1H-Pyrazole Analogs and Methods and Uses Thereof

Abstract

A compound having the structure of Formula (I), a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a tautomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, an N-oxide thereof, a metabolite thereof, an isotopomer thereof, an isotopologue thereof, a prodrug thereof, or a combination thereof. The compound / composition can be used for the prevention and / or treatment of diseases, conditions, and / or disorders associated with oxidative stress, such as, but not limited to, neurodegeneration, aging, etc. JPEG2025535388000031.jpg80166

Description

[Technical Field]

[0001] The present disclosure relates to compounds, and methods and uses thereof. Specifically, the present disclosure relates to 1H-pyrazole analogs, and methods and uses thereof. [Background technology]

[0002] Current evidence collectively demonstrates that amyotrophic lateral sclerosis (ALS) is an extremely complex, multifactorial, life-threatening, degenerative motor neuron disease with distinct pathophysiology and progression due to a cascade of potential mechanisms.Unfortunately, evidence regarding the pathomechanisms of ALS is unclear, and there is currently no cure for the disease.

[0003] Therapeutic strategies to combat this disease have minimal therapeutic efficacy and scope due to modest survival benefits, high economic burden, and difficulty in synthesis. One such therapeutic strategy, edaravone (EDR; 3-methyl-1-phenyl-2-pyrazolin-5-one), has been approved for ALS in some jurisdictions (e.g., by the FDA (May 2017) [1] and by Health Canada (October 2018) [2] for the treatment of ALS).

[0004] The structure of the EDR is shown below.

[0005] [ka]

[0006] However, EDR has limitations, including those related to patient compliance, pharmacokinetics, and oral bioavailability.

[0007] New DER analogs and compositions thereof are needed to provide useful alternatives to EDR.

[0008] The background art herein is included solely to explain the context of the application and should not be construed as an admission that any of the material referenced was published, publicly known, or part of the general knowledge as of the priority date. Summary of the Invention

[0009] In one aspect, Formula I:

[0010] [ka]

[0011] a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a tautomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, an N-oxide thereof, a metabolite thereof, an isotopomer thereof, an isotopologue thereof, a prodrug thereof, or a combination thereof. (In the formula, X1-BR 8 R 9 or -BR 10 R 11 R 12 Selected from; R 1 From R 7 , R 10 , R 11 , and R 12 each independently represents H, a halo group, a hydroxyl group, a cyano group, a nitro group, a thiol group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterogeneous group, -BR 13 R 14 , -BR 15 R 16 R 17 , a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group; R 13 From R 17are each independently selected from H, a halo group, a hydroxyl group, a cyano group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group; or R 13 and R 14 taken together form a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group, R 8 and R 9 are each independently selected from H, a halo group, a hydroxyl group, a cyano group, a nitro group, a thiol group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterogeneous group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, or together form a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group).

[0012] In another aspect, there are pharmaceutical compositions comprising the compounds described herein.

[0013] In another aspect, there is a method for preventing and / or treating diseases, conditions, and / or disorders associated with oxidative stress, comprising administering to a mammal a therapeutically effective amount of a compound described herein or a composition described herein.

[0014] In yet another aspect, there is the use of a therapeutically effective amount of a compound described herein or a composition described herein for preventing and / or treating diseases, conditions, and / or disorders associated with oxidative stress.

[0015] It will be understood that one or more of the embodiments described herein (and described above) may be combined in any suitable manner. The novel features of the present invention will become apparent to those skilled in the art upon examination of the detailed description that follows. However, the detailed description and the specific examples presented, while illustrating certain particular embodiments of the invention, are provided for illustrative purposes only, as various changes and modifications within the scope of the invention will become apparent to those skilled in the art from the detailed description and the claims that follow.

[0016] The invention will be better understood from the following description taken in conjunction with the drawings. [Brief explanation of the drawings]

[0017] [Figure 1] 1 shows the chemical structures of edaravone (EDR) in both keto and enol forms. [Figure 2] An example of the chemical structure of the 1H-pyrazole analogue (B5-EDR) of the EDR of Figure 1 is shown. [Figure 3] 1 shows an illustration of an example of a B5-EDR analog from FIG. 2 that acts as a prodrug, generating EDR in vivo via H 2 O 2 metabolism. [Figure 4A] An example of the chemical reaction of B5-EDR analog with HO to produce edaravone (EDR) and the corresponding TLC plots are shown. TLC A: SM = starting material; Mix = mixture of SM and CRM; CRM = crude reaction mixture; TLC B: ISO = isolated product; Mix = mixture of isolated product and EDR; and EDR = edaravone. [Figure 4B] An example of the chemical reaction of B5-EDR analog with HO to produce edaravone (EDR) and the corresponding TLC plots are shown. TLC A: SM = starting material; Mix = mixture of SM and CRM; CRM = crude reaction mixture; TLC B: ISO = isolated product; Mix = mixture of isolated product and EDR; and EDR = edaravone. [Figure 5] 1 shows exemplary structures of B5-EDR synthetic analogs of the present disclosure. [Figure 6A]An example graph showing the percentage viability of primary neuronal cell cultures (PNCCs) treated with EDR and B5-EDR analogs NS-1-2, NS-1-12, NS-1-13, NS-19, and NS-1-21 is shown. Data are presented as mean ± standard error (error bars), with an n = 12 data points or sample size. Data were analyzed using one-way AVONA followed by Dunnett's multiple comparison test (*P < 0.05, **P = 0.01, and ***P = 0.001 vs. control (DMSO)). Data are representative of two independent experiments, and each measurement or dose was tested six times. [Figure 6B] An example graph showing the percentage viability of primary neuronal cell cultures (PNCCs) treated with EDR and B5-EDR analogs NS-1-2, NS-1-12, NS-1-13, NS-19, and NS-1-21 is shown. Data are presented as mean ± standard error (error bars), with an n = 12 data points or sample size. Data were analyzed using one-way AVONA followed by Dunnett's multiple comparison test (*P < 0.05, **P = 0.01, and ***P = 0.001 vs. control (DMSO)). Data are representative of two independent experiments, and each measurement or dose was tested six times. [Figure 7A] An example graph showing the percent viability of neuroblastoma spinal cord NSC-34 cells treated with EDR and B5-EDR analogs NS-1-2, NS-1-12, NS-1-13, NS-19, and NS-1-21 is shown. Data are presented as mean ± standard error (error bars), with an n = 9 data point or sample size. Data were analyzed using one-way analysis of variance (ANOVA) followed by Dunnett's multiple comparison test (*P < 0.05 vs. control (DMSO)). Data are representative of three independent experiments, and each measurement or dose was tested in triplicate. [Figure 7B]An example graph showing the percent viability of neuroblastoma spinal cord NSC-34 cells treated with EDR and B5-EDR analogs NS-1-2, NS-1-12, NS-1-13, NS-19, and NS-1-21 is shown. Data are presented as mean ± standard error (error bars), with an n = 9 data point or sample size. Data were analyzed using one-way analysis of variance (ANOVA) followed by Dunnett's multiple comparison test (*P < 0.05 vs. control (DMSO)). Data are representative of three independent experiments, and each measurement or dose was tested in triplicate. [Figure 7C] An example graph showing the percent viability of neuroblastoma spinal cord NSC-34 cells treated with EDR and B5-EDR analogs NS-1-2, NS-1-12, NS-1-13, NS-19, and NS-1-21 is shown. Data are presented as mean ± standard error (error bars), with an n = 9 data point or sample size. Data were analyzed using one-way analysis of variance (ANOVA) followed by Dunnett's multiple comparison test (*P < 0.05 vs. control (DMSO)). Data are representative of three independent experiments, and each measurement or dose was tested in triplicate. [Figure 8A] Figure 1 shows an example graph depicting the percent viability of neuroblastoma spinal cord NSC-34 cells treated with the EDR and B5-EDR analogs NS-1-2, NS-1-12, NS-1-13, NS-19, and NS-1-21 in response to hydrogen peroxide-induced oxidative stress. Data are presented as mean ± standard error (error bars), with an n = 9 data points or sample size. Data were analyzed using one-way analysis of variance (ANOVA) followed by Dunnett's multiple comparison test (vs. HO, DMSO: ####P<0.0001 vs. control (DMSO), *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001; ns=not significant). All data are representative of three independent experiments, and each measurement or dose was tested in triplicate. [Figure 8B]Figure 1 shows an example graph depicting the percent viability of neuroblastoma spinal cord NSC-34 cells treated with the EDR and B5-EDR analogs NS-1-2, NS-1-12, NS-1-13, NS-19, and NS-1-21 in response to hydrogen peroxide-induced oxidative stress. Data are presented as mean ± standard error (error bars), with an n = 9 data points or sample size. Data were analyzed using one-way analysis of variance (ANOVA) followed by Dunnett's multiple comparison test (vs. HO, DMSO: ####P<0.0001 vs. control (DMSO), *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001; ns=not significant). All data are representative of three independent experiments, and each measurement or dose was tested in triplicate. [Figure 9] FIG. 1 shows an example of a schematic timeline of ALS development in an experimental mouse model (SOD1G37R), with reference to representative human endpoints. [Figure 10] 1 shows an example plot depicting the mean body weight of the entire set of WG37R control and treated animal groups during the 14-day acute toxicity assessment. Data are presented as mean ± SEM. [Figure 11] 1 shows an example plot depicting the mean body weight of the entire set of WG37R control and treated animal groups during the 120-day chronic toxicity assessment. Data are presented as mean ± SEM. [Figure 12] Example photomicrographs of hematoxylin and eosin (H&E) stained sections from two representative G37RWT male mice during the 14-day acute toxicity assessment are shown. There were six mice (three males and three females) in each group. Original magnification 10x (scale bar represents 20 μm). [Figure 13] Example photomicrographs of hematoxylin and eosin (H&E) stained sections from two representative G37RWT female mice during the 14-day acute toxicity assessment are shown. There were six mice (three males and three females) in each group. Original magnification 10x (scale bar represents 20 μm). [Figure 14]An example graph of survival (human endpoint) in G37R (strain 42) mice is shown. Data are presented as mean ± SEM (n = 10). n = number of animals of the indicated genotype. Differences in survival (days) were analyzed using a two-tailed (unpaired t-test) to compare relative differences between NS-1-2 (treated) and vehicle-treated G37R (strain 42) mice, with the significance level set at P < 0.05. *P < 0.05 vs. control G37R. [Figure 15] An example of a plot of percent survival in G37R (strain 42) mice is shown. Data are presented as mean ± SEM (n = 10), where n = number of animals of the indicated genotype. Data were analyzed for statistical significance (P < 0.05) using the Kaplan-Meier log-rank (Mantel-Cox) test for plots of percent survival (human endpoints) in Het G37R (strain 42) ALS model mice. [Figure 16] An example graph showing the percentage of weight loss (human endpoint) based on the highest weight recorded in G37R (strain 42) mice is shown. n = number of animals of the indicated genotype. Data are presented as mean ± SEM (n = 10). Percentage of weight loss at the human endpoint was analyzed using a two-tailed (unpaired t-test) to compare the relative differences between NS-1-2 (treated) and vehicle-treated G37R (strain 42) mice, with the significance level set at P < 0.05. ****P < 0.0001 vs. control G37R. [Figure 17] An example graph showing the age at disease onset (10% weight loss accompanied by muscle weakness) is shown. Data are presented as mean ± SEM (n=10). n=number of animals of the indicated genotype. Disease onset was analyzed using a two-tailed (unpaired t-test) and the number of days to disease onset, defined as 10% weight loss accompanied by muscle weakness, is shown, with the significance level set at P<0.05. **P<0.01 vs. control G37R. [Figure 18]An example graph showing age at disease onset (time to peak weight in days) is shown. Data are presented as mean ± SEM (n=10). n=number of animals of the indicated genotype. Disease onset was analyzed using a two-tailed (unpaired t-test) and represents the number of days to disease onset, retrospectively defined as the age at which mice reach peak weight, with significance set at P<0.05. **P<0.01 vs. control G37R. [Figure 19] An example graph showing age of disease onset (time to peak weight in days) is shown. Data are presented as mean ± SEM (n = 10). n = number of animals of the indicated genotype. Data were analyzed using the Kaplan-Meier log-rank (Mantel-Cox) test to determine the age of disease onset (age at reaching peak weight) in Het G37R (strain 42) ALS model mice with statistical significance (**P < 0.01). DETAILED DESCRIPTION OF THE INVENTION

[0018] definition Unless otherwise specified, all technical and scientific terms used herein have the same meaning as that commonly understood by those skilled in the art to which this disclosure belongs.The definition of common terms in molecular biology can be found in Benjamin Lewin, Genes V, Oxford University Press, 1994 (ISBN 0-19-854287-9); Kendrew et al. (ed.), The Encyclopedia of Molecular Biology, Blackwell Science Ltd., 1994 (ISBN 0-632-02182-9); and Robert A. Meyers (ed.), Molecular Biology and Biotechnology: a Comprehensive Desk Reference, VCH Publishers, Inc., 1995 (ISBN 1-56081-569-8).Any method and material similar to or equivalent to the method and material described herein can be used to practice the test of the present invention, but typical materials and methods are described herein. In describing and claiming the present invention, the following terminology will be used.

[0019] It should also be understood that the terms used herein are for the purpose of describing particular embodiments only and are not intended to be limiting. Any patent applications, patents, and publications are cited herein to aid in the understanding of the described embodiments. All such references cited herein are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication or patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. To the extent that the publications and patents or patent applications incorporated by reference conflict with the disclosure contained in the specification, the present specification is intended to supersede and / or take precedence over any such conflicting matter.

[0020] In understanding the scope of this application, the articles "a," "an," "the," and "said" are intended to mean that one or more elements are present. Accordingly, the term "comprising" and its variants, as used herein, are intended to be open-ended terms that specify the presence of stated features, elements, components, groups, integers, and / or steps, but do not exclude the presence of other features, elements, components, groups, integers, and / or steps that are not recited. The foregoing also applies to words of similar meaning, such as the terms "including," "having," and variants thereof.

[0021] Any embodiment described as "comprising" certain components may also be "consist of" or "consist essentially of," with "consisting" having a closed-ended or restrictive meaning, and "consisting essentially of" being understood to mean including the specified components, but excluding other components other than materials present as impurities that are unavoidable constituents present as a result of the process used to provide the components, and as components added for purposes other than achieving the technical effects of the invention. For example, a composition defined using the phrase "consisting essentially of" encompasses any known acceptable additives, excipients, diluents, carriers, etc. Typically, a composition consisting essentially of a set of components contains less than 5% by weight, typically less than 3% by weight, more typically less than 1% by weight, and even more typically less than 0.1% by weight of the unspecified components.

[0022] It is understood that any component defined herein to be included may be expressly excluded from the claimed invention by proviso or negative limitation.

[0023] In addition, all ranges presented herein include the endpoints of the range, whether or not explicitly stated, and also include any intermediate points of the range.

[0024] Terms of degree, such as "substantially," "about," and "approximately," as used herein, refer to a reasonable amount of deviation from the modified term such that the end result is not significantly altered. These terms of degree should be construed to include a deviation of at least ±5% from the modified term, provided that such deviation does not negate the meaning of the word they modify.

[0025] The abbreviation "eg" is derived from the Latin "exempli gratia," and is used herein to indicate a non-limiting example. Thus, the abbreviation "eg" is synonymous with the term "for example."

[0026] The phrase "at least one of" is understood to mean one or more. The phrase "at least one of... and...", if not explicitly listed, is understood to mean at least one of the listed elements, or a combination thereof. For example, "at least one of A, B, and C" is understood to mean A only, or B only, or C only, or a combination of A and B, or A and C, or a combination of B and C, or a combination of A, B, and C.

[0027] The terms "formulation" and "composition" may be used interchangeably.

[0028] The terms "therapeutically effective amount," "effective amount," or "sufficient amount" can be considered to be an amount sufficient to achieve a desired result, for example, an amount effective to alleviate to some extent one or more of the symptoms of the disorder / disease being treated, when administered to a subject, including a mammal (e.g., a human). The effective amount of the compounds described herein may vary depending on factors such as the age, sex, and weight of the subject. The dosage or treatment regimen may be adjusted to provide an optimal therapeutic response, as will be understood by those skilled in the art. Furthermore, a treatment regimen for a subject using a therapeutically effective amount may consist of a single administration or, alternatively, may include a series of applications. The length of the treatment period depends on various factors, such as the compound used, the age of the subject, the concentration of the compound, the patient's responsiveness to the compound, or a combination thereof. It is also understood that the effective dosage of the compound used for treatment may increase or decrease over the course of a particular treatment regimen. Changes in dosage may result and be evident through standard diagnostic assays known in the art.

[0029] As used herein, unless otherwise specified, the terms "prevent," "preventing," and "prevention" may be considered to be the prevention of the onset, recurrence, or spread of a disease, condition, and / or disorder, or one or more symptoms thereof. In certain embodiments, the term particularly refers to treatment or administration of a compound described herein, with or without one or more other additional active agents, to a subject at risk of a disease, condition, and / or disorder provided herein, prior to the onset of symptoms. The term encompasses the inhibition or reduction of symptoms of a particular disease. Subjects with a family history of a disease may be candidates for a preventative regimen in certain embodiments. In this regard, the term "prevention" may be used interchangeably with the term "prophylactic treatment."

[0030] "Administration" with reference to the compounds described herein (e.g., "administering" a compound) can be considered the introduction of the compound into the system of an animal in need of treatment. When a compound of the present disclosure is provided in combination with one or more other therapeutically active agents, "administration" and variants thereof can be understood to include simultaneous and sequential introduction of the compound or a prodrug thereof and the other agent(s), respectively. Administration "in combination with" one or more additional therapeutic agents includes simultaneous (concurrent) and sequential administration, in any order.

[0031] "Amelioration" is considered to be a reduction in the severity of at least one indicator of a condition or disease. In certain embodiments, amelioration includes delaying or slowing the progression of one or more indicators of a condition or disease. The severity of an indicator can be determined by subjective or objective measurements, which are known to those skilled in the art.

[0032] An "analog" generally refers to a compound in which, for example, one or more individual atoms have been replaced with a different atom or a different functional group.

[0033] "Oxidative stress-associated diseases, disorders, and / or conditions" refers to diseases, disorders, and / or conditions in which at least a portion of the pathology / pathophysiology is related to / related to / caused by oxidative stress (definition provided below). Within the context of the present disclosure, this includes, but is not limited to, neurodegenerative diseases, disorders, and / or conditions, metabolic syndrome, cardiovascular diseases, disorders, and / or conditions, autoimmune diseases, disorders, and / or conditions, inflammatory lung diseases, disorders, and / or conditions, kidney diseases, disorders, and / or conditions, liver diseases, disorders, and / or conditions, digestive diseases, disorders, and / or conditions, aging, disorders, and / or conditions, viral infectious diseases, disorders, and / or conditions, cancer, inflammation, sepsis, septic shock, systemic inflammatory response syndrome (SIRS). Examples of oxidative stress-associated diseases, disorders, and / or conditions are provided below.

[0034] "Inhibiting" may be considered to partially, substantially, or completely slow, block, reduce, delay, or prevent. The terms inhibit, reduce, prevent, delay, and slow may be used interchangeably.

[0035] An "integer" may be considered to be any natural number, including zero.

[0036] "Oxidative stress" reflects the systemic expression of reactive oxygen species (ROS) / reactive nitrogen species (RNS) and an imbalance between antioxidants and the excessive expression of free radicals. This process leads to the oxidation of biomolecules with subsequent loss of biological function and / or homeostatic imbalance, and this expression is potentially oxidative damage to cells and tissues. The accumulation of ROS / RNS can produce numerous harmful effects, such as lipid peroxidation, protein oxidation, and DNA damage (including base damage and strand breaks). Furthermore, some reactive oxidative species act as cellular messengers in redox signaling. Thus, oxidative stress can cause disruption to normal mechanisms of cell signaling.

[0037] "Parenteral" administration includes, for example, subcutaneous (sc), intravenous (iv), intramuscular (im), intraperitoneal (ip), or intrasternal injection, infusion techniques, or absorption through mucous membranes.

[0038] "Pharmaceutically acceptable" may be considered, for example, suitable for pharmaceutical use. In embodiments, a compound that is generally safe for administration to mammals (e.g., humans) according to established government standards, including standards promulgated by the U.S. Food and Drug Administration.

[0039] "Pharmaceutically acceptable carriers" include carriers suitable for pharmaceutical use, including, but not limited to, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and / or absorption delaying agents, etc. The use of pharmaceutically acceptable carriers is well known in the art.

[0040] "Prodrug," as used herein, can be considered a compound that is a drug precursor that, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound having the structure of Formula I, or a salt and / or solvate thereof. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) ACS Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, both of which are incorporated herein by reference.

[0041] "Synergistic" or "synergistic therapeutic effect" refers to a greater than additive therapeutic effect produced by the combination of at least two agents that exceeds the effect produced by the individual administration of the agents. For example, lower doses of one or more agents, such as one or more therapeutic agents used to treat ALS, can be used to treat ALS, resulting in increased therapeutic efficacy and reduced side effects.

[0042] A "subject" is considered to be any member of the animal kingdom, typically a mammal. The term "mammal" refers to any animal classified as a mammal, including humans and other higher primates. Typically, the mammal is a human.

[0043] "Treatment" or "treating" may be considered the application of one or more specific procedures used to cure or ameliorate a disease or condition. In certain embodiments, the specific procedure is the administration of one or more pharmaceutical agents.

[0044] The phrase "oxidative stress-associated disease, disorder, and / or condition" is understood to mean at least one of an oxidative stress-associated disease, an oxidative stress-associated disorder, and an oxidative stress-associated condition. Examples of oxidative stress-associated diseases, disorders, and / or conditions are provided below.

[0045] The compounds described herein may have asymmetric centers, chiral axes, and chiral planes (e.g., as described in E.L. Eliel and S.H. Wilen, Stereo-chemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pp. 1119-1190) and may occur as racemates, racemic mixtures, scalemic mixtures, and individual diastereomers, including optical isomers, and all possible isomers (e.g., geometric isomers) and mixtures thereof are included. In addition, the compounds described herein may exist as tautomers, and both tautomeric forms are intended to be encompassed within the scope of the present invention, even if only one tautomeric structure is depicted. The compounds described herein may also include isotopologues (e.g., compounds differing only in isotopic composition (number of isotopic substitutions), e.g., CH3, CH2D, CHD2) and isotopomers (e.g., isomers having the same number of isotopic atoms but differing in their positions).

[0046] Any aspect / embodiment described as a compound, a pharmaceutically acceptable salt thereof, a hydrate, a solvate, a tautomer, a racemic mixture, a scalemic mixture, an enantiomer, a diastereomer, an isotopomer, an isotopologue, a prodrug, or a combination thereof, is understood to mean any one of the compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a tautomer thereof, a racemic mixture thereof, a scalemic mixture thereof, an enantiomer thereof, a diastereomer thereof, an isotopomer thereof, an isotopologue thereof, or a prodrug thereof, in addition to or as an alternative to various combinations thereof.

[0047] In general, with respect to specific compound terms, reference to a particular element, such as hydrogen or H, includes all isotopes of that element, where appropriate.

[0048] The term "alkyl group," whether used alone or within other terms such as "haloalkyl group" and "alkylamino group," encompasses, for example, straight- or branched-chain carbon radicals having from 1 to about 20 carbon atoms, or in certain embodiments, from 1 to about 12 carbon atoms. In other embodiments, alkyl groups are "lower alkyl" groups having from 1 to 6 carbon atoms. Examples of such groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, and the like. In more specific embodiments, lower alkyl groups have from 1 to 4 carbon atoms.

[0049] The term "alkenyl group" encompasses straight- or branched-chain carbon radicals having at least one carbon-carbon double bond. The term "alkenyl group" can encompass conjugated and non-conjugated carbon-carbon double bonds, or a combination thereof. Alkenyl groups can include, for example, without limitation, from 2 to about 20 carbon atoms, or in certain embodiments, from 2 to about 12 carbon atoms. In embodiments, alkenyl groups are "lower alkenyl" groups having from 2 to about 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. The terms "alkenyl group" and "lower alkenyl group" encompass groups having "cis" and "trans" configurations, or alternatively, "E" and "Z" configurations.

[0050] The term "alkoxy group" encompasses, for example, but not limited to, straight-chain or branched-chain oxy-containing groups, each having an alkyl portion of 1 to about 10 carbon atoms. In embodiments, an alkoxy group is a "lower alkoxy" group having 1 to 6 carbon atoms. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, and tert-butoxy. In certain embodiments, a lower alkoxy group has 1 to 3 carbon atoms. An "alkoxy" group can be further substituted with one or more halo atoms, such as fluoro, chloro, or bromo, to provide a "haloalkoxy" group. In other embodiments, a lower haloalkoxy group has 1 to 3 carbon atoms. Examples of such groups include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy, and fluoropropoxy.

[0051] The term "alkylamino group" refers to an amino group substituted with one alkyl group and with two alkyl groups, and includes the terms "N-alkylamino" and "N,N-dialkylamino." In embodiments, an alkylamino group is a "lower alkylamino" group having one or two alkyl groups of 1 to 6 carbon atoms attached to the nitrogen atom. In other embodiments, a lower alkylamino group has 1 to 3 carbon atoms. Suitable "alkylamino" groups can be mono- or dialkylamino, for example, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, etc.

[0052] The term "alkylaminoalkyl group" encompasses aminoalkyl groups having a nitrogen atom independently substituted with an alkyl group. In certain embodiments, alkylaminoalkyl groups are "lower alkylaminoalkyl" groups having alkyl groups of 1 to 6 carbon atoms. In other embodiments, lower alkylaminoalkyl groups have alkyl groups of 1 to 3 carbon atoms. Suitable alkylaminoalkyl groups may be mono- or di-alkyl substituted, such as N-methylaminomethyl, N,N-dimethylaminoethyl, N,N-diethylaminomethyl, and the like.

[0053] The term "alkylaminoalkylamino group" refers to an alkylamino group substituted with one or two alkylamino groups. In embodiments, there are C1-C3 alkylamino-C1-C3 alkylamino groups.

[0054] The term "alkylcarbonyl" refers to a carbonyl group substituted with an alkyl group. In certain embodiments, a "lower alkylcarbonyl" has a lower alkyl group as described above attached to a carbonyl group.

[0055] The term "alkylene group," whether used alone or within other terms such as "haloalkylene group," encompasses, for example, straight- or branched-chain carbon radicals having from 1 to about 20 carbon atoms, or in certain embodiments, from 1 to about 12 carbon atoms. In other embodiments, alkylene groups are "lower alkylene" groups having from 1 to 6 carbon atoms. Examples of such groups include, but are not limited to, methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, tert-butylene, pentylene, iso-amylene, hexylene, and the like. In more specific embodiments, lower alkylene groups have from 1 to 4 carbon atoms.

[0056] The term "alkylthio group" embraces groups containing a straight- or branched-chain alkyl group of 1 to 10 carbon atoms attached to a divalent sulfur atom. In certain embodiments, lower alkylthio groups have 1 to 3 carbon atoms. An example of an "alkylthio" is methylthio, (CH3S-).

[0057] The term "alkynyl group" refers to a straight- or branched-chain carbon radical having at least one carbon-carbon triple bond. The term "alkynyl group" can include conjugated and non-conjugated carbon-carbon triple bonds, or a combination thereof. Alkynyl groups can include, for example, without limitation, from 2 to about 20 carbon atoms, or in certain embodiments, from 2 to about 12 carbon atoms. In embodiments, alkynyl groups are "lower alkynyl" groups having from 2 to about 10 carbon atoms. Some examples are lower alkynyl groups having from 2 to about 4 carbon atoms. Examples of such groups include propargyl, butynyl, and the like.

[0058] The term "aminoalkyl group" embraces straight-chain or branched-chain alkyl groups having from 1 to about 10 carbon atoms, any one of which may be substituted with one or more amino groups. In some embodiments, aminoalkyl groups are "lower aminoalkyl" groups having from 1 to 6 carbon atoms and one or more amino groups. Examples of such groups include aminomethyl, aminoethyl, aminopropyl, aminobutyl, and aminohexyl.

[0059] The term "aralkoxy group" encompasses oxy-containing aralkyl groups that are bonded to other groups through an oxygen atom. In certain embodiments, aralkoxy groups are "lower aralkoxy" groups having an optionally substituted phenyl group bonded to a lower alkoxy group as described above.

[0060] The term "aralkyl group" encompasses aryl-substituted alkyl groups. In embodiments, aralkyl groups are "lower aralkyl" groups having an aryl group bonded to an alkyl group having 1 to 6 carbon atoms. In other embodiments, the phenyl in a lower aralkyl group is bonded to an alkyl moiety having 1 to 3 carbon atoms. Examples of such groups include benzyl, diphenylmethyl, and phenylethyl. The aryl in the aralkyl may be additionally substituted with halo, alkyl, alkoxy, haloalkyl, and haloalkoxy.

[0061] The term "aralkylamino" refers to an amino group substituted with one or two aralkyl groups. In another embodiment are phenyl-C1-C3 alkylamino groups, such as N-benzylamino. "Aralkylamino" groups may be further substituted on the aryl ring portion of the group.

[0062] The term "aromatic group" or "aryl group" refers to an aromatic group having one or more rings, which may be pendantly bonded together or fused together. In certain embodiments, the aromatic group has one, two, or three rings. Monocyclic aromatic groups can contain 4 to 10 carbon atoms, typically 4 to 7 carbon atoms, and more typically 4 to 6 carbon atoms in the ring. Typical polycyclic aromatic groups have two or three rings. Polycyclic aromatic groups having two rings typically have 8 to 12 carbon atoms, preferably 8 to 10 carbon atoms in the ring. Examples of aromatic groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl, or acenaphthyl.

[0063] The term "arylamino" refers to an amino group substituted with one or two aryl groups, such as N-phenylamino. "Arylamino" groups may be further substituted on the aryl ring portion of the group.

[0064] The term "arylalkenyl group" encompasses aryl-substituted alkenyl groups. In embodiments, arylalkenyl groups are "lower arylalkenyl" groups having an aryl group bonded to an alkenyl group having 2 to 6 carbon atoms. Examples of such groups include phenylethenyl. The aryl in the arylalkenyl may be additionally substituted with halo, alkyl, alkoxy, haloalkyl, and haloalkoxy.

[0065] The term "arylalkynyl group" encompasses aryl-substituted alkynyl groups. In embodiments, arylalkynyl groups are "lower arylalkynyl" groups having an aryl group bonded to an alkynyl group having 2 to 6 carbon atoms. Examples of such groups include phenylethynyl. The aryl in the aralkyl may be additionally substituted with halo, alkyl, alkoxy, haloalkyl, and haloalkoxy. The terms benzyl and phenylmethyl are used interchangeably.

[0066] The term "aryloxy group" embraces optionally substituted aryl groups, as defined above, attached to an oxygen atom. Examples of such groups include phenoxy.

[0067] The term "arylthio group" embraces aryl groups of 6 to 10 carbon atoms bonded to a divalent sulfur atom. An example of an "arylthio" is phenylthio. The term "aralkylthio group" embraces the aralkyl groups described above bonded to a divalent sulfur atom. In certain embodiments, there is a phenyl-C1-C3 alkylthio group. An example of an "aralkylthio" is benzylthio.

[0068] The term "carbocyclic group" refers to a saturated or unsaturated carbocyclic hydrocarbon ring. Carbocyclic groups are not aromatic. Carbocyclic groups are monocyclic or polycyclic. Polycyclic carbocyclic groups can be fused, spiro, or bridged ring systems. Monocyclic carbocyclic groups can contain 4 to 10 carbon atoms, typically 4 to 7 carbon atoms, more typically 5 to 6 carbon atoms, in the ring. Bicyclic carbocyclic groups can contain 8 to 12 carbon atoms, typically 9 to 10 carbon atoms in the ring.

[0069] The term "carbonyl group," whether used alone or with other terms such as "aminocarbonyl group," refers to --(C.dbd.O)--.

[0070] The terms "carboxy" or "carboxyl" whether used alone or with other terms such as "carboxyalkyl" refer to -(C=O)-O-.

[0071] The term "cycloalkyl group" includes saturated carbocyclic groups. In certain embodiments, cycloalkyl groups include C3-C6 rings. In embodiments, compounds include cyclopentyl, cyclopropyl, and cyclohexyl.

[0072] The term "cycloalkenyl group" includes carbocyclic groups having one or more carbon-carbon double bonds, conjugated or non-conjugated, or a combination thereof. "Cycloalkenyl" and "cycloalkyldienyl" compounds are included within the term "cycloalkenyl." In certain embodiments, a cycloalkenyl group contains a C3-C6 ring. Examples include cyclopentenyl, cyclopentadienyl, cyclohexenyl, and cycloheptadienyl. "Cycloalkenyl" groups can have one to three substituents, such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, lower alkylamino, and the like.

[0073] The term "fused" means that two or more carbon / member atoms are common to two adjacent rings, e.g., the rings are "fused rings."

[0074] The term "halo" refers to halogens such as fluorine, chlorine, bromine, or iodine atoms.

[0075] The term "haloalkyl group" encompasses groups in which one or more alkyl carbon atoms are substituted with halo as defined above. Specifically encompassed are monohaloalkyl, dihaloalkyl, and polyhaloalkyl groups, including perhaloalkyl. Monohaloalkyl groups, by way of example, may contain either an iodo atom, a bromo atom, a chloro atom, or a fluoro atom within the group. Dihalo and polyhaloalkyl groups may contain two or more of the same halo atoms or a combination of different halo groups. "Lower haloalkyl groups" encompass groups having 1 to 6 carbon atoms. In some embodiments, lower haloalkyl groups have 1 to 3 carbon atoms. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl.

[0076] The terms "heteroaromatic group" or "heteroaryl group" refer to an aromatic group having one or more rings, which may be pendantly bonded or fused together, and which have at least one heteroatom. Monocyclic heteroaromatic groups can contain 4 to 10 member atoms, typically 4 to 7 member atoms, and more typically 4 to 6 member atoms, in the ring. Typical polycyclic heteroaromatic groups have two or three rings. Polycyclic aromatic groups having two rings typically have 8 to 12 member atoms, more typically 8 to 10 member atoms, in the ring. Examples of heterocyclic aromatic groups include, but are not limited to, pyrrole, imidazole, thiazole, oxazole, furan, thiophene, triazole, pyrazole, isoxazole, isothiazole, pyridine, pyrazine, pyridazine, pyrimidine, triazine, indole, benzofuran, benzothiophene, benzimidazole, benzthiazole, quinoline, isoquinoline, quinazoline, quinoxaline, and the like.

[0077] The term "heteroarylamino" refers to an amino group substituted with one or two heteroaryl groups, such as N-thienylamino. The "heteroarylamino" groups may be further substituted on the heteroaryl ring portion of the group.

[0078] The term "heteroatom" refers to an atom other than carbon. Typically, heteroatoms are selected from the group consisting of sulfur, phosphorus, nitrogen, and oxygen atoms. Groups containing more than one heteroatom may contain different heteroatoms.

[0079] The term "heterocyclic group" refers to a saturated or unsaturated ring structure containing carbon atoms and one or more heteroatoms in the ring. Heterocyclic groups are not aromatic. Heterocyclic groups are monocyclic or polycyclic. Polycyclic heterocyclic groups can be fused, spiro, or bridged ring systems. Monocyclic heterocyclic groups can contain 4 to 10 member atoms (i.e., including both carbon atoms and at least one heteroatom), typically 4 to 7, more typically 5 to 6, in the ring. Bicyclic heterocyclic groups can contain 8 to 18 member atoms, typically 9 to 10, in the ring. Representative heterocyclic groups include, by way of example, pyrrolidine, imidazolidine, pyrazolidine, piperidine, 1,4-dioxane, morpholine, thiomorpholine, piperazine, 3-pyrroline, and the like.

[0080] The term "heterogeneous group" refers to a saturated or unsaturated chain (e.g., an ether group, an ether group, etc.) comprising carbon atoms and at least one heteroatom. Heterogeneous groups typically have 1 to 25 member atoms. More typically, the chain contains 1 to 12 member atoms, 1 to 10, and most typically 1 to 6. The chain can be straight or branched. Typical branched heterogeneous groups have one or two branches, more typically one branch. Typically, heterogeneous groups are saturated. Unsaturated heterogeneous groups can have one or more double bonds, one or more triple bonds, or both. Typical unsaturated heterogeneous groups have one or two double bonds or one triple bond. More typically, unsaturated heterogeneous groups have one double bond.

[0081] The term "hydrocarbon group" or "hydrocarbyl group" refers to a chain of 1 to 25 carbon atoms, typically 1 to 12 carbon atoms, more typically 1 to 10 carbon atoms, and most typically 1 to 8 carbon atoms. The hydrocarbon group can have a straight or branched chain structure. Typical hydrocarbon groups have one or two branches, typically one branch. Typically, hydrocarbon groups are saturated. Unsaturated hydrocarbons can have one or more double bonds, one or more triple bonds, or a combination thereof. Typical unsaturated hydrocarbon groups have one or two double bonds, or one triple bond, and more typically, unsaturated hydrocarbon groups have one double bond.

[0082] The term "hydroalkyl group" includes, for example and without limitation, straight-chain or branched-chain alkyl groups having from 1 to about 10 carbon atoms, any one of which may be substituted with one or more hydroxyl groups. In embodiments, hydroxyalkyl groups are "lower hydroxyalkyl" groups having from 1 to 6 carbon atoms and one or more hydroxyl groups. Examples of such groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, and hydroxyhexyl.

[0083] The terms "suitable substituents," "substituents," or "substituted," as used in conjunction with groups described herein, refer to chemically and pharmaceutically acceptable groups, i.e., moieties that do not negate the therapeutic activity of the compounds of the present invention. It is understood that substituents and substitution patterns in the compounds of the present invention can be selected by those skilled in the art to provide compounds that are chemically stable and can be readily synthesized by techniques known in the art and by the methods described below. When a substituent is itself substituted with more than one group, it is understood that these multiple groups can be on the same carbon / member atom or different carbon / member atoms, so long as a stable structure results. Illustrative examples of some suitable substituents include halo, haloalkyl, perfluoroalkyl, perfluoroalkoxy, alkyl, alkenyl, alkynyl, hydroxy, oxo, mercapto, alkylthio, alkoxy, cycloalkyl, heterocyclyl, hydroxyalkyl, benzyl, carbonyl, aryl or heteroaryl, aryloxy or heteroaryloxy, aralkyl or heteroaralkyl, aralkoxy or heteroaralkoxy, HO--(C=O)--, amido, amino, alkyl- and dialkylamino, cyano, nitro, carbamoyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylcarbonyl, aryloxycarbonyl, alkylsulfonyl, and arylsulfonyl. Typical substituents include halo, hydroxyl, cyano, amino, hydrocarbon groups including alkyl groups such as methyl, substituted hydrocarbon groups such as benzyl, heterogeneous groups including alkoxy groups such as methoxy, aromatic groups, or substituted aromatic groups.

[0084] When the term "unsaturated" is used with any group, the group may be fully unsaturated or partially unsaturated. However, when the term "unsaturated" is used with a specific group defined herein, the term maintains the limitations of the specific group. For example, an unsaturated "carbocyclic group" does not include aromatic groups, based on the limitations of a "carbocyclic group" defined herein.

[0085] The pharmaceutically acceptable salts of the compounds described herein include, for example, the conventional non-toxic salts of compounds formed from non-toxic inorganic or organic acids.For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc., and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, etc.

[0086] The pharmaceutically acceptable salts of the compounds described herein can be synthesized from the compounds described herein that contain basic or acidic moieties by conventional chemical methods.Generally, the salts of basic compounds are prepared by ion exchange chromatography or by reacting free bases with the stoichiometric amount or excess amount of the desired salt-forming inorganic or organic acid in a suitable solvent or in various combinations of solvents.Similarly, the salts of acidic compounds are formed by reacting with suitable inorganic or organic bases.

[0087] The compounds described herein can include pharmaceutically acceptable salts, hydrates, solvates, metabolites, and prodrugs of the compounds described herein, and any suitable combinations thereof.

[0088] The compounds described herein are 1H-pyrazole analogs, and compositions comprising at least one of the analogs, methods of administering the same, and uses thereof are provided. 1H-Pyrazole Analogs of Formula I In embodiments, the H-pyrazole analog has Formula I:

[0089] [ka]

[0090] a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a tautomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, an N-oxide thereof, a metabolite thereof, an isotopomer thereof, an isotopologue thereof, a prodrug thereof, or a combination thereof. (In the formula, X1-BR 8 R 9 or -BR 10 R 11 R 12 Selected from; R 1 From R 7 , R 10 , R 11 , and R 12 each independently represents H, a halo group, a hydroxyl group, a cyano group, a nitro group, a thiol group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterogeneous group, -BR 13 R 14 , -BR 15 R 16 R 17 , a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group; R 13 From R 17 are each independently selected from H, a halo group, a hydroxyl group, a cyano group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group; or R 13 and R 14 taken together form a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group, R 8 and R 9are each independently selected from H, a halo group, a hydroxyl group, a cyano group, a nitro group, a thiol group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterogeneous group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, or together form a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group).

[0091] Additional embodiments are outlined below in i) to iii) for compounds having the structure of Formula I, and these embodiments may be combined in any suitable order. It is understood that with respect to one or more embodiments, one or more atoms may be isotopes. It is understood that in certain embodiments, one or more H may be replaced by D (deuterium).

[0092] i) Embodiments of X1 a) X1 is -BR 3 R 9 Selected from R 8 and R 9 do not join to form a ring: In embodiments, R 8 and R 9 are each independently selected from H, a halo group, a hydroxyl group, a cyano group, a nitro group, a thiol group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterogeneous group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

[0093] In other embodiments, R 8 and R 9are each independently selected from H, a halo group, a hydroxyl group, a cyano group, a nitro group, a sulfate group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alkoxy group, —C(O)H, a substituted carbonyl group, a substituted carboxyl group, —C(O)OH, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

[0094] In other embodiments, R 8 and R 9 are each independently selected from H, a halo group, a hydroxyl group, a cyano group, a nitro group, a sulfate group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, —C(O)H, a substituted carbonyl group, a substituted carboxyl group, —C(O)OH, a substituted or heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

[0095] In another embodiment, R 8 and R 9 are each independently selected from H, a halo group, a hydroxyl group, a cyano group, a nitro group, a sulfate group, a substituted or unsubstituted alkyl group, a haloalkyl group, a substituted or unsubstituted alkylheteroalkyl group, a substituted or unsubstituted alkoxy group, —C(O)H, a substituted or unsubstituted alkylcarbonyl group, a substituted or unsubstituted alkylcarbonylalkyl group, a substituted or unsubstituted alkyl-C(O)O— group, a substituted or unsubstituted alkyl-C(O)O-alkylene group, a substituted or unsubstituted alkyl-OC(O)— group, —C(O)OH, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

[0096] In another embodiment, R 8 and R 9are each independently H, a halo group, a hydroxyl group, a cyano group, a nitro group, a sulfate group, a substituted or unsubstituted C1-C6 alkyl group, a C1-C6 haloalkyl group, a substituted or unsubstituted (C1-C6 alkyl)hetero(C1-C6 alkyl) group, a substituted or unsubstituted C1-C6 alkoxy group, -C(O)H, a substituted or unsubstituted C1-C6 alkylcarbonyl group, a substituted or unsubstituted (C1-C6 alkyl)carbonyl(C1-C6 alkyl) a substituted or unsubstituted C1-C6 alkyl) group, a substituted or unsubstituted C1-C6 alkyl-C(O)O- group, a substituted or unsubstituted C1-C6 alkyl-OC(O)- group, a substituted or unsubstituted C1-C6 alkyl-OC(O)-C1-C6 alkylene group, -C(O)OH, a substituted or unsubstituted C1-C6 cycloalkyl group, a substituted or unsubstituted C1-C6 heterocyclic group, a substituted or unsubstituted C1-C6 aromatic group, or a substituted or unsubstituted C1-C6 heteroaromatic group.

[0097] In another embodiment, R 8 and R 9 are each independently H, a halo group, a hydroxyl group, a substituted or unsubstituted C1-C6 alkyl group, a C1-C6 haloalkyl group, a substituted or unsubstituted (C1-C6 alkyl)hetero(C1-C6 alkyl) group, a substituted or unsubstituted C1-C6 alkoxy group, -C(O)H, a substituted or unsubstituted C1-C6 alkylcarbonyl group, a substituted or unsubstituted (C1-C6 alkyl)carbonyl(C1-C6 alkyl) group, a substituted or unsubstituted C1-C6 alkyl and n is 0 or 1. The alkyl group is selected from a substituted or unsubstituted -C(O)O- group, a substituted or unsubstituted C1-C6 alkyl-OC(O)- group, a substituted or unsubstituted C1-C6 alkyl-OC(O)-C1-C6 alkylene group, -C(O)OH, a substituted or unsubstituted C1-C6 cycloalkyl group, a substituted or unsubstituted C1-C6 heterocyclic group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted alkylheteroaryl group, a substituted or unsubstituted pyridinyl group, and a substituted or unsubstituted pyrrolyl group.

[0098] In another embodiment, R 8 and R 9are each independently selected from H, halo, hydroxyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cyanoalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted alkylcycloalkenyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkylheterocycloalkyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted alkylheterocycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted alkylheteroaryl, alkylene-O-alkyl, alkylene-O-cycloalkyl, alkylene-O-heterocycloalkyl, alkylene-O-alkylene-cycloalkyl, or alkylene-O-alkylene-heterocycloalkyl.

[0099] In another embodiment, R 8 and R 9 are each independently selected from a halo group, a hydroxyl group, or an alkoxy group. 8 and R 9 are each independently selected from a fluoro group, a chloro group, a bromo group, a hydroxyl group, or an alkoxy group. 8 and R 9 are each independently selected from a fluoro group, a hydroxyl group, or an alkoxy group.

[0100] In another embodiment, R 8 and R 9 are each independently selected from a halo group or a hydroxyl group. 8 and R 9 are each independently selected from a fluoro group, a chloro group, a bromo group, or a hydroxyl group. 8 and R 9are each independently selected from a fluoro group or a hydroxyl group. R 8 and R 9 together form a ring: In embodiments, R 8 and R 9 taken together form a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group.

[0101] In embodiments, R 8 and R 9 taken together form a substituted or unsubstituted heterocyclic group. 8 and R 9 taken together form a substituted or unsubstituted —O(C-C alkylene)O— ring. 8 and R 9 are taken together to form a substituted or unsubstituted —O(C-C alkylene)O— ring. In other embodiments, R 8 and R 9 taken together form a substituted or unsubstituted —O(C alkylene)O— ring. In other embodiments, R 8 and R 9 taken together form a substituted or unsubstituted —O(C alkylene)O— ring. In other embodiments, R 8 and R 9 taken together form a substituted or unsubstituted —O(C alkylene)O— ring. In an embodiment, R 8 and R 9 together form OCR1R2CR3R4O-, and R1, R2, R3, and R4 are each independently R 1 From R 7 , R 10 , R 11 , and R 12 In an embodiment, R 8 and R 9 together form -OCH2CH2O-, -OC(CH3)2CH2O-, or -OC(CH3)2C(CH3)2O-.

[0102] In embodiments, R 8 and R 9 taken together form a substituted or unsubstituted -O(C1-C2 alkylene)NH(C1-C2 alkylene)O- ring. 8 and R 9 taken together form a substituted or unsubstituted -O(C1-C2 alkylene)N(alkyl)(C1-C2 alkylene)O- ring. 8 and R 9 taken together form a substituted or unsubstituted —O(C alkylene)NH(C alkylene)O— ring. In an embodiment, R 8 and R 9 are taken together to form a substituted or unsubstituted —O(C alkylene)N(alkyl)(C alkylene)O— ring. In other embodiments, R 8 and R 9 together form -OCH2CH2NHCH2CH2O-, -OCH2CH2N(CH3)CH2CH2O-, -OCH2C(CH3)2NHCH2CH2O-, -OCH2C(CH3)2N(CH3)CH2CH2O-, -OCH2C(CH3)2NHC(CH3)2CH2O, -OC(CH3)2CH2N(CH3)C(CH3)2CH2O-, or -OC(CH3)2C(CH3)2N(CH3)C(CH3)2C(CH3)2O-.

[0103] b) X1 is -BR 10 R 11 R 12 Selected from In embodiments, R 10 , R 11 , and R 12 are each independently selected from H, a halo group, a hydroxyl group, a cyano group, a nitro group, a thiol group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

[0104] In other embodiments, R 10 , R 11 , and R 12 are each independently selected from H, a halo group, a hydroxyl group, a cyano group, a nitro group, a sulfate group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alkoxy group, —C(O)H, a substituted carbonyl group, a substituted carboxyl group, —C(O)OH, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

[0105] In other embodiments, R 10 , R 11 , and R 12 are each independently selected from H, a halo group, a hydroxyl group, a cyano group, a nitro group, a sulfate group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, —C(O)H, a substituted carbonyl group, a substituted carboxyl group, —C(O)OH, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

[0106] In another embodiment, R 10 , R 11 , and R 12are each independently selected from H, a halo group, a hydroxyl group, a cyano group, a nitro group, a sulfate group, a substituted or unsubstituted alkyl group, a haloalkyl group, a substituted or unsubstituted alkylheteroalkyl group, a substituted or unsubstituted alkoxy group, —C(O)H, a substituted or unsubstituted alkylcarbonyl group, a substituted or unsubstituted alkylcarbonylalkyl group, a substituted or unsubstituted alkyl-C(O)O— group, a substituted or unsubstituted alkyl-C(O)O-alkylene group, a substituted or unsubstituted alkyl-OC(O)— group, —C(O)OH, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

[0107] In another embodiment, R 10 , R 11 , and R 12 are each independently H, a halo group, a hydroxyl group, a cyano group, a nitro group, a sulfate group, a substituted or unsubstituted C1-C6 alkyl group, a C1-C6 haloalkyl group, a substituted or unsubstituted (C1-C6 alkyl)hetero(C1-C6 alkyl) group, a substituted or unsubstituted C1-C6 alkoxy group, -C(O)H, a substituted or unsubstituted C1-C6 alkylcarbonyl group, a substituted or unsubstituted (C1-C6 alkyl)carbonyl(C1-C6 alkyl) a substituted or unsubstituted C1-C6 alkyl) group, a substituted or unsubstituted C1-C6 alkyl-C(O)O- group, a substituted or unsubstituted C1-C6 alkyl-OC(O)- group, a substituted or unsubstituted C1-C6 alkyl-OC(O)-C1-C6 alkylene group, -C(O)OH, a substituted or unsubstituted C1-C6 cycloalkyl group, a substituted or unsubstituted C1-C6 heterocyclic group, a substituted or unsubstituted C1-C6 aromatic group, or a substituted or unsubstituted C1-C6 heteroaromatic group.

[0108] In another embodiment, R 10 , R 11 , and R 12are each independently H, a halo group, a hydroxyl group, a substituted or unsubstituted C1-C6 alkyl group, a C1-C6 haloalkyl group, a substituted or unsubstituted (C1-C6 alkyl)hetero(C1-C6 alkyl) group, a substituted or unsubstituted C1-C6 alkoxy group, -C(O)H, a substituted or unsubstituted C1-C6 alkylcarbonyl group, a substituted or unsubstituted (C1-C6 alkyl)carbonyl(C1-C6 alkyl) group, a substituted or unsubstituted C1-C6 alkyl and n is 0 or 1. The alkyl group is selected from a substituted or unsubstituted -C(O)O- group, a substituted or unsubstituted C1-C6 alkyl-OC(O)- group, a substituted or unsubstituted C1-C6 alkyl-OC(O)-C1-C6 alkylene group, -C(O)OH, a substituted or unsubstituted C1-C6 cycloalkyl group, a substituted or unsubstituted C1-C6 heterocyclic group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted alkylheteroaryl group, a substituted or unsubstituted pyridinyl group, and a substituted or unsubstituted pyrrolyl group.

[0109] In another embodiment, R 10 , R 11 , and R 12 are each independently selected from H, halo, hydroxyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cyanoalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted alkylcycloalkenyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkylheterocycloalkyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted alkylheterocycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted alkylheteroaryl, alkylene-O-alkyl, alkylene-O-cycloalkyl, alkylene-O-heterocycloalkyl, alkylene-O-alkylene-cycloalkyl, or alkylene-O-alkylene-heterocycloalkyl.

[0110] In another embodiment, R 10 , R 11 , and R 12 are each independently selected from a halo group, a hydroxyl group, or an alkoxy group. 10 , R 11 , and R 12 are each independently selected from a fluoro group, a chloro group, a bromo group, a hydroxyl group, or an alkoxy group. 10 , R 11 , and R 12 are each independently selected from a fluoro group, a hydroxyl group, or an alkoxy group.

[0111] In another embodiment, R 10 , R 11 , and R 12 are each independently selected from a halo group or a hydroxyl group. 10 , R 11 , and R 12 are each independently selected from a fluoro group, a chloro group, a bromo group, or a hydroxyl group. 10 , R 11 , and R 12 are each independently selected from a fluoro group or a hydroxyl group. ii)R 1 and R 2 Embodiments of the present invention In embodiments, R 1 and R 2 are each independently selected from H, a halo group, a hydroxyl group, a cyano group, a nitro group, a thiol group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterogeneous group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

[0112] In a further embodiment, R 1 and R 2are each independently selected from H, a halo group, a hydroxyl group, a cyano group, a substituted or unsubstituted amino group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

[0113] In still further embodiments, R 1 and R 2 are each independently selected from H, a halo group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

[0114] In another embodiment, R 1 and R 2 are each independently selected from H, a halo group, a substituted or unsubstituted C1-C6 alkyl group, a C1-C6 haloalkyl group, a substituted or unsubstituted (C1-C6 alkyl)hetero(C1-C6 alkyl) group, a substituted or unsubstituted C1-C6 cycloalkyl group, a substituted or unsubstituted C1-C6 heterocyclic group, a substituted or unsubstituted C1-C6 aromatic group, or a substituted or unsubstituted C1-C6 heteroaromatic group.

[0115] In another embodiment, R 1 and R 2 are each independently selected from H, a halo group, a substituted or unsubstituted C1-C6 alkyl group, a C1-C6 haloalkyl group, a substituted or unsubstituted (C1-C6 alkyl)hetero(C1-C6 alkyl) group, a substituted or unsubstituted C1-C6 cycloalkyl group, a substituted or unsubstituted C1-C6 heterocyclic group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted pyridinyl group, or a substituted or unsubstituted pyrrolyl group.

[0116] In another embodiment, R 1 and R 2are each independently selected from H, halo, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cyanoalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted alkylcycloalkenyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkylheterocycloalkyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted alkylheterocycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted alkylheteroaryl, alkylene-O-alkyl, alkylene-O-cycloalkyl, alkylene-O-heterocycloalkyl, alkylene-O-alkylene-cycloalkyl, or alkylene-O-alkylene-heterocycloalkyl.

[0117] In another embodiment, R 1 is H or a substituted or unsubstituted alkyl group, and R 2 is selected from H, a halo group, a hydroxyl group, a cyano group, a substituted or unsubstituted amino group, an unsubstituted hydrocarbon group, a substituted or unsubstituted heterogeneous group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

[0118] In a further embodiment, R 1 is H or a substituted or unsubstituted alkyl group, and R 2 is selected from H, a halo group, a hydroxyl group, a cyano group, a substituted or unsubstituted amino group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

[0119] In still further embodiments, R1 is H or a substituted or unsubstituted alkyl group, and R 2 is selected from H, a halo group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

[0120] In another embodiment, R 1 is H or a substituted or unsubstituted C1-C6 alkyl group, and R 2 is selected from H, a halo group, a substituted or unsubstituted C1-C6 alkyl group, a C1-C6 haloalkyl group, a substituted or unsubstituted (C1-C6 alkyl)hetero(C1-C6 alkyl) group, a substituted or unsubstituted C1-C6 cycloalkyl group, a substituted or unsubstituted C1-C6 heterocyclic group, a substituted or unsubstituted C1-C6 aromatic group, or a substituted or unsubstituted C1-C6 heteroaromatic group.

[0121] In another embodiment, R 1 is H or a substituted or unsubstituted C1-C6 alkyl group, and R 2 is selected from H, a halo group, a substituted or unsubstituted C1-C6 alkyl group, a C1-C6 haloalkyl group, a substituted or unsubstituted (C1-C6 alkyl)hetero(C1-C6 alkyl) group, a substituted or unsubstituted C1-C6 cycloalkyl group, a substituted or unsubstituted C1-C6 heterocyclic group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted pyridinyl group, or a substituted or unsubstituted pyrrolyl group.

[0122] In another embodiment, R 1 is H, -CH3, -CH2CH3, or -CH2CH2CH3, and R 2 is selected from H, F, Cl, CN, —CH 3 , —CH 2 F, —CHF 2 , or —CF 3 .

[0123] iii)R 3 From R 7 Embodiments of the present invention In embodiments, R 3 From R7 each independently represents H, a halo group, a hydroxyl group, a cyano group, a nitro group, a thiol group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterogeneous group, -BR 13 R 14 , -BR 15 R 16 R 17 , a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group; R 13 From R 17 are each independently selected from H, a halo group, a hydroxyl group, a cyano group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group; or R 13 and R 14 taken together form a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group.

[0124] In embodiments, R 3 From R 7 each independently represents H, a halo group, a hydroxyl group, a cyano group, a nitro group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterogeneous group, -BR 13 R 14 , -BR 15 R 16 R 17 , a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group; R 13 From R 17 are each independently selected from H, a halo group, a hydroxyl group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group; or R 13 and R14 taken together form a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group.

[0125] In embodiments, R 3 From R 7 are each independently selected from H, a halo group, a cyano group, a nitro group, a sulfate group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

[0126] In embodiments, R 3 From R 7 are each independently selected from H, a halo group, a cyano group, a nitro group, a sulfate group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alkoxy group, —C(O)H, a substituted carbonyl group, a substituted carboxyl group, —C(O)OH, a boronic acid group, a substituted or unsubstituted alkylboronate group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

[0127] In yet another embodiment, R 3 From R 7 are each independently selected from H, a halo group, a cyano group, a nitro group, a sulfate group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, —C(O)H, a substituted carbonyl group, a substituted carboxyl group, —C(O)OH, a boronic acid group, a substituted or unsubstituted alkylboronate group, a substituted or heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

[0128] In another embodiment, R 3 From R 7are each independently selected from H, a halo group, a cyano group, a nitro group, a sulfate group, a substituted or unsubstituted alkyl group, a haloalkyl group, a substituted or unsubstituted alkylheteroalkyl group, a substituted or unsubstituted alkoxy group, —C(O)H, a substituted or unsubstituted alkylcarbonyl group, a substituted or unsubstituted alkylcarbonylalkyl group, a substituted or unsubstituted alkyl-C(O)O— group, a substituted or unsubstituted alkyl-C(O)O-alkylene group, a substituted or unsubstituted alkyl-OC(O)— group, —C(O)OH, a boronic acid group, a substituted or unsubstituted alkylboronate group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

[0129] In another embodiment, R 3 From R 7 are each independently H, a halo group, a cyano group, a nitro group, a sulfate group, a substituted or unsubstituted C1-C6 alkyl group, a C1-C6 haloalkyl group, a substituted or unsubstituted (C1-C6 alkyl)hetero(C1-C6 alkyl) group, a substituted or unsubstituted C1-C6 alkoxy group, -C(O)H, a substituted or unsubstituted C1-C6 alkylcarbonyl group, a substituted or unsubstituted (C1-C6 alkyl)carbonyl(C1-C6 alkyl) group, a substituted or unsubstituted C1-C6 It is selected from an alkyl-C(O)O- group, a substituted or unsubstituted C1-C6 alkyl-OC(O)- group, a substituted or unsubstituted C1-C6 alkyl-OC(O)-C1-C6 alkylene group, -C(O)OH, a boronic acid group, a substituted or unsubstituted C1-C6 alkylboronate group, a substituted or unsubstituted C1-C6 cycloalkyl group, a substituted or unsubstituted C1-C6 heterocyclic group, a substituted or unsubstituted C1-C6 aromatic group, or a substituted or unsubstituted C1-C6 heteroaromatic group.

[0130] In another embodiment, R 3 From R 7are each independently H, a halo group, a substituted or unsubstituted C1-C6 alkyl group, a C1-C6 haloalkyl group, a substituted or unsubstituted (C1-C6 alkyl)hetero(C1-C6 alkyl) group, a substituted or unsubstituted C1-C6 alkoxy group, -C(O)H, a substituted or unsubstituted C1-C6 alkylcarbonyl group, a substituted or unsubstituted (C1-C6 alkyl)carbonyl(C1-C6 alkyl) group, a substituted or unsubstituted C1-C6 alkyl-C(O)O- group, a substituted or unsubstituted It is selected from a C1-C6 alkyl-OC(O)- group, a substituted or unsubstituted C1-C6 alkyl-OC(O)-C1-C6 alkylene group, -C(O)OH, a boronic acid group, a substituted or unsubstituted C1-C6 alkylboronate group, a substituted or unsubstituted C1-C6 cycloalkyl group, a substituted or unsubstituted C1-C6 heterocyclic group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted alkylheteroaryl group, a substituted or unsubstituted pyridinyl group, or a substituted or unsubstituted pyrrolyl group.

[0131] In another embodiment, R 3 From R 7 are each independently selected from H, halo, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cyanoalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted alkylcycloalkenyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkylheterocycloalkyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted alkylheterocycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted alkylheteroaryl, alkylene-O-alkyl, alkylene-O-cycloalkyl, alkylene-O-heterocycloalkyl, alkylene-O-alkylene-cycloalkyl, or alkylene-O-alkylene-heterocycloalkyl.

[0132] In another embodiment, R3 , R 4 , R 6 , and R 7 are each independently selected from H or a substituted or unsubstituted alkyl group; R 5 is H, a halo group, a hydroxyl group, a cyano group, a nitro group, a thiol group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterogeneous group, -BR 13 R 14 , -BR 15 R 16 R 17 , a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group; R 13 From R 17 are each independently selected from H, a halo group, a hydroxyl group, a cyano group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group; or R 13 and R 14 taken together form a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group.

[0133] In another embodiment, R 3 , R 4 , R 6 , and R 7 are each independently selected from H or a substituted or unsubstituted alkyl group; R 5 is selected from H, a halo group, a cyano group, a nitro group, a sulfate group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

[0134] In yet another embodiment, R 3 , R 4 , R 6 , and R 7are each independently selected from H or a substituted or unsubstituted alkyl group; R 5 is selected from H, a halo group, a cyano group, a nitro group, a sulfate group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alkoxy group, —C(O)H, a substituted carbonyl group, a substituted carboxyl group, —C(O)OH, a boronic acid group, a substituted or unsubstituted alkylboronate group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

[0135] In yet another embodiment, R 3 , R 4 , R 6 , and R 7 are each independently selected from H or a substituted or unsubstituted alkyl group; R 5 is selected from H, a halo group, a cyano group, a nitro group, a sulfate group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, —C(O)H, a substituted carbonyl group, a substituted carboxyl group, —C(O)OH, a boronic acid group, a substituted or unsubstituted alkylboronate group, a substituted or heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

[0136] In yet another embodiment, R 3 , R 4 , R 6 , and R 7 are each independently selected from H or a substituted or unsubstituted alkyl group; R 5is selected from H, a halo group, a cyano group, a nitro group, a sulfate group, a substituted or unsubstituted alkyl group, a haloalkyl group, a substituted or unsubstituted alkylheteroalkyl group, a substituted or unsubstituted alkoxy group, —C(O)H, a substituted or unsubstituted alkylcarbonyl group, a substituted or unsubstituted alkylcarbonylalkyl group, a substituted or unsubstituted alkyl-C(O)O— group, a substituted or unsubstituted alkyl-C(O)O-alkylene group, a substituted or unsubstituted alkyl-OC(O)— group, —C(O)OH, a boronic acid group, a substituted or unsubstituted alkylboronate group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

[0137] In another embodiment, R 3 , R 4 , R 6 , and R 7 are each independently selected from H or a substituted or unsubstituted C1-C6 alkyl group; R 5 is H, a halo group, a cyano group, a nitro group, a sulfate group, a substituted or unsubstituted C1-C6 alkyl group, a C1-C6 haloalkyl group, a substituted or unsubstituted (C1-C6 alkyl)hetero(C1-C6 alkyl) group, a substituted or unsubstituted C1-C6 alkoxy group, -C(O)H, a substituted or unsubstituted C1-C6 alkylcarbonyl group, a substituted or unsubstituted (C1-C6 alkyl)carbonyl(C1-C6 alkyl) group, a substituted or unsubstituted C1-C6 alkyl- It is selected from a C(O)O- group, a substituted or unsubstituted C1-C6 alkyl-OC(O)- group, a substituted or unsubstituted C1-C6 alkyl-OC(O)-C1-C6 alkylene group, -C(O)OH, a boronic acid group, a substituted or unsubstituted C1-C6 alkylboronate group, a substituted or unsubstituted C1-C6 cycloalkyl group, a substituted or unsubstituted C1-C6 heterocyclic group, a substituted or unsubstituted C1-C6 aromatic group, or a substituted or unsubstituted C1-C6 heteroaromatic group.

[0138] In another embodiment, R 3 , R 4 , R 6 , and R7 are each independently selected from H or a substituted or unsubstituted C1-C6 alkyl group; R 5 is H, a halo group, a substituted or unsubstituted C1-C6 alkyl group, a C1-C6 haloalkyl group, a substituted or unsubstituted (C1-C6 alkyl)hetero(C1-C6 alkyl) group, a substituted or unsubstituted C1-C6 alkoxy group, -C(O)H, a substituted or unsubstituted C1-C6 alkylcarbonyl group, a substituted or unsubstituted (C1-C6 alkyl)carbonyl(C1-C6 alkyl) group, a substituted or unsubstituted C1-C6 alkyl-C(O)O- group, a substituted or unsubstituted C1-C6 It is selected from an alkyl-OC(O)- group, a substituted or unsubstituted C1-C6 alkyl-OC(O)-C1-C6 alkylene group, -C(O)OH, a boronic acid group, a substituted or unsubstituted C1-C6 alkylboronate group, a substituted or unsubstituted C1-C6 cycloalkyl group, a substituted or unsubstituted C1-C6 heterocyclic group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted alkylheteroaryl group, a substituted or unsubstituted pyridinyl group, or a substituted or unsubstituted pyrrolyl group.

[0139] In another embodiment, R 3 , R 4 , R 6 , and R 7 are each independently selected from H or a substituted or unsubstituted C1-C6 alkyl group; R 5is selected from H, halo, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cyanoalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted alkylcycloalkenyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkylheterocycloalkyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted alkylheterocycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted alkylheteroaryl, alkylene-O-alkyl, alkylene-O-cycloalkyl, alkylene-O-heterocycloalkyl, alkylene-O-alkylene-cycloalkyl, or alkylene-O-alkylene-heterocycloalkyl.

[0140] In another embodiment, R 3 , R 4 , R 6 , and R 7 are each independently selected from H, -CH3, -CH2CH3, or -CH2CH2CH3; R 5 is selected from H, F, Cl, CN, —CH 3 , —CH 2 F, —CHF 2 , or —CF 3 .

[0141] In embodiments, the compound of formula I is:

[0142] [ka]

[0143] X1, and R may be selected from a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a tautomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, an N-oxide thereof, a metabolite thereof, an isotopomer thereof, an isotopologue thereof, a prodrug thereof, or a combination thereof. 2 From R 5are each independently selected from any one of the groups listed in i) to iii) above.

[0144] In embodiments, the compound of formula I is:

[0145] [ka]

[0146] R1 through R4, and R may be selected from a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a tautomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, an N-oxide thereof, a metabolite thereof, an isotopomer thereof, an isotopologue thereof, a prodrug thereof, or a combination thereof. 2 From R 5 are each independently selected from any one of the groups listed in i) to iii) above.

[0147] In embodiments, the compound of formula I is:

[0148] [ka]

[0149] It may be selected from a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a tautomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, an N-oxide thereof, a metabolite thereof, an isotopomer thereof, an isotopologue thereof, a prodrug thereof, or a combination thereof. + is any suitable counterion (e.g., Na, K, etc.), and R 3 From R 5 are each independently selected from any one of the groups listed in i) through iii) above. 3 From R 5 are each independently selected from H, F, Cl, CN, —CH 3 , —CH 2 F, —CHF 2 , or —CF 3 .

[0150] In embodiments, the compound of formula I is:

[0151] [ka]

[0152] It may be selected from a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a tautomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, an N-oxide thereof, a metabolite thereof, an isotopomer thereof, an isotopologue thereof, a prodrug thereof, or a combination thereof. + is any suitable counterion (e.g., Na, K, etc.), and R 3 From R 5 are each independently selected from any one of the groups listed in i) through iii) above. 3 From R 5 are each independently selected from H, F, Cl, CN, —CH 3 , —CH 2 F, —CHF 2 , or —CF 3 .

[0153] It is understood that in various embodiments, the compounds described herein may be a single compound or a combination of compounds, including compounds having the structure of Formula I, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, tautomers thereof, enantiomers thereof, diastereomers thereof, isotopomers thereof, isotopologues thereof, and prodrugs thereof. For example, they may be pharmaceutically acceptable salts, either alone or in various combinations with other compounds described herein. In embodiments, the compounds may be racemic or scalenic mixtures.

[0154] Compounds of Formula I, including their pharmaceutically acceptable salts, hydrates, solvates, tautomers, enantiomers, diastereomers, isotopomers, isotopologues, prodrugs, or combinations thereof, are known in the literature or can be prepared by using reactions and standard procedures exemplified herein. [46-48] Exemplary synthetic procedures for making compounds of Formula I are provided below.

[0155] [ka]

[0156] Another specific example is the following:

[0157] [ka]

[0158] Methods and Uses of 1H-Pyrazole Analogs and Compositions Thereof In embodiments, the 1H-pyrazole analogs described herein may act as metal chelators. Thus, the 1H-pyrazole analogs may be capable of reducing heavy metal-induced genotoxicity. In embodiments, the heavy metal may be selected from arsenic trioxide, colloidal bismuth subcitrate, cadmium chloride, mercury chloride, and / or lead chloride. Because low doses of heavy metals are associated with, for example, neurodegenerative diseases, the ability of the 1H-pyrazole analogs described herein to chelate heavy metals may provide additional therapeutic benefits. Without being bound by theory in this regard, the 1H-pyrazole analogs described herein can form reversible complexes with metalloenzymes due to their Lewis acid properties and vacant p-orbitals, and thus can form stable complexes with metals such as copper and zinc in the scaffold of the protein SOD1 (which is associated with neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS)), thereby making it more stable.

[0159] In other embodiments, the 1H-pyrazole analogs described herein can act as antioxidants. Thus, the 1H-pyrazole analogs described herein can reduce oxidative stress. This can play a role, for example, in alleviating symptoms (described below) associated with diseases, disorders, and / or conditions associated with oxidative stress.

[0160] Oxidative stress reflects the systemic expression of reactive oxygen species (ROS) / reactive nitrogen species (RNS) and an imbalance between antioxidants and the excessive expression of free radicals. This process leads to the oxidation of biomolecules with subsequent loss of biological function and / or homeostatic imbalance, and this expression is a potential oxidative damage to cells and tissues. The accumulation of ROS / RNS can produce numerous harmful effects, such as lipid peroxidation, protein oxidation, and DNA damage (including base damage and strand breaks). Furthermore, some reactive oxidative species act as cellular messengers in redox signaling. Thus, oxidative stress can cause disruption to normal mechanisms of cell signaling.

[0161] "ROS" and "RNS" are terms that collectively describe free radicals, also known as oxidants, and other nonradical reactive derivatives. Radicals are less stable than nonradical species but generally more reactive. Molecules with one or more unpaired electrons in their outer shell are called free radicals. Free radicals are formed from molecules through chemical bond cleavage, with each fragment retaining one electron, by the cleavage of a radical to give another radical, and through redox reactions.

[0162] The reduction of oxidative stress by the 1H-pyrazole analogs described herein can be through several different mechanisms. For example, the 1H-pyrazole analogs can reduce oxidative damage / oxidative stress by scavenging ROS and / or RNS. Thus, as antioxidants, the 1H-pyrazole analogs described herein can be capable of scavenging ROS and / or RNS. In embodiments, scavenging ROS and / or RNS can be the elimination of ROS and / or RNS. In other embodiments, scavenging ROS and / or RNS can be a reduction in the amount of ROS and / or RNS. Scavenging mechanisms will be understood by those skilled in the art and can include, for example, by donating a hydrogen atom to ROS, converting it into another molecule, such as water, which is more stable. In some embodiments, the reduction of oxidative damage / oxidative stress is in vitro, while in other embodiments, the reduction of oxidative damage / oxidative stress is in vivo.

[0163] In embodiments, the ROS and / or RNS include free radicals and / or oxidants, including hydroxyl radical (HO), superoxide radical anion radical (O), nitric oxide (NO), nitrogen dioxide (NO), peroxyl (ROO), and lipid peroxyl (LOO), hydrogen peroxide (HO), ozone (O), singlet oxygen ( 1 O2), hypochlorous acid (HOCl), hydroperoxide nucleophiles ( - As will be appreciated, other peroxides include, but are not limited to, hydrogen peroxide (HO), ozone (O), singlet oxygen (OOH), nitrous acid (HNO), nitrous trioxide (NO), and lipid peroxides (LOOH). 1 O2), nitrous acid (HNO2), peroxynitrite (ONOO - ), nitrous oxide (N2O3), and lipid peroxides (LOOH), which are commonly referred to as oxidants rather than free radicals, can easily lead to free radical reactions in vivo.

[0164] In typical embodiments, the free radical and / or oxidant is hydrogen peroxide (HO). In certain embodiments, the 1H-pyrazole analogs described herein can react with hydrogen peroxide to reduce the amount of ROS / oxidative stress in vitro, and in other certain embodiments, the 1H-pyrazole analogs described herein can react with hydrogen peroxide to reduce the amount of ROS / oxidative stress in vivo.

[0165] In embodiments, the 1H-pyrazole analogs described herein can react with hydrogen peroxide to generate edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one; EDR; FIG. 1 ). Thus, in embodiments, the 1H-pyrazole analogs described herein can act as prodrugs of EDR. Such generation of EDR can be in vitro or in vivo. Regarding the prodrug function of the 1H-pyrazole analogs, in certain embodiments, derivatization of carbon-5 of EDR to generate the 1H-pyrazole analogs described herein ( FIG. 2 ) can enable the 1H-pyrazole analogs to be activated by ROS (e.g., HO) and release / scavenge EDR ( FIG. 3 ). In these embodiments, in vivo reaction with HO or ROS can insert an oxygen atom into carbon-5 of EDR, forming a new CO bond in the 1H-pyrazole analogs described herein. Following hydrolysis, the enol form of EDR may be generated, and thus the 1H-pyrazole analogs function as prodrugs for the in vivo generation of EDR intracellularly and / or directly to sites of oxidative stress (Figure 3). These characteristics may aid the 1H-pyrazole analogs described herein in being useful as therapeutic agents for the prevention and / or treatment of diseases, disorders, and / or conditions associated with oxidative stress (described below).

[0166] Without being bound by theory, it is believed that 1H-pyrazole analogs (i.e., B) act as prodrugs of EDR. 5Not only can 1H-pyrazole analogs (-EDR analogs) directly generate EDR within cells, but 1H-pyrazole analogs can also alleviate oxidative stress, e.g., by reacting with HO / ROS to alleviate oxidative stress. Thus, 1H-pyrazole analogs may be able to treat and / or alleviate some of the symptomatology caused by oxidative stress-related diseases, disorders, and / or conditions (described in more detail below), e.g., by targeting and / or eliminating molecules involved in oxidative stress pathways (e.g., HO / ROS). In other embodiments, the 1H-pyrazole analogs described herein are antioxidants and prodrugs of EDR.

[0167] EDR has poor water solubility (approximately 1.85 mg / ml), low permeability (Peff = approximately 3.18 ± 0.0706 *EDR is a biopharmaceutics classification system (BCS) Class IV amphiphilic molecule with a low molecular weight (approximately 174.2 g / mol) due to its high energy density (10-7 cm / s), short half-life of approximately 0.1 to 5.16 hours, and PKa of approximately 7 [3, 22]. EDR is a redox regulator of cellular processes and acts by reducing both ROS / RNS free radicals (i.e., superoxide anion, hydroxyl radical, singlet oxygen, peroxy radical, hydrogen peroxide, and peroxynitrite) to their stable conformational states. Because EDR is an amphiphilic molecule, it can reduce both water-soluble and oil-soluble free radicals by donating one electron to complete an octet state and electronically stabilizing them. This mechanism is called the single electron transfer process (SET)

[18] . Additionally, EDR is a substrate for the P-glycoprotein (Pgp) efflux pump and is systemically metabolized by CYP3A4 enzymes. It also undergoes extensive phase II metabolism, including glucuronidation (from about 68 to about 83%) by uridine glucoronosyltransferase (UGT) enzymes and sulfation (from about 5 to about 13%) by sulfotransferases, to form pharmacologically inactive glucuronide sulfate conjugates, which can result in high passive permeability to target sites and low therapeutic concentrations [3, 23].

[0168] EDR exists as a solid in the keto tautomer form, while the tautomeric enol form exists as a highly unstable anion in aqueous solution (Figure 1). The pKa of EDR is approximately 7.0, and its solubility in aqueous solution is pH-dependent. As the pH of a solution increases above approximately 8, EDR acts as an acid, donating a hydronium ion to form the conjugate base, the EDR anion. At physiological pH (approximately 7.4), approximately 71.5% of EDR exists as an anion, while the remaining approximately 28.5% exists as a neutral form

[18] . The anion can reduce radicals or even molecular oxygen by a single-electron transfer process to form a stable EDR radical, which is stabilized by three resonance structures (enol, keto, and amine forms) and subsequently forms an inactive EDR trimer in the absence of oxygen, which appears as a yellow precipitate

[24] . Decomposition of EDR occurs, forming stable oxidative products such as OPB, 4-oxo EDR, EDR peroxy radical, BPOH, and phenylhydrazine.

[25] The poor oral bioavailability of EDR is due to its low aqueous solubility, low permeability, poor stability, and extensive systemic metabolism. Therefore, analogs of EDR that can act as prodrugs may improve the properties of the analogs compared to EDR because the compounds do not exist as keto-enol tautomers.

[0169] EDR diffuses throughout most organs, including highly metabolically demanding organs such as the brain and heart, and controls the oxidation-reduction cycle [19, 20]. As a result, EDR was the first neuroprotective drug developed in Japan for the treatment of cerebral ischemic stroke [3] and has been approved for ALS in numerous jurisdictions, including by the FDA (May 2017) [1] and Health Canada (October 2018) [2]. EDR acts as a free radical scavenger (antioxidant), reducing oxidative stress in cells and proving a potential therapeutic agent for helping patients recover from stroke. In a randomized clinical trial, EDR was found to slow the progression of ALS in patients with early-stage disease when administered for more than six months [4]. Although EDR's efficacy is modest, it remains one of the few therapeutic agents clinically shown to improve patient outcomes. Furthermore, although the precise cellular and molecular targets of EDR are not yet known with certainty, antioxidant pathways have been proposed as one possible mechanism. However, EDR has limitations in terms of patient compliance, pharmacokinetics, oral bioavailability, and can be unstable as an aqueous IV formulation. The recommended intravenous (IV) dose of edaravone for ALS is 60 mg administered over 60 minutes for 14 days, followed by a 14-day rest period [1], making it problematic for geriatric patients to administer the drug. For these patients, the oral route is highly preferred due to ease of administration, dosage flexibility, reduced long-term hospitalization, cost-effectiveness, and improved quality of life. In certain embodiments, the 1H-pyrazole analogs described herein may be able to circumvent some of the aforementioned limitations of EDR.

[0170] In embodiments, the 1H-pyrazole analogs described herein may be useful for the prevention and / or treatment of diseases, disorders, and / or conditions associated with oxidative stress. In other words, the 1H-pyrazole analogs described herein may be useful for the prevention, stabilization, reduction of severity, reduction of progression, and / or treatment of diseases, disorders, and / or conditions associated with oxidative stress. In embodiments, the 1H-pyrazole analogs described herein may be useful, for example, for the alleviation of oxidative stress and / or neurotoxicity, resulting in neuroprotection and, for example, a reduction in progression of diseases, disorders, and / or conditions associated with oxidative stress. For example, in embodiments, the 1H-pyrazole analogs described herein are useful for the alleviation of oxidative stress and / or neurotoxicity, resulting in neuroprotection and, for example, a reduction in progression of neurodegenerative diseases, disorders, and / or conditions associated with oxidative stress. In embodiments, the oxidative stress is caused by ROS and / or reactive nitrogen species RNA as described herein.

[0171] In exemplary embodiments, the oxidative stress-associated disease, condition, and / or disorder is selected from neurodegenerative diseases, disorders, and / or conditions, muscle diseases, disorders, and / or conditions, vascular diseases, disorders, and / or conditions, systemic inflammatory diseases, disorders, and / or conditions, local inflammatory diseases, disorders, and / or conditions, metabolic syndrome, cardiovascular diseases, disorders, and / or conditions, autoimmune diseases, disorders, and / or conditions, inflammatory lung diseases, disorders, and / or conditions, kidney diseases, disorders, and / or conditions, liver diseases, disorders, and / or conditions, digestive diseases, disorders, and / or conditions, aging, disorders, and / or conditions, viral infectious diseases, disorders, and / or conditions, cancer, and sepsis / septic shock. In exemplary embodiments, the oxidative stress-associated disease, condition, and / or disorder comprises a neurodegenerative disease, disorder, and / or condition. In other exemplary embodiments, the neurodegenerative disease, disorder, and / or condition is associated with motor dysfunction, and in further exemplary embodiments, the neurodegenerative disease, disorder, and / or condition is associated with cognitive dysfunction.

[0172] Neurodegenerative diseases, disorders, and / or conditions associated with motor dysfunction include, but are not limited to, amyotrophic lateral sclerosis (ALS), Parkinson's disease, tardive dyskinesia (TD), epilepsy, ischemic attack, cerebral ischemic injury, seizures, and / or spinocerebellar degeneration. Neurodegenerative diseases, disorders, and / or conditions associated with cognitive dysfunction include, but are not limited to, Alzheimer's disease, dementia, and / or Huntington's disease. In typical embodiments, the oxidative stress-related disease, disorder, and / or condition is a neurodegenerative disease, disorder, and / or condition associated with motor dysfunction, and in other typical embodiments, the neurodegenerative disease, disorder, and / or condition associated with motor dysfunction is ALS. In some embodiments, the ALS is familial ALS, and in other embodiments, the ALS is sporadic ALS. In further embodiments, the ALS is caused by a mutation in the superoxide dismutase 1 (SOD1) gene or the TARDBP gene.

[0173] ALS, also known as Lou Gehrig's disease, is an idiopathic, fatal neuromuscular disease of the motor nervous system that results in voluntary skeletal muscle dysfunction and ultimately death from respiratory failure. Voluntary muscles weaken and become immobile, while the sensory system and intellect are largely unaffected. Briefly, ALS is defined as a neurodegenerative disorder, and considerable research has shown that misfolding and / or aggregation of specific proteins serves as a hallmark of the disease, with ROS and RNS contributing to this pathophysiology [3]. Perturbations in the normal cellular redox cycle can lead to the generation of highly toxic ROS / RNS species, subsequently causing neuronal death. The oxidative cellular environment induces the formation of abnormal disulfide bonds and peroxynitrite-nitrated tyrosine residues in proteins, resulting in the abnormal formation of protein aggregates or abnormal enzyme activity [5]. Although various factors contribute to the onset and progression of ALS, oxidative stress caused by free radicals is responsible for the protein oxidation that is a prominent feature of neurodegenerative disorders, leading to the accumulation of misfolded proteins and potentially causing cellular dysfunction and death [6].

[0174] ALS is broadly classified into two forms: sporadic (S)ALS (85–90% of cases) and genetically related familial (F)ALS (10–15% of cases). Approximately 20% of FALS cases have been found to be caused by mutations in the superoxide dismutase 1 (SOD1) gene [7], and the pathophysiology of FALS and SALS share similar pathological and clinical mechanisms. The disease is thought to be caused by mutations in a single gene, SOD1, and over 100 mutations in the SOD1 gene have been identified in patients with ALS [8]. Substantial evidence indicates that mutant SOD1 proteins acquire toxic functions that cause neuronal degeneration, leading to the breeding of transgenic mice overexpressing mutant SOD1-G93A and SOD1-G37R for use in ALS animal models. Oxidative stress, which induces SOD1 misfolding, is a pathological marker of SOD1 mutations associated with ALS [9]. Research findings suggest that pathological concentrations of moderate oxidants, such as hydrogen peroxide (HO), an uncharged and non-ionized free radical initiator, are involved in controlling the aggregation and toxicity of both wild-type and mutant SOD1, leading to motor neuron death [10-12]. Pathological concentrations of HO can induce fibrillization and misfolding of the SOD1 enzyme through oxidative modification of the amino acid Cys-111. Oxidized SOD1 has the potential to cause protein misfolding and exhibit toxicity, leading to motor neuron death [13, 14].

[0175] Hydrogen peroxide (HO) is a paradoxical redox molecule that can cause cell signaling or cell death, depending on its concentration in living cells. At physiological concentrations of approximately 1 to 10 nM, it can create oxidative eustress and initiate cellular processes, such as proliferation and changes in cell shape / size. Higher concentrations, ranging above approximately 100 nM, can cause destructive redox signaling, oxidative distress, and thus oxidation of biomolecules

[15] . SOD1 regulates HO levels during normal physiological processes. It converts highly reactive and toxic superoxide into relatively unreactive, uncharged, and freely diffusible hydrogen peroxide. Although the concentration of SOD1 in cells is low, its pathological concentration ranges from approximately 10 to 100 μM, and can increase to approximately 150 μM under conditions of high oxidative stress

[16] . At concentrations of approximately 20 to 200 nM HO, fibrillation of SOD1 protein occurs, gradually forming amyloid fibrils rich in beta-sheet conformation in neuronal cells via oxidative modification of amino acid Cys-111 to an unstable, short-lived cysteine ​​sulfenic acid (C-SOH). Sulfenic acid-modified SOD1 oligomers can cause the redistribution of TDP-43 from the nucleus to the cytoplasm, inducing the formation of SOD1 / TDP-43 amyloid fibrils, a phenomenon observed during the progression of ALS

[17] . Thus, HO may contribute to the misfolding and toxicity of SOD1 in the nucleus of motor neurons, leading to death

[13] . Therefore, alleviating oxidative stress and / or SOD1 oxidation / misfolding may be a therapeutic strategy for the treatment of ALS.

[0176] In embodiments, treatment of a disease, disorder, and / or condition includes, for example, alleviating the progression of the disease, disorder, and / or condition, curing the disease, disorder, and / or condition, preventing the onset of the disease, disorder, and / or preventing recurrence, and may refer to treatment of symptoms caused by the above-described disease, disorder, and / or condition. In embodiments, treatment of a symptom includes, for example, inhibiting the progression of the symptom, alleviating the symptom, curing the symptom, preventing the onset of the symptom, and / or preventing the recurrence of the symptom. The symptom is, for example, a dysfunction caused by a disease, disorder, and / or condition associated with oxidative stress, such as motor dysfunction, or cognitive dysfunction in a neurodegenerative disease, disorder, and / or condition. For example, in embodiments, the use of the 1H-pyrazole analogs described herein can help alleviate the decline in motor function associated with ALS (e.g., the 1H-pyrazole analogs described herein can increase motor function in subjects with ALS).

[0177] In embodiments, the 1H-pyrazole analogs described herein can affect the therapeutic index of ALS. In embodiments, the 1H-pyrazole analogs described herein can improve the therapeutic index of ALS compared to edaravone (EDR). The therapeutic index can be a measure of many different symptoms of ALS, such as muscle weakness, muscle wasting (atrophy), weight loss (cachexia), muscle spasms, muscle cramps, slowness of movement, poor balance, incoordination, changes in voice quality, dysarthria, dysphagia, incomplete eye closure, salivation, pseudobulbar involvement, and / or early death. In embodiments, an improved therapeutic index includes an improvement in any one or more of the above-listed symptoms when comparing subjects receiving a 1H-pyrazole analog described herein compared to subjects receiving EDR. In some embodiments, an improved therapeutic index is measured by increased survival / lifespan in subjects receiving a 1H-pyrazole analog compared to subjects receiving edaravone (EDR). In another embodiment, the improved therapeutic index is measured by increased motor function in subjects receiving the 1H-pyrazole analog compared to subjects receiving edaravone (EDR). In a further embodiment, the improved therapeutic index is measured by a lower percentage of weight loss in subjects receiving the 1H-pyrazole analog compared to subjects receiving edaravone (EDR).

[0178] In some embodiments, treatment and / or prevention of ALS with the 1H-pyrazole analogs described herein ameliorates or eliminates one or more of the following ALS symptoms: muscle weakness, muscle wasting (atrophy), muscle spasms, muscle cramps, slowness of movement, impaired balance, incoordination, changes in voice quality, dysarthria, dysphagia, insufficient eyelid closure, drooling, pseudobulbar involvement, and / or premature death. In other embodiments, treatment with the 1H-pyrazole analogs described herein can prevent or delay the onset of one or more of the above-listed symptoms.

[0179] In some embodiments, the improvement in the therapeutic index may be determined by detecting an improvement in the subject's symptoms compared to one or more of: (1) baseline measurement or symptom levels detected before or at the start of treatment; (2) measurement or symptom levels of a control subject or control population in which the control subject exhibits one or more symptoms of ALS and (i) is not administered a 1H-pyrazole analog described herein or (ii) is administered a control analog; or (3) a standard.

[0180] In other embodiments, the 1H-pyrazole analogs described herein may have improved pharmacokinetics compared to edaravone (EDR). Because pharmacokinetics may be determined by the 1H-pyrazole analog acting as a prodrug, the 1H-pyrazole analogs may have favorable drug-like properties, such as greater lipophilicity, increased membrane permeability, reduced Pgp recognition, and a longer half-life, compared to EDR. Thus, subjects receiving the 1H-pyrazole analogs described herein may benefit from the increased in vivo bioavailability (e.g., the 1H-pyrazole analogs described herein have a longer half-life in vivo and / or are more resistant to in vivo degradation) compared to EDR. The increased bioavailability of the 1H-pyrazole analogs described herein can contribute to, for example, greater chelation of heavy metals, increased scavenging of ROS and / or RNS, reduced oxidative damage / oxidative stress, and thus increased therapeutic benefit for diseases, disorders, and / or conditions associated with oxidative stress. Furthermore, based on the ability of the 1H-pyrazole analogs described herein to possess the multiple functions described herein, in embodiments, the 1H-pyrazole analogs described herein can function as therapeutics for the prevention and / or treatment of diseases, disorders, and / or conditions associated with oxidative stress, for example, as ALS therapeutics in vivo.

[0181] In another embodiment, the muscle disease, disorder, and / or condition comprises muscular dystrophy. In another embodiment, the vascular disease, disorder, and / or condition comprises cerebral infarction. In another embodiment, the systemic inflammatory disease, disorder, and / or condition comprises multiple sclerosis and / or systemic sclerosis. In another embodiment, the local inflammatory disease, disorder, and / or condition comprises stomatitis.

[0182] Other specific diseases, disorders, and / or conditions associated with oxidative stress include, for example, (i) metabolic syndrome, including, but not limited to, insulin resistance, obesity, hyperglycemia, dyslipidemia, hypertension, and / or diabetes; (ii) cardiovascular diseases, disorders, and / or conditions, including, but not limited to, atherosclerosis, hypertension, heart failure, cardiovascular ischemia, and / or myocardial infarction; (iii) autoimmune diseases, disorders, and / or conditions, including, but not limited to, rheumatoid arthritis and / or systemic lupus erythematosus; (iv) inflammatory lung diseases, disorders, and / or conditions, including, but not limited to, chronic obstructive pulmonary disease (COPD), emphysema, and / or asthma; and (v) nephrotoxicity (drug-induced kidney disease), acute kidney injury (AKI), chronic kidney disease (CKD), diabetic nephropathy, and / or end-stage renal disease (ESRD). (vi) kidney diseases, disorders, and / or conditions, including but not limited to hepatotoxicity, viral hepatitis, and cirrhosis; (vii) digestive diseases, disorders, and / or conditions, including but not limited to inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, gastritis, pancreatitis, and / or peptic ulcers; (viii) viral infectious diseases, disorders, and / or conditions, including but not limited to blood-borne hepatitis viruses (B, C, and D), human immunodeficiency virus (HIV), influenza A, Epstein-Barr virus, and / or respiratory syncytial virus; (ix) cancer, including but not limited to prostate cancer, breast cancer, lung cancer, colorectal cancer, bladder cancer, ovarian cancer, skin cancer, stomach cancer, and / or liver cancer; and (x) sepsis / septic shock. A subject suffering from any of the aforementioned diseases, disorders, and / or conditions associated with oxidative stress can be identified by any or a combination of diagnostic or prognostic assays known in the art.

[0183] The 1H-pyrazole analogs described herein can be used in methods for preventing and / or treating oxidative stress diseases, conditions, and / or disorders. Thus, oxidative stress diseases, conditions, and / or disorders can be treatable and / or preventable by administering or delivering the 1H-pyrazole analogs described herein. In embodiments, the method includes administering a 1H-pyrazole analog to a subject in need thereof.

[0184] The subject referred to herein is typically someone suffering from one or more oxidative stress diseases, conditions, and / or disorders, and / or someone at risk of suffering from one or more oxidative stress diseases, conditions, and / or disorders. Thus, the uses and methods described herein can be used to prevent the onset of oxidative stress diseases, disorders, and / or conditions, for example, when a 1H-pyrazole analog is provided (administered) to a subject at risk of developing the oxidative stress diseases, disorders, and / or conditions described herein. Alternatively, the uses and methods described herein can be used to treat oxidative stress-related diseases, disorders, and / or conditions, for example, when a 1H-pyrazole analog is provided (administered) to a subject suffering from an oxidative stress-related disease, condition, and / or disorder. For purposes of this disclosure, a subject may have a single oxidative stress-related disease, condition, and / or disorder, or a group of oxidative stress-related diseases, conditions, and / or disorders, to be treated by the uses and methods described herein.

[0185] In other embodiments, the 1H-pyrazole analogs described herein can be used in the manufacture of a medicament, typically for the prevention and / or treatment of a disease, condition, and / or disorder associated with oxidative stress described herein. In typical embodiments, the 1H-pyrazole analogs as medicaments are for administration to a subject (e.g., a mammal, typically a human) in need thereof.

[0186] 1H-pyrazole analogues can be administered to mammals, typically humans.When administered as pharmaceutical compositions, 1H-pyrazole analogues can be provided in combination with pharmaceutically acceptable carriers or diluents, optionally with pharmaceutically acceptable adjuvants, such as alum.Therefore, 1H-pyrazole analogues can be suitably formulated into pharmaceutical compositions for administration to human subjects in the biologically compatible form suitable for in vivo administration.

[0187] Thus, in an embodiment, the pharmaceutical composition comprises a 1H-pyrazole analog combined with a suitable diluent or carrier. Compositions containing 1H-pyrazole analogs can be prepared by known methods for preparing pharmaceutically acceptable compositions that can be administered to a subject, such that an effective amount of the 1H-pyrazole analog is combined in a mixture with a pharmaceutically acceptable carrier. Suitable carriers are described, for example, in Remington's Pharmaceutical Sciences (2003-20th Edition), The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999, and Handbook of Pharmaceutical Additives (Michael and Irene Ash, eds., Gower Publishing Limited, Aldershot, England (1995)), which are incorporated by reference in their entirety. Based on this, the composition can include a solution that is associated with one or more pharmaceutically acceptable carriers or diluents and contained in a buffer solution having a pH and isotonicity suitable for physiological fluids. The solution of 1H-pyrazole analogues can be prepared in water by suitably mixing with suitable excipients.Under normal conditions of storage and use, these preparations can contain preservatives to prevent microbial growth.Those skilled in the art know how to prepare suitable formulations / compositions.In this regard, reference can be made to U.S. Patent No. 5,843,456, which is incorporated herein by reference.

[0188] The 1H-pyrazole analogs can be administered alone or in combination with other components / ingredients / active substances. For example, the 1H-pyrazole analogs can be administered as pharmaceutical compositions. The described 1H-pyrazole analogs and / or compositions thereof can be administered to a subject in various forms depending on the selected administration route, as will be understood by those skilled in the art. The 1H-pyrazole analogs and compositions thereof can be administered, for example, orally, parenterally (e.g., intravenously, intraperitoneally, subcutaneously, intramuscularly, transepithelially, intranasally, intrapulmonary, intrathecally, intrarectally, and topically), bucally, sublingually, by patch, pump, or transdermal administration. In a typical embodiment, the 1H-pyrazole analogs described herein are administered or are intended for administration using oral or intravenous routes of administration.

[0189] When 1H-pyrazole analogs are administered orally, the selected compound can be administered, for example, in the form of an ingestible powder (e.g., pure powder), tablet, or capsule, or as an aqueous solution or suspension. Examples include ingestible tablets, oral tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, etc. In tablet dosage forms, depending on the dosage, the 1H-pyrazole analogs can comprise 1 wt% to 99 wt% of the dosage form, more typically 5 wt% to 60 wt% of the dosage form. In addition, commonly used carriers include lactose and corn starch, and lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate are commonly added. In addition, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Useful diluents include lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and calcium hydrogen phosphate dihydrate, and suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose, and hydroxypropylmethylcellulose. Other conventional ingredients include antioxidants, colorants, flavorings, preservatives, and taste-masking agents. Tablet blends can be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting. The final formulation may comprise one or more layers and may be coated, uncoated, or encapsulated.Tablet formulations are discussed in detail in "Pharmaceutical Dosage Forms: Tablets, Volume 1," H. Lieberman and L. Lachman, Marcel Dekker, NY, NY, 1980 (ISBN 0 8247 6918 X), the disclosure of which is incorporated herein by reference in its entirety.

[0190] When aqueous suspensions are prepared for oral use, the active ingredient can be combined with emulsifiers and suspending agents.If desired, certain sweeteners and / or flavoring agents can be added.1H-pyrazole analogs can be orally administered, for example, with inert diluents or with assimilable edible carriers, or can be enclosed in hard or soft shell gelatin capsules, or compressed into tablets, or can be directly incorporated into food.For therapeutic oral administration, 1H-pyrazole analogs can be incorporated into excipients and used in the form of ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, etc.

[0191] When 1H-pyrazole analogs are administered parenterally, parenteral administration may be by continuous infusion, bolus, or intermittent bolus, and may be administered over a selected period of time. Suitable examples of devices for parenteral administration include needle (including microneedle) syringes, needleless syringes, and infusion techniques. For intramuscular, intraperitoneal, subcutaneous, and intravenous use, sterile solutions of active ingredients are usually prepared, and the pH of the solution should be appropriately adjusted and buffered. For intravenous use, the total concentration of solutes can be controlled to make the preparation isotonic. Thus, in embodiments, one or more 1H-pyrazole analogs described herein can be prepared in an isotonic medium and administered intravenously.

[0192] Pharmaceutical forms suitable for injection use can include sterile aqueous solutions or dispersions and sterile powders for the immediate preparation of sterile injectable solutions or dispersions.In some embodiments, the form is sterile, and the fluid is easily syringable.For example, the preparation of a parenteral kit for reconstitution at the point of care under sterile conditions by lyophilization can be easily achieved using standard pharmaceutical techniques known to those skilled in the art.

[0193] 1H-pyrazole analogs for nasal administration (including pharmaceutical compositions thereof) can be conveniently formulated into aerosols, drops, gels, and powders. Aerosol formulations typically contain a solution or fine suspension of an active substance in a physiologically acceptable aqueous or non-aqueous solvent, and are usually presented in a sealed container in a single- or multi-dose sterile form. The sealed container can be in the form of a cartridge or refill used in an atomizing device (e.g., a nebulizer, for example, to produce a mist-like dispersion of 1H-pyrazole analogs in an aqueous vehicle (e.g., saline)). Alternatively, the sealed container can be a unit-dispensing device, such as a single-dose nasal inhaler or aerosol dispenser, with a metering valve, intended to be discarded after use. When the dosage form includes an aerosol dispenser, it contains a propellant that can be a compressed gas, such as compressed air, or an organic propellant, such as fluorochlorohydrocarbon. The aerosol dosage form can also be in the form of a pump-type atomizing device.

[0194] Suitable 1H-pyrazole analogs (including pharmaceutical compositions thereof) for buccal or sublingual administration include tablets, lozenges, and pastilles, and the active ingredient is formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerin.Compositions for rectal administration are conveniently in the form of suppositories containing conventional suppository bases such as cocoa butter.In embodiments, a delivery system can be used to deliver 1H-pyrazole analogs (e.g., formulations or pharmaceutical compositions).It is understood that the delivery system itself can include a device such as an implantable device.

[0195] The 1H-pyrazole analogs can be combined with soluble polymeric entities, such as cyclodextrins and suitable analogs thereof, or polyethylene glycol-containing polymers, to improve solubility, dissolution rate, taste masking, bioavailability, and / or stability for use in any of the aforementioned modes of administration. Regardless of the selected route of administration, the 1H-pyrazole analogs (which may be used in a suitable hydrated form) and / or pharmaceutical compositions thereof can be formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

[0196] The actual dosage level of the v analogue may vary to obtain an effective amount for achieving the desired therapeutic response in a specific patient, composition, and administration method.In this regard, the dosage of the 1H-pyrazole analogue may be influenced by the pharmacokinetic and pharmacodynamic characteristics of the 1H-pyrazole analogue, and its administration method and route; the release rate of the 1H-pyrazole analogue, the recipient's age, sex, health, medical condition, the nature and severity of symptoms, and body weight, the patient's renal and hepatic function; the frequency of treatment and, if any, the type of concurrent treatment, and the clearance rate of the 1H-pyrazole analogue in the treated subject, and the desired effect.The selected dosage level may also be influenced by additional factors, including the activity of the specific 1H-pyrazole analogue and pharmaceutical composition described herein, the administration time, the excretion or metabolic rate of the specific 1H-pyrazole analogue used, the rate and degree of absorption, the duration of treatment, other drugs that may be administered to the patient, the compounds and / or materials used in combination with the specific 1H-pyrazole analogue used, and similar factors well known in the medical field.Those skilled in the art can determine the appropriate dosage based on the above factors.

[0197] A physician or veterinarian with ordinary skill in the art can easily determine and prescribe the effective amount of 1H-pyrazole analogues or pharmaceutical compositions thereof.For example, a physician or veterinarian can start the dosage of 1H-pyrazole analogues used in pharmaceutical compositions at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.In general, the suitable daily dose of 1H-pyrazole analogues is the amount of the compound that is the lowest dose effective to produce a therapeutic effect.Such an effective dose generally depends on the factors described above.

[0198] The 1H-pyrazole analog can be initially administered at a suitable dosage, which can be adjusted as needed depending on the clinical response. For short-term ex vivo treatment of cells, e.g., 30 minutes to an hour or more, higher doses of the 1H-pyrazole analog can be used than those used for long-term in vivo therapy.

[0199] In some embodiments, the 1H-pyrazole analog is administered in an amount of about 0.001 mg / kg to about 1000 mg / kg of body weight per day, e.g., about 0.01 mg / kg to about 500 mg / kg of body weight per day, about 0.01 mg / kg to about 250 mg / kg of body weight per day, or about 0.01 mg / kg to about 100 mg / kg of body weight per day, and any intermediate range or specific amount, e.g., about 0.001 mg / kg, about 0.01 mg / kg, about 0.1 mg / kg, about 1 mg / kg, about 10 mg / kg, about 25 mg of body weight per day, hourly, weekly, or dose. / kg, about 50mg / kg, about 75mg / kg, about 100mg / kg, about 150mg / kg, about 200mg / kg, about 250mg / kg, about 300mg / kg, about 350mg / kg, about 400mg / kg, about 450mg / kg, about 500mg / kg, about 600mg / kg, about 700mg / kg, about 800mg / kg, about 900mg / kg, or about 1000mg / kg, to about 0.001mg / kg, about 0.01mg / kg, about 0.1mg / kg, about 1mg / kg, about 10mg / kg, about 25mg / kg, about 50mg / kg, about 75mg / kg, about 100mg / kg, about 150mg / kg, about 200 mg / kg, about 250 mg / kg, about 300 mg / kg, about 350 mg / kg, about 400 mg / kg, about 450 mg / kg, about 500 mg / kg, about 600 mg / kg, about 700 mg / kg, about 800 mg / kg, about 900 mg / kg or about 1000 mg / kg may be administered.

[0200] As a typical specific example, in terms of the dose per administration of the pharmaceutical composition, for an adult human dose of an 1H-pyrazole analog, the lower limit is, for example, about 40 mg to about 70 mg, and the upper limit is, for example, about 400 mg, about 140 mg, about 120 mg, or about 105 mg, with ranges of, for example, about 40 mg to about 400 mg, preferably about 40 to about 140 mg, more preferably about 40 to about 120 mg, and even more preferably about 40 mg to about 105 mg, with doses of about 40 mg, about 50 mg, about 60 mg, or about 70 mg being particularly preferred, about 45 mg or about 55 mg being particularly preferred, and most preferably about 50 mg. When intravenous administration is desired, in a typical embodiment, the dose is in the range of about 0.01 to about 10 mg / kg / min via constant rate infusion.

[0201] When formulated as a fixed dose, such combination products contain the 1H-pyrazole analog within the dosage ranges described above and the other pharmaceutically active agent within an appropriate dosage range. Alternatively, the 1H-pyrazole analog can be used sequentially with a known pharmaceutically acceptable agent when a combination formulation is inappropriate.

[0202] The therapeutically effective amount of compound generally ranges up to the maximum tolerated dose, but can vary widely.The exact amount used by the attending physician will naturally vary depending on the 1H-pyrazole analog, the route of administration, the patient's physical condition (for example, the age, weight and response of each individual patient, and the severity of the patient's symptoms), and other factors.The daily dosage can be administered as a single dose, or can be divided into multiple doses, for example, 2, 3 or 4 times a day.Alternatively, the dosage can be provided weekly, biweekly or monthly.In some embodiments, a reduced dosage can be used compared with the conventional therapeutic dosage of known drugs.

[0203] The 1H-pyrazole analogs may also be combined with and / or co-administered with other therapeutic agents selected for their particular usefulness against the oxidative stress-related diseases, conditions, and / or disorders described herein. In other words, the 1H-pyrazole analogs may be combined with and / or co-administered with therapeutic agents to treat and / or prevent the oxidative stress-related diseases, conditions, and / or disorders described herein. Examples of therapeutic agents that may be useful in combination with the 1H-pyrazole analogs described herein for the treatment and / or prevention of ALS include, but are not limited to, riluzole (Rilutek™), edaravone (Radicava™), mecasermin, baclofen (Lioresal™), diazepam (Valium™), dantrolene (Dantrium™), nonsteroidal anti-inflammatory agents, anticonvulsants (e.g., carbamazepine (Tegretol) or phenytoin (Dilantin™)), amitriptyline (Elavil™), nortriptyline (Pamelor™), and lorazepam (Ativan™). In some embodiments, additional therapy includes co-administration of elamipretide (aka SS-31 or Bendavia). In these embodiments, therapeutic agents administered in combination with the 1H-pyrazole analogs described herein may produce a synergistic therapeutic effect, for example, where the combination has more than additive effects in the prevention and / or treatment of ALS. Thus, using lower doses of one or more of the individual therapeutic agents in combination with the 1H-pyrazole analogs described herein to treat or prevent ALS may result in increased therapeutic efficacy and reduced side effects. The combination of the 1H-pyrazole analogs and the therapeutic agents described herein may be concurrent or sequential, in any order. In embodiments, the 1H-pyrazole analogs and the therapeutic agents act additively or synergistically to prevent and / or treat oxidative stress diseases, conditions, and / or disorders.

[0204] Additional embodiments include the following:

[0205] Embodiment 1. Formula I:

[0206] [ka]

[0207] a compound having the structure: (In the formula, X1-BR 8 R 9 or -BR 10 R 11 R 12 Selected from; R 1 From R 7 , R 10 , R 11 , and R 12 each independently represents H, a halo group, a hydroxyl group, a cyano group, a nitro group, a thiol group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterogeneous group, -BR 13 R 14 , -BR 15 R 16 R 17 , a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group; R 13 From R 17 are each independently selected from H, a halo group, a hydroxyl group, a cyano group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group; or R 13 and R 14taken together form a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group, R 8 and R 9 are each independently selected from H, a halo group, a hydroxyl group, a cyano group, a nitro group, a thiol group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterogeneous group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, or together form a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group).

[0208] Embodiment 2.X1 is -BR 8 R 9 2. The compound of embodiment 1, wherein

[0209] Embodiment 3.R 8 and R 9 are each independently selected from H, a halo group, a hydroxyl group, a cyano group, a nitro group, a thiol group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterogeneous group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, and a substituted or unsubstituted heteroaromatic group.

[0210] Embodiment 4.R 8 and R 9 are each independently selected from H, a halo group, a hydroxyl group, a cyano group, a nitro group, a sulfate group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alkoxy group, —C(O)H, a substituted carbonyl group, a substituted carboxyl group, —C(O)OH, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

[0211] Embodiment 5.R8 and R 9 are each independently H, a halo group, a hydroxyl group, a cyano group, a nitro group, a sulfate group, a substituted or unsubstituted C1-C6 alkyl group, a C1-C6 haloalkyl group, a substituted or unsubstituted (C1-C6 alkyl)hetero(C1-C6 alkyl) group, a substituted or unsubstituted C1-C6 alkoxy group, -C(O)H, a substituted or unsubstituted C1-C6 alkylcarbonyl group, a substituted or unsubstituted (C1-C6 alkyl)carbonyl(C1-C6 alkyl) group, a substituted or unsubstituted The compound of any one of embodiments 1 to 4, wherein the alkyl group is selected from an unsubstituted C1-C6 alkyl-C(O)O- group, a substituted or unsubstituted C1-C6 alkyl-OC(O)- group, a substituted or unsubstituted C1-C6 alkyl-OC(O)-C1-C6 alkylene group, —C(O)OH, a substituted or unsubstituted C1-C6 cycloalkyl group, a substituted or unsubstituted C1-C6 heterocyclic group, a substituted or unsubstituted C1-C6 aromatic group, or a substituted or unsubstituted C1-C6 heteroaromatic group.

[0212] Embodiment 6.R 8 and R 9 is each independently selected from a fluoro group, a chloro group, a bromo group, a hydroxyl group, or an alkoxy group.

[0213] Embodiment 7.R 8 and R 9 The compound of embodiment 1 or 2, wherein together form a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group.

[0214] Embodiment 8.R 8 and R 9 The compound of any one of embodiments 1, 2, and 7, wherein taken together form a substituted or unsubstituted heterocyclic group.

[0215] Embodiment 9.R 8 and R 9taken together form a substituted or unsubstituted -O(C2-C8 alkylene)O- ring.

[0216] Embodiment 10.R 8 and R 9 taken together to form —OCH2CH2O—, —OC(CH3)2CH2O—, or —OC(CH3)2C(CH3)2O—.

[0217] Embodiment 11.R 8 and R 9 taken together form a substituted or unsubstituted -O(C1-C2 alkylene)NH(C1-C2 alkylene)O- ring.

[0218] Embodiment 12.R 8 and R 9 taken together to form —OCH2CH2NHCH2CH2O—, —OCH2CH2N(CH3)CH2CH2O—, —OCH2C(CH3)2NHCH2CH2O—, —OCH2C(CH3)2N(CH3)CH2CH2O—, —OCH2C(CH3)2NHC(CH3)2CH2O, —OC(CH3)2CH2N(CH3)C(CH3)2CH2O—, or —OC(CH3)2C(CH3)2N(CH3)C(CH3)2C(CH3)2O—.

[0219] Embodiment 13.X1 is -BR 10 R 11 R 12 2. The compound of embodiment 1, wherein

[0220] Embodiment 14.R 10 , R 11 , and R 12are each independently selected from H, a halo group, a hydroxyl group, a cyano group, a nitro group, a thiol group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterogeneous group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, and a substituted or unsubstituted heteroaromatic group.

[0221] Embodiment 15.R 10 , R 11 , and R 12 are each independently selected from H, a halo group, a hydroxyl group, a cyano group, a nitro group, a sulfate group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alkoxy group, —C(O)H, a substituted carbonyl group, a substituted carboxyl group, —C(O)OH, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

[0222] Embodiment 16.R 10 , R 11 , and R 12are each independently H, a halo group, a hydroxyl group, a cyano group, a nitro group, a sulfate group, a substituted or unsubstituted C1-C6 alkyl group, a C1-C6 haloalkyl group, a substituted or unsubstituted (C1-C6 alkyl)hetero(C1-C6 alkyl) group, a substituted or unsubstituted C1-C6 alkoxy group, -C(O)H, a substituted or unsubstituted C1-C6 alkylcarbonyl group, a substituted or unsubstituted (C1-C6 alkyl)carbonyl(C1-C6 alkyl) group, a substituted or unsubstituted C 16. The compound of any one of embodiments 1 and 13-15, wherein the C alkyl is selected from a C(O)O— group, a substituted or unsubstituted C-C alkyl-OC(O)— group, a substituted or unsubstituted C-C alkyl-OC(O)—C-C alkylene group, —C(O)OH, a substituted or unsubstituted C-C cycloalkyl group, a substituted or unsubstituted C-C heterocyclic group, a substituted or unsubstituted C-C aromatic group, or a substituted or unsubstituted C-C heteroaromatic group.

[0223] Embodiment 17.R 10 , R 11 , and R 12 is each independently selected from a fluoro group, a chloro group, a bromo group, a hydroxyl group, or an alkoxy group.

[0224] Embodiment 18.R 1 and R 2 are each independently selected from H, a halo group, a hydroxyl group, a cyano group, a nitro group, a thiol group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterogeneous group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

[0225] Embodiment 19.R 1 and R 2are each independently selected from H, a halo group, a hydroxyl group, a cyano group, a substituted or unsubstituted amino group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

[0226] Embodiment 20.R 1 and R 2 are each independently selected from H, a halo group, a substituted or unsubstituted C1-C6 alkyl group, a C1-C6 haloalkyl group, a substituted or unsubstituted (C1-C6 alkyl)hetero(C1-C6 alkyl) group, a substituted or unsubstituted C1-C6 cycloalkyl group, a substituted or unsubstituted C1-C6 heterocyclic group, a substituted or unsubstituted C1-C6 aromatic group, or a substituted or unsubstituted C1-C6 heteroaromatic group.

[0227] Embodiment 21.R 1 is H or a substituted or unsubstituted alkyl group, and R 2 is selected from H, a halo group, a hydroxyl group, a cyano group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterogeneous group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

[0228] Embodiment 22.R 1 is H, -CH3, -CH2CH3, or -CH2CH2CH3, and R 2 is selected from H, F, Cl, CN, —CH 3 , —CH 2 F, —CHF 2 , or —CF 3 .

[0229] Embodiment 23.R 3 From R 7each independently represents H, a halo group, a hydroxyl group, a cyano group, a nitro group, a thiol group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterogeneous group, -BR 13 R 14 , -BR 15 R 16 R 17 , a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group; R 13 From R 17 are each independently selected from H, a halo group, a hydroxyl group, a cyano group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group; or R 13 and R 14

[0082] Embodiment 23. The compound of any one of embodiments 1 to 22, wherein together form a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group.

[0230] Embodiment 24.R 3 From R 7 are each independently selected from H, a halo group, a cyano group, a nitro group, a sulfate group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterogeneous group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

[0231] Embodiment 25.R 3 From R 7are each independently selected from H, a halo group, a cyano group, a nitro group, a sulfate group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alkoxy group, —C(O)H, a substituted carbonyl group, a substituted carboxyl group, —C(O)OH, a boronic acid group, a substituted or unsubstituted alkylboronate group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

[0232] Embodiment 26.R 3 From R 7 are each independently H, a halo group, a substituted or unsubstituted C1-C6 alkyl group, a C1-C6 haloalkyl group, a substituted or unsubstituted (C1-C6 alkyl)hetero(C1-C6 alkyl) group, a substituted or unsubstituted C1-C6 alkoxy group, -C(O)H, a substituted or unsubstituted C1-C6 alkylcarbonyl group, a substituted or unsubstituted (C1-C6 alkyl)carbonyl(C1-C6 alkyl) group, a substituted or unsubstituted C1-C6 alkyl-C(O)O- group, or a substituted or unsubstituted C1-C6 alkyl-OC 26. The compound of any one of embodiments 1 to 25, wherein the group is selected from an (O)- group, a substituted or unsubstituted C1-C6 alkyl-OC(O)-C1-C6 alkylene group, —C(O)OH, a boronic acid group, a substituted or unsubstituted C1-C6 alkylboronate group, a substituted or unsubstituted C1-C6 cycloalkyl group, a substituted or unsubstituted C1-C6 heterocyclic group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted alkylheteroaryl group, a substituted or unsubstituted pyridinyl group, or a substituted or unsubstituted pyrrolyl group.

[0233] Embodiment 27.R 3 , R 4 , R 6 , and R 7 are each independently selected from H, -CH3, -CH2CH3, or -CH2CH2CH3; R 5is selected from H, F, Cl, CN, —CH 3 , —CH 2 F, —CHF 2 , or —CF 3 .

[0234] Embodiment 28. The compound is:

[0235] [ka]

[0236] 28. The compound of any one of embodiments 1 to 27, selected from a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a tautomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, an N-oxide thereof, a metabolite thereof, an isotopomer thereof, an isotopologue thereof, a prodrug thereof, or a combination thereof.

[0237] Embodiment 29. The compound is:

[0238] [ka]

[0239] a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a tautomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, an N-oxide thereof, a metabolite thereof, an isotopomer thereof, an isotopologue thereof, a prodrug thereof, or a combination thereof; and R1 to R4 are each independently selected from R 3 From R 7 29. The compound of any one of embodiments 1 to 28, wherein the compound is selected from any of the groups:

[0240] Embodiment 30. The compound is:

[0241] [ka]

[0242] is selected from a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a tautomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, an N-oxide thereof, a metabolite thereof, an isotopomer thereof, an isotopologue thereof, a prodrug thereof, or a combination thereof; and X + 30. The compound of any one of embodiments 1 to 29, wherein: is any suitable counterion.

[0243] Embodiment 31. The compound is:

[0244] [ka]

[0245] is selected from a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a tautomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, an N-oxide thereof, a metabolite thereof, an isotopomer thereof, an isotopologue thereof, a prodrug thereof, or a combination thereof; and X + 31. The compound of any one of embodiments 1 to 30, wherein: is any suitable counterion.

[0246] Embodiment 32 The compound of any one of embodiments 1 to 31, which is a racemic mixture.

[0247] Embodiment 33. A compound according to any one of embodiments 1 to 32 which is a scalemic mixture.

[0248] Embodiment 34. A compound of any one of embodiments 1 to 33, which is a pharmaceutically acceptable salt.

[0249] Embodiment 35. A compound according to any one of embodiments 1 to 34, which can act as a metal chelator.

[0250] Embodiment 36. A compound according to any one of embodiments 1 to 35, which may act as an antioxidant.

[0251] Embodiment 37 A compound according to any one of embodiments 1 to 36, which reduces oxidative stress.

[0252] Embodiment 38. A compound according to any one of embodiments 1 to 37, which reduces oxidative damage / oxidative stress by scavenging reactive oxygen species (ROS) and / or reactive nitrogen species (RNS).

[0253] Embodiment 39. A compound according to any one of embodiments 1 to 38, which is capable of reducing reactive oxygen species (ROS) and / or reactive nitrogen species (RNS) in vitro.

[0254] Embodiment 40. A compound according to any one of embodiments 1 to 39, which is capable of reducing reactive oxygen species (ROS) and / or reactive nitrogen species (RNS) in vivo.

[0255] Embodiment 41. A compound according to any one of embodiments 38 to 40, wherein the ROS and / or RNS comprise free radicals and / or oxidants.

[0256] Embodiment 42. The free radicals and / or oxidants are selected from the group consisting of hydroxyl radical (HO·), superoxide radical anion radical (O2·-), nitric oxide (NO·), nitrogen dioxide (NO2·), peroxyl (ROO·) and lipid peroxyl (LOO·), hydrogen peroxide (H2O2), ozone (O3), singlet oxygen ( 1 O2), hypochlorous acid (HOCl), hydroperoxide nucleophiles ( - 42. The compound of embodiment 41, wherein the compound is selected from: nitrous oxide (NOOH), nitrous acid (HNO2), nitrous oxide (NO3), and lipid peroxide (LOOH).

[0257] Embodiment 43. The compound of embodiment 41, wherein the free radical and / or oxidant is hydrogen peroxide (H2O2).

[0258] Embodiment 44 The compound of any one of embodiments 1 to 43, which can react with hydrogen peroxide in vivo to produce edaravone (EDR).

[0259] Embodiment 45 The compound of any one of embodiments 1 to 44, which can be reacted with hydrogen peroxide in vitro to produce edaravone (EDR).

[0260] Embodiment 46 The compound of any one of embodiments 1 to 45, which is a prodrug of edaravone (EDR).

[0261] Embodiment 47 The compound of any one of embodiments 1 to 46, which is an antioxidant and a prodrug of edaravone (EDR).

[0262] Embodiment 48. A compound of any one of embodiments 1 to 47 that is an agent for treating amyotrophic lateral sclerosis (ALS) in vivo.

[0263] Embodiment 49. A compound according to any one of embodiments 1 to 48, which is a therapeutic agent for the prevention and / or treatment of diseases, conditions, and / or disorders associated with oxidative stress.

[0264] Embodiment 50. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 49.

[0265] Embodiment 51. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 49 and at least one pharmaceutically acceptable carrier and / or diluent.

[0266] Embodiment 52. A compound according to any one of embodiments 1 to 49, or a composition according to embodiment 50 or 51, for the prevention and / or treatment of diseases, conditions, and / or disorders associated with oxidative stress.

[0267] Embodiment 53. The compound or composition of embodiment 52, wherein the oxidative stress is caused by reactive oxygen species (ROS) and / or reactive nitrogen species (RNS).

[0268] Embodiment 54. A compound or composition according to embodiment 53, wherein the ROS and / or RNS comprise free radicals and / or oxidants.

[0269] Embodiment 55. The free radicals and / or oxidants are selected from the group consisting of hydroxyl radical (HO·), superoxide radical anion radical (O2·-), nitric oxide (NO·), nitrogen dioxide (NO2·), peroxyl (ROO·) and lipid peroxyl (LOO·), hydrogen peroxide (H2O2), ozone (O3), singlet oxygen ( 1 O2), hypochlorous acid (HOCl), hydroperoxide nucleophiles ( - 55. The compound or composition of any one of embodiments 52 to 54, wherein the nitrite is selected from: nitrous oxide (NOOH), nitrous acid (HNO2), dinitrogen trioxide (N2O3), and lipid peroxide (LOOH).

[0270] Embodiment 56. The compound or composition of embodiment 54, wherein the free radical and / or oxidant is hydrogen peroxide (H2O2).

[0271] Embodiment 57. The compound or composition of any one of embodiments 52 to 56, wherein the disease, condition, and / or disorder associated with oxidative stress is selected from neurodegenerative diseases, disorders and / or conditions, muscle diseases, disorders and / or conditions, vascular diseases, disorders and / or conditions, systemic inflammatory diseases, disorders and / or conditions, local inflammatory diseases, disorders and / or conditions, metabolic syndrome, cardiovascular diseases, disorders and / or conditions, autoimmune diseases, disorders and / or conditions, inflammatory lung diseases, disorders and / or conditions, kidney diseases, disorders and / or conditions, liver diseases, disorders and / or conditions, digestive diseases, disorders and / or conditions, aging, disorders and / or conditions, viral infectious diseases, disorders and / or conditions, cancer, and sepsis / septic shock.

[0272] Embodiment 58. The compound or composition of embodiment 57, wherein the neurodegenerative disease, condition and / or disorder is associated with motor dysfunction.

[0273] Embodiment 59. The compound or composition of embodiment 58, wherein the neurodegenerative disease, condition and / or disorder associated with motor dysfunction is amyotrophic lateral sclerosis (ALS).

[0274] Embodiment 60. The compound or composition of embodiment 59, wherein the ALS is familial ALS.

[0275] Embodiment 61 The compound or composition of embodiment 59, wherein the ALS is sporadic ALS.

[0276] Embodiment 62. A compound or composition according to any one of embodiments 59 to 61, wherein the ALS is caused by a mutation in the superoxide dismutase 1 (SOD1) gene or the TARDBP gene.

[0277] Embodiment 63. A compound or composition according to any one of embodiments 59 to 62, which delays the onset of ALS.

[0278] Embodiment 64. The compound or composition of any one of embodiments 52 to 63, which has an improved therapeutic index for ALS compared to edaravone (EDR).

[0279] Embodiment 65. The compound or composition of embodiment 64, wherein the therapeutic index is a measure of one or more of the following symptoms: muscle weakness, muscle wasting (atrophy), weight loss (cachexia), muscle spasms, muscle cramps, slowness of movement, impaired balance, incoordination, changes in voice quality, dysarthria, dysphagia, insufficient eyelid closure, salivation, pseudobulbar ulceration, and / or premature death.

[0280] Embodiment 66. The compound or composition of embodiment 64 or 65, wherein the improved therapeutic index is measured by increased survival / longevity in subjects receiving the compound or composition compared to subjects receiving edaravone (EDR).

[0281] Embodiment 67. The compound or composition of any one of embodiments 64 to 66, wherein the improved therapeutic index is measured by increased motor function in subjects receiving the compound or composition compared to subjects receiving edaravone (EDR).

[0282] Embodiment 68. The compound or composition of any one of embodiments 64 to 67, wherein the improved therapeutic index is measured by a lower percentage of weight loss (cachexia) in subjects receiving the compound or composition compared to subjects receiving edaravone (EDR).

[0283] Embodiment 69. A compound or composition according to any one of embodiments 52 to 68, which has improved pharmacokinetics compared to edaravone (EDR).

[0284] Embodiment 70. The compound or composition of embodiment 69, wherein the improved pharmacokinetics comprises increased bioavailability of the compound or composition compared to edaravone (EDR).

[0285] Embodiment 71. A method for preventing and / or treating a disease, condition, and / or disorder associated with oxidative stress, comprising administering to a mammal a therapeutically effective amount of a compound of any one of embodiments 1 to 49, or a composition of embodiment 50 or 51.

[0286] Embodiment 72. The method of embodiment 71, wherein the oxidative stress is caused by reactive oxygen species (ROS) and / or reactive nitrogen species (RNS).

[0287] Embodiment 73. The method of embodiment 72, wherein the ROS and / or RNS comprise free radicals and / or oxidants.

[0288] Embodiment 74. The free radicals and / or oxidants are hydroxyl radical (HO·), superoxide radical anion radical (O2·-), nitric oxide (NO·), nitrogen dioxide (NO2·), peroxyl (ROO·) and lipid peroxyl (LOO·), hydrogen peroxide (H2O2), ozone (O3), singlet oxygen ( 1 O2), hypochlorous acid (HOCl), hydroperoxide nucleophiles ( - 74. The method of embodiment 73, wherein the active ingredient is selected from: nitrous acid (NOOH), nitrous acid (HNO), dinitrogen trioxide (NO), and lipid peroxide (LOOH).

[0289] Embodiment 75. The method of embodiment 73, wherein the free radical and / or oxidant is hydrogen peroxide (H2O2).

[0290] Embodiment 76. The method of any one of embodiments 71 to 75, wherein the disease, condition, and / or disorder associated with oxidative stress is selected from neurodegenerative diseases, disorders and / or conditions, muscle diseases, disorders and / or conditions, vascular diseases, disorders and / or conditions, systemic inflammatory diseases, disorders and / or conditions, local inflammatory diseases, disorders and / or conditions, metabolic syndrome, cardiovascular diseases, disorders and / or conditions, autoimmune diseases, disorders and / or conditions, inflammatory lung diseases, disorders and / or conditions, kidney diseases, disorders and / or conditions, liver diseases, disorders and / or conditions, digestive diseases, disorders and / or conditions, aging, disorders and / or conditions, viral infectious diseases, disorders and / or conditions, cancer, and sepsis / septic shock.

[0291] Embodiment 77. The method of embodiment 76, wherein the neurodegenerative disease, condition and / or disorder is associated with motor dysfunction.

[0292] Embodiment 78. The method of embodiment 77, wherein the neurodegenerative disease, condition and / or disorder associated with motor dysfunction is amyotrophic lateral sclerosis (ALS).

[0293] Embodiment 79. The method of embodiment 78, wherein the ALS is familial ALS.

[0294] Embodiment 80. The method of embodiment 78, wherein the ALS is sporadic ALS.

[0295] Embodiment 81 The method of any one of embodiments 78 to 80, wherein the ALS is caused by a mutation in the superoxide dismutase 1 (SOD1) gene or the TARDBP gene.

[0296] Embodiment 82 The method of any one of embodiments 78 to 81, wherein the compound or composition delays the onset of ALS.

[0297] Embodiment 83 The method of any one of embodiments 71 to 82, wherein the compound or composition has an improved therapeutic index for ALS compared to edaravone (EDR).

[0298] Embodiment 84. The method of embodiment 83, wherein the therapeutic index is a measure of one or more of the following symptoms: muscle weakness, muscle wasting (atrophy), weight loss (cachexia), muscle spasms, muscle cramps, slowness of movement, impaired balance, incoordination, changes in voice quality, dysarthria, dysphagia, insufficient eyelid closure, salivation, pseudobulbar eczema, and / or premature death.

[0299] Embodiment 85. The method of embodiment 83 or 84, wherein the improved therapeutic index is measured by increased survival / longevity in subjects receiving the compound or composition compared to subjects receiving edaravone (EDR).

[0300] Embodiment 86 The method of any one of embodiments 83 to 85, wherein the improved therapeutic index is measured by increased motor function in subjects receiving the compound or composition compared to subjects receiving edaravone (EDR).

[0301] Embodiment 87. The method of any one of embodiments 83 to 86, wherein the improved therapeutic index is measured by a lower percentage of weight loss (cachexia) in subjects receiving the compound or composition compared to subjects receiving edaravone (EDR).

[0302] Embodiment 88 The method of any one of embodiments 71 to 87, wherein the compound or composition has improved pharmacokinetics compared to edaravone (EDR).

[0303] Embodiment 89. The method of embodiment 88, wherein the improved pharmacokinetics comprises increased bioavailability of the compound or composition compared to edaravone (EDR).

[0304] Embodiment 90 The method of any one of embodiments 71 to 89, wherein the mammal is a human.

[0305] Embodiment 91 The method of any one of embodiments 71 to 90, wherein the compound or composition is administered orally and / or intravenously.

[0306] Embodiment 92. Use of a therapeutically effective amount of a compound according to any one of embodiments 1 to 49, or a composition according to embodiment 50 or 51, for the prevention and / or treatment of diseases, conditions, and / or disorders associated with oxidative stress.

[0307] Embodiment 93. The use according to embodiment 92, wherein the oxidative stress is caused by reactive oxygen species (ROS) and / or reactive nitrogen species (RNS).

[0308] Embodiment 94. The use according to embodiment 93, wherein the ROS and / or RNS comprise free radicals and / or oxidants.

[0309] Embodiment 95. The free radicals and / or oxidants are hydroxyl radical (HO·), superoxide radical anion radical (O2·-), nitric oxide (NO·), nitrogen dioxide (NO2·), peroxyl (ROO·) and lipid peroxyl (LOO·), hydrogen peroxide (H2O2), ozone (O3), singlet oxygen ( 1 O2), hypochlorous acid (HOCl), hydroperoxide nucleophiles ( - 95. The use of embodiment 94, wherein the active ingredient is selected from: nitrous acid (NOOH), nitrous acid (HNO), dinitrogen trioxide (NO), and lipid peroxide (LOOH).

[0310] Embodiment 96. The use of embodiment 94, wherein the free radical and / or oxidant is hydrogen peroxide (H2O2).

[0311] Embodiment 97. The use according to any one of embodiments 92 to 96, wherein the disease, condition, and / or disorder associated with oxidative stress is selected from neurodegenerative diseases, disorders and / or conditions, muscle diseases, disorders and / or conditions, vascular diseases, disorders and / or conditions, systemic inflammatory diseases, disorders and / or conditions, local inflammatory diseases, disorders and / or conditions, metabolic syndrome, cardiovascular diseases, disorders and / or conditions, autoimmune diseases, disorders and / or conditions, inflammatory lung diseases, disorders and / or conditions, kidney diseases, disorders and / or conditions, liver diseases, disorders and / or conditions, digestive diseases, disorders and / or conditions, aging, disorders and / or conditions, viral infectious diseases, disorders and / or conditions, cancer, and sepsis / septic shock.

[0312] Embodiment 98. The use according to embodiment 97, wherein the neurodegenerative disease, condition and / or disorder is associated with motor dysfunction.

[0313] Embodiment 99. The use of embodiment 98, wherein the neurodegenerative disease, condition and / or disorder associated with motor dysfunction is amyotrophic lateral sclerosis (ALS).

[0314] Embodiment 100. The use of embodiment 99, wherein the ALS is familial ALS.

[0315] Embodiment 101. The use of embodiment 99, wherein the ALS is sporadic ALS.

[0316] Embodiment 102. Use according to any one of embodiments 99 to 101, wherein the ALS is caused by a mutation in the superoxide dismutase 1 (SOD1) gene or the TARDBP gene.

[0317] Embodiment 103. The use according to any one of embodiments 99 to 102, wherein the compound or composition delays the onset of ALS.

[0318] Embodiment 104. The use according to any one of embodiments 92 to 103, wherein the compound or composition has an improved therapeutic index for ALS compared to edaravone (EDR).

[0319] Embodiment 105. The use of embodiment 104, wherein the therapeutic index is a measure of one or more of the following symptoms: muscle weakness, muscle wasting (atrophy), weight loss (cachexia), muscle spasms, muscle cramps, slowness of movement, impaired balance, incoordination, changes in voice quality, dysarthria, dysphagia, insufficient eyelid closure, salivation, pseudobulbar ulcers, and / or premature death.

[0320] Embodiment 106. The use of embodiment 104 or 105, wherein the improved therapeutic index is measured by increased survival / longevity in subjects receiving the compound or composition compared to subjects receiving edaravone (EDR).

[0321] Embodiment 107. The use of any one of embodiments 104 to 106, wherein the improved therapeutic index is measured by increased motor function in subjects receiving the compound or composition compared to subjects receiving edaravone (EDR).

[0322] Embodiment 108. The use of any one of embodiments 104 to 107, wherein the improved therapeutic index is measured by a lower percentage of weight loss (cachexia) in subjects receiving the compound or composition compared to subjects receiving edaravone (EDR).

[0323] Embodiment 109. The use according to any one of embodiments 92 to 108, wherein the compound or composition has improved pharmacokinetics compared to edaravone (EDR).

[0324] Embodiment 110. The use according to embodiment 109, wherein the improved pharmacokinetics comprises increased bioavailability of the compound or composition compared to edaravone (EDR).

[0325] Embodiment 111. The use according to any one of embodiments 92 to 110, wherein the mammal is a human.

[0326] Embodiment 112. The use according to any one of embodiments 92 to 111, wherein the compound or composition is administered orally and / or intravenously.

[0327] The above disclosure generally describes the present invention. A more complete understanding can be obtained by reference to the following specific examples. These examples are provided for illustrative purposes only and are not intended to be limiting, unless otherwise specified. Thus, the present invention should in no way be construed as being limited to the following examples, but rather as embracing any and all modifications, which will become apparent from the teachings provided herein.

[0328] Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the disclosed compounds and practice the claimed invention. Accordingly, the following examples specifically set forth exemplary embodiments, and are not to be construed as limiting the disclosure in any way.

[0329] [Example] [Example 1] Synthesis, characterization, and generation of boron-based EDR analogues B 5 -EDR analogs can function as prodrugs via oxidative transformation.

[0330] Method:B 5 -EDR analogues were synthesized and B 5 The in vitro transformation of -EDR analogs to EDR as prodrugs was assessed.

[0331] The compounds synthesized are as follows:

[0332] [ka]

[0333] experiment overview: 1 H and 13C nuclear magnetic resonance (NMR) spectra were recorded on Bruker 400 MHz and 300 MHz spectrometers, Billerica, MA, USA, using DMSO-d (CAS-2206-27-1), acetone-d (CAS-666-52-4), chloroform-d (CAS-865-49-6), and methanol-d (CAS-811-98-3) from Acros organics, Switzerland as solvents and trimethylsilane (TMS) as an internal standard. n-Butyllithium, a 2.5 M solution in hexane, was a product of Acros organics, Germany (CAS-109-72-8), 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS-61676-62-8) was purchased from Sigma-Aldrich, St. Louis, MO, USA, 3-methyl-1-phenyl-1H-pyrazole (number: AK139802) was purchased from Ark Pharm, Inc., Arlington Heights, IL, USA, and 3-(trifluoromethyl)-1-phenyl-1H-pyrazole (CAS-99498-65-4) was purchased from AK Scientific, Ahern. Ave., City, CA, USA. Copper(I) oxide (CAS-1317-39-1) was purchased from Sigma-Aldrich, St. Louis, MO, USA. Potassium bifluoride (CAS-7789-29-9) was purchased from Sigma-Aldrich, St. Louis, MO, USA. The reaction was analyzed by TLC (Sigma, Silica Gel 60F). 254 The crude reaction mixture was purified by silica gel column chromatography on a CombiFlash® Rf200 purification system, Teledyne Isco, USA. Organic solvents were ordered from BDH, VWR Analytical unless otherwise specified. All chemicals were used without further purification unless otherwise indicated.

[0334] Scheme I for the synthesis of N-arylated boronic acid pinacol esters from commercially available N-arylated substituted pyrazole starting materials via an in situ two-step synthetic procedure The synthetic route involves the synthesis of N-arylated pyrazoleboronic acid pinacol esters from commercially available N-arylated substituted pyrazole starting materials via an in situ two-step synthetic procedure. The first step involves the lithiation of the N-arylated substituted pyrazole at the C5 position using N-butyllithium (n-BuLi) via a direct orthometalation (DOM) mechanism. The second step involves the electrophilic substitution of lithium at the C5 position with isopropoxy 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (PINBOP). This is followed by an acidic workup to convert the N-arylated substituted pyrazoleboronic acid pinacol esters to N-arylated pyrazoleboronic acid pinacol esters via the EDR (Equivalent Dissociation Ratio) method originally proposed by the inventors. 5 -EDR) prodrug.

[0335] [ka]

[0336] Scheme I. Synthesis of N-arylated boronic acid pinacol esters from commercially available N-arylated substituted pyrazoles A representative experimental procedure for the synthesis of 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-phenyl 1H-pyrazole was carried out following the reported procedure with slight modifications of Scheme 1 in

[46] .

[0337] n-Butyllithium (2.5 M in hexane, 1.5 cm 3 , 3.793 mmol) in anhydrous THF (22 cm 3 N-arylated substituted pyrazole (500 mg, 0.471 m 3, 3.161 mmol) was added dropwise to a solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (646.93 mg, 709.5 μL, 3.477 mmol) at −78° C. under argon. The reaction mixture was stirred at −78° C. for 45 minutes. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (646.93 mg, 709.5 μL, 3.477 mmol) was added dropwise to the reaction mixture at −78° C., and the mixture was stirred for 1.5 hours. The mixture was allowed to warm to room temperature over 1 hour, and glacial acetic acid (208.79 mg, 199 μL, 3.477 mmol) was added. The mixture was filtered through a pad of Celite, which was then diluted with EtOAc (100 cm 3 ) The organic solvent was removed under vacuum to give the crude product. Confirmation of the expected product was confirmed by TLC (20% EtOAc / Hex). The crude product was then purified by silica gel column chromatography on a CombiFlash® Rf200 purification system, Teledyne Isco, USA, using ethyl acetate and hexane from 0% to 10%. The residual solvent was evaporated under vacuum to give the product as a light brown crystalline solid (815 mg, 90%).

[0338] Following this reaction procedure, compound (NS-1-2) was synthesized. 1 H and 13 It was characterized by C NMR.

[0339] 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-phenyl 1H-pyrazole (NS-1-2): a prodrug of edaravone. Crystalline solid (815mg, 90%);1H NMR(400MHz,CDCl3-d6)δ 7.52-7.49(2H,m,J=12Hz),δ 7.40-7.36(2H,m,J=16Hz),7.33-7.29(1H,m,J=16Hz),δ 6.66(1H,S),δ 2.35(3H,S)δ 1.26(12H,S);13C NMR(300MHz,DMSO-d6)δ 147.4,139.4,127.0,125.7,122.4,115.9,82.7,22.9,11.4 (Cipso for B is not accepted).

[0340] [ka]

[0341] A representative experimental procedure for the synthesis of 3-trifluoromethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-phenyl 1H-pyrazole was carried out following the reported procedure with slight modifications of Scheme 1 in

[46] .

[0342] n-Butyllithium (2.5 M in hexane, 1.4 cm 3 , 3.5 mmol, 1 eq.) in anhydrous THF (20 cm 3 N-arylated substituted pyrazole (617 mg, 0.61 m 3 , 2.9 mmol) was added dropwise at −78° C. under argon. The reaction mixture was stirred at −78° C. for 45 minutes. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (620 μL, 3.1 mmol, 1 equiv.) was added dropwise to the reaction mixture at −78° C., and the mixture was stirred for 1.5 hours. The mixture was allowed to warm to room temperature over 1 hour, and glacial acetic acid (180 μL, 3.2 mmol) was added. The mixture was filtered through a pad of Celite, which was then diluted with EtOAc (100 cm 3 ) The organic solvent was removed under vacuum to give the crude product. Confirmation of the expected product was confirmed by TLC (5% EtOAc / Hex). The crude product was then purified by silica gel column chromatography on a CombiFlash® Rf200 purification system, Teledyne Isco, USA, using ethyl acetate and hexane from 0% to 10%. Residual solvent was evaporated under vacuum to give the product as a light brown crystalline solid (815 mg, 90%).

[0343] Following this reaction procedure, compound (NS-1-12) was synthesized. 1 H and 13 It was characterized by C NMR. 3-Trifluoromethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-phenyl 1H-pyrazole (NS-1-12): Crystalline solid (902 mg, 91.9%); 1H NMR (400 MHz, CDCL3-d6) δ 7.55-7.52 (2H, m, J = 12 Hz), δ 7.45-7.41 (3H, m, J = 16 Hz), 7.11 (1H, S), δ 1.26 (12H, S); 13C NMR (300 MHz, DMSO-d6) δ 142.6, 142.1, 140.4, 129.3, 129.2, 125.3, 115.2, 85.1, 24.7 (Cipso for B not observed).

[0344] [ka]

[0345] Scheme II for the synthesis of N-arylated pyrazole potassium trifluoroborates from N-arylated substituted pyrazoleboronic acid pinacol esters The synthetic route involved the synthesis of N-arylated substituted pyrazoleboronic acid pinacol esters to N-arylated pyrazole potassium trifluoroborates. This is a three-step synthesis involving lithiation in the first step, boronation in the second step to give the N-arylated pyrazoleboronic acid pinacol ester, followed by conversion of the pinacolyl boronate to the corresponding trifluoroborate using aqueous potassium bifluoride.

[0346] [ka]

[0347] Scheme II: Synthesis of N-arylated pyrazole potassium trifluoroborates from N-arylated substituted pyrazole boronic acid pinacol esters A representative synthetic procedure from N-arylated substituted pyrazoleboronic acid pinacol ester to N-arylated pyrazole potassium trifluoroborate was carried out according to the procedure reported below with slight modifications from

[47] .

[0348] To a stirred solution of the boronic ester (0.5 mmol) in methanol (3 mL) was added dropwise KHF2 (0.5 mL of 4.5 M saturated aqueous solution, 0.5 mmol, 2.25 equivalents, 1.125-fold excess). The resulting mixture was stirred at room temperature, and the reaction progress was monitored by TLC every 15 minutes. The reaction was completed by the appearance of new spots on TLC after 1 hour and 2.5 hours. The resulting crude reaction mixture was filtered using 11 cm Whatman filter paper, and the filter paper was washed thoroughly with hot acetone to filter all the product from the crude reaction mixture. The residue remaining on the filter paper was a colored amorphous solid, which was dissolved in ethyl acetate, and TLC was observed under UV. No spots corresponding to the product were present. The filtrate was concentrated under vacuum to remove all volatile materials. The resulting waxy syrup was redissolved in 50% aqueous MeOH (4 mL), and all volatile materials were evaporated again by rotary evaporation (5-1 mbar / 45-50 °C; unwanted bumping of the mixture can be significantly minimized by adjusting the rotation speed). This evaporation-dissolution cycle was repeated for an aliquot of the reaction mixture. 1 The reaction was repeated until H NMR analysis showed less than 1 mol% pinacol. The evaporation-dissolution cycle was optimized for the synthesis of the prodrug. The optimized cycle was 10 times for the synthesis of the prodrug. The final concentrated residue was obtained as an amorphous solid, which was finally dried in an oven overnight to obtain the product as a white amorphous solid (815 mg, 90%). Some minor losses of the product are mainly related to the evaporation / drying / mass transfer procedures. Following this reaction procedure, all compounds (NS-1-21, NS-1-19) were synthesized. Their structures are shown in Table 1. 1 H and 13 It was characterized by C NMR.

[0349] Potassium trifluoro(3-methyl-1phenyl-1H-pyrazol-5-yl)borate (NS-1-21): A prodrug of edaravone.

[0350] Amorphous solid (125.2 mg, 94.8%); 1H NMR (400 MHz, acetone-d6) δ 7.27-7.20 (2H, m, J = 16 Hz), δ 6.54-6.50 (2H, m, J = 16 Hz), 6.36-6.31 (1H, m, J = 20 Hz), δ 5.35 (1H, S), δ 1.42 (3H, S); 13C NMR (300 MHz, MeOD-d6) δ 127.8, 125.7, 123.9, 111.3, 74.4, 23.6, 11.5 (Cipso for B not observed).

[0351] [ka]

[0352] Potassium trifluoro(3-trifluoromethyl-1phenyl-1H-pyrazol-5-yl)borate (NS-1-19): Amorphous solid (143.5 mg, 90.2%); 1H NMR (400 MHz, acetone-d6) δ 7.27-7.20 (2H, m, J = 28 Hz), δ 6.67-6.63 (2H, m, J = 16 Hz), 6.56-6.52 (1H, m, J = 16 Hz), δ 5.86 (1H, S); 13C NMR (300 MHz, acetone-d6) δ 129.6, 127.9, 127.6, 126.1, 123.5, 119.4, 28.9 (Cipso for B not observed).

[0353] [ka]

[0354] Scheme III. Synthesis of 4-fluoro-N-arylated pyrazole boronic acid pinacol esters from 4-fluoro-N-arylated substituted pyrazole starting materials via an in situ two-step synthetic procedure The synthetic route involved the in situ synthesis of 4-fluoro-N-arylated pyrazoleboronic acid pinacol esters from 4-fluoro-N-arylated pyrazole starting materials via a two-step synthesis procedure. The first step involved N-arylation of pyrazoles with arylboronic acids using heterogeneous copper(I) oxide in methanol at room temperature under basic conditions. The second step involved lithiation at the C5 position of the N-arylated pyrazoles using N-butyllithium (n-BuLi) via a direct orthometalation (DOM) mechanism. The second step involved electrophilic substitution of lithium at the C5 position with isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (PINBOP). This was followed by an acidic workup to afford 4-fluoro-N-arylated pyrazoleboronic acid pinacol esters.

[48]

[0355] [ka]

[0356] Figure III: Synthesis of 4-fluoro-N-arylated pyrazole boronic acid pinacol ester from 4-fluoro-N-arylated substituted pyrazole starting material A representative experimental procedure for the synthesis of 3-trifluoromethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-fluoro-1-phenyl 1H-pyrazole was carried out following the reported procedure [46, 48] with slight modifications.

[0357] The first step involved N-arylation of pyrazole with arylboronic acid under ambient conditions. 1 mol% CuO (10 mol, 1.02 equiv.) was added to a mixture of pyrazole (10 mmol, 1 equiv.) and arylboronic acid (10 mmol, 1.2 equiv.) in MeOH (3 mL / mol) at room temperature, and the mixture was stirred under air for 5 h. The reaction progress was monitored by TLC, and upon completion, the crude reaction product was concentrated under reduced pressure to give the crude product. The crude product was then purified by silica gel column chromatography on a CombiFlash® Rf200 purification system (Teledyne Isco, USA) using ethyl acetate and hexane at 0% to 2%. The residual solvent was evaporated under vacuum to give a light green, waxy syrup, which was kept in an ice bath for 20 min, at which point green crystals appeared, affording the product in the form of light green crystals (2096 mg, 90.8%). Following this reaction procedure, compound (NS-1-22) is synthesized. 1 H and 13 It was characterized by C NMR.

[0358] In the second step, n-butyllithium (2.5 M in hexane, 1.4 cm 3 , 3.5 mmol, 1 eq.) in anhydrous THF (20 cm 3 To a solution of N-arylated substituted pyrazole (667 mg, 2.9 mmol, 1 equiv.) in HCl (2.5 mL) was added dropwise at −78° C. under argon. The reaction mixture was stirred at −78° C. for 45 minutes. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (620 μL, 3.1 mmol, 1 equiv.) was added dropwise to the reaction mixture at −78° C., and the mixture was stirred for 1.5 hours. The mixture was allowed to warm to room temperature over 1 hour, and glacial acetic acid (180 μL, 3.2 mmol) was added. The mixture was filtered through a pad of Celite, which was then diluted with EtOAc (100 cm 3) The organic solvent was removed under vacuum to give the crude product. Confirmation of the expected product was confirmed by TLC (20% EtOAc / Hex). The crude product was then purified by silica gel column chromatography on a CombiFlash® Rf200 purification system (Teledyne Isco, USA) using ethyl acetate and hexane from 0% to 5%. The residual solvent was evaporated under vacuum to give the crude product in the form of a waxy syrup. The syrup was dissolved in pure hexane and kept at -80°C overnight. After 12 hours, the hexane was removed by rotary evaporation, and the product was isolated as crystals (556 mg, 53.8%) at room temperature. Following this reaction procedure, compound (NS-1-23) was synthesized. These structures are 1 H and 13 It was characterized by C NMR.

[0359] 3-Trifluoromethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-fluoro-1-phenyl 1H-pyrazole (NS-1-23): crystalline solid (556 mg, 53.8%); 1H NMR (300 MHz, DMSO-d6) δ 7.66-7.61 (2H, m, J = 15 Hz), δ 7.36-7.22 (2H, m, J = 42 Hz), 7.22 (1H, S), δ 1.20 (12H, S); 13C NMR (300 MHz, DMSO-d6) δ 142.6, 136.9, 127.8, 127.7, 116.1, 115.8, 115.2, 85.0, 24.8 (Cipso for B not observed); F19 NMR(300MHz,DMSO-d6)δ -60.32.

[0360] [ka]

[0361] The C5 position of the pyrazole scaffold of EDR was modified using the “boron prodrug approach” (Figure 3 ).

[0362] Results: As shown in Figure 4A-B, these analogs undergo near quantitative conversion to EDR using hydrogen peroxide in vitro. In fact, B using H2O2 5 The conversion of -EDR to EDR was successful with a yield of 95%. 5 The -EDR compounds can function as EDR prodrugs under oxidative conditions. In addition, Figure 5 shows the results of various B 5 -EDR analogs are shown.

[0363] [Example 2] Testing the ability of boron-based EDR analogues to be redox regulators B 5 -EDR analogs can function as independent redox regulators via the antioxidant effects of boron, contain neurotoxicity / cell viability profiles similar to EDR, and can function as neurocytoprotective agents in a manner similar to EDR.

[0364] Method: Synthesized B 5 The in vitro properties and antioxidant capacity of the -EDR analogs were assessed using cell-based assays. 5 The B-EDR analog was synthesized as described in Example 1. 5 The neurotoxicity / neuroprotection of EDR-EDR analogs, EDR, and HO, compared to control / EDR, was assessed by WST-8 analysis (a marker of neurotoxicity) in (i) primary cortical neurons (Figure 6), and (ii) neuroblastoma-spinal cord hybrid NSC-34 cells (Figures 7A-C and 8A-B). The methods used for each of these assays are detailed below.

[0365] (i) Method for neurotoxicity / cell viability analysis in primary cortical neurons (Figure 6A-B): Briefly, cerebral cortices were isolated from mouse fetuses at approximately 17–18 days of gestation. After removing meninges and blood vessels, the tissue was digested with trypsin for approximately 15 minutes at approximately 37°C, then incubated with DNase for an additional 15 minutes at approximately 37°C, and stopped with DMEM plus approximately 10% fetal bovine serum. After removing the supernatant, approximately 5 ml of neurobasal medium (Life Technologies Inc.) was added to the tissue and triturated by gentle pipetting. The neurons contained in the supernatant were transferred to poly-D-lysine-coated plastic culture plates, adjusted to approximately 10 cells / ml, and cultured at approximately 37°C under approximately 5% CO2 in neurobasal medium containing GS21 supplement (Sigma-Aldrich Canada), 1x GlutaMax (Life Technologies Inc.), and approximately 1% penicillin-streptomycin. Approximately 100k cells / 100 μl / well were seeded into 96-well plates 2 days later. At 2 days later, neurons were treated with different concentrations of EDR (1, 10, and 25 μM) and the EDR analogs NS-1-2, NS-1-12, NS-1-13, NS-1-19, and NS-1-21 (1, 10, and 25 μM) and incubated until 8 days later. For neurons at 8 days later, approximately 10 μl of WST reagent was added to each well and incubated for approximately 2 hours. After approximately 2 hours of incubation, the absorbance of the soluble colored formazan dye was measured calorimetrically at approximately 450 nM using a microplate reader (Biotek Instruments) with a blank as a background control. Cell viability was determined by comparing the absorbance of compound-treated cells with that of control cells. Data are representative of two independent experiments, and each measurement or dose was tested six times.

[0366] (ii) Method for neurotoxicity / cell viability analysis in NSC-34 cells (Figure 7A-C): Briefly, approximately 20k NSC-34 cells per well of a 96-well plate were cultured for approximately 20 hours in complete medium consisting of high-glucose Dulbecco's modified Eagle's medium (DMEM) (Thermo Fisher Scientific) supplemented with approximately 10% fetal bovine serum (USA) (Thermo Fisher Scientific), approximately 200mM (100x) GlutaMAX-1 (Thermo Fisher Scientific), approximately 1% 100mM sodium pyruvate, and approximately 1% 10,000U / mL penicillin-streptomycin solution (Thermo Fisher Scientific) until they reached approximately 70% to 75% confluence. All cells were cultured in an incubator at approximately 37°C with approximately 5% CO2. Approximately 20k cells / 100µl / well were seeded in triplicate into a 96-well plate for approximately 20 hours. Cells were treated with different concentrations of compounds and incubated for approximately 20 hours. Approximately 10 μl of WST reagent was added to each well and incubated for approximately 2.5 hours. After approximately 2.5 hours of incubation, the absorbance of the soluble colored formazan dye was measured calorimetrically at approximately 450 nM using a microplate reader (Biotek instruments) with a blank as a background control. Cell viability was determined by comparing the absorbance of compound-treated cells with that of control cells. All experiments were repeated at least three times and measurements were performed in triplicate.

[0367] (iii) Method for neuroprotection / cell viability analysis in NSC-34 cells (Figure 8A-B): Briefly, approximately 20k NSC-34 cells per well of a 96-well plate were cultured for approximately 20 hours in complete medium consisting of high-glucose Dulbecco's modified Eagle's medium (DMEM) (Thermo Fisher Scientific) supplemented with approximately 10% fetal bovine serum (USA) (Thermo Fisher Scientific), approximately 200mM (100x) GlutaMAX-1 (Thermo Fisher Scientific), approximately 1% 100mM sodium pyruvate, and approximately 1% 10,000U / mL penicillin-streptomycin solution (Thermo Fisher Scientific) until they reached approximately 70% to 75% confluence. All cells were cultured at approximately 37°C in an incubator with approximately 5% CO2. Approximately 20k cells / 100 μl / well were seeded in triplicate into a 96-well plate for approximately 20 h. After approximately 20 h, the medium was changed, and the cells were pre-treated or prophylactically treated with different doses of EDR analogs and EDR for approximately 1 h. After approximately 1 h, the cells were treated with 250 μM H2O2 for approximately 2 h. After a total period of approximately 3 h, approximately 10 μl of WST-8 reagent was added to each well, and absorbance readings were recorded at approximately 450 nm after approximately 2.5 h. All experiments were repeated at least three times, and measurements were performed in triplicate.

[0368] result: (i) Neurotoxicity / Cell Viability Analysis in Primary Cortical Neurons: As can be seen from Figure 6A, both tested analogs (NS-1-2 and NS-1-12) had similar cell viability results as EDR, and did not appear to reduce cell viability at concentrations of 1 μM and 10 μM. All EDR-containing compounds showed a reduction in cell viability only at the significantly higher concentration of 25 μM. Therefore, based on these results, B 5The EDR analogs did not appear to reduce cell viability to a greater extent than EDR. As shown in Figure 6B, low concentrations (10 μM and 1 μM) of the EDR analogs NS-1-2, NS-1-12, NS-1-21, NS-1-19, NS-1-13, and EDR showed nearly 100% better cell viability for PCNCs compared to the control. In addition, the cell viability of the analogs was similar to that of EDR. Furthermore, high concentrations (25 μM) of EDR and EDR analogs showed a nearly (70 ± 10%) decrease in cell viability for PCNCs compared to the control (DMSO).

[0369] (ii) Neurotoxicity / Cell Viability Analysis in NSC-34 Cells: As shown in Figure 7A, prophylactic treatment with both EDR and NS-1-2 protected NSC-34 cells from the loss of cell viability induced by 250 μM HO, demonstrating neuroprotection against HO-induced oxidative stress. Both EDR and NS-1-2 were found to be neuroprotective in this PCNC and NSC-34 cell assay (NSC-34 cells are shown in Figure 7A). As shown in Figure 7B, the synthesized EDR analogs demonstrated increased viability without cytotoxicity or neurotoxicity compared to the control group. In addition, all test compounds demonstrated approximately 90–100% viability at almost all concentrations (1–100 μM). Similar to the PCNC study above, the test compounds demonstrated equivalent viability compared to the EDR group. Finally, application of 1 to 100 μM EDR and EDR analogs did not exhibit neurotoxicity or cytotoxicity to NSC-34 motor neurons. Based on these viability results, EDR analogs were evaluated for neuroprotection in the experiments described in (iii). The results of these experiments are presented below.

[0370] (iii) Neuroprotective effect / cell viability analysis in NSC-34 cells: As shown in Figure 8A-B, EDR exhibited significant HO scavenging effects in a dose-dependent manner. In addition, the results showed that all five EDR analogs (NS-1-2, NS-1-13, NS-1-21, NS-1-19, and NS-1-12) exhibited nearly equal viability at 50 μM compared to EDR (which was statistically significant). Furthermore, all five tested EDR analogs (NS-1-2, NS-1-13, NS-1-21, NS-1-19, and NS-1-12) exhibited better neuroprotection in scavenging the neurotoxic effects of HO compared to EDR at a lower dose of 25 μM. This suggests that EDR analogs are more potent than EDR in scavenging HO at low doses.

[0371] Additionally, four EDR analogs (NS-1-2, NS-1-13, NS-1-21, and NS-1-19) showed better neuroprotection in scavenging the neurotoxic effects of HO compared to EDR at the lower dose of 1 μM, suggesting again that EDR analogs are more potent than EDR in scavenging the neurotoxic effects of HO at lower doses. Finally, although these analogs had high neuroprotection at low doses of 1 μM and 25 μM, and comparable neuroprotection at 50 μM, the higher dose of these analogs (i.e., 100 μM) showed reduced viability (10–15%) compared to EDR.

[0372] [Example 3] Evaluation of the therapeutic index and pharmacokinetic properties of boron-based EDR analogs Synthesized B 5 -EDR analogs can also function as dual therapeutic agents, by virtue of the boron functionality and acting as prodrugs of EDR, resulting in similar or improved therapeutic indices and improved pharmacokinetic properties to EDR.

[0373] Methods: To evaluate the drug conductance and biodistribution of B5-EDR analogs compared with EDR, initial studies focused on acute single IV dose administration to rats using the most promising lead compounds. Using a population pharmacokinetics approach, rats (n = 2 per time point) were dosed with the novel compounds via tail vein IV and sacrificed at 10, 20, 30, 60, and 120 minutes, followed by 4, 8, 12, and 24 hours. Blood was drawn at sacrifice, and drug concentration-time curves were constructed for each cohort by liquid-liquid extraction to purify the blood and perform LC / MS analysis of compound levels. Specific parameters for AUC, Cmax, Kel, and Tpeak were determined using pharmacokinetic modeling. Organs including brain, heart, kidney, liver, pancreas, spleen, and stomach will be harvested, and organ samples will be homogenized (1:3 in Tris-HCl containing a protease inhibitor cocktail), subjected to liquid:liquid extraction, and then analyzed for organ compound levels by LC / MS. This ensures the absence of preferential drug compartmentalization. Gross necropsy and detailed microscopic examination will also be performed, collectively generating basic safety pharmacology / toxicology data. Additional cohorts of rats will be dosed by oral gavage, and further analyses will be performed to determine oral pharmacokinetics and biodistribution data. Methods will also be developed to detect EDR in vivo (rats and SOD1-G37R) as a proof-of-concept biomarker for the B5-EDR compound's function as a prodrug of EDR (including kinetics). Following rat PK studies, similar experiments will be performed using a single acute IP dose in SOD1-G37R mice. Additionally, the activity of UGT and CYP enzymes toward novel compounds will be assessed using a substrate deprivation reaction phenotyping approach.Using specific mass spectrometry conditions, the metabolic profiles of selected B5-EDR analogs will be examined by UGT and CYP enzymes to identify potential metabolic pathways.Briefly, the novel B5-EDR analogs are placed in test tubes containing buffer, recombinant active liver UGT (UGT1A1, 1A3, 1A4, 1A6, 1A9, 2B4, 2B7, 2B15, 2B17) and CYP (1A2, 2C9, 2C19, 2D6, 3A4) isoforms, and, if necessary, coactivators UDPGA or NADPH. The supernatant is analyzed by mass spectrometry, and compound loss is compared to an initial spiked tube incubated under the same conditions but without cofactors. A positive control is used for each selective / specific substrate; for example, for UGT1A1, bilirubin is the positive control. If no compound loss is observed, the compound is declared "not a substrate." If metabolism is observed, a kinetic curve is determined (e.g., either Caelis-Menten or sigmoidal kinetics). Km and Vmax parameters are determined, which allow for estimation of intrinsic clearance. Intrinsic clearance can generally be used for CYP isoforms to obtain a good measure of in vivo clearance. Additional experiments will be performed to examine the p-glycoprotein liabilities

[42]

[43] of B5-EDR analogs, including studies assessing blood-brain barrier penetration

[44]

[45] .

[0374] [Example 4] In vivo studies of B5-EDR analogs in mouse models of ALS Synthesized B 5 The -EDR analogs may serve as candidate drugs for the development of effective therapeutic agents for ALS patients. Therefore, their therapeutic efficacy and acute toxicity were evaluated in a mouse model of ALS.

[0375] Method:B 5The -EDR analogs were synthesized as described in Example 1. The specific methods used in this example are described below. All statistical analyses were performed using GraphPad Prism 8 software (version 9.5.1(733)) (GraphPad Software, La Jolla, CA). Statistical significance was determined using a two-tailed unpaired t-test, which was used to compare body weight assessment, disease onset, survival, and weight loss. Kaplan-Meier survival analysis and the log-rank test were also used for survival analysis. In these in vivo studies, disease onset or symptom onset was defined by two criteria. The first criterion was defined by a 10% weight loss based on the highest weight recorded at the age of the mice after the pre-symptomatic treatment study. A 10% weight loss is often accompanied by the appearance of symptoms of muscle weakness and a second criterion of disease onset, which is retrospectively defined as the age at which the mice reached their peak weight. Mice were assessed and monitored daily by trained staff for weight and muscle weakness, beginning at 90 days of age, i.e., well before the clinical onset of disease. In accordance with consensus in the ALS scientific community, disease onset is defined as the time when mice reach peak weight well before denervation-induced muscle atrophy and weight loss.

[0376] (i) Mouse and tissue preparation: Transgenic mice carrying human G37R mutation SOD1 [B6.Cg Tg(SOD1 *G37R)42Dpr / J] were obtained from Jackson Laboratory (Bar Harbor, ME, USA). These mice were mated with female mice on a C57BL / 6 background for at least four generations. The colony is maintained at Central Animal Care Services (CACS), University of Manitoba. Mice were used in accordance with the Canadian Council on Animal Care's Guide of Care and Use of Experimental Animals. Transgenic offspring were genotyped by PCR of DNA obtained by ear biopsy using a protocol provided by Jackson Laboratory (see (ia) below).

[0377] (ia) DNA isolation and genotyping The ear samples were dissolved overnight at approximately 55°C in approximately 300 μl of TNES buffer (approximately 1 M Tris, approximately pH 8.5, approximately 0.5 M EDTA, approximately 10% SDS, approximately 5 M NaCl, distilled water) and approximately 20 μg / μl of proteinase K (Sigma). An approximately equal volume of phenol / chloroform (approximately 1:1) was added to the mixture and gently mixed. The debris was then separated from the sample by centrifugation at approximately 14,500 rpm for approximately 15 minutes, and the supernatant containing the DNA was collected. The DNA was precipitated using an approximately equal volume of approximately 95% cold ethanol (-20°C), and the DNA was pelleted by centrifugation at approximately 14,500 rpm for approximately 10 minutes. The supernatant was discarded, and the pellet was washed with approximately 70% ethanol. The centrifugation was repeated, and the ethanol was discarded. The tubes were placed in a fume hood to allow the residual ethanol to evaporate for approximately 1 hour. The DNA was then resuspended in approximately 30 μl of distilled water and stored at approximately 4° C. until genotyping using PCR. The isolated DNA was used to genotype the progeny. Approximately 450 mice were genotyped during breeding. Approximately 19 μl of ultrapure water (ThermoFisher), approximately 2.5 μl of 10× PCR buffer (approximately 200 mM Tris-HCl, approximately pH 8.4, approximately 500 mM KCl) (ThermoFisher), approximately 1 μl of approximately 50 mM MgCl, approximately 0.25 μl of approximately 10 mM dNTPs, approximately 0.5 μl of approximately 10 μM forward primer (5′-CATCAGCCCTAATCCATCTGA-3′), approximately 0.5 μl of approximately 10 μM reverse primer (5′-CGCGACTAACAATCAAAGTGA-3′), and approximately 0.25 μl of approximately 5 U / μl Taq DNA polymerase (ThermoFisher) were added to approximately 2 μl of sample DNA. The PCR conditions for the above reaction included an initial denaturation at about 95°C for 3 minutes, followed by about 35 cycles of a denaturation step at about 95°C for about 30 seconds, an annealing step at about 55°C for about 30 seconds, and an extension step at about 73°C for about 45 seconds, followed by a final extension step at about 72°C for about 10 minutes. The PCP products mixed with the red gel were separated on an about 1% agarose gel.Gels were then visualized on a G:BOX imager using GeneSys imager software (Syngene, UK).

[0378] (ii) Group assignment, drug formulation, storage, and compound dose group assignment for determination of acute toxicity in WG37R mice: WG37R mice were randomly assigned to two groups. In the first set of experiments, a total of six animals (three males and three females) per group were used for the study. Group 1: sham treatment 1 (DMSO / PBS 1:20) and Group 2: NS-1-2 (10 mg / kg body weight). According to the requirements for acute toxicity studies, six to ten animals should be used to evaluate the effects of a substance. However, because the new analogues are structurally similar to edaravone, which has a single-dose safety profile of 450 mg / kg, mortality was not expected for the edaravone analogues at a dose of 10 mg / kg body weight / day. Considering the above facts, the minimum number of animals in this acute study was six per group. Morphological changes, histological changes, and mean body weight assessments in the entire set of animals in both the WG37R control group (N=6, 1:20 DMSO:PBS) and the WG37R treated group (N=6, NS-1-2, 10 mg / kg body weight) were assessed at a 14-day acute toxicity assessment by administering a single IP injection to 2-month-old mice (see (iia) below for further details).

[0379] (ii) Group assignment, drug formulation, storage, and compound dose group assignment for determination of chronic toxicity in WG37R mice: WG37R mice were randomly assigned to two groups. In the second set of experiments, a total of six animals (three males and three females) per group were used for the study. Group 3: sham treatment 1 (1:20 DMSO / PBS) and Group 4: NS-1-2 (10 mg / kg body weight). According to the requirements for acute toxicity studies, six to ten animals should be used to evaluate the effects of a substance. However, because the new analogue is structurally similar to edaravone, which has a single-dose safety profile of 450 mg / kg, mortality was not expected for the edaravone analogue at a dose of 10 mg / kg body weight / day. Considering the above facts, the suggested minimum number of animals for this acute study was six per group. Morphological changes, histological changes, and average body weight assessments in the entire set of animals in both the WG37R control group (N = 6, 1:20 DMSO:PBS) and the WG37R-treated group (N = 6, NS-1-2, 10 mg / kg body weight) were assessed in a 120-day chronic toxicity assessment by administering 120 daily IP injections to 3-month-old mice. Only one mouse in group 3 (control) unexpectedly terminated, likely due to an accidental error in injection (discussed with Central Animal Care Services, veterinarians, and staff). IP injections can be difficult due to mouse aggressiveness, especially in physically restrained male mice. A total of 1440 (12 × 120) daily IP injections were proposed for the chronic toxicity assessment (see (iia) below for further details).

[0380] (iia) Determining drug formulation, storage, and route of administration for acute and chronic toxicity: For intraperitoneal administration, approximately 1:20 DMSO / PBS was used to suspend the NS-1-2 test substance at a pH of approximately 7.4. Edaravone was dissolved in approximately 1 mL of approximately 1 mol / L NaOH, adjusted to approximately pH 7.4 by adding approximately 1 mol / L HCl, and then diluted with saline. Approximately 400 μl of the final reconstituted solution was aliquoted and stored at approximately -80°C until further use. For acute toxicity experiments, a single dose of approximately 10 mg / kg body weight of NS-1-2 was intraperitoneally injected into Group 2 WG37R mice at 2 months of age. Group 1 WG37R mice instead received an injection of an equal volume (approximately 1:20, DMSO:PBS). For chronic toxicity experiments, 120 daily doses of approximately 10 mg / kg body weight of NS-1-2 were intraperitoneally injected into Group 4 WG37R mice at 3 months of age for 120 days until they were 7 months of age. WG37R mice in group 3 received an injection of an equal volume (approximately 1:20, DMSO:PBS) instead.

[0381] (iib) Hematoxylin and eosin (H&E) staining and microscopy Wild-type (WT) G37R mice received a single IP injection of sham (approximately 0.2 ml) suspended in DMSO:PBS (approximately 1:20). At 2 months of age, they received a single IP injection of approximately 10 mg / kg body weight (approximately 0.2 ml) of NS-1-2 suspended in DMSO:PBS (approximately 1:20). Mice were observed for 2 weeks. At the experimental endpoint, mice were first deeply anesthetized with a mixture of approximately 20% v / v isoflurane / propylene glycol (approximately 1 ml of the mixture per approximately 500 ml of bell jar space, University of Manitoba animal care SOP A003). The animals were then exsanguinated by cutting the right atrium, followed by intracardiac perfusion with approximately 0.9% NaCl. A syringe barrel nose cone was used to prolong the anesthesia during perfusion. Intracardiac perfusion was followed by perfusion with approximately 4% paraformaldehyde for histological (H&E staining) analysis. Mouse tissues (brain, heart, spinal cord, kidney, liver, muscle, lung, and spleen) were fixed in approximately 4% buffered formalin for approximately 48 hours at approximately 4°C. The spinal cord alone was processed approximately 24 hours later to remove the vertebrae and re-fixed for approximately 24 hours. Samples were processed and embedded in paraffin blocks at the Histomorphology and Ultrastructural Imaging platform, Department of Human Anatomy and Cell Science, University of Manitoba. Briefly, embedded tissues were cut to approximately 5 μm thickness, mounted on Super Frost Plus slides, and dried overnight at approximately 37°C. Slides were deparaffinized with approximately two changes of xylene and rehydrated with descending alcohols (approximately two changes of approximately 100% ethanol and approximately two changes of approximately 95% ethanol) and tap water. Slides were stained with Harris's hematoxylin and subsequently differentiated with acid alcohol. After rinsing with tap water, saturated lithium carbonate was used to tint the nuclei blue. Slides were then rinsed with tap water and counterstained with eosin. Following eosin staining, slides were rehydrated using ascending alcohols, cleared with xylene, and sections were overslip mounted with paramount.

[0382] The mounted slides were then visualized and images were taken using an Axioskop 2 mot plus microscope (Carl Zeiss, Inc., Thornwood, NY) using AxioVision software version 4.8.

[0383] Similar to the acute toxicity experiments, hematoxylin and eosin (H&E) staining and microscopic examination were performed on animals assigned to the chronic toxicity group (data not shown here).

[0384] (iii) Group assignment to determine the therapeutic efficacy of B5-EDR analogs in reducing weight loss (cachexia), delaying disease onset, and increasing survival in the SOD1-G37R mouse model of ALS, compared directly with control / sham.

[0385] In these experiments, a set of experiments was performed with two groups of mice.

[0386] Group 1: sham treatment (1:20 DMSO / PBS), and Group 2: NS-1-2 treatment (1:20 DMSO / PBS) (10 mg / kg / body weight / day).

[0387] In these experiments, age-matched Het G37R (strain 42) mice were administered vehicle (1:20, DMSO:PBS) or treatment (NS-1-2, 10 mg / kg body weight) daily starting at 90 days of age and continued until 210 days of age, and monitored daily for several significant human endpoints, including: a) inability of the mouse to sit up for 15 seconds, b) weight loss of 25% relative to the highest recorded weight, c) complete paralysis of one or more hind limbs, d) loss of bladder function, e) eye discharge / blindness, and / or f) penile prolapse.

[0388] In weight loss studies, weight loss was based on the highest weight recorded (human endpoint).

[0389] In disease onset experiments, symptom onset (i.e., muscle weakness resulting in a 10% weight loss based on the highest recorded weight) and the time (in days) to reach peak weight were assessed and monitored daily by trained staff starting from 90 days of age, i.e., well before the clinical onset of disease, and several significant human endpoints were monitored daily, including: a) inability of mice to sit up for 15 seconds, b) 25% weight loss based on the highest recorded weight, c) complete paralysis of one or more hind limbs, d) loss of bladder function, e) eye discharge / blindness, and f) penile prolapse. A one-tailed (unpaired t-test) was performed to analyze the age at which (10%) weight loss was reached.

[0390] The injection site was also rotated between the right and left sides of the animals to reduce pain / inflammation. To examine the effects of treatment in these experiments, a sample size of 12 animals per group was used. The mean deviation for oxidized SOD1 levels was 20%. For at least a 30% reduction in oxidized SOD1 by treatment, a signal-to-noise ratio of 1.5, a power of 0.9, and a significance level of 0.05, a sample size of 12 animals was required. If a smaller sample size was used, the data would not be statistically significant. This study included two additional groups: a sham treatment (1 M NaOH) and edaravone (10 mg / kg body weight / day) in 1 M NaOH. If these groups were added to the experimental protocol, a total of 12 animals (6 males and 6 females) would be used per group. Therefore, if all experiments were performed, a total of 48 mice would be used.

[0391] result: Determination of acute toxicity in WG37R mice: (i) Morphological changes: After receiving a single IP injection of NS-1-2 (approximately 1:20, DMSO:PBS) at 2 months of age at a dose of 10 mg / kg body weight (approximately 0.2 ml), mice were observed for two weeks. Daily monitoring of various significant indicators of intended endpoints, such as body weight, appearance, physical condition, and general behavior (see Figure 9 and method (iii) above for examples of human endpoints), began on the first day of treatment and continued through day 14. No acute treatment-related deaths occurred during the two-week monitoring period. Daily general observations revealed normal appearance, normal general behavior, and a healthy physical condition. Furthermore, a single dose of NS-1-2 at 10 mg / kg body weight did not alter the skin, hair color, eyes, or mucous membranes of the tested mice, nor did it alter secretory and excretory activity, locomotion, or autonomic nervous system activity (data not shown).

[0392] Chronic toxicity studies were conducted with daily dosing for 120 days, starting at 3 months of age and continuing through 7 months of age. The results of these experiments were similar to those of the acute toxicity studies described above, with six animals per group. Daily IP administration of NS-1-2 (10 mg / kg / day) for 120 days (a total of 120 IP IJs over 120 days and a total dose of 1200 mg) appeared to be well tolerated by wild-type G37R mice. No chronic treatment-related deaths occurred during the 4-month monitoring period. Daily general observations revealed normal appearance and general behavior, accompanied by a healthy physical condition. Furthermore, a total of 120 doses of 10 mg / kg body weight of NS-1-2 did not alter the skin, hair color, eyes, or mucous membranes of the tested mice, nor did it alter the production of secretions and excretions, movement, or autonomic nervous system activity (data not shown). Daily chronic IP administration of NS-1-2 (10 mg / kg / day) for 120 days appeared to be well tolerated by wild-type G37R mice. Furthermore, NS-1-2-treated mice did not develop clinical signs of toxicity, including decreased mean body weight, hunched posture, orbital tightening, piloerection, and reduced activity, compared with vehicle-treated (1:20, DMSO:PBS) mice.

[0393] (ii) Body weight assessment (assessment of acute toxicity): As shown in Figure 10, acute treatment with the EDR analog NS-1-2 at a dose of 10 mg / kg body weight in the wild-type G37R model did not induce any abnormal changes in the body weight of the mice. Furthermore, there was no significant difference in the body weight changes between the control and treated groups, further supporting the absence of toxicity.

[0394] (ii) Body weight assessment (assessment of chronic toxicity): As shown in Figure 11, chronic treatment of the wild-type G37R model with the EDR analog NS-1-2 at a dose of 10 mg / kg body weight for 120 days did not induce any abnormal changes in the body weight of the mice. Furthermore, there was no significant difference in the body weight changes between the control and treated groups, further supporting the absence of toxicity.

[0395] (iii) Histological Analysis: As shown in Figure 12, G37RWT male mice receiving a single intraperitoneal (IP) injection of NS-1-2 at 10 mg / kg body weight starting at 60 days of age showed no significant differences in stained tissue samples compared to control mice. In addition, there were no obvious signs of degeneration, inflammation, or necrosis in any of the tissues examined. In particular, in the liver, both control and treated (NS-1-2) male mice exhibited normal lobular structure with central veins and radial hepatic cords. Hepatocytes were observed to be normal, and neither control nor NS-1-2-treated liver tissue showed signs of an inflammatory response. In the kidney, both control and treated (NS-1-2) male mice exhibited normal glomerular structure in the kidney, and no pathological changes were observed in either group. In the spleen, both control and treated (NS-1-2) male mice exhibited normal microarchitecture of the white and red pulp without morphological changes. In the heart, both control and treated (NS-1-2) male mice had normal myocardial morphology. In the lungs, both control and treated (NS-1-2) male mice exhibited normal lung structure with no signs of changes in alveolar structure. In the muscles, both control and treated (NS-1-2) male mice demonstrated normal, uniform distribution of polygonal muscle fibers with marginal nuclei. There was no fiber degeneration, and both groups had normal morphology. In the spinal cord, both control and treated (NS-1-2) male mice demonstrated normal morphology with a central canal, neurons, and glial cells. In the brain, both control and treated (NS-1-2) male mice demonstrated normal hippocampal morphology, demonstrating the regular structure of the CA3 region, where pyramidal cell layer neurons (P) were found to be uniform in size and evenly distributed.

[0396] Similarly, as shown in Figure 13, G37RWT female mice receiving a single intraperitoneal (IP) injection of NS-1-2 at 10 mg / kg body weight starting at 60 days of age showed no significant differences in stained tissue samples compared to control mice. In addition, there were no obvious signs of degeneration, inflammation, or necrosis in any of the tissues examined. In particular, in the liver, both control and treated (NS-1-2) female mice exhibited normal lobular structure with central veins and radial hepatic cords. Hepatocytes were observed to be normal, and both control and NS-1-2-treated liver tissues showed no signs of an inflammatory response. In the kidney, both control and treated (NS-1-2) female mice exhibited normal glomerular structure in the kidney, and no pathological changes were observed in either group. In the spleen, both control and treated (NS-1-2) female mice exhibited normal microarchitecture of the white and red pulp without morphological changes. In the heart, both control and treated (NS-1-2) female mice had normal myocardial morphology. In the lungs, both control and treated (NS-1-2) female mice exhibited normal pulmonary structure with no signs of alterations in alveolar structure. In the muscles, both control and treated (NS-1-2) female mice demonstrated normal, uniform distribution of polygonal muscle fibers with marginal nuclei. There was no fiber degeneration, and both groups had normal morphology. In the spinal cord, both control and treated (NS-1-2) female mice demonstrated normal morphology with a central canal, neurons, and glial cells. In the brain, both control and treated (NS-1-2) female mice demonstrated normal hippocampal morphology, demonstrating the regular structure of the CA3 region, where pyramidal cell layer neurons (P) were found to be uniform in size and evenly distributed.

[0397] Determination of the therapeutic efficacy of B5-EDR analogues: (i) Survival: Survival of mice receiving EDR analogs was also assessed. Daily IP injections in Het G37R (strain 42) mice beginning at 90 days of age through 210 days of age were found to extend survival in treated Het G37R (strain 42) mice (n = 10 / treated) compared to untreated mice (n = 10 / control). As shown in Figure 14, the mean age of survival extended from 183.4 days for untreated mice (n = 10 / control) to 196.7 days for treated mice (n = 10 / treated). This value was statistically significant (P = 0.0276) using a two-tailed unpaired t-test.

[0398] Given the difference in survival of 13.3 days or nearly 2 weeks, B 5 The -EDR compound NS-1-2 appears to function as an effective therapeutic agent in the G37R mouse model. Additionally, as shown in Figure 15, using the Kaplan-Meier log-rank (Mantel-Cox) test for survival (human endpoint) in Het G37R (strain 42) ALS model mice, daily intraperitoneal injections (IP IJ) starting at 90 days of age through 210 days of age in mice extended median survival from 185 days for untreated mice (n = 10 / control) to 199.5 days for treated mice (n = 10 / treatment). This was statistically significant (log-rank (Mantel-Cox) test: P = 0.0107). Furthermore, the Kaplan-Meier survival curves indicated that long-term treatment with NS-1-2 extended the survival age or lifespan of mutant G37R ALS mice by 14.5 days compared with control mutant G37R ALS mice. The survival data are also presented in tabular form (Table 1) below.

[0399] (ii) Weight loss: Changes in weight loss as a marker of ALS progression were also assessed in mice. As shown in Figure 16, daily intraperitoneal (IP) injection (IJ) NS-1-2 treatment, starting at 90 days of age and continuing until 210 days of age, significantly prevented the mean weight loss percentage (human endpoint) or ALS-induced cachectic weight loss percentage (human endpoint), from 26.76% in untreated mice (n = 10 / control) to 17.55% in treated mice (n = 10 / treatment). Thus, these results demonstrate that 6 of 10 animals in the control group lost >25% body weight at the human endpoint, and the remaining 4 of 10 animals lost >23.5% body weight, whereas in the treatment group, none of the animals lost >25% body weight, and none of the treated animals lost >23.5% body weight, indicating that the treatment group resisted weight loss, a traditional hallmark of ALS progression. Furthermore, weight loss is considered to be a predictor of shorter survival. Weight loss data is also presented in tabular form below (Table 1).

[0400] (iii) Disease onset (age to 10% weight loss (accompanied by muscle weakness)): Disease onset was also assessed in mice by measuring the age at which 10% weight loss (accompanied by muscle weakness) was reached based on the highest recorded body weight. As shown in Figure 17, daily intraperitoneal injection (IP IJ) in mice starting from 90 days of age to 210 days of age delayed disease onset, with the mean age (10% weight loss) ranging from 164.9 days for mice (n = 10 / control) to 188.1 days for mice (n = 10 / treated). Furthermore, disease onset was delayed by approximately 23.2 days in the NS-1-2-treated group compared with the control group without treatment. This was statistically significant (P = 0.0018) using a two-tailed unpaired t-test. Thus, the EDR analog NS-1-2 can delay disease onset in direct comparison with the control group. Disease onset data are also presented in tabular form (Table 1) below.

[0401] (iv) Disease onset (age (days) to reach peak weight): Disease onset is retrospectively defined as the age at which mice reach peak weight. As shown in Figure 18, daily intraperitoneal injection (IP IJ) in mice starting from 90 days of age to 210 days of age delayed disease onset, with the mean age (time to reach peak weight) being 131.4 days for mice (n = 10 / control) and 155 days for mice (n = 10 / treated). Furthermore, disease onset was delayed by approximately 23.6 days in the NS-1-2-treated group compared with the control group without treatment. This was statistically significant (P = 0.0011). Thus, the EDR analog NS-1-2 can delay disease onset in direct comparison with the control group. In addition, as shown in Figure 19, using the Kaplan-Meier log-rank (Mantel-Cox) test for the probability of disease onset (age to reach peak weight) in Het G37R (strain 42) ALS model mice, we found that daily intraperitoneal injections (IP IJ) in mice starting at 90 days of age until 210 days of age delayed median survival from 131 days for untreated mice (n = 10 / control) to 151 days for treated mice (n = 10 / treatment). This was statistically significant (log-rank (Mantel-Cox) test: P = 0.0013). Furthermore, the Kaplan-Meier survival curves indicate that treatment with NS-1-2 delayed disease onset in mutant G37R ALS mice by 20 days compared with control mutant G37R ALS mice.

[0402] Disease incidence data are also presented in tabular form below (Table 1).

[0403] Table 1 below presents a summary of the data provided for the treatment efficacy studies described in results (i)-(iv) above.

[0404] [Table 1]

[0405] The examples provided herein suggest that boron-based EDR analogs may have neuroprotective capabilities and limited neurotoxicity. The examples also suggest that EDR analog (e.g., NS-1-2)-treated mice have reduced weight loss (cachexia), delayed disease onset, and increased survival age in the SOD1-G37R mouse model of ALS compared to control / sham-treated mice. Thus, taken together, these results suggest that B 5 -EDR analogs are not acutely toxic and are well tolerated. 5 This suggests that B5-EDR analogs may be useful in the treatment and / or prevention of (neurodegenerative) diseases, conditions and / or disorders associated with oxidative stress, such as ALS. In this regard, B5-EDR analogs may be stand-alone compounds that can function as described and exemplified herein, and / or B5-EDR analogs may be used in the treatment and / or prevention of oxidative stress-related (neurodegenerative) diseases, conditions and / or disorders, such as ALS. 5 -EDR analogs may be prodrugs of EDR and may confer improved pharmacokinetic properties to EDR, resulting in improved drug-like properties, such as a long half-life and good oral formulation.

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Beyond neurological disease: new targets for edaravone (Review). Int J Mol Med. 2011 Dec;28(6):899-906. 20. Kikuchi K, Takeshige N, Miura N, Morimoto Y, Ito T, Tancharoen S, et al. Beyond free radical scavenging: Beneficial effects of edaravone (Radicut) in various diseases (Review). Exp Ther Med [Internet]. 2012;3(1):3-8. Available from: https: / / doi.org / 10.3892 / etm.2011.352 21. Otomo E, Tohgi H, Kogure K, Hirai S, Takakura K, Terashi A, et al. Effect of a novel free radical scavenger, edaravone (MCI-186), on acute brain infarction: Randomized, placebo-controlled, double-blind study at multicenters. Cerebrovasc Dis. 2003;15(3):222-9. 22. Rong W-T, Lu Y-P, Tao Q, Guo M, Lu Y, Ren Y, et al. Hydroxypropyl-sulfobutyl-β-cyclodextrin improves the oral bioavailability of edaravone by modulating drug efflux pump of enterocytes. J Pharm Sci. 2014 Feb;103(2):730-42. 23. Ma L, Sun J, Peng Y, Zhang R, Shao F, Hu X, et al. Glucuronidation of edaravone by human liver and kidney microsomes: biphasic kinetics and identification of UGT1A9 as the major UDP-glucuronosyltransferase isoform. Drug Metab Dispos. 2012 Apr;40(4):734-41. 24. Tanaka M, Sugimura N, Fujisawa A, Yamamoto Y. Stabilizers of edaravone aqueous solution and their action mechanisms. 1. Sodium bisulfite. J Clin Biochem Nutr [Internet]. 2017 / 10 / 26. 2017 Nov;61(3):159-63. Available from: https: / / pubmed.ncbi.nlm.nih.gov / 29203955 25. Tanaka M, Motomiya S, Fujisawa A, Yamamoto Y. Stabilizers of edaravone aqueous solution and their action mechanisms. 2. Glutathione. J Clin Biochem Nutr. 2017 Nov;61(3):164-8. 26. Hunt CD. Dietary boron: progress in establishing essential roles in human physiology. J trace Elem Med Biol organ Soc Miner Trace Elem. 2012 Jun;26(2-3):157-60. 27. Silva MP, Saraiva L, Pinto M, Sousa ME. Boronic Acids and Their Analogues in Medicinal Chemistry: Synthesis and Biological Applications. 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Barber SC, Higginbottom A, Mead RJ, Barber S, Shaw PJ. An in vitro screening cascade to identify neuroprotective antioxidants in ALS. Free Radic Biol Med [Internet]. 2009 / 01 / 30. 2009 Apr 15;46(8):1127-38. Available from: https: / / pubmed.ncbi.nlm.nih.gov / 19439221 39. Hemendinger RA, Armstrong EJ 3rd, Radio N, Brooks BR. Neurotoxic injury pathways in differentiated mouse motor neuron-neuroblastoma hybrid (NSC-34D) cells in vitro--limited effect of riluzole on thapsigargin, but not staurosporine, hydrogen peroxide and homocysteine neurotoxicity. Toxicol Appl Pharmacol. 2012 Jan;258(2):208-15. 40. Tovar-y-Romo LB, Santa-Cruz LD, Tapia R. Experimental models for the study of neurodegeneration in amyotrophic lateral sclerosis. Mol Neurodegener [Internet]. 2009;4(1):31. Available from: https: / / doi.org / 10.1186 / 1750-1326-4-31 41. Ito H, Wate R, Zhang J, Ohnishi S, Kaneko S, Ito H, Nakano S, Kusaka H. Treatment with edaravone, initiated at symptom onset, slows motor decline and decreases SOD1 deposition in ALS Mice. Experimental Neurology, 2008, 213(2):448-455. 42. Balimane P V, Han Y-H, Chong S. Current industrial practices of assessing permeability and P-glycoprotein interaction. AAPS J. 2006 Jan;8(1):E1-13. 43. Ohashi R, Watanabe R, Esaki T, Taniguchi T, Torimoto-Katori N, Watanabe T, et al. Development of Simplified in Vitro P-Glycoprotein Substrate Assay and in Silico Prediction Models To Evaluate Transport Potential of P-Glycoprotein. Mol Pharm [Internet]. 2019 May 6;16(5):1851-63. Available from: https: / / doi.org / 10.1021 / acs.molpharmaceut.8b01143 44. Di L, Kerns EH, Carter GT. Strategies to assess blood-brain barrier penetration. Expert Opin Drug Discov. 2008 Jun;3(6):677-87. 45. Kuhnline Sloan CD, Nandi P, Linz TH, Aldrich J V, Audus KL, Lunte SM. Analytical and biological methods for probing the blood-brain barrier. 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Claims

1. Formula I: 【Chemical 1】 a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a tautomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, an N-oxide thereof, a metabolite thereof, an isotopomer thereof, an isotopologue thereof, a prodrug thereof, or a combination thereof. (In the formula, X １ Is -BR ８ R ９ or -BR １０ R １１ R １２ Selected from: R １ From R ７ , R １０ , R １１ , and R １２ are each independently H, a halo group, a hydroxyl group, a cyano group, a nitro group, a thiol group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterogeneous group, -BR １３ R １４ , -BR １５ R １６ R １７ , a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group; R １３ From R １７ are each independently selected from H, a halo group, a hydroxyl group, a cyano group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group, or R １３ and R １４ taken together form a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group, R ８ and R ９ are each independently selected from H, halo, hydroxyl, cyano, nitro, thiol, sulfonyl, sulfate, substituted or unsubstituted amino, substituted or unsubstituted hydrocarbon, substituted or unsubstituted heterocyclic, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aromatic, substituted or unsubstituted heteroaromatic, or together form a substituted or unsubstituted carbocyclic or substituted or unsubstituted heterocyclic group.

2. X １ Ga-BR ８ R ９ 2. The compound of claim 1, wherein:

3. R ８ and R ９ are each independently selected from H, a halo group, a hydroxyl group, a cyano group, a nitro group, a thiol group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterogeneous group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, and a substituted or unsubstituted heteroaromatic group.

4. R ８ and R ９ are each independently selected from H, halo, hydroxyl, cyano, nitro, sulfate, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, -C(O)H, substituted carbonyl, substituted carboxyl, -C(O)OH, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aromatic, or substituted or unsubstituted heteroaromatic.

5. R ８ and R ９ each independently represents H, a halo group, a hydroxyl group, a cyano group, a nitro group, a sulfate group, a substituted or unsubstituted C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl groups, substituted or unsubstituted (C １ ~C ６ alkyl) hetero(C １ ~C ６ alkyl) group, substituted or unsubstituted C １ ~C ６ Alkoxy group, —C(O)H, substituted or unsubstituted C １ ~C ６ Alkylcarbonyl group, substituted or unsubstituted (C １ ~C ６ alkyl) carbonyl (C １ ~C ６ alkyl) group, substituted or unsubstituted C １ ~C ６ Alkyl-C(O)O- group, substituted or unsubstituted C １ ~C ６ Alkyl-O—C(O)— group, substituted or unsubstituted C １ ~C ６ Alkyl-O—C(O)—C １ ~C ６ Alkylene group, —C(O)OH, substituted or unsubstituted C １ ~C ６ Cycloalkyl groups, substituted or unsubstituted C １ ~C ６ Heterocyclic group, substituted or unsubstituted C １ ~C ６ Aromatic group, or substituted or unsubstituted C １ ~C ６ The compound according to any one of claims 1 to 4, selected from heteroaromatic groups.

6. R ８ and R ９ is independently selected from a fluoro group, a chloro group, a bromo group, a hydroxyl group, or an alkoxy group.

7. R ８ and R ９ The compound of claim 1 or 2, wherein: combined to form a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group.

8. R ８ and R ９ The compound of any one of claims 1, 2, and 7, wherein: taken together form a substituted or unsubstituted heterocyclic group.

9. R ８ and R ９ together form a substituted or unsubstituted —O(C ２ ~C ８ 9. The compound of any one of claims 1, 2, 7, and 8, wherein the compound forms an alkylene)O-ring.

10. R ８ and R ９ But together, -OCH ２ CH ２ O-, -OC(CH ３ ) ２ CH ２ O-, or -OC(CH ３ ) ２ C(CH ３ ) ２ The compound according to any one of claims 1, 2, and 7 to 9, which forms O-.

11. R ８ and R ９ together form a substituted or unsubstituted —O(C １ ~C ２ alkylene)NH(C １ ~C ２ 9. The compound of any one of claims 1, 2, 7, and 8, wherein the compound forms an alkylene)O-ring.

12. R ８ and R ９ But together, -OCH ２ CH ２ NHCH ２ CH ２ O-, -OCH ２ CH ２ N (CH ３ ) CH ２ CH ２ O-, -OCH ２ C(CH ３ ) ２ NHCH ２ CH ２ O-, -OCH ２ C(CH ３ ) ２ N (CH ３ ) CH ２ CH ２ O-, -OCH ２ C(CH ３ ) ２ NHC (CH ３ ) ２ CH ２ O-, -OC(CH ３ ) ２ CH ２ N (CH ３ ) C(CH ３ ) ２ CH ２ O-, or -OC(CH ３ ) ２ C(CH ３ ) ２ N (CH ３ ) C(CH ３ ) ２ C(CH ３ ) ２ The compound according to any one of claims 1, 2, and 7 to 9, which forms O-.

13. X １ Ga-BR １０ R １１ R １２ 2. The compound of claim 1, wherein:

14. R １０ , R １１ , and R １２ are each independently selected from H, a halo group, a hydroxyl group, a cyano group, a nitro group, a thiol group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterogeneous group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, and a substituted or unsubstituted heteroaromatic group.

15. R １０ , R １１ , and R １２ are each independently selected from H, a halo group, a hydroxyl group, a cyano group, a nitro group, a sulfate group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alkoxy group, —C(O)H, a substituted carbonyl group, a substituted carboxyl group, —C(O)OH, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

16. R １０ , R １１ , and R １２ each independently represents H, a halo group, a hydroxyl group, a cyano group, a nitro group, a sulfate group, a substituted or unsubstituted C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl groups, substituted or unsubstituted (C １ ~C ６ alkyl) hetero(C １ ~C ６ alkyl) group, substituted or unsubstituted C １ ~C ６ Alkoxy group, —C(O)H, substituted or unsubstituted C １ ~C ６ Alkylcarbonyl group, substituted or unsubstituted (C １ ~C ６ alkyl) carbonyl (C １ ~C ６ alkyl) group, substituted or unsubstituted C １ ~C ６ Alkyl-C(O)O- group, substituted or unsubstituted C １ ~C ６ Alkyl-O—C(O)— group, substituted or unsubstituted C １ ~C ６ Alkyl-O—C(O)—C １ ~C ６ Alkylene group, —C(O)OH, substituted or unsubstituted C １ ~C ６ Cycloalkyl groups, substituted or unsubstituted C １ ~C ６ Heterocyclic group, substituted or unsubstituted C １ ~C ６ Aromatic group, or substituted or unsubstituted C １ ~C ６ 16. The compound of any one of claims 1 and 13 to 15, wherein the compound is selected from heteroaromatic groups.

17. R １０ , R １１ , and R １２ is independently selected from a fluoro group, a chloro group, a bromo group, a hydroxyl group, or an alkoxy group.

18. R １ and R ２ are each independently selected from H, a halo group, a hydroxyl group, a cyano group, a nitro group, a thiol group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterogeneous group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

19. R １ and R ２ are each independently selected from H, a halo group, a hydroxyl group, a cyano group, a substituted or unsubstituted amino group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

20. R １ and R ２ are each independently H, a halo group, or a substituted or unsubstituted C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl groups, substituted or unsubstituted (C １ ~C ６ alkyl) hetero(C １ ~C ６ alkyl) group, substituted or unsubstituted C １ ~C ６ Cycloalkyl groups, substituted or unsubstituted C １ ~C ６ Heterocyclic group, substituted or unsubstituted C １ ~C ６ Aromatic group, or substituted or unsubstituted C １ ~C ６ A compound according to any one of claims 1 to 19, selected from heteroaromatic groups.

21. R １ is H or a substituted or unsubstituted alkyl group, and R ２ is selected from H, a halo group, a hydroxyl group, a cyano group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterogeneous group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

22. R １ is H, -CH ３ , -CH ２ CH ３ , or -CH ２ CH ２ CH ３ and R ２ is H, F, Cl, CN, -CH ３ , -CH ２ F, -CHF ２ , or -CF ３ The compound according to any one of claims 1 to 21, selected from:

23. R ３ From R ７ each independently represents H, a halo group, a hydroxyl group, a cyano group, a nitro group, a thiol group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterogeneous group, -BR １３ R １４ , -BR １５ R １６ R １７ , a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group; R １３ From R １７ are each independently selected from H, a halo group, a hydroxyl group, a cyano group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group; or R １３ and R １４ The compound of any one of claims 1 to 22, wherein together form a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group.

24. R ３ From R ７ are each independently selected from H, a halo group, a cyano group, a nitro group, a sulfate group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterogeneous group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

25. R ３ From R ７ are each independently selected from H, a halo group, a cyano group, a nitro group, a sulfate group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alkoxy group, —C(O)H, a substituted carbonyl group, a substituted carboxyl group, —C(O)OH, a boronic acid group, a substituted or unsubstituted alkylboronate group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

26. R ３ From R ７ are each independently H, a halo group, or a substituted or unsubstituted C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl groups, substituted or unsubstituted (C １ ~C ６ alkyl) hetero(C １ ~C ６ alkyl) group, substituted or unsubstituted C １ ~C ６ Alkoxy group, —C(O)H, substituted or unsubstituted C １ ~C ６ Alkylcarbonyl group, substituted or unsubstituted (C １ ~C ６ alkyl) carbonyl (C １ ~C ６ alkyl) group, substituted or unsubstituted C １ ~C ６ Alkyl-C(O)O- group, substituted or unsubstituted C １ ~C ６ Alkyl-O—C(O)— group, substituted or unsubstituted C １ ~C ６ Alkyl-O—C(O)—C １ ~C ６ Alkylene group, —C(O)OH, boronic acid group, substituted or unsubstituted C １ ~C ６ Alkylboronate group, substituted or unsubstituted C １ ~C ６ Cycloalkyl groups, substituted or unsubstituted C １ ~C ６ 26. The compound of any one of claims 1 to 25, wherein the heterocyclic group is selected from a substituted or unsubstituted phenyl group, a substituted or unsubstituted alkylheteroaryl group, a substituted or unsubstituted pyridinyl group, or a substituted or unsubstituted pyrrolyl group.

27. R ３ , R ４ , R ６ , and R ７ are each independently H, —CH ３ , -CH ２ CH ３ , or -CH ２ CH ２ CH ３ and R ５ is H, F, Cl, CN, -CH ３ , -CH ２ F, -CHF ２ , or -CF ３ The compound according to any one of claims 1 to 26, selected from:

28. The compound is: 【Chemistry 2】 28. The compound of any one of claims 1 to 27, selected from a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a tautomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, an N-oxide thereof, a metabolite thereof, an isotopomer thereof, an isotopologue thereof, a prodrug thereof, or a combination thereof.

29. The compound is: 【Chemistry 3】 is selected from a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a tautomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, an N-oxide thereof, a metabolite thereof, an isotopomer thereof, an isotopologue thereof, a prodrug thereof, or a combination thereof; １ ~R ４ are each independently R ３ ~R ７ 29. The compound according to any one of claims 1 to 28, wherein the compound is selected from any of the groups

30. The compound is: 【Chemistry 4】 a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a tautomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, an N-oxide thereof, a metabolite thereof, an isotopomer thereof, an isotopologue thereof, a prodrug thereof, or a combination thereof; and X ＋ 30. The compound of any one of claims 1 to 29, wherein is any suitable counter ion.

31. The compound is: 【Chemistry 5】 a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a tautomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, an N-oxide thereof, a metabolite thereof, an isotopomer thereof, an isotopologue thereof, a prodrug thereof, or a combination thereof; and X ＋ 31. The compound of any one of claims 1 to 30, wherein is any suitable counter ion.

32. The compound of any one of claims 1 to 31, which is a racemic mixture.

33. 33. The compound according to any one of claims 1 to 32, which is a scalemic mixture.

34. The compound of any one of claims 1 to 33, which is a pharmaceutically acceptable salt.

35. A compound according to any one of claims 1 to 34, which can act as a metal chelator.

36. A compound according to any one of claims 1 to 35, which can act as an antioxidant.

37. A compound according to any one of claims 1 to 36, which reduces oxidative stress.

38. 38. A compound according to any one of claims 1 to 37, which reduces oxidative damage / oxidative stress by scavenging reactive oxygen species (ROS) and / or reactive nitrogen species (RNS).

39. A compound according to any one of claims 1 to 38, capable of reducing reactive oxygen species (ROS) and / or reactive nitrogen species (RNS) in vitro.

40. 40. A compound according to any one of claims 1 to 39, capable of reducing reactive oxygen species (ROS) and / or reactive nitrogen species (RNS) in vivo.

41. 41. The compound of any one of claims 38 to 40, wherein the ROS and / or RNS comprise free radicals and / or oxidants.

42. The free radicals and / or oxidants include hydroxyl radical (HO.), superoxide radical anion radical (O2.-), nitric oxide (NO.), nitrogen dioxide (NO ２ ·), peroxyl (ROO·) and lipid peroxyl (LOO·), hydrogen peroxide (H ２ O ２ ), ozone (O ３ ), singlet oxygen ( １ O ２ ), hypochlorous acid (HOCl), hydroperoxide nucleophiles ( － OOH), nitrous acid (HNO ２ ), nitrogen trioxide (N ２ O ３ 42. The compound of claim 41, wherein the compound is selected from: lipid peroxide (LOOH);

43. The free radicals and / or oxidants are hydrogen peroxide (H ２ O ２ 42. The compound of claim 41, wherein

44. The compound according to any one of claims 1 to 43, which can react with hydrogen peroxide in vivo to produce edaravone (EDR).

45. The compound according to any one of claims 1 to 44, which can react with hydrogen peroxide in vitro to produce edaravone (EDR).

46. The compound according to any one of claims 1 to 45, which is a prodrug of edaravone (EDR).

47. The compound according to any one of claims 1 to 46, which is an antioxidant and a prodrug of edaravone (EDR).

48. 48. The compound of any one of claims 1 to 47, which is an agent for treating amyotrophic lateral sclerosis (ALS) in vivo.

49. 49. The compound of any one of claims 1 to 48, which is a therapeutic agent for the prevention and / or treatment of diseases, conditions and / or disorders associated with oxidative stress.

50. A pharmaceutical composition comprising a compound according to any one of claims 1 to 49.

51. A pharmaceutical composition comprising a compound according to any one of claims 1 to 49 and at least one pharmaceutically acceptable carrier and / or diluent.

52. A compound according to any one of claims 1 to 49 or a composition according to claim 50 or 51 for the prevention and / or treatment of diseases, conditions and / or disorders associated with oxidative stress.

53. 53. The compound or composition of claim 52, wherein the oxidative stress is caused by reactive oxygen species (ROS) and / or reactive nitrogen species (RNS).

54. 54. The compound or composition of claim 53, wherein the ROS and / or RNS comprise free radicals and / or oxidants.

55. The free radicals and / or oxidants include hydroxyl radical (HO.), superoxide radical anion radical (O2.-), nitric oxide (NO.), nitrogen dioxide (NO ２ ·), peroxyl (ROO·) and lipid peroxyl (LOO·), hydrogen peroxide (H ２ O ２ ), ozone (O ３ ), singlet oxygen ( １ O ２ ), hypochlorous acid (HOCl), hydroperoxide nucleophiles ( － OOH), nitrous acid (HNO ２ ), nitrogen trioxide (N ２ O ３ 55. The compound or composition of any one of claims 52 to 54, wherein the compound or composition is selected from: lipid peroxides (LOOH);

56. The free radicals and / or oxidants are hydrogen peroxide (H ２ O ２ 55. The compound or composition of claim 54, wherein

57. 57. The compound or composition of any one of claims 52 to 56, wherein the oxidative stress associated disease, condition and / or disorder is selected from neurodegenerative diseases, disorders and / or conditions, muscle diseases, disorders and / or conditions, vascular diseases, disorders and / or conditions, systemic inflammatory diseases, disorders and / or conditions, local inflammatory diseases, disorders and / or conditions, metabolic syndrome, cardiovascular diseases, disorders and / or conditions, autoimmune diseases, disorders and / or conditions, inflammatory lung diseases, disorders and / or conditions, kidney diseases, disorders and / or conditions, liver diseases, disorders and / or conditions, digestive diseases, disorders and / or conditions, aging, disorders and / or conditions, viral infectious diseases, disorders and / or conditions, cancer, and sepsis / septic shock.

58. 58. The compound or composition of claim 57, wherein the neurodegenerative disease, condition and / or disorder is associated with motor dysfunction.

59. 59. The compound or composition of claim 58, wherein the neurodegenerative disease, condition and / or disorder associated with motor dysfunction is amyotrophic lateral sclerosis (ALS).

60. 60. The compound or composition of claim 59, wherein the ALS is familial ALS.

61. 60. The compound or composition of claim 59, wherein the ALS is sporadic ALS.

62. 62. The compound or composition of any one of claims 59 to 61, wherein the ALS is caused by a mutation in the superoxide dismutase 1 (SOD1) gene or the TARDBP gene.

63. 63. The compound or composition of any one of claims 59 to 62, which delays the onset of ALS.

64. 64. The compound or composition of any one of claims 52 to 63, which has an improved therapeutic index for ALS compared to edaravone (EDR).

65. 65. The compound or composition of claim 64, wherein the therapeutic index is a measure of one or more of the following symptoms: muscle weakness, muscle wasting (atrophy), weight loss (cachexia), muscle spasms, muscle cramps, slowness of movement, impaired balance, incoordination, changes in voice quality, dysarthria, dysphagia, insufficient eyelid closure, salivation, pseudobulbar ulceration, and / or premature death.

66. 66. The compound or composition of claim 64 or 65, wherein the improved therapeutic index is measured by increased survival / longevity in subjects receiving the compound or composition compared to subjects receiving edaravone (EDR).

67. 67. The compound or composition of any one of claims 64 to 66, wherein the improved therapeutic index is measured by increased motor function in subjects receiving the compound or composition compared to subjects receiving edaravone (EDR).

68. 68. The compound or composition of any one of claims 64-67, wherein the improved therapeutic index is measured by a lower percentage of weight loss (cachexia) in subjects receiving the compound or composition compared to subjects receiving edaravone (EDR).

69. 69. The compound or composition according to any one of claims 52 to 68, which has improved pharmacokinetics compared to edaravone (EDR).

70. 70. The compound or composition of claim 69, wherein the improved pharmacokinetics comprises increased bioavailability of the compound or composition compared to edaravone (EDR).

71. 52. A method for preventing and / or treating diseases, conditions and / or disorders associated with oxidative stress, comprising administering to a mammal a therapeutically effective amount of a compound according to any one of claims 1 to 49, or a composition according to claim 50 or 51.

72. 72. The method of claim 71, wherein the oxidative stress is caused by reactive oxygen species (ROS) and / or reactive nitrogen species (RNS).

73. 73. The method of claim 72, wherein the ROS and / or RNS comprise free radicals and / or oxidants.

74. The free radicals and / or oxidants include hydroxyl radical (HO.), superoxide radical anion radical (O2.-), nitric oxide (NO.), nitrogen dioxide (NO ２ ·), peroxyl (ROO·) and lipid peroxyl (LOO·), hydrogen peroxide (H ２ O ２ ), ozone (O ３ ), singlet oxygen ( １ O ２ ), hypochlorous acid (HOCl), hydroperoxide nucleophiles ( － OOH), nitrous acid (HNO ２ ), nitrogen trioxide (N ２ O ３ 74. The method of claim 73, wherein the oxidizing agent is selected from the group consisting of lipid peroxides (LOOH), and lipid peroxides (LOOH).

75. The free radicals and / or oxidants are hydrogen peroxide (H ２ O ２ 74. The method of claim 73, wherein

76. 76. The method of any one of claims 71 to 75, wherein the oxidative stress associated disease, condition and / or disorder is selected from neurodegenerative diseases, disorders and / or conditions, muscle diseases, disorders and / or conditions, vascular diseases, disorders and / or conditions, systemic inflammatory diseases, disorders and / or conditions, local inflammatory diseases, disorders and / or conditions, metabolic syndrome, cardiovascular diseases, disorders and / or conditions, autoimmune diseases, disorders and / or conditions, inflammatory lung diseases, disorders and / or conditions, kidney diseases, disorders and / or conditions, liver diseases, disorders and / or conditions, digestive diseases, disorders and / or conditions, aging, disorders and / or conditions, viral infectious diseases, disorders and / or conditions, cancer, and sepsis / septic shock.

77. 77. The method of claim 76, wherein the neurodegenerative disease, condition and / or disorder is associated with motor dysfunction.

78. 78. The method of claim 77, wherein the neurodegenerative disease, condition and / or disorder associated with motor dysfunction is amyotrophic lateral sclerosis (ALS).

79. 79. The method of claim 78, wherein the ALS is familial ALS.

80. 79. The method of claim 78, wherein the ALS is sporadic ALS.

81. 81. The method of any one of claims 78 to 80, wherein the ALS is caused by a mutation in the superoxide dismutase 1 (SOD1) gene or the TARDBP gene.

82. 82. The method of any one of claims 78-81, wherein the compound or composition delays the onset of the ALS.

83. 83. The method of any one of claims 71 to 82, wherein the compound or composition has an improved therapeutic index for ALS compared to edaravone (EDR).

84. 84. The method of claim 83, wherein the therapeutic index is a measure of one or more of the following symptoms: muscle weakness, muscle wasting (atrophy), weight loss (cachexia), muscle spasms, muscle cramps, slowness of movement, impaired balance, incoordination, changes in voice quality, dysarthria, dysphagia, insufficient eyelid closure, drooling, pseudobulbar ulceration, and / or premature death.

85. 85. The method of claim 83 or 84, wherein the improved therapeutic index is measured by increased survival / lifespan in subjects receiving the compound or composition compared to subjects receiving edaravone (EDR).

86. 86. The method of any one of claims 83-85, wherein the improved therapeutic index is measured by increased motor function in subjects receiving the compound or composition compared to subjects receiving edaravone (EDR).

87. 87. The method of any one of claims 83-86, wherein the improved therapeutic index is measured by a lower percentage of weight loss (cachexia) in subjects receiving the compound or composition compared to subjects receiving edaravone (EDR).

88. The method of any one of claims 71 to 87, wherein the compound or composition has improved pharmacokinetics compared to edaravone (EDR).

89. 89. The method of claim 88, wherein the improved pharmacokinetics comprises increased bioavailability of the compound or composition compared to edaravone (EDR).

90. 90. The method of any one of claims 71 to 89, wherein the mammal is a human.

91. 91. The method of any one of claims 71 to 90, wherein the compound or composition is administered orally and / or intravenously.

92. Use of a therapeutically effective amount of a compound according to any one of claims 1 to 49, or a composition according to claim 50 or 51, for the prevention and / or treatment of diseases, conditions and / or disorders associated with oxidative stress.

93. 93. The use of claim 92, wherein the oxidative stress is caused by reactive oxygen species (ROS) and / or reactive nitrogen species (RNS).

94. 94. The use of claim 93, wherein the ROS and / or RNS comprise free radicals and / or oxidants.

95. The free radicals and / or oxidants include hydroxyl radical (HO.), superoxide radical anion radical (O2.-), nitric oxide (NO.), nitrogen dioxide (NO ２ ·), peroxyl (ROO·) and lipid peroxyl (LOO·), hydrogen peroxide (H ２ O ２ ), ozone (O ３ ), singlet oxygen ( １ O ２ ), hypochlorous acid (HOCl), hydroperoxide nucleophiles ( － OOH), nitrous acid (HNO ２ ), nitrogen trioxide (N ２ O ３ 95. The use of claim 94, wherein the lipid peroxide is selected from the group consisting of lipid peroxides (LOOH), ... and lipid peroxides (LOOH).

96. The free radicals and / or oxidants are hydrogen peroxide (H ２ O ２ 95. The use according to claim 94, wherein

97. 97. The use according to any one of claims 92 to 96, wherein the disease, condition and / or disorder associated with oxidative stress is selected from neurodegenerative diseases, disorders and / or conditions, muscle diseases, disorders and / or conditions, vascular diseases, disorders and / or conditions, systemic inflammatory diseases, disorders and / or conditions, local inflammatory diseases, disorders and / or conditions, metabolic syndrome, cardiovascular diseases, disorders and / or conditions, autoimmune diseases, disorders and / or conditions, inflammatory lung diseases, disorders and / or conditions, kidney diseases, disorders and / or conditions, liver diseases, disorders and / or conditions, digestive diseases, disorders and / or conditions, aging, disorders and / or conditions, viral infectious diseases, disorders and / or conditions, cancer, and sepsis / septic shock.

98. 98. The use of claim 97, wherein the neurodegenerative disease, condition and / or disorder is associated with motor dysfunction.

99. 99. The use of claim 98, wherein the neurodegenerative disease, condition and / or disorder associated with motor dysfunction is amyotrophic lateral sclerosis (ALS).

100. 100. The use of claim 99, wherein the ALS is familial ALS.

101. 100. The use of claim 99, wherein the ALS is sporadic ALS.

102. The use according to any one of claims 99 to 101, wherein the ALS is caused by a mutation in the superoxide dismutase 1 (SOD1) gene or the TARDBP gene.

103. 103. The use of any one of claims 99 to 102, wherein the compound or composition delays the onset of ALS.

104. The use according to any one of claims 92 to 103, wherein the compound or composition has an improved therapeutic index for ALS compared to edaravone (EDR).

105. 105. The use of claim 104, wherein the therapeutic index is a measure of one or more of the following symptoms: muscle weakness, muscle wasting (atrophy), weight loss (cachexia), muscle spasms, muscle cramps, slowness of movement, impaired balance, incoordination, changes in voice quality, dysarthria, dysphagia, insufficient eyelid closure, drooling, pseudobulbar ulceration, and / or premature death.

106. The use of claim 104 or 105, wherein the improved therapeutic index is measured by increased survival / longevity in subjects receiving the compound or composition compared to subjects receiving edaravone (EDR).

107. The use of any one of claims 104 to 106, wherein the improved therapeutic index is measured by increased motor function in subjects receiving the compound or composition compared to subjects receiving edaravone (EDR).

108. The use of any one of claims 104 to 107, wherein the improved therapeutic index is measured by a lower percentage of weight loss (cachexia) in subjects receiving the compound or composition compared to subjects receiving edaravone (EDR).

109. The use according to any one of claims 92 to 108, wherein the compound or composition has improved pharmacokinetics compared to edaravone (EDR).

110. The use of claim 109, wherein the improved pharmacokinetics comprises increased bioavailability of the compound or composition compared to edaravone (EDR).

111. The use according to any one of claims 92 to 110, wherein the mammal is a human.

112. The use according to any one of claims 92 to 111, wherein the compound or composition is administered orally and / or intravenously.

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