQ00 63 / 150#14596547vlbenzoxazolyl, optionally substituted benzisoxazolyl, optionally substituted benzoxadiazolyl, optionally substituted benzthiazolyl, optionally substituted benzisothiazolyl, optionally substituted benzthiadiazolyl, optionally substituted indolizinyl, optionally substituted purinyl. In some embodiments, R1is optionally substituted naphthyridinyl, optionally substituted pteridinyl, optionally substituted quinolinyl, optionally substituted isoquinolinyl, optionally substituted cinnolinyl, optionally substituted quinoxalinyl, optionally substituted phthalazinyl, or optionally substituted quinazolinyl. In some embodiments, R1is optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted indolyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted pyrazolyl, optionally substituted imidazolyl, optionally substituted benzimidazolyl, or optionally substituted indazolyl. In some embodiments, R1is heteroaryl substituted with one or more of halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -ORA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORA)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, and / or -B(ORA)2groups.

[0208] In some embodiments, R1is optionally substituted pyridyl, optionally substituted thiazolyl, optionally substituted pyrazolyl, or optionally substituted thiophenyl. In some embodiments, R1is optionally substituted pyridyl, optionally substituted thiazolyl, or optionally substituted pyrazolyl. In some embodiments, R1is optionally substituted pyridyl. In some embodiments, R1is pyridyl substituted with one or more of halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -ORA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA,L0907.70047WO00 64 / 150#14596547vl-OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORA)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(ORA)2. In some embodiments, R1is optionally substituted thiazolyl or optionally substituted pyrazolyl.

[0209] In some embodiments, R1is optionally substituted thiophenyl. In some embodiments, R1is thiophenyl substituted with one or more of halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -ORA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORA)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(ORA)2.

[0210] In some embodiments, R1is heteroaryl substituted with one or more of halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2. In some embodiments, R1is pyridyl substituted with one or more of halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2. In some embodiments, R1is heteroaryl substituted with halogen. In some embodiments, R1is heteroaryl substituted with -F, -Cl, -Br, and / or -I. In some embodiments, R1is heteroaryl substituted with -F. In some embodiments, R1is heteroaryl substituted with -Cl.

[0211] In some embodiments, R1is heteroaryl substituted with optionally substituted alkyl. In some embodiments, R1is heteroaryl substituted with optionally substituted C1-12 alkyl. In some embodiments, R1is heteroaryl substituted with optionally substituted Ci-6 alkyl. In some embodiments, R1is heteroaryl substituted with unsubstituted Ci-6 alkyl. In some embodiments, R1is heteroaryl substituted with substituted Ci-6 alkyl. In some embodiments, R1is heteroaryl substituted with optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, optionally substituted isopropyl,L0907.70047WO00 65 / 150#14596547vloptionally substituted n-butyl, optionally substituted tert-butyl, optionally substituted sec-butyl, optionally substituted isobutyl, optionally substituted n-pentyl, optionally substituted 3-pentanyl, optionally substituted amyl, optionally substituted neopentyl, optionally substituted 3-methyl-2-butanyl, optionally substituted tert-amyl, or optionally substituted n-hexyl. In some embodiments, R1is heteroaryl substituted with optionally substituted methyl. In some embodiments, R1is heteroaryl substituted with substituted methyl. In some embodiments, R1is heteroaryl substituted with unsubstituted methyl. In some embodiments, R1is heteroaryl substituted with optionally substituted ethyl. In some embodiments, R1is heteroaryl substituted with substituted ethyl. In some embodiments, R1is heteroaryl substituted with unsubstituted ethyl. In some embodiments, R1is heteroaryl substituted with optionally substituted isopropyl. In some embodiments, R1is heteroaryl substituted with substituted isopropyl. In some embodiments, R1is heteroaryl substituted with unsubstituted isopropyl. In some embodiments, R1is heteroaryl substituted with optionally substituted tert-butyl. In some embodiments, R1is heteroaryl substituted with substituted tert-butyl. In some embodiments, R1is heteroaryl substituted with unsubstituted tert-butyl. In some embodiments, R1is heteroaryl substituted with methyl, ethyl, isopropyl, or tert-butyl.

[0212] In some embodiments, R1is heteroaryl substituted with optionally substituted alkyl substituted with at least one halogen. In some embodiments, R1is heteroaryl substituted with optionally substituted Ci-12 alkyl substituted with at least one halogen. In some embodiments, R1is heteroaryl substituted with optionally substituted Ci-6 alkyl substituted with at least one halogen. In some embodiments, R1is heteroaryl substituted with substituted Ci-6 alkyl substituted with at least one halogen. In some embodiments, R1is heteroaryl substituted with optionally substituted methyl substituted with at least one halogen, optionally substituted ethyl substituted with at least one halogen, optionally substituted n-propyl substituted with at least one halogen, optionally substituted isopropyl substituted with at least one halogen, optionally substituted n-butyl substituted with at least one halogen, optionally substituted tertbutyl substituted with at least one halogen, optionally substituted sec-butyl substituted with at least one halogen, optionally substituted isobutyl substituted with at least one halogen, optionally substituted n-pentyl substituted with at least one halogen, optionally substituted 3-pentanyl substituted with at least one halogen, optionally substituted amyl substituted with at least one halogen, optionally substituted neopentyl substituted with at least one halogen, optionally substituted 3-methyl-2-butanyl substituted with at least one halogen, optionally substituted tert-amyl substituted with at least one halogen, or optionally substituted n-hexyl substituted with at least one halogen.

[0213] In some embodiments, R1is heteroaryl substituted with optionally substituted carbocyclyl. In some embodiments, R1is heteroaryl substituted with optionally substituted, monocyclic carbocyclyl (e.g., optionally substituted, monocyclic, 3- to 10-membered carbocyclyl). In some embodiments, R1is heteroaryl substituted with optionally substituted, polycyclic carbocyclyl (e.g., optionally substituted, bicyclic or tricyclic, 3- to 14-membered carbocyclyl). In some embodiments, R1is heteroaryl substituted with optionally substituted saturated carbocyclyl. In some embodiments, R1is heteroaryl substituted with optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl,L0907.70047WO00 66 / 150#14596547vloptionally substituted cyclohexyl, optionally substituted cycloheptyl, optionally substituted cyclooctyl, optionally substituted cyclononyl, or optionally substituted cyclodecyl. In some embodiments, R1is heteroaryl substituted with optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl. In some embodiments, R1is heteroaryl substituted with optionally substituted cyclopropyl. In some embodiments, R1is heteroaryl substituted with substituted carbocyclyl. In some embodiments, R1is heteroaryl substituted with substituted saturated carbocyclyl. In some embodiments, R1is heteroaryl substituted with unsubstituted carbocyclyl. In some embodiments, R1is heteroaryl substituted with unsubstituted saturated carbocyclyl. In some embodiments, R1is heteroaryl substituted with substituted cyclopropyl. In some embodiments, R1is heteroaryl substituted with unsubstituted cyclopropyl.

[0214] In some embodiments, R1is heteroaryl substituted with optionally substituted aryl. In some embodiments, R1is heteroaryl substituted with optionally substituted Ce-i4 aryl. In some embodiments, R1is heteroaryl substituted with optionally substituted phenyl. In some embodiments, R1is heteroaryl substituted with unsubstituted phenyl. In some embodiments, R1is heteroaryl substituted with substituted phenyl. In some embodiments, R1is heteroaryl substituted with phenyl substituted with one or more of halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -ORA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORA)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, and / or -B(ORA)2groups. In some embodiments, R1is heteroaryl substituted with phenyl. In some embodiments, R1is heteroaryl substituted with phenyl substituted with -OCF3.

[0215] In some embodiments, R1is heteroaryl substituted with -ORA. In some embodiments, R1is heteroaryl substituted with -Oioptionally substituted alkyl). In some embodiments, R1is heteroaryl substituted with -O(optionally substituted C1-12 alkyl). In some embodiments, R1is heteroaryl substituted with -O(optionally substituted C1-6 alkyl). In some embodiments, R1is heteroaryl substituted with -O(unsubstituted C1-6 alkyl). In some embodiments, R1is heteroaryl substituted with -O(substituted C1-6 alkyl). In some embodiments, R1is heteroaryl substituted with -O(optionally substituted methyl),L0907.70047WO00 67 / 150#14596547vl-O(optionally substituted ethyl), -O(optionally substituted n-propyl), -O(optionally substituted isopropyl), -O(optionally substituted n-butyl), -O(optionally substituted tert-butyl), -O(optionally substituted sec-butyl), -O(optionally substituted isobutyl), -O(optionally substituted n-pentyl), -O(optionally substituted 3-pentanyl), -O(optionally substituted amyl), -O(optionally substituted neopentyl), -O(optionally substituted 3-methyl-2-butanyl), -O(optionally substituted tert-amyl), or -O(optionally substituted n-hexyl). In some embodiments, R1is heteroaryl substituted with -OCH3. In some embodiments, R1is heteroaryl substituted with -OCH(CH3)2.

[0216] In some embodiments, R1is heteroaryl substituted with -ORAsubstituted with at least one halogen. In some embodiments, R1is heteroaryl substituted with -Oioptionally substituted alkyl substituted with at least one halogen). In some embodiments, R1is heteroaryl substituted with -O(optionally substituted C1-12 alkyl substituted with at least one halogen). In some embodiments, R1is heteroaryl substituted with -O(optionally substituted C1-6 alkyl substituted with at least one halogen). In some embodiments, R1is heteroaryl substituted with -O(substituted C1-6 alkyl substituted with at least one halogen). In some embodiments, R1is heteroaryl substituted with -O(optionally substituted methyl substituted with at least one halogen), -O(optionally substituted ethyl substituted with at least one halogen), -O(optionally substituted n-propyl substituted with at least one halogen), -O(optionally substituted isopropyl substituted with at least one halogen), -O(optionally substituted n-butyl substituted with at least one halogen), -O(optionally substituted tert-butyl substituted with at least one halogen), -O(optionally substituted sec-butyl substituted with at least one halogen), -O(optionally substituted isobutyl substituted with at least one halogen), -O(optionally substituted n-pentyl substituted with at least one halogen), -O(optionally substituted 3-pentanyl substituted with at least one halogen), -O(optionally substituted amyl substituted with at least one halogen), -O(optionally substituted neopentyl substituted with at least one halogen), -O(optionally substituted 3-methyl-2-butanyl substituted with at least one halogen), -O(optionally substituted tert-amyl substituted with at least one halogen), or -O(optionally substituted n-hexyl substituted with at least one halogen).

[0217] In some embodiments, R1is heteroaryl substituted with -ORAsubstituted with at least one -F. In some embodiments, R1is heteroaryl substituted with -O(optionally substituted alkyl substituted with at least one -F). In some embodiments, R1is heteroaryl substituted with -O(optionally substituted C1-12 alkyl substituted with at least one -F). In some embodiments, R1is heteroaryl substituted with -O(optionally substituted C1-6 alkyl substituted with at least one -F). In some embodiments, R1is heteroaryl substituted with -O(substituted C1-6 alkyl substituted with at least one -F). In some embodiments, R1is heteroaryl substituted with -O(optionally substituted methyl substituted with at least one -F), -O(optionally substituted ethyl substituted with at least one -F), -O(optionally substituted n-propyl substituted with at least one -F), -O(optionally substituted isopropyl substituted with at least one -F), -O(optionally substituted n-butyl substituted with at least one -F), -O(optionally substituted tertbutyl substituted with at least one -F), -O(optionally substituted sec-butyl substituted with at least one -F), -O(optionally substituted isobutyl substituted with at least one -F), -O(optionally substituted n-pentyl substituted with at least one -F), -O(optionally substituted 3-pentanyl substituted with at least oneL0907.70047WO00 68 / 150#14596547vl-F), -O(optionally substituted amyl substituted with at least one -F), -O(optionally substituted neopentyl substituted with at least one -F), -O(optionally substituted 3-methyl-2-butanyl substituted with at least one -F), -O(optionally substituted tert-amyl substituted with at least one -F), or -O(optionally substituted n-hexyl substituted with at least one -F). In some embodiments, R1is heteroaryl substituted with -OCF3. In some embodiments, R1is heteroaryl substituted with -OCHF2.

[0218] In some embodiments, R1is heteroaryl substituted with -O(optionally substituted carbocyclyl). In some embodiments, R1is heteroaryl substituted with -O(optionally substituted, monocyclic carbocyclyl (e.g., optionally substituted, monocyclic, 3- to 10-membered carbocyclyl)). In some embodiments, R1is heteroaryl substituted with -O(optionally substituted, polycyclic carbocyclyl (e.g., optionally substituted, bicyclic or tricyclic, 3- to 14-membered carbocyclyl)). In some embodiments, R1is heteroaryl substituted with -O(optionally substituted saturated carbocyclyl). In some embodiments, R1is heteroaryl substituted with -O(optionally substituted cyclopropyl), -Ofoptionally substituted cyclobutyl), -O(optionally substituted cyclopentyl), -O(optionally substituted cyclohexyl), -O(optionally substituted cycloheptyl), -O(optionally substituted cyclooctyl), -O(optionally substituted cyclononyl), or -O(optionally substituted cyclodecyl). In some embodiments, R1is heteroaryl substituted with -O(optionally substituted cyclopropyl), -O(optionally substitituted cyclobutyl), -O(optionally substituted cyclopentyl), or -O(optionally substituted cyclohexyl). In some embodiments, R1is heteroaryl substituted with -O(optionally substituted cyclopropyl). In some embodiments, R1is heteroaryl substituted with -O(optionally substituted cyclohexyl). In some embodiments, R1is heteroaryl substituted with -O(substituted carbocyclyl). In some embodiments, R1is heteroaryl substituted with -O(substituted saturated carbocyclyl). In some embodiments, R1is heteroaryl substituted with -O(unsubstituted carbocyclyl). In some embodiments, R1is heteroaryl substituted with -O(unsubstituted saturated carbocyclyl). In some embodiments, R1is heteroaryl substituted with -O(substituted cyclopropyl). In some embodiments, R1is heteroaryl substituted with -O(substituted cyclohexyl). In some embodiments, R1is heteroaryl substituted with -O(unsubstituted cyclopropyl). In some embodiments, R1is heteroaryl substituted with -O(unsubstituted cyclobutyl).

[0219] In some embodiments, R1is heteroaryl substituted with -N(RA)2. In some embodiments, at least one occurrence of RAis hydrogen. In some embodiments, at least one occurrence of RAis -CH3. In some embodiments, R1is heteroaryl substituted with -N( RA)(optional ly substituted alkyl). In some embodiments, R1is heteroaryl substituted with -N(RA)(optionally substituted C1-12 alkyl). In some embodiments, R1is heteroaryl substituted with -N(RA)(optionally substituted C1-6 alkyl). In some embodiments, R1is heteroaryl substituted with -N(RA)(unsubstituted C1-6 alkyl). In some embodiments, R1is heteroaryl substituted with -N(RA)(substituted C1-6 alkyl). In some embodiments, R1is heteroaryl substituted with -N(RA)(optionally substituted methyl), -N( RA)(optionally substituted ethyl), -N(RA)(optionally substituted n-propyl), -N(RA)(optionally substituted isopropyl), -N(RA)(optionally substituted n-butyl), -N(RA) (optionally substituted tert-butyl), -N(RA)(optionally substituted sec-butyl), -N(RA)(optionally substituted isobutyl), -N(RA)(optionally substituted n-pentyl), -N(RA)(optionally substituted 3-pentanyl), -N(RA) (optionally substituted amyl), -N(RA)(optionally substituted neopentyl),L0907.70047WO00 69 / 150#14596547vl-N(RA)(optionally substituted 3-methyl-2-butanyl), -N(RA) (optionally substituted tert-amyl), or -N(RA)(optionally substituted n-hexyl). In some embodiments, R1is heteroaryl substituted with -N(RA)CH3. In some embodiments, R1is heteroaryl substituted with -N(CH3)2.^(R1a)m2

[0220] In some embodiments, R1is of formula:(a- 2), wherein each occurrence of Rlais independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -ORA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORA)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(ORA)2; and m2 is 0, 1, 2, 3, or 4. In some embodiments, R1is of formula (a-2), and at least one occurrence of Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl,-ORA, or -N(RA)2. In some embodiments, the R1of formula (a-2) is of formula:(a-2-i), R1ap1a(a-2-ii), or (a-2-iii), and at least one occurrence of Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2. In some embodiments, R1is of formula (a-2), and at least one occurrence of Rlais optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2. In some embodiments, R1is of formula (a-2-i), (a-2-ii), or (a-2-iii), and at least one occurrence of Rlais optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2.L0907.70047WO00 70 / 150#14596547vl(R1a)m3

[0222] In some embodiments, R1is of formula: (a-3), wherein each occurrence of Rlais independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted L0907.70047WQ00 71 / 150#14596547vlalkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -ORA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORA)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(ORA)2; and m3 is 0, 1, 2, or 3. In some embodiments, R1is of formula (a- 3), and at least one occurrence of Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, R1aS-ORA, or -N(RA)2. In some embodiments, the R1of formula (a- 3) is of formula:(a-3-i), ^CSRlaJ^X( / S(a-3-ii), or(a-3-iii), and Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2. In some embodiments, R1is of formula (a- 3), and at least one occurrence of Rlais halogen or optionally substituted alkyl. In some embodiments, R1is of formula: (a-3-i), (a-3-ii), or (a-3-iii), and Rlais halogen or optionally substituted alkyl.L0907.70047WQ00 72 / 150#14596547vl

[0224] In some embodiments, the compound of Formula (I) is of Formula (I-c):or a pharmaceutically acceptable salt thereof, wherein:each occurrence of Rlais independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -ORA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORA)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(ORA)2; andm2 is 0, 1, 2, 3, or 4.

[0225] In some embodiments, the compound of Formula (I-c) is of Formulae (I-c-1), (I-c-2), or (I-c-3):(I-c-1),L0907.70047WQ00 73 / 150#14596547vlor a pharmaceutically acceptable salt thereof.

[0226] In some embodiments, the compound of Formula (I) is of Formula (I-p):or a pharmaceutically acceptable salt thereof, wherein:each occurrence of Rlais independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -ORA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORA)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(ORA)2; andm3 is 0, 1, 2, or 3.L0907.70047WQ00 74 / 150#14596547vl

[0227] In some embodiments, the compound of Formula (I-p) is of Formula (I-p-1):or a pharmaceutically acceptable salt thereof.

[0228] In some embodiments, R2is hydrogen, optionally substituted alkyl, -ORA, or -N(RA)2. In some embodiments, R2is hydrogen, optionally substituted alkyl, or -ORA. In some embodiments, R2is hydrogen or -ORA. In some embodiments, R2is hydrogen.

[0229] In some embodiments, R2is optionally substituted alkyl. In some embodiments, R2is optionally substituted C1-12 alkyl. In some embodiments, R2is optionally substituted C1-6 alkyl. In some embodiments, R2is unsubstituted C1-6 alkyl. In some embodiments, R2is substituted C1-6 alkyl. In some embodiments, R2is optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, optionally substituted isopropyl, optionally substituted n-butyl, optionally substituted tert-butyl, optionally substituted sec-butyl, optionally substituted isobutyl, optionally substituted n-pentyl, optionally substituted 3-pentanyl, optionally substituted amyl, optionally substituted neopentyl, optionally substituted 3-methyl-2-butanyl, optionally substituted tert-amyl, or optionally substituted n-hexyl. In some embodiments, R2is optionally substituted methyl. In some embodiments, R2is substituted methyl. In some embodiments, R2is unsubstituted methyl. In some embodiments, R2is -CH3.

[0230] In some embodiments, R2is -ORA. In some embodiments, R2is -O(optionally substituted alkyl). In some embodiments, R2is -O(optionally substituted C1-12 alkyl). In some embodiments, R2is -O(optionally substituted C1-6 alkyl). In some embodiments, R2is -O(unsubstituted C1-6 alkyl). In some embodiments, R2is -O(substituted C1-6 alkyl). In some embodiments, R2is -O(optionally substituted methyl), -O(optionally substituted ethyl), -O(optionally substituted n-propyl), -O(optionally substituted isopropyl), -O(optionally substituted n-butyl), -O(optionally substituted tert-butyl), -O(optionally substituted sec-butyl), -O(optionally substituted isobutyl), -O(optionally substituted n-pentyl), -O(optionally substituted 3-pentanyl), -O(optionally substituted amyl), -O(optionally substituted neopentyl), -O(optionally substituted 3-methyl-2-butanyl), -O(optionally substituted tert-amyl), or -O(optionally substituted n-hexyl). In some embodiments, R2is -OCH3. In some embodiments, R2is -OCD3. In some embodiments, R2is -OCH2CH3. In some embodiments, R2is -OCH2F, -OCHF2, or -OCF3. In some embodiments, R2is -OCHF2.

[0231] In some embodiments, R2is -N(RA)2. In some embodiments, at least one occurrence of RAis hydrogen. In some embodiments, at least one occurrence of RAis -CH3. In some embodiments, at least two occurrences of RAare -CH3. In some embodiments, R2is -N(RA)(optionally substituted alkyl). In some embodiments, R2is -N(RA) (optionally substituted C1-12 alkyl). In some embodiments, R2is -N(RA)(optionally substituted C1-6 alkyl). In some embodiments, R2is -N(RA)(unsubstituted C1-6 alkyl).L0907.70047WQ00 75 / 150#14596547vlIn some embodiments, R2is -N(RA)(substituted Ci-6 alkyl). In some embodiments, R2is -N(RA)(optionally substituted methyl), -N(RA)(optionally substituted ethyl), -N(RA) (optionally substituted n-propyl), -N(RA)(optionally substituted isopropyl), -N( RA)(optionally substituted n-butyl), -N(RA)(optionally substituted tert-butyl), -N(RA)(optionally substituted sec-butyl), -N(RA)(optionally substituted isobutyl), -N(RA)(optionally substituted n-pentyl), -N(RA)(optionally substituted 3-pentanyl), -N(RA)(optionally substituted amyl), -N(RA) (optionally substituted neopentyl), -N(RA) (optionally substituted 3-methyl-2-butanyl), -N(RA)(optionally substituted tert-amyl), or -N(RA) (optionally substituted n-hexyl). In some embodiments, R2is -N(RA)CH3. In some embodiments, R2is -N(CH3)2.

[0232] In some embodiments, R2is hydrogen, -CH3, -OCH3, -OCD3, -OCH2CH3, -OCHF2, or -N(CH3)2. In some embodiments, R2is hydrogen, -CH3, -OCH3, or -N(CH3)2. In some embodiments, R2is hydrogen, -CH3, -OCH3, -OCD3 -OCH2CH3, or -OCHF2. In some embodiments, R2is hydrogen, -CH3, or -OCH3. In some embodiments, R2is hydrogen, -CH3, or -N(CH3)2. In some embodiments, R2is -CH3, -OCH3, or -N(CH3)2. In some embodiments, R2is hydrogen, -OCH3, or -N(CH3)2. In some embodiments, R2is hydrogen or -OCH3. In some embodiments, R2is hydrogen or -N(CH3)2. In some embodiments, R2is -OCH3 or -N(CH3)2.

[0233] In some embodiments, each occurrence of RYis independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, =0, =S, -CN, -ORA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORA)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(ORA)2.

[0234] In some embodiments, at least one occurrence of RYis halogen or optionally substituted alkyl. In some embodiments, at least one occurrence of RYis halogen. In some embodiments, at least one occurrence of RYis -F, -Cl, -Br, and / or -I. In some embodiments, at least one occurrence of RYis -F.

[0235] In some embodiments, at least one occurrence of RYis optionally substituted alkyl. In some embodiments, at least one occurrence of RYis optionally substituted C1-12 alkyl. In some embodiments, at least one occurrence of RYis optionally substituted C1-6 alkyl. In some embodiments, at least one occurrence of RYis unsubstituted C1-6 alkyl. In some embodiments, at least one occurrence of RYisL0907.70047WO00 76 / 150#14596547vlsubstituted Ci-6 alkyl. In some embodiments, at least one occurrence of RYis optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, optionally substituted isopropyl, optionally substituted n-butyl, optionally substituted tert-butyl, optionally substituted sec-butyl, optionally substituted isobutyl, optionally substituted n-pentyl, optionally substituted 3-pentanyl, optionally substituted amyl, optionally substituted neopentyl, optionally substituted 3-methyl-2-butanyl, optionally substituted tert-amyl, or optionally substituted n-hexyl. In some embodiments, at least one occurrence of RYis optionally substituted methyl. In some embodiments, at least one occurrence of RYis substituted methyl. In some embodiments, at least one occurrence of RYis unsubstituted methyl. In some embodiments, at least one occurrence of RYis -F or -CH3.

[0236] In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 1, and at least one instance of RYis -F. In some embodiments, n is 1, and at least one instance of RYis -CH3. In some embodiments, n is 2, and at least one instance of RYis -F. In some embodiments, n is 2, and at least one instance of RYis -CH3._f N— | / /

[0237] In some embodiments of Formula (I), the moiety(R )n is of formula:_ V°\— \f N— | [ N— - 1Formula (I), the moietyis of formula:. In some embodiments ofL0907.70047WQ00 77 / 150#14596547vlmoiety In some embodiments of Formula (I-a), the

[0238] In some embodiments, the compound of Formula (I-a) is of Formula (I-a-1):or a pharmaceutically acceptable salt thereof.

[0239] In some embodiments, the compound of Formula (I-a) is of Formulae (I-a- 2), (I-a-3), (I-a-4), or (I-a-5):or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I-a) is of Formula (I-a- 2). In some embodiments, the compound of Formula (I-a) is of Formula (I-a-3). In some embodiments, the compound of Formula (I-a) is of Formula (I-a-4). In some embodiments, the compound of Formula (I-a) is of Formula (I-a-5). In some embodiments, the compound of Formula (I-a) is of Formulae (I-a- 2), (I-a-3), (I-a-4), or (I-a-5), and RYis -F. In some embodiments, the compound of Formula (I-a) is of Formula (I-a-3), and RYis -F.

[0240] In some embodiments, Z is CR3Aor N. In some embodiments, each of R3A, R3Band R3Cis independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionallyL0907.70047WO00 78 / 150#14596547vlsubstituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -ORA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORA)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(ORA)2.

[0241] In some embodiments, at least one of R3A, R3Band R3Cis hydrogen or halogen. In some embodiments, at least one of R3A, R3Band R3Cis hydrogen. In some embodiments, R3Ais hydrogen. In some embodiments, R3Bis hydrogen. In some embodiments, R3Cis hydrogen. In some embodiments, R3Ais hydrogen and R3Bis hydrogen. In some embodiments, all of R3A, R3Band R3Care hydrogen. In some embodiments, at least one of R3A, R3Band R3Cis halogen. In some embodiments, R3Cis halogen. In some embodiments, R3Cis -Cl. In some embodiments, R3Ais hydrogen, R3Bis hydrogen, and R3Cis -Cl. In some embodiments, R3Bis hydrogen and R3Cis -Cl.

[0242] In some embodiments, Z is CR3Aand R3Ais hydrogen. In some embodiments, Z is CR3Aand R3Bis hydrogen. In some embodiments, Z is CR3Aand R3Cis hydrogen. In some embodiments, Z is CR3Aand R3Cis halogen. In some embodiments, Z is CR3Aand R3Cis -Cl. In some embodiments, Z is CR3A, R3Ais hydrogen, and R3Bis hydrogen. In some embodiments, Z is CR3A, R3Ais hydrogen, and R3Cis hydrogen. In some embodiments, Z is CR3A, R3Ais hydrogen, R3Bis hydrogen, and R3Cis hydrogen. In some embodiments, Z is CR3A, R3Ais hydrogen, and R3Cis halogen. In some embodiments, Z is CR3A, R3Ais hydrogen, R3Bis hydrogen, and R3Cis halogen. In some embodiments, Z is CR3A, R3Ais hydrogen, R3Bis hydrogen, and R3Cis -Cl.

[0243] In some embodiments, Z is N and R3Bis hydrogen. In some embodiments, Z is N and R3Cis hydrogen. In some embodiments, Z is N and R3Cis halogen. In some embodiments, Z is N and R3Cis -Cl. In some embodiments, Z is N, R3Bis hydrogen, and R3Cis hydrogen. In some embodiments, Z is N, R3Bis hydrogen, and R3Cis halogen. In some embodiments, Z is N, R3Bis hydrogen, and R3Cis -Cl.R3B

[0244] In some embodiments, the moietyN is of formula:N N or N NL0907.70047WQ00 79 / 150#14596547vlR3BIn some embodiments, the moietyis of formula:. In some embodiments, the R3BLZ=KI \\ / / — R3CI V z / — ClmoietyN~N is of formula:N— N

[0245] In some embodiments, the compound of Formula (I) is of Formula (I-d):or a pharmaceutically acceptable salt thereof.

[0246] In some embodiments, the compound of Formula (I-d) is of Formula (I-d- 1):or a pharmaceutically acceptable salt thereof.

[0247] In some embodiments, the compound of Formula (I-d) is of Formula (I-d- 2) or (I-d-3):or a pharmaceutically acceptable salt thereof.

[0248] In some embodiments, the compound of Formula (I) is of Formula (I-e):or a pharmaceutically acceptable salt thereof.L0907.70047WO00 80 / 150#14596547vl

[0249] In some embodiments, the compound of Formula (I-e) is of Formula (I-e-1):or a pharmaceutically acceptable salt thereof.

[0250] In some embodiments, the compound of Formula (I-e) is of Formula (I-e-2) or (I-e-3):or a pharmaceutically acceptable salt thereof.

[0251] In some embodiments, each occurrence of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring. In some embodiments, at least one occurrence of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring. In some embodiments, at least one occurrence of RAis hydrogen. In some embodiments, at least one occurrence of RAis optionally substituted acyl. In some embodiments, at least one occurrence of RAis optionally substituted C1-12 alkyl. In some embodiments, at least one occurrence of RAis optionally substituted C1-6 alkyl. In some embodiments, at least one occurrence of RAis unsubstituted C1-6 alkyl. In some embodiments, at least one occurrence of RAis substituted C1-6 alkyl. In some embodiments, at least one occurrence of RAis optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, optionally substituted isopropyl,L0907.70047WO00 81 / 150#14596547vloptionally substituted n-butyl, optionally substituted tert-butyl, optionally substituted sec-butyl, optionally substituted isobutyl, optionally substituted n-pentyl, optionally substituted 3-pentanyl, optionally substituted amyl, optionally substituted neopentyl, optionally substituted 3-methyl-2-butanyl, optionally substituted tert-amyl, or optionally substituted n-hexyl. In some embodiments, at least one occurrence of RAis optionally substituted C2-12 alkenyl. In some embodiments, at least one occurrence of RAis optionally substituted C2-6 alkenyl. In some embodiments, at least one occurrence of RAis optionally substituted ethenyl, optionally substituted 1-propenyl, optionally substituted 2-propenyl, optionally substituted 1-butenyl, optionally substituted 2-butenyl, optionally substituted butadienyl, optionally substituted pentenyl, optionally substituted pentadienyl, or optionally substituted hexenyl. In some embodiments, at least one occurrence of RAis optionally substituted C2-12 alkynyl. In some embodiments, at least one occurrence of RAis optionally substituted C2-6 alkynyl. In some embodiments, at least one occurrence of RAis optionally substituted ethynyl, optionally substituted 1-propynyl, optionally substituted 2-propynyl, optionally substituted 1-butynyl, optionally substituted 2-butynyl, optionally substituted pentynyl, or optionally substituted hexynyl. In some embodiments, at least one occurrence of RAis optionally substituted heteroCi-12 alkyl. In some embodiments, at least one occurrence of RAis optionally substituted heteroCi-6 alkyl. In some embodiments, at least one occurrence of RAis optionally substituted heteroCi-12 alkenyl. In some embodiments, at least one occurrence of RAis optionally substituted heteroCi-6 alkenyl. In some embodiments, at least one occurrence of RAis optionally substituted heteroCi-12 alkynyl. In some embodiments, at least one occurrence of RAis optionally substituted heteroCi-6 alkynyl. In some embodiments, at least one occurrence of RAis optionally substituted C3-14 cycloalkyl. In some embodiments, at least one occurrence of RAis optionally substituted 5-10 membered heterocyclyl. In some embodiments, at least one occurrence of RAis optionally substituted 6-14 membered aryl. In some embodiments, at least one occurrence of RAis optionally substituted 5-14 membered heteroaryl. In some embodiments, at least one occurrence of RAis a nitrogen protecting group when attached to a nitrogen atom. In some embodiments, at least one occurrence of RAis an oxygen protecting group when attached to an oxygen atom. In some embodiments, at least one occurrence of RAis a sulfur protecting group when attached to a sulfur atom. In some embodiments, at least two occurrences of RAare joined together with their intervening atom to form an optionally substituted 5-10 membered heterocyclic ring. In some embodiments, at least two occurrences of RAare joined together with their intervening atom to form an optionally substituted 5-14 membered heteroaryl ring.

[0252] In some embodiments, RBis hydrogen, optionally substituted alkyl, or nitrogen protecting group. In some embodiments, RBis hydrogen. In some embodiments, RBis optionally substituted acyl. In some embodiments, RBis optionally substituted C1-12 alkyl. In some embodiments, RBis optionally substituted C1-6 alkyl. In some embodiments, RBis unsubstituted C1-6 alkyl. In some embodiments, RBis substituted C1-6 alkyl. In some embodiments, RBis optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, optionally substituted isopropyl, optionally substituted n-butyl, optionally substituted tert-butyl, optionally substituted sec-butyl, optionally substituted isobutyl, optionallyL0907.70047WO00 82 / 150#14596547vlsubstituted n-pentyl, optionally substituted 3-pentanyl, optionally substituted amyl, optionally substituted neopentyl, optionally substituted 3-methyl-2-butanyl, optionally substituted tert-amyl, or optionally substituted n-hexyl. In some embodiments, RBis a nitrogen protecting group.

[0253] In some embodiments, R1is of formula:(a-1), at least one occurrence of Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is optionally substituted Ci-6 alkyl. In some embodiments, R1is of formula (a-1), at least one occurrence of Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is -ORA. In some embodiments, R1is of formula (a-1), at least one occurrence of Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is -O(optionally substituted Ci-6 alkyl). In some embodiments, R1is of formula (a-1), at least one occurrence of Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is -N(RA)2. In some embodiments, R1is of formula (a-1), at least one occurrence of Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is hydrogen, -CH3, -OCH3, or -N(CH3)2. In some embodiments, R1is of formula (a-1), at least one occurrence of Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is hydrogen or -OCH3. In some embodiments, R1is of formula (a-1), at least one occurrence of Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is hydrogen. In some embodiments, R1is of formula (a-1), at least one occurrence of Rlais halogen, optional ly substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is -OCH3. In some embodiments, R1is of formula (a-1), at least one occurrence of Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is -CH3. In some embodiments, R1is of formula (a-1), at least one occurrence of Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is -N(CH3)2.R1a

[0254] In some embodiments, R1is of formula:(a-l-i) or (a-l-ii), Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is optionally substituted Ci-6 alkyl. In some embodiments, R1is of formula (a-l-i) or (a-1-ii), Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is -ORA. In some embodiments, R1of formula (a-l-i) or (a-l-ii), Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is -O(optionally substituted Ci-6 alkyl). In some embodiments, R1is of L0907.70047WO00 83 / 150#14596547vlformula (a-l-i) or (a-l-ii), Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is -N(RA)2. In some embodiments, R1is of formula (a-l-i) or (a-l-ii), Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is hydrogen, -CH3, -OCH3, or -N(CH3)2. In some embodiments, R1is of formula (a-l-i) or (a-l-ii), Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is hydrogen or -OCH3. In some embodiments, R1is of formula (a-l-i) or (a-l-ii), Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is hydrogen. In some embodiments, R1is of formula (a-l-i) or (a-l-ii), Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is -OCH3. In some embodiments, R1is of formula (a-l-i) or (a-l-ii), Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is -CH3. In some embodiments, R1is of formula (a-l-i) or (a-l-ii), Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is -N(CH3)2.

[0255] In some embodiments, R1is of formula (a-1), at least one occurrence of Rlais halogen, optionally substituted alkyl, or -ORA, and R2is optionally substituted C1-6 alkyl. In some embodiments, R1is of formula (a-1), at least one occurrence of Rlais halogen, optionally substituted alkyl, or -ORA, and R2is -ORA. In some embodiments, R1is of formula (a-1), at least one occurrence of Rlais halogen, optionally substituted alkyl, or -ORA, and R2is -Ofoptionally substituted C1-6 alkyl). In some embodiments, R1is of formula (a-1), at least one occurrence of Rlais halogen, optionally substituted alkyl, or -ORA, and R2is -N(RA)2. In some embodiments, R1is of formula (a-1), at least one occurrence of Rlais halogen, optionally substituted alkyl, or -ORA, and R2is hydrogen, -CH3, -OCH3, or -N(CH3)2. In some embodiments, R1is of formula (a-1), at least one occurrence of Rlais halogen, optionally substituted alkyl, or -ORA, and R2is hydrogen or -OCH3. In some embodiments, R1is of formula (a-1), at least one occurrence of Rlais halogen, optionally substituted alkyl, or -ORA, and R2is hydrogen. In some embodiments, R1is of formula (a-1), at least one occurrence of Rlais halogen, optionally substituted alkyl, or -ORA, and R2is -OCH3. In some embodiments, R1is of formula (a-1), at least one occurrence of Rlais halogen, optionally substituted alkyl, or -ORA, and R2is -CH3. In some embodiments, R1is of formula (a-1), at least one occurrence of Rlais halogen, optionally substituted alkyl, or -ORA, and R2is -N(CH3)2.

[0256] In some embodiments, R1is of formula (a-l-i) or (a-l-ii), Rlais halogen, optionally substituted alkyl, or -ORA, and R2is optionally substituted C1-6 alkyl. In some embodiments, R1is of formula (a-l-i) or (a-l-ii), Rlais halogen, optionally substituted alkyl, or -ORA, and R2is -ORA. In some embodiments, R1is of formula (a-l-i) or (a-l-ii), Rlais halogen, optionally substituted alkyl, or -ORA, and R2is -O(optionally substituted C1-6 alkyl). In some embodiments, R1is of formula (a-l-i) or (a-l-ii), Rlais halogen, optionally substituted alkyl, or -ORA, and R2is -N(RA)2. In some embodiments, R1is of formula (a-l-i) or (a-l-ii), Rlais halogen, optionally substituted alkyl, or -ORA, and R2is hydrogen, -CH3, -OCH3, or -N(CH3)2. In some embodiments, R1is of formula (a-l-i) or (a-l-ii), Rlais halogen,L0907.70047WO00 84 / 150#14596547vloptionally substituted alkyl, or -ORA, and R2is hydrogen or -OCH3. In some embodiments, R1is of formula (a-l-i) or (a-l-ii), Rlais halogen, optionally substituted alkyl, or -ORA, and R2is hydrogen. In some embodiments, R1is of formula (a-l-i) or (a-l-ii), Rlais halogen, optionally substituted alkyl, or -ORA, and R2is -OCH3. In some embodiments, R1is of formula (a-l-i) or (a-l-ii), Rlais halogen, optionally substituted alkyl, or -ORA, and R2is -CH3. In some embodiments, R1is of formula (a-l-i) or (a-l-ii), Rlais halogen, optionally substituted alkyl, or -ORA, and R2is -N(CH3)2.L0907.70047WO00 85 / 150#14596547vl(R1a)m2

[0258] In some embodiments, R1is of formula:(a- 2), at least one occurrence of Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is optionally substituted Ci-6 alkyl. In some embodiments, R1is of formula (a-2), at least one occurrence of Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is -ORA. In some embodiments, R1is of formula (a-2), at least one occurrence of Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is -O(optionallyL0907.70047WO00 86 / 150#14596547vlsubstituted C1-6 alkyl). In some embodiments, R1is of formula (a- 2), at least one occurrence of Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is -N(RA)2. In some embodiments, R1is of formula (a-2), at least one occurrence of Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is hydrogen, -CH3, -OCH3, or -N(CH3)2. In some embodiments, R1is of formula (a-2), at least one occurrence of Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is hydrogen or -OCH3. In some embodiments, R1is of formula (a-2), at least one occurrence of Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is hydrogen. In some embodiments, R1is of formula (a-2), at least one occurrence of Rlais halogen, optional ly substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is -OCH3. In some embodiments, R1is of formula (a-2), at least one occurrence of Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is -CH3. In some embodiments, R1is of formula (a-2), at least one occurrence of Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is -N(CH3)2.R1aR1t / ^

[0259] In some embodiments, R1is of formula:(a-2-i), (a-2-ii), oro1a(a-2-iii), at least one occurrence of Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is optionally substituted C1-6 alkyl. In some embodiments, R1is of formula (a-2-i), (a-2-ii), or (a-2-iii), at least one occurrence of Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is -ORA. In some embodiments, R1is of formula (a-2-i), (a-2-ii), or (a-2-iii), at least one occurrence of Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is -O(optionally substituted Ci-6 alkyl). In some embodiments, R1is of formula (a-2-i), (a-2-ii), or (a-2-iii), at least one occurrence of Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is -N(RA)2. In some embodiments, R1is of formula (a-2-i), (a-2-ii), or (a-2-iii), at least one occurrence of Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is hydrogen, -CH3, -OCH3, or -N(CH3)2. In some embodiments, R1is of formula (a-2-i), (a-2-ii), or (a-2-iii), at least one occurrence of Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is hydrogen or -OCH3. In some embodiments, R1is ofL0907.70047WO00 87 / 150#14596547vlformula (a-2-i), (a-2-ii), or (a-2-iii), at least one occurrence of Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is hydrogen. In some embodiments, R1is of formula (a-2-i), (a-2-ii), or (a-2-iii), at least one occurrence of Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is -OCH3. In some embodiments, R1is of formula (a-2-i), (a-2-ii), or (a-2-iii), at least one occurrence of Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is -CH3. In some embodiments, R1is of formula (a-2-i), (a-2-ii), or (a-2-iii), at least one occurrence of Rlais halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is -N(CH3)2.

[0260] In some embodiments, R1is of formula (a-2), at least one occurrence of Rlais optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, andR2is optionally substituted Ci-6 alkyl. In some embodiments, R1is at least one occurrence of Rlais optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is -ORA. In some embodiments, R1is of formula (a- 2), at least one occurrence of Rlais optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is -O(optionally substituted C1-6 alkyl). In some embodiments, R1is of formula (a-2), at least one occurrence of Rlais optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is -N(RA)2. In some embodiments, R1is of formula (a-2), at least one occurrence of Rlais optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is hydrogen, -CH3, -OCH3, or -N(CH3)2. In some embodiments, R1is of formula (a-2), at least one occurrence of Rlais optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is hydrogen or -OCH3. In some embodiments, R1is of formula (a-2), at least one occurrence of Rlais optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is hydrogen. In some embodiments, R1is of formula (a-2), at least one occurrence of Rlais optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is -OCH3. In some embodiments, R1is of formula (a-2), at least one occurrence of Rlais optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is -CH3. In some embodiments, R1is of formula (a-2), at least one occurrence of Rlais optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is -N(CH3)2.

[0261] In some embodiments, R1is of formula (a-2-i), (a-2-ii), or (a-2-iii), at least one occurrence of Rlais optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is optionally substituted C1-6 alkyl. In some embodiments, R1is of formula (a-2-i), (a-2-ii), or (a-2-iii), at least one occurrence of Rlais optionally substituted alkyl, optionally substitutedL0907.70047WO00 88 / 150#14596547vlcarbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is -ORA. In some embodiments, R1is of formula (a-2-i), (a-2-ii), or (a-2-iii), at least one occurrence of Rlais optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is -O(optionally substituted Ci-6 alkyl). In some embodiments, R1is of formula (a-2-i), (a-2-ii), or (a-2-iii), at least one occurrence of Rlais optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is -N(RA)2. In some embodiments, R1is of formula (a-2-i), (a-2-ii), or (a-2-iii), at least one occurrence of Rlais optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is hydrogen, -CH3, -OCH3, or -N(CH3)2. In some embodiments, R1is of formula (a-2-i), (a-2-ii), or (a-2-iii), at least one occurrence of Rlais optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is hydrogen or -OCH3. In some embodiments, R1is of formula (a-2-i), (a-2-ii), or (a-2-iii), at least one occurrence of Rlais optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is hydrogen. In some embodiments, R1is of formula (a-2-i), (a-2-ii), or (a-2-iii), at least one occurrence of Rlais optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is -OCH3. In some embodiments, R1is of formula (a-2-i), (a-2-ii), or (a-2-iii), at least one occurrence of Rlais optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is -CH3. In some embodiments, R1is of formula (a-2-i), (a-2-ii), or (a-2-iii), at least one occurrence of Rlais optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2, and R2is -N(CH3)2.L0907.70047WO00 89 / 150#14596547vl#14596547v1#14596547v1-N(CH3)2.L0907.70047WO00 92 / 150#14596547vl#14596547v1

[0265] In some embodiments, the compound of Formula (I-b) is of Formula (I-f):or a pharmaceutically acceptable salt thereof.

[0266] In some embodiments, the compound of Formula (I-f) is of Formulae (I-f- 1), (I-f- 2), or (I-f-3):L0907.70047WO00 94 / 150#14596547vlor a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I-f) is of Formula (I-f- 1), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I-f) is of Formula (I-f- 2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I-f) is of Formula (I-f-3), or a pharmaceutically acceptable salt thereof.

[0267] In some embodiments, the compound of Formula (I-b) is of Formula (I-g):or a pharmaceutically acceptable salt thereof.

[0268] In some embodiments, the compound of Formula (I-g) is of Formulae (I-g-1), (I-g-2), or (I-g-3):or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I-g) is of Formula (I-g-1), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I-g) is of Formula (I-g-2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I-g) is of Formula (I-g-3), or a pharmaceutically acceptable salt thereof.L0907.70047WO00 95 / 150#14596547vl

[0269] In some embodiments, the compound of Formula (I-c) is of Formula (I-h):or a pharmaceutically acceptable salt thereof.

[0270] In some embodiments, the compound of Formula (I-c) is of Formula (I-i):or a pharmaceutically acceptable salt thereof.

[0271] In some embodiments, the compound of Formula (I-h) is of Formulae (I-h-1), (I-h-2), or (I-h-3):or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I-h) is of Formula (I-h-1), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I-h) is of Formula (I-h-2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I-h) is of Formula (I-h-3), or a pharmaceutically acceptable salt thereof.L0907.70047WO00 96 / 150#14596547vl

[0272] In some embodiments, the compound of Formula (I-i) is of Formulae (I-i-1), (I-i-2), or (I-i-3):or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I-i) is of Formula (I-i-1), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I-i) is of Formula (I-i-2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I-i) is of Formula (I-i-3), or a pharmaceutically acceptable salt thereof.

[0273] In some embodiments, the compound of Formula (I) is of Formulae (I-j-1), (I-j-2), or (I-j-3):or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (I-j-1), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (I-j-2), or a pharmaceutically acceptable salt thereof. In some embodiments,L0907.70047WO00 97 / 150#14596547vlthe compound of Formula (I) is of Formula (I-j-3), or a pharmaceutically acceptable salt thereof.

[0274] In some embodiments, the compound of Formula (I) is of Formulae (I-k-1), (I-k-2), or (I-k-3):N~N (I-k-1),pi i_i- IM — INR (I-k-3), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (I-k-1), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (I-k-2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is of Formula (I-k-3), or a pharmaceutically acceptable salt thereof.

[0275] In some embodiments, the compound of Formula (I-c) is of Formulae (I-m-1), (I-m-2), or (I-m-3):or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I-c) is ofL0907.70047WO00 98 / 150#14596547vlFormula (I-m-1), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I-c) is of Formula (I-m-2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I-c) is of Formula (I-m-3), or a pharmaceutically acceptable salt thereof.

[0276] In some embodiments, the compound of Formula (I-m-1) is of Formula (I-m-4):N~N (I-m-4), or a pharmaceutically acceptable salt thereof.

[0277] In some embodiments, the compound of Formula (I-b) is of Formula (I-n):or a pharmaceutically acceptable salt thereof.

[0278] In some embodiments, the compound of Formula (I-n) is of Formulae (I-n-1) or (I-n- 2):or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I-n) is of Formula (I-n-1), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I-n) is of Formula (I-n- 2), or a pharmaceutically acceptable salt thereof.

[0279] In some embodiments, the compound of Formula (I-b) is of Formula (I-o):or a pharmaceutically acceptable salt thereof.L0907.70047WO00 99 / 150#14596547vl

[0280] In some embodiments, the compound of Formula (I-o) is of Formulae (I-o-l), (I-O-2), (1-0-3), (I-o-4), (1-0-5), or (I-o-6):R1aN~N (I-o-l),or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I-o) is of Formula (I-o-l), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I-o) is of Formula (1-0-2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I-o) is of Formula (1-0-3), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I-o) is of Formula (1-0-4), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I-o) is of Formula (1-0-5), or a L0907.70047WO00 100 / 150#14596547vlpharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I-o) is of Formula (I-0-6), or a pharmaceutically acceptable salt thereof.O=\ — /

[0281] In some embodiments, the compound of Formula (I) is selected from those in Table 1, and pharmac ye(u o= —tically acceptable salts thereof.ZT\ Zz^Table 1. Compounds of Formula (I)Q I J0I N..s. Z jC / Csv-o.Ct Af n H \-^\ z _,c; 1 \ 0 N-NN-N 1 2O O O\\ / / \ < / =\bN'NCM ) bN'NCM ) N-N N-N 3 4OHSV / N^< \-CL'' Il T \ N— N ON~N<^ / N— —Cl6U N OHsV x-oz^rf \\ / / - y N— N M VV\0 N-N r N-Z^A '0N'NW / )N-N 7 8F=C'°7UZ^NM Z. N T Hk^N SK\Hq n if Z°\ YTVV 0 N-NO N-N f N-Z’XW / / N-N N'N^9 10L0907.70047WO00 101 / 150#14596547vl#14596547v1U \HT c U \HT QZY on~nr»-A -O-V o A N-VN VW / ) r\ _ Wz= / \ / N-N N-N 23A (Isomer 1) 23B (Isomer 2) Qf00N-N ^N-Z00W Z / ) N-N ^N-Z^A N-N N-N 24 A (Isomer 1) 24B (Isomer 2) / \ZCI / ^ / Clo oZyN^^o00 N-N N— <f===\00 N-N N-ZZ W / / N-N N-N 25 A (Isomer 1) 25 B (Isomer 2)U FFCJ A\HQ \HQo N-N ( kA -o-Z o ^ N-vN v rx\_ z=\V / / N-N N-N 26 A (Isomer 1) 26B (Isomer 2)o CJHQHQ-o'V^VVx -oZ -<>vON-N rvn W / / o N-N rvA\N-N N-N 27 A (Isomer 1) 27B (Isomer 2)0 0ZV^XSZ°V--A00 N-N Y^ N-ZZW / / o N-N Y^N-Z W Z / / N-N N-N28 A (Isomer 1) 28B (Isomer 2)L0907.70047WO00 103 / 150#14596547vl#14596547v1#14596547v1

[0282] In some embodiments, the compound is of formula:L0907.70047WO00 106 / 150#14596547vlor a pharmaceutically acceptable salt thereof.

[0283] In some embodiments, the compound is of formula:or a pharmaceutically acceptable salt thereof.

[0284] In some embodiments, the compound is of formula:or a pharmaceutically acceptable salt thereof.

[0285] In some embodiments, the compound is of formula:or a pharmaceutically acceptable salt thereof.

[0286] In some embodiments, the compound is of formula:or a pharmaceutically acceptable salt thereof.L0907.70047WO00 107 / 150#14596547vl

[0287] In some embodiments, the compound is of formula:or a pharmaceutically acceptable salt thereof.

[0288] In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, is present in a therapeutically effective amount. In some embodiments, the therapeutically effective amount is an amount effective for treating an age-related disease or disorder in a subject in need thereof.

[0289] In some embodiments, the therapeutically effective amount is an amount sufficient for modulating mitochondrial function in a subject in need thereof. In some embodiments, the therapeutically effective amount is an amount sufficient for reducing reactive oxygen species levels in a subject in need thereof. In some embodiments, the therapeutically effective amount is an amount sufficient for reducing pro-inflammatory signaling in a subject in need thereof. In some embodiments, the therapeutically effective amount is an amount sufficient for preventing or inhibiting cellular senescence in a subject in need thereof.

[0290] In some embodiments, the therapeutically effective amount is an amount sufficient for treating an age-related disease or disorder and modulating mitochondrial function in a subject in need thereof. In some embodiments, the therapeutically effective amount is an amount sufficient for treating an age-related disease or disorder and reducing reactive oxygen species levels in a subject in need thereof. In some embodiments, the therapeutically effective amount is an amount sufficient for treating an age-related disease or disorder and reducing pro-inflammatory signaling in a subject in need thereof. In some embodiments, the therapeutically effective amount is an amount sufficient for treating an age-related disease or disorder and preventing or inhibiting cellular senescence in a subject in need thereof.

[0291] In some embodiments, the therapeutically effective amount is an amount effective for reducing reactive oxygen species levels in a subject in need thereof by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%. In some embodiments, the therapeutically effective amount is an amount effective for reducing reactive oxygen species levels in a subject in need thereof by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.

[0292] In some embodiments, the therapeutically effective amount is an amount effective for reducing pro-inflammatory signaling in a subject in need thereof by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%. In some embodiments, the therapeutically effective amount is an amount effective for reducing pro-inflammatory signaling in a subject in need thereof by a range between a percentage described in this L0907.70047WO00 108 / 150#14596547vlparagraph and another percentage described in this paragraph, inclusive.

[0293] In some embodiments, the compound of Formula (I), or pharmaceutical ly acceptable salt thereof, is present in a prophylactical ly effective amount. In some embodiments, the prophylactically effective amount is an amount effective for preventing an age-related disease or disorder in a subject in need thereof. In some embodiments, the prophylactically effective amount is an amount effective for reducing the risk of developing an age-related disease or disorder in a subject in need thereof.

[0294] In some embodiments, the prophylactically effective amount is an amount sufficient for preventing an age-related disease or disorder and modulating mitochondrial function in a subject in need thereof. In some embodiments, the prophylactically effective amount is an amount sufficient for preventing an age-related disease or disorder and reducing reactive oxygen species levels in a subject in need thereof. In some embodiments, the prophylactically effective amount is an amount sufficient for preventing an age-related disease or disorder and reducing pro-inflammatory signaling in a subject in need thereof. In some embodiments, the prophylactically effective amount is an amount sufficient for preventing an age-related disease or disorder and preventing or inhibiting cellular senescence in a subject in need thereof.

[0295] In some embodiments, the prophylactically effective amount is an amount sufficient for reducing the risk of developing an age-related disease or disorder and modulating mitochondrial function in a subject in need thereof. In some embodiments, the prophylactically effective amount is an amount sufficient for reducing the risk of developing an age-related disease or disorder and reducing reactive oxygen species levels in a subject in need thereof. In some embodiments, the prophylactically effective amount is an amount sufficient for reducing the risk of developing an age-related disease or disorder and reducing pro-inflammatory signaling in a subject in need thereof. In some embodiments, the prophylactically effective amount is an amount sufficient for reducing the risk of developing an age-related disease or disorder and preventing or inhibiting cellular senescence in a subject in need thereof.

[0296] In some embodiments, the prophylactically effective amount is an amount effective for reducing reactive oxygen species levels in a subject in need thereof by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%. In some embodiments, the prophylactically effective amount is an amount effective for reducing reactive oxygen species levels in a subject in need thereof by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.

[0297] In some embodiments, the prophylactically effective amount is an amount effective for reducing pro-inflammatory signaling in a subject in need thereof by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%. In some embodiments, the prophylactically effective amount is an amount effective for reducing pro-inflammatory signaling in a subject in need thereof by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.L0907.70047WO00 109 / 150#14596547vlPharmaceutical Compositions

[0298] The present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, a compound described herein is provided in an effective amount in the pharmaceutical composition. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount.

[0299] In some embodiments, the effective amount is an amount effective for treating an age-related disease or disorder in a subject in need thereof. In some embodiments, the effective amount is an amount effective for preventing an age-related disease or disorder in a subject in need thereof. In some embodiments, the effective amount is an amount effective for reducing the risk of developing an age-related disease or disorder in a subject in need thereof.

[0300] In some embodiments, the effective amount is an amount sufficient for modulating mitochondrial function in a subject in need thereof or in a cell, tissue, or biological sample. In some embodiments, the effective amount is an amount sufficient for reducing reactive oxygen species levels in a subject in need thereof or in a cell, tissue, or biological sample. In some embodiments, the effective amount is an amount sufficient for reducing pro-inflammatory signaling in a subject in need thereof or in a cell, tissue, or biological sample. In some embodiments, the effective amount is an amount sufficient for preventing or inhibiting cellular senescence in a subject in need thereof or in a cell, tissue, or biological sample.

[0301] In some embodiments, the effective amount is an amount effective for reducing reactive oxygen species levels in a subject in need thereof or in a cell, tissue, or biological sample by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%. In some embodiments, the effective amount is an amount effective for reducing reactive oxygen species levels in a subject in need thereof or in a cell, tissue, or biological sample by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.

[0302] In some embodiments, the effective amount is an amount effective for reducing pro-inflammatory signaling in a subject in need thereof or in a cell, tissue, or biological sample by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%. In some embodiments, the effective amount is an amount effective for reducing pro-inflammatory signaling in a subject in need thereof or in a cell, tissue, or biological sample by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.

[0303] In some embodiments, the therapeutically effective amount is an amount effective for treating an age-related disease or disorder in a subject in need thereof.

[0304] In some embodiments, the therapeutically effective amount is an amount sufficient for modulating mitochondrial function in a subject in need thereof. In some embodiments, the therapeuticallyL0907.70047WO00 110 / 150#14596547vleffective amount is an amount sufficient for reducing reactive oxygen species levels in a subject in need thereof. In some embodiments, the therapeutically effective amount is an amount sufficient for reducing pro-inflammatory signaling in a subject in need thereof. In some embodiments, the therapeutically effective amount is an amount sufficient for preventing or inhibiting cellular senescence in a subject in need thereof.

[0305] In some embodiments, the therapeutically effective amount is an amount sufficient for treating an age-related disease or disorder and modulating mitochondrial function in a subject in need thereof. In some embodiments, the therapeutically effective amount is an amount sufficient for treating an age-related disease or disorder and reducing reactive oxygen species levels in a subject in need thereof. In some embodiments, the therapeutically effective amount is an amount sufficient for treating an age-related disease or disorder and reducing pro-inflammatory signaling in a subject in need thereof. In some embodiments, the therapeutically effective amount is an amount sufficient for treating an age-related disease or disorder and preventing or inhibiting cellular senescence in a subject in need thereof.

[0306] In some embodiments, the therapeutically effective amount is an amount effective for reducing reactive oxygen species levels in a subject in need thereof by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%. In some embodiments, the therapeutically effective amount is an amount effective for reducing reactive oxygen species levels in a subject in need thereof by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.

[0307] In some embodiments, the therapeutically effective amount is an amount effective for reducing pro-inflammatory signaling in a subject in need thereof by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%. In some embodiments, the therapeutically effective amount is an amount effective for reducing pro-inflammatory signaling in a subject in need thereof by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.

[0308] In some embodiments, the prophylactically effective amount is an amount effective for preventing an age-related disease or disorder in a subject in need thereof. In some embodiments, the prophylactically effective amount is an amount effective for reducing the risk of developing an age-related disease or disorder in a subject in need thereof.

[0309] In some embodiments, the prophylactically effective amount is an amount sufficient for preventing an age-related disease or disorder and modulating mitochondrial function in a subject in need thereof. In some embodiments, the prophylactically effective amount is an amount sufficient for preventing an age-related disease or disorder and reducing reactive oxygen species levels in a subject in need thereof. In some embodiments, the prophylactically effective amount is an amount sufficient for preventing an age-related disease or disorder and reducing pro-inflammatory signaling in a subject in need thereof. In some embodiments, the prophylactically effective amount is an amount sufficient forL0907.70047WO00 111 / 150#14596547vlpreventing an age-related disease or disorder and preventing or inhibiting cellular senescence in a subject in need thereof.

[0310] In some embodiments, the prophylactically effective amount is an amount sufficient for reducing the risk of developing an age-related disease or disorder and modulating mitochondrial function in a subject in need thereof. In some embodiments, the prophylactically effective amount is an amount sufficient for reducing the risk of developing an age-related disease or disorder and reducing reactive oxygen species levels in a subject in need thereof. In some embodiments, the prophylactically effective amount is an amount sufficient for reducing the risk of developing an age-related disease or disorder and reducing pro-inflammatory signaling in a subject in need thereof. In some embodiments, the prophylactically effective amount is an amount sufficient for reducing the risk of developing an age-related disease or disorder and preventing or inhibiting cellular senescence in a subject in need thereof.

[0311] In some embodiments, the prophylactically effective amount is an amount effective for reducing reactive oxygen species levels in a subject in need thereof by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%. In some embodiments, the prophylactically effective amount is an amount effective for reducing reactive oxygen species levels in a subject in need thereof by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.

[0312] In some embodiments, the prophylactically effective amount is an amount effective for reducing pro-inflammatory signaling in a subject in need thereof by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%. In some embodiments, the prophylactically effective amount is an amount effective for reducing pro-inflammatory signaling in a subject in need thereof by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.

[0313] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, into association with a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping, and / or packaging the product into a desired single- or multi-dose unit.

[0314] Relative amounts of the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, the pharmaceutically acceptable carrier, and / or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered.

[0315] Pharmaceutically acceptable carriers used in the manufacture of provided pharmaceutical compositions include inert diluents, solvents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricatingL0907.70047WO00 112 / 150#14596547vlagents, oils, butters, and / or waxes. Excipients such as coloring agents, coating agents, sweetening agents, flavoring agents, and fragrances may also be present in the composition.

[0316] The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, intradermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, buccal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and / or lymph supply, and / or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the compound (e.g., its stability in the environment of the gastrointestinal tract), and / or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).

[0317] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with ordinary experimentation.

[0318] Compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0319] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In some embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of a compound described herein.

[0320] In some embodiments, the provided compound is provided in a dose. In some embodiments, theL0907.70047WO00 113 / 150#14596547vldose is about 5 mg / kg. In some embodiments, the dose is about 12.5 mg / kg. In some embodiments, the dose is about 25 mg / kg. In some embodiments, the dose is about 37.5 mg / kg. In some embodiments, the dose is a range between about one amount described in this paragraph and about another amount described in this paragraph, inclusive.

[0321] A compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophylactically active agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents, for example, to improve the compound or composition activity (e.g., potency and / or efficacy) in treating a disease, disorder, or condition in a subject in need thereof, in preventing a disease, disorder, or condition in a subject in need thereof e.g., in reducing the risk of developing a disease, disorder, or condition in a subject with such a predisposition), and / or to improve bioavailability and / or safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in a subject or cell. It will also be appreciated that the treatment employed may achieve a desired effect for the same disease, disorder, or condition, and / or it may achieve different effects.

[0322] In some embodiments, the pharmaceutical composition is for use in treating an age-related disease or disorder associated with the glutamate pathway in a subject in need thereof. In some embodiments, the pharmaceutical composition is for use in preventing an age-related disease or disorder associated with the glutamate pathway in a subject in need thereof. In some embodiments, the pharmaceutical composition is for use in treating an age-related disease or disorder associated...

Claims

1. CLAIMS2.What is claimed is:

1. A method of treating an age-related disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof:4.a therapeutically effective amount of a compound of Formula (I):

6. 8.or a pharmaceutically acceptable salt thereof; or9.a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and an excipient; wherein:10.R1is optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;11.R2is hydrogen, optionally substituted alkyl, -ORA, or -N(RA)2;12.Z is CR3AorN;13.each occurrence of RYis independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, =0, =S, -CN, -0RA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORa)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(ORA)2; each of R3A, R3Band R3Cis independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -0RA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA,14.L0907.70047WO00 130 / 15015.#14596547vl -C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORa)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(ORA)2; each occurrence of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; and16.n is 0, 1, 2, 3, 4, 5, 6, or 7.

2. The method of claim 1, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

3. The method of claim 1, comprising administering to the subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and an excipient.

4. A method of preventing an age-related disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof:20.a prophylactically effective amount of a compound of Formula (I):

22. 24.or a pharmaceutically acceptable salt thereof; or25.a pharmaceutical composition comprising a prophylactically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and an excipient; wherein:26.L0907.70047WQ00 131 / 15027.#14596547vl R1is optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;28.R2is hydrogen, optionally substituted alkyl, -ORA, or -N(RA)2;29.Z is CR3AorN;30.each occurrence of RYis independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, =0, =S, -CN, -0RA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -N02, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=0)N(RA)2, -C(=NRA)RA, -C(=NRA)0RA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -0C(=0)N(RA)2, -0C(=NRA)RA, -0C(=NRA)0RA, -OC(=NRA)SRA, -0C(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -0N(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=0)RA, -NRAC(=0)0RA, -NRAC(=O)SRA, -NRAC(=0)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)0RA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORa)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(ORA)2; each of R3A, R3Band R3Cis independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -0RA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -N02, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=0)N(RA)2, -C(=NRA)RA, -C(=NRA)0RA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -0C(=0)N(RA)2, -0C(=NRA)RA, -0C(=NRA)0RA, -OC(=NRA)SRA, -0C(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -0N(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=0)RA, -NRAC(=0)0RA, -NRAC(=O)SRA, -NRAC(=0)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)0RA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORa)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(ORA)2; each occurrence of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted31.L0907.70047WO00 132 / 15032.#14596547vl heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; and33.n is 0, 1, 2, 3, 4, 5, 6, or 7.

5. The method of claim 4, comprising administering to the subject in need thereof a prophylactically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

6. The method of claim 4, comprising administering to the subject in need thereof a pharmaceutical composition comprising a prophylactically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and an excipient.

7. The method of any one of claims 1-6, wherein the age-related disease or disorder is a metabolic disorder associated with ageing (e.g., obesity, diabetes, a liver disease (e.g., non-alcoholic fatty liver disease)), adipose tissue dysfunction, muscular atrophy (e.g., muscle wasting, such as age-related muscular atrophy, frailty, etc.), organ dysfunction associated with ageing (e.g. lung fibrosis, etc.), or a cardiovascular disease (e.g., atherosclerosis).

8. The method of any one of claims 1-7, wherein the age-related disease or disorder is a metabolic disorder associated with ageing (e.g., obesity, diabetes, a liver disease (e.g., non-alcoholic fatty liver disease)).

9. The method of any one of claims 1-8, wherein the age-related disease or disorder is obesity.

10. The method of any one of claims 1-7, wherein the age-related disease or disorder is adipose tissue dysfunction.

11. The method of any one of claims 1-7, wherein the age-related disease or disorder is muscular atrophy (e.g., muscle wasting, such as age-related muscular atrophy, frailty, etc.).

12. The method of any one of claims 1-7, wherein the age-related disease or disorder is organ dysfunction associated with ageing (e.g. lung fibrosis, etc.).

13. The method of any one of claims 1-7, wherein the age-related disease or disorder is a43.L0907.70047WO00 133 / 15044.#14596547vl cardiovascular disease (e.g., atherosclerosis).

14. A method of modulating mitochondrial function in a cell, tissue, or biological sample, or in a subject in need thereof, comprising contacting the cell, tissue, or biological sample with or administering to the subject in need thereof:46.an effective amount of a compound of Formula (I):

48. 50.or a pharmaceutically acceptable salt thereof; or51.a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and an excipient; wherein:52.R1is optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;53.R2is hydrogen, optionally substituted alkyl, -ORA, or -N(RA)2;54.Z is CR3AorN;55.each occurrence of RYis independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, =0, =S, -CN, -0RA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORa)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(ORA)2; each of R3A, R3Band R3Cis independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -0RA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA,56.L0907.70047WQ00 134 / 15057.#14596547vl -C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, — Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORa)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(ORA)2; each occurrence of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; and58.n is 0, 1, 2, 3, 4, 5, 6, or 7.

15. A method of reducing reactive oxygen species levels in a cell, tissue, or biological sample, or in a subject in need thereof, comprising contacting the cell, tissue, or biological sample with or administering to the subject in need thereof:60.an effective amount of a compound of Formula (I):61.R- Z= / 62.N64.

65. (I),66.or a pharmaceutically acceptable salt thereof; or67.a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and an excipient; wherein:68.R1is optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;69.R2is hydrogen, optionally substituted alkyl, -ORA, or -N(RA)2;70.Z is CR3AorN;71.each occurrence of RYis independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally72.L0907.70047WO00 135 / 15073.#14596547vl substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, =0, =S, -CN, -0RA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -N02, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=0)N(RA)2, -C(=NRA)RA, -C(=NRA)0RA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -0C(=0)N(RA)2, -0C(=NRA)RA, -0C(=NRA)0RA, -OC(=NRA)SRA, -0C(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -0N(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=0)RA, -NRAC(=0)0RA, -NRAC(=O)SRA, -NRAC(=0)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)0RA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, — Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORa)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(ORA)2; each of R3A, R3Band R3Cis independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -ORA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=0)N(RA)2, -C(=NRA)RA, -C(=NRA)0RA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -0C(=0)N(RA)2, -0C(=NRA)RA, -0C(=NRA)0RA, -OC(=NRA)SRA, -0C(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -0N(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=0)RA, -NRAC(=0)0RA, -NRAC(=O)SRA, -NRAC(=0)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)0RA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=0)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, — Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORa)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(0RA)2; each occurrence of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; and74.L0907.70047WO00 136 / 15075.#14596547vl nis 0, 1, 2, 3,4, 5, 6, or 7.

16. A method of reducing pro-inflammatory signaling in a cell, tissue, or biological sample, or in a subject in need thereof, comprising contacting the cell, tissue, or biological sample with or administering to the subject in need thereof:77.an effective amount of a compound of Formula (I):

79. 81.or a pharmaceutically acceptable salt thereof; or82.a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and an excipient; wherein:83.R1is optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;84.R2is hydrogen, optionally substituted alkyl, -ORA, or -N(RA)2;85.Z is CR3AorN;86.each occurrence of RYis independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, =0, =S, -CN, -0RA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORa)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(ORA)2; each of R3A, R3Band R3Cis independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -0RA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA,87.L0907.70047WQ00 137 / 15088.#14596547vl -C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, — Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORa)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(ORA)2; each occurrence of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; and89.n is 0, 1, 2, 3, 4, 5, 6, or 7.

17. A method of preventing or inhibiting cellular senescence in a cell, tissue, or biological sample, or in a subject in need thereof, comprising contacting the cell, tissue, or biological sample with or administering to the subject in need thereof:91.an effective amount of a compound of Formula (I):92.R- Z= / 93.N95.

96. (I),97.or a pharmaceutically acceptable salt thereof; or98.a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and an excipient; wherein:99.R1is optionally substituted carbocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;100.R2is hydrogen, optionally substituted alkyl, -ORA, or -N(RA)2;101.Z is CR3AorN;102.each occurrence of RYis independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally103.L0907.70047WO00 138 / 150104.#14596547vl substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, =0, =S, -CN, -0RA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -N02, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=0)N(RA)2, -C(=NRA)RA, -C(=NRA)0RA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -0C(=0)N(RA)2, -0C(=NRA)RA, -0C(=NRA)0RA, -OC(=NRA)SRA, -0C(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -0N(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=0)RA, -NRAC(=0)0RA, -NRAC(=O)SRA, -NRAC(=0)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)0RA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, — Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORa)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(ORA)2; each of R3A, R3Band R3Cis independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -ORA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=0)N(RA)2, -C(=NRA)RA, -C(=NRA)0RA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -0C(=0)N(RA)2, -0C(=NRA)RA, -0C(=NRA)0RA, -OC(=NRA)SRA, -0C(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -0N(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=0)RA, -NRAC(=0)0RA, -NRAC(=O)SRA, -NRAC(=0)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)0RA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=0)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, — Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORa)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(0RA)2; each occurrence of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of RAare joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; and105.L0907.70047WO00 139 / 150106.#14596547vl n is 0, 1, 2, 3, 4, 5, 6, or 7.

18. The method of any one of claims 1-17, wherein the subject has or is suspected of having a metabolic disorder associated with ageing (e.g., obesity, diabetes, a liver disease (e.g., non-alcoholic fatty liver disease)), adipose tissue dysfunction, muscular atrophy (e.g., muscle wasting, such as age-related muscular atrophy, frailty, etc.), organ dysfunction associated with ageing (e.g. lung fibrosis, etc.), or a cardiovascular disease (e.g., atherosclerosis).

19. The method of any one of claims 1-18, wherein the subject is characterized as having decreased glutamine levels, increased glutamate levels, increased pro-inflammatory signaling, adipose tissue dysfunction, mitochondrial dysfunction, increased cellular senescence, and / or increased reactive oxygen species production.

20. The method of any one of claims 1-19, wherein the subject is a human subject.

21. The method of claim 16, wherein the reduction in pro-inflammatory signaling comprises decreasing a level of a cytokine.

22. The method of any one of claims 14-21, comprising contacting the cell, tissue, or biological sample with or administering to the subject in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

23. The method of any one of claims 14-21, comprising contacting the cell, tissue, or biological sample with or administering to the subject in need thereof a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and an excipient.

24. The method of any one of claims 1-23, wherein the administration comprises peripheral administration.

25. The method of claim 24, wherein the peripheral administration comprises intrathecal injection, subcutaneous injection, intramuscular injection or intravenous injection.

26. The method of claim 24 or 25, wherein the peripheral administration comprises direct administration to a target tissue.

27. The method of any one of claims 24-26, wherein the peripheral administration comprises direct administration to heart tissue, liver tissue, muscle tissue, or brain tissue.117.L0907.70047WO00 140 / 150118.#14596547vl 28. The method of any one of claims 14-23, wherein the cell is a human cell, optionally wherein the cell is in a subject.

29. The method of any one of claims 14-23 and 28, wherein the cell is a senescent cell.

30. The method of any one of claims 14-23, 28, and 29, wherein the cell is an adipose cell.

31. The method of any one of claims 14-23, 28, and 29, wherein the cell is a muscle cell, optionally wherein the muscle cell is a skeletal muscle cell.

32. The method of any one of claims 14-23, 28, and 29, wherein the cell is a liver cell.

33. The method of any one of claims 1-32, wherein the compound is of Formula (I-a):

125.

126. (I-a), or a pharmaceutically acceptable salt thereof.

34. The method of any one of claims 1-33, wherein the compound is of Formula (I-a- 1 ) or (I-a-3):

129. 131.or a pharmaceutically acceptable salt thereof.

35. The method of any one of claims 1-33, wherein the compound is of Formula (I-d-1):

134. 136.or a pharmaceutically acceptable salt thereof.137.L0907.70047WO00 141 / 150138.#14596547vl 36. The method of any one of claims 1-33 and 35, wherein the compound is of Formula (I-d-2) or (I-d-3):

140. 142.or a pharmaceutically acceptable salt thereof.

37. The method of any one of claims 1-36, wherein R1is optionally substituted aryl.

38. The method of any one of claims 1-37, wherein R1is optionally substituted phenyl.

39. The method of any one of claims 1-38, wherein R1is phenyl.

40. The method of any one of claims 1-39, wherein R1is phenyl substituted with one or more of halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -ORA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORa)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(ORA)2.

41. The method of any one of claims 1-40, wherein R1is phenyl substituted with one or more of halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2.148.L0907.70047WO00 142 / 150149.#14596547vl 42. The method of any one of claims 1-40, wherein:

151. 153.each occurrence of Rlais independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -ORA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORa)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(ORA)2; and154.ml is 0, 1, 2, 3, 4, or 5.

43. The method of claim 42, wherein R1is:156.R1a158.

44. The method of any one of claims 1-43, wherein R161. 162.1is164.

45. The method of any one of claims 1-36, wherein R1is optionally substituted heteroaryl.167.L0907.70047WO00 143 / 150168.#14596547vl 46. The method of any one of claims 1-36 and 45, wherein R1is pyridyl substituted with one or more of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -ORA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORa)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(ORA)2.

47. The method of any one of claims 1-36, 45, and 46, wherein R1is pyridyl substituted with one or more of halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, -ORA, or -N(RA)2.

48. The method of any one of claims 1-36, 45, and 46, wherein:171.(R1a)m2172.R1is of formula173.

174. (a-2);175.each occurrence of Rlais independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -ORA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA,176.L0907.70047WO00 144 / 150177.#14596547vl -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORa)2, -Si(ORA)3, -OSi(RA)3, - OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(ORA)2; and178.m2 is 0, 1, 2, 3, or 4.

49. The method of claim 48, wherein R1is:

181.

50. The method of any one of claims 1-36 and 45-49, wherein R1is:

185.

51. The method of any one of claims 1-36 and 45, wherein:188.R1is of formula:

189.

190. (a-3);191.each occurrence of Rlais independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -ORA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA,192.L0907.70047WO00 145 / 150193.#14596547vl -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORa)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(ORA)2; and194.and m3 is 0, 1, 2, or 3.

196.

53. The method of any one of claims 1-50, wherein the compound is of Formula (I-f-1), (I-f-2), (I-f- 3), (I-h-1), (I-h-2), or (I-h-3):

200. 202.L0907.70047WO00 146 / 150203.#14596547vl (I-f-3),205. 207.or a pharmaceutically acceptable salt thereof.

54. The method of any one of claims 1-50 and 53, wherein the compound is of Formula (I-o):

210. 212.or a pharmaceutically acceptable salt thereof.

55. The method of any one of claims 1-50, 53, and 54, wherein the compound is of Formula (I-O-2)214.L0907.70047WO00 147 / 150215.#14596547vl or (I-o-3):

217. 219.or a pharmaceutically acceptable salt thereof.

56. The method of any one of claims 1-50, 53, and 54, wherein the compound is of Formula (I-O-5) or (I-o-6):

222. 224.or a pharmaceutically acceptable salt thereof.

57. The method of any one of claims 1-56, wherein at least one occurrence of RYis -F or -CH3.

58. The method of any one of claims 1-57, wherein n is 0, 1, or 2.

59. The method of any one of claims 1-53, wherein at least one of R3A, R3Band R3Cis hydrogen or halogen.

60. The method of any one of claims 1-53 and 59, wherein R3Cis hydrogen or -Cl.

61. The method of any one of claims 1-60, wherein R2is hydrogen, -ORA, or -N(RA)2.230.L0907.70047WO00 148 / 150231.#14596547vl 62. The method of any one of claims 1-61, wherein R2is hydrogen or -ORA.

63. The method of any one of claims 1-61, wherein R2is hydrogen, -OCH3, or -N(CH3)2.

64. The method of any one of claims 1-63, wherein the compound is selected from those in Table 1, and pharmaceutical ly acceptable salts thereof.234.L0907.70047WO00 149 / 150235.#14596547vl

Images