1H-pyrazole analogs and methods and uses thereof

Abstract

Compounds having the structure of formula I, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, tautomers thereof, geometric isomers thereof, enantiomers thereof, diastereoisomers thereof, N-oxides thereof, metabolites thereof, isotope isomers thereof, isotope variants thereof, prodrugs thereof or combinations thereof. The compounds / compositions are useful in the prevention and / or treatment of diseases, conditions and / or disorders associated with oxidative stress, such as, but not limited to, neurodegenerative disorders, aging, and the like. # imgabs0 #

Description

Technical Field

[0001] The present disclosure relates to compounds and their methods and uses. In particular, the present disclosure relates to 1H-pyrazole analogs and their methods and uses. Background Art

[0002] Current evidence collectively indicates that amyotrophic lateral sclerosis (ALS) is a highly complex, multifactorial, life-threatening motor neurodegenerative disease with different pathophysiologies and disease progressions due to the action of a series of underlying mechanisms. Unfortunately, the evidence for the pathological mechanisms of ALS is not clear, and there is currently no cure for the disease.

[0003] Due to limited survival benefits, high economic burdens, and synthetic obstacles, the therapeutic effects and scopes of treatment strategies against the disease are limited. Edaravone (EDR; 3-methyl-1-phenyl-2-pyrazolin-5-one), as such a treatment strategy, has been approved for the treatment of ALS in multiple jurisdictions (e.g., approved by the FDA (in May 2017) for the treatment of ALS [1], and approved by Health Canada (in October 2018) [2]).

[0004] The structure of EDR is shown below:

[0005]

[0006] However, EDR has limitations, including, for example, in terms of patient compliance, pharmacokinetics, and oral bioavailability.

[0007] There is a need for new EDR analogs and their compositions to provide useful alternatives to EDR.

[0008] The background art contained herein is only for explaining the background of the present application. This should not be regarded as an admission that any of the materials mentioned was publicly disclosed, known, or part of common general knowledge before the priority date. Summary of the Invention

[0009] In one aspect, there are compounds having the structure of Formula I:

[0010]

[0011]

[0012] Their pharmaceutically acceptable salts, their hydrates, their solvates, their tautomers, their geometric isomers, their enantiomers, their diastereomers, their N-oxides, their metabolites, their isotopomers, their isotopologues, their prodrugs, or combinations thereof,

[0013] Wherein:

[0014] X1 is selected from -BR 8 R 9 or -BR 10 R 11 R 12 ;

[0015] R 1 to R 7 、R 10 、R 11 and R 12 each independently is selected from H, a halogen group, a hydroxyl group, a cyano group, a nitro group, a mercapto group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heteroatom-containing 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, wherein R 13 to R 17 each independently is selected from H, a halogen group, a hydroxyl group, a cyano group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heteroatom-containing 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 together form a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group; and

[0016] R 8 and R 9 each independently is selected from H, a halogen group, a hydroxyl group, a cyano group, a nitro group, a mercapto group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heteroatom-containing 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.

[0017] On the other hand, there is a pharmaceutical composition comprising the compound described herein.

[0018] On the other hand, there is a method for preventing and / or treating diseases, disorders and / or conditions associated with oxidative stress, comprising administering to a mammal a therapeutically effective amount of the compound described herein or the composition described herein.

[0019] In yet another aspect, there is provided a use of a therapeutically effective amount of a compound described herein or a composition described herein for preventing and / or treating diseases, disorders and / or conditions associated with oxidative stress.

[0020] It should be understood that one or more aspects described herein (and above) can be combined in any suitable manner. The novel features of the invention will become apparent to those skilled in the art upon reading the following detailed description of the invention. However, it should be understood that although the detailed description and the specific examples given herein illustrate certain aspects of the invention, they are for illustrative purposes only, since various changes and modifications within the spirit and scope of the invention will be apparent to those skilled in the art from the detailed description and the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] The present invention can be further understood by the following description with reference to the accompanying drawings, in which:

[0022] Figure 1 The chemical structures of the keto and enol forms of edaravone (EDR) are shown.

[0023] Figure 2 Shows Figure 1 Examples of the chemical structures of 1H-pyrazole analogs of EDR (B 5 -EDR) in.

[0024] Figure 3 Shows Figure 2 B in 5 -EDR analog as a prodrug, schematic diagram of generating EDR through in vivo H2O2 metabolism.

[0025] Figures 4A - 4B Shows B 5 -EDR analog and the chemical reaction between H2O2 to generate edaravone (EDR) and the corresponding TLC chromatogram. 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; EDR = edaravone.

[0026] Figure 5 Shows an example of the structure of the B 5 -EDR synthetic analog of the present disclosure.

[0027] Figures 6A - 6B Shows the representation using EDR and B 5Example graph of the percentage of viable primary neuron cell cultures (PNCC) treated with EDR analogs NS-1-2, NS-1-12, NS-1-13, NS-19, and NS-1-21. Data are presented as mean ± standard error of the mean (error bars); n = 12 data points or sample size; data were analyzed by one-way analysis of variance (AVONA), followed by Dunnett's multiple comparison test for statistical analysis (*P < 0.05, **P = 0.01, and ***P = 0.001, compared to control (DMSO)). Data represent two independent experiments, with each measurement or dose tested six times.

[0028] Figures 7A - 7C Shows a representation of treatment with EDR and B 5 Example graph of the percentage of viable neuroblastoma-spinal cord NSC-34 cells treated with EDR analogs NS-1-2, NS-1-12, NS-1-13, NS-19, and NS-1-21. Data are presented as mean ± standard error of the mean (error bars); where n = 9 data points or sample size; data were analyzed by one-way analysis of variance (ANOVA), followed by Dunnett's multiple comparison test for statistical analysis (*P < 0.05, compared to control (DMSO)). Data represent three independent experiments, with each measurement or dose tested in triplicate.

[0029] Figures 8A - 8B Shows a representation of treatment with EDR and B 5 Example graph of the percentage of viable neuroblastoma-spinal cord NSC-34 cells treated with EDR analogs NS-1-2, NS-1-12, NS-1-13, NS-19, and NS-1-21 against hydrogen peroxide-induced oxidative stress. Data are presented as mean ± standard error (error bars); where n = 9 data points or sample size; data were analyzed by one-way analysis of variance (ANOVA), followed by Dunnett's multiple comparison test for statistical analysis (#P < 0.0001 control (DMSO), *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, ns = no significant difference, compared to H2O2, DMSO). All data represent three independent experiments, and each measurement or dose was tested in triplicate.

[0030] Figure 9 Shows an exemplary timeline schematic of ALS progression in an experimental mouse model (SOD1 G37R ), including the annotation of representative humane endpoints.

[0031] Figure 10An exemplary graph showing the mean body weights of all WG37R control and treatment group animals during the 14-day acute toxicity assessment is presented. Data are expressed as mean ± SEM (standard error of the mean).

[0032] Figure 11 An exemplary graph showing the mean body weights of all WG37R control and treatment group animals during the 120-day chronic toxicity assessment is presented. Data are expressed as mean ± SEM.

[0033] Figure 12 Exemplary micrographs of hematoxylin and eosin (H&E)-stained sections of two representative G37RWT male mice during the 14-day acute toxicity assessment are shown. There were six mice per group (3 males and 3 females). Original magnification 10× (scale bar represents 20 μm).

[0034] Figure 13 Exemplary micrographs of hematoxylin and eosin (H&E)-stained sections of two representative G37RWT female mice during the 14-day acute toxicity assessment are shown. There were six mice per group (3 males and 3 females). Original magnification 10× (scale bar represents 20 μm).

[0035] Figure 14 An exemplary graph showing the survival time (humane endpoint) of G37R (42 line) mice is presented. Data are expressed as mean ± SEM (n = 10). n = number of animals of the designated genotype. The difference in survival time (days) was analyzed using a two-tailed (unpaired t-test) to compare the relative difference between NS-1-2 (treatment group) and vehicle-treated G37R (42 line) mice, with a significance level set at P < 0.05. *P < 0.05, compared to control G37R.

[0036] Figure 15 An exemplary graph showing the percentage of survival of G37R (42 line) mice is presented. Data are expressed as mean ± SEM (n = 10); n = number of animals of the designated genotype; data were analyzed using the Kaplan-Meier Log-rank (Mantel-Cox) test for the survival percentage curves (humane endpoint) of HetG37R (42 line) ALS model mice to determine statistical significance (P < 0.05).

[0037] Figure 16 An exemplary graph showing the percentage of weight loss (humane endpoint) based on the highest recorded body weight of G37R (42 line) mice is presented. n = number of animals of the designated genotype. Data are expressed as mean ± SEM (n = 10). The percentage of weight loss at the humane endpoint was analyzed using a two-tailed (unpaired t-test) to compare the relative difference between NS-1-2 (treatment group) and vehicle-treated G37R (42 line) mice, with a significance level set at P < 0.05. ****P < 0.0001, compared with the control G37R.

[0038] Figure 17 Shows an example graph representing the age of onset (10% weight loss accompanied by muscle weakness). Data are presented as mean ± SEM (n = 10). n = number of animals of the specified genotype. The time to onset was analyzed using a two-tailed (unpaired t-test), showing the number of days until onset (defined as 10% weight loss accompanied by muscle weakness), with significance set at P < 0.05. **P < 0.01, compared with the control G37R.

[0039] Figure 18 Shows an example graph representing the age of onset (days to peak body weight). Data are presented as mean ± SEM (n = 10). n = number of animals of the specified genotype. The time to onset was analyzed using a two-tailed (unpaired t-test), showing the number of days until onset (retrospectively defined as the age at which the mice reached peak body weight), with significance set at P < 0.05. **P < 0.01, compared with the control G37R.

[0040] Figure 19 Shows an example graph representing the age of onset (days to peak body weight). Data are presented as mean ± SEM (n = 10). n = number of animals of the specified genotype. The data were analyzed using the Kaplan-Meier Log-rank (Mantel-Cox) test to determine the age of onset (age at peak body weight) of the Het G37R (line 42) ALS model mice to determine statistical significance (**P < 0.01). Detailed implementation

[0041] Definition

[0042] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Definitions of common terms in molecular biology can be found in the following references: Benjamin Lewin, Genes V, published by Oxford University Press, 1994 (ISBN 0-19-854287-9); Kendrew et al. (eds.), The Encyclopedia of Molecular Biology, published by Blackwell Science Ltd., 1994 (ISBN 0-632-02182-9); and Robert A. Meyers (ed.), Molecular Biology and Biotechnology: a Comprehensive Desk Reference, published by VCH Publishers, Inc., 1995 (ISBN 1-56081-569-8). Although any methods and materials similar or equivalent to those described herein can be used in the practice for testing the present invention, only typical materials and methods are described herein. The following terms will be used when describing and claiming the present invention.

[0043] It should also be understood that the terms used herein are for the purpose of describing particular aspects only and are not intended to be limiting. Any patent applications, patents, and publications are cited herein to assist in understanding the described aspects. All such references cited herein are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. In the event of a conflict between a publication, patent, or patent application incorporated by reference and the disclosure contained in this specification, then this specification is intended to supersede and / or take precedence over any such conflicting material.

[0044] In understanding the scope of the present application, the articles "a", "an", "the", and "said" are intended to mean that there is one or more than one element. In addition, the term "comprising" and its like used herein are intended to be open-ended terms, specifying the presence of the described features, elements, components, groups, wholes, and / or steps, but not excluding the presence of other features, elements, components, groups, wholes, and / or steps not mentioned. The foregoing also applies to words having similar meanings, such as the terms "including", "having", and their like.

[0045] It should be understood that any aspect described as "comprising" certain components may also be described as "consisting of" or "consisting essentially of", where "consisting of" has a closed or restrictive meaning, and "consisting essentially of" means including the specified components, but not including other components except for substances present as impurities, substances inevitable due to the processes used to provide the components, and components added for purposes other than achieving the technical effects of the present invention. For example, a composition defined using the phrase "consisting essentially of" encompasses any known acceptable additives, excipients, diluents, carriers, etc. Generally, a composition consisting essentially of a group of components will contain less than 5% by weight, usually less than 3% by weight, more usually less than 1% by weight, and even more usually less than 0.1% by weight of non-specified components.

[0046] It should be understood that any component defined as being included herein may be explicitly excluded from the claimed invention by way of provisos or negative limitations.

[0047] In addition, all ranges given herein include the endpoints of the range as well as any intermediate range points, whether or not explicitly stated.

[0048] Degree terms such as "substantially", "about", and "approximately" used herein mean a reasonable deviation from the modified term such that the final result does not change significantly. These degree terms should be understood to include a deviation of at least ±5% from the modified term, provided that such deviation does not negate the meaning of the term it modifies.

[0049] The abbreviation "e.g." is derived from the Latin exempli gratia and is used herein to denote non-limiting examples. Thus, the abbreviation "e.g." is synonymous with "for example".

[0050] The phrase "at least one" should be understood to mean one or more. The phrase "at least one of... and..." should be understood to mean at least one of the listed elements or a combination of these elements if not explicitly stated. For example, "at least one of A, B, and C" should be understood to mean A alone, or B alone, or C alone, or a combination of A and B, or a combination of A and C, or a combination of B and C, or a combination of A, B, and C.

[0051] The terms "formulation" and "composition" may be used interchangeably.

[0052] The terms "therapeutically effective amount", "effective amount", or "sufficient amount" can be understood as an amount sufficient to achieve the desired effect when administered to a subject (including a mammal (e.g., a human)), e.g., an amount effective to alleviate to some extent one or more symptoms of the disorder / disease being treated. The effective amount of the compounds described herein can vary depending on factors such as the age, sex, and weight of the subject. Those skilled in the art understand that the dosage or treatment regimen can be adjusted to provide an optimal therapeutic response. In addition, the treatment regimen for a therapeutically effective amount for a subject can consist of a single administration or can include a series of administrations. 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 reactivity of the patient to the compound, or a combination thereof. It should also be understood that the effective dose of the compound used for treatment may increase or decrease during the course of a particular treatment regimen. Changes in dosage may occur and become apparent through standard diagnostic assays known in the art.

[0053] Unless otherwise indicated, the terms "prevent", "preventing", and "prevention" as used herein can be understood to prevent the occurrence, recurrence, or spread of a disease, disorder, and / or condition or one or more of its symptoms. In certain embodiments, these terms refer to treating or administering the compounds described herein (with or without one or more other additional active agents) prior to the appearance of symptoms, particularly to a subject at risk of developing a disease, disorder, and / or condition described herein. These terms encompass the inhibition or alleviation of specific disease symptoms. In certain embodiments, a subject with a family history of a disease may be a candidate for a prevention regimen. In this regard, the term "prevention" can be used interchangeably with the term "preventive treatment".

[0054] With respect to the compounds described herein, "administer" (e.g., "administer" a compound) can be understood to introduce the compound into the system of an animal in need of treatment. When the compounds of the present disclosure are used in combination with one or more other therapeutic active agents, "administer" and its variants can each be understood to include the simultaneous or sequential introduction of the compound or its prodrug and the other drug. "Administering" in combination with one or more other therapeutic agents includes simultaneous (synchronous) and sequential administration in any order.

[0055] "Amelioration" can be understood as a reduction in the severity of at least one measure of a disorder or disease. In certain embodiments, amelioration includes delaying or slowing the progression of one or more measures of a disorder or disease. The severity of the measure can be determined by subjective or objective measures known to those skilled in the art.

[0056] "Analog" generally refers to a compound, e.g., in which one or more individual atoms are replaced by different atoms or different functional groups.

[0057] "Diseases, disorders, and / or conditions associated with oxidative stress" refers to diseases, disorders, and / or conditions whose pathology / pathophysiology is at least partially associated with, related to, or caused by oxidative stress (as defined below). In 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 system 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 diseases, disorders, and / or conditions associated with oxidative stress will be provided below.

[0058] "Inhibit" can be understood to mean partially, substantially, or completely slowing, impeding, reducing, delaying, or preventing. The terms "inhibit", "reduce", "prevent", "delay", and "slow" are used interchangeably.

[0059] "Integer" can be considered to be any integer, including zero.

[0060] "Oxidative stress" reflects an imbalance between the systemic manifestation of reactive oxygen species (ROS) / reactive nitrogen species (RNS) and antioxidants, which prompts the overproduction of free radicals. This process leads to the oxidation of biomolecules, thereby losing their biological functions and / or homeostatic imbalance, which is manifested as potential oxidative damage to cells and tissues. The accumulation of ROS / RNS can cause a variety of harmful effects, such as lipid peroxidation, protein oxidation, and DNA damage (including base damage and strand breaks). In addition, some reactive oxygen species act as cellular messengers in redox signaling. Therefore, oxidative stress disrupts the normal signal transduction mechanism of cells.

[0061] "Parenteral" administration includes, for example, subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.), intraperitoneal (i.p.), or intrasternal injection, infusion techniques, or absorption through mucous membranes.

[0062] "Pharmaceutically acceptable" can be understood to mean, for example, suitable for pharmaceutical use. In various embodiments, it refers to a compound that can generally be safely administered to mammals (such as humans) according to established government standards (including those promulgated by the US Food and Drug Administration).

[0063] "Pharmaceutically acceptable carrier" includes carriers suitable for pharmaceutical use but not limited to solvents, dispersion media, coatings, antibacterial agents, antifungal agents, isotonic agents, and / or absorption delaying agents, etc. The use of pharmaceutically acceptable carriers is well known in the art.

[0064] As used herein, a "prodrug" can be understood as a compound that is a precursor of a drug and that undergoes a chemical transformation through a metabolic or chemical process after administration to a subject to produce a compound having the structure of Formula I or a salt and / or solvate thereof. Discussions of prodrugs can be found in: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) Volume 14 of the A.C.S. Symposium Series, 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.

[0065] "Synergistic" or "synergistic therapeutic effect" means that the combined use of at least two agents produces a therapeutic effect greater than additive, which exceeds the effect that might be produced by administering the agents individually. For example, one or more lower doses of an agent (e.g., one or more therapeutic agents for treating ALS) can be used to treat ALS, thereby improving the therapeutic effect and reducing side effects.

[0066] A "subject" can be considered 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.

[0067] "Treatment" or "treating" can be understood as applying one or more specific procedures to cure or ameliorate a disease or disorder. In certain embodiments, the specific procedure refers to administering one or more agents.

[0068] The phrase "diseases, disorders, and / or conditions associated with oxidative stress" should be understood to refer to at least one of a disease associated with oxidative stress, a disorder associated with oxidative stress, and a condition associated with oxidative stress. Examples of diseases, disorders, and / or conditions associated with oxidative stress will be provided below.

[0069] The compounds described herein may have asymmetric centers, chiral axes, and chiral planes (see, e.g., E.L. Eliel and S.H.Wilen, Stereo-chemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190), and exist as racemates, racemic mixtures, scalemic mixtures, and individual diastereoisomers, and all possible isomers (e.g., geometric isomers) and their mixtures (including optical isomers) are included. In addition, the compounds described herein may exist as tautomers, and even if only one tautomeric structure may be depicted, it is intended that both tautomeric forms are included within the scope of the present invention. The compounds described herein may also include isotopic variants (e.g., compounds that differ only in their isotopic composition (number of isotopic substitutions), e.g., CH3, CH2D, CHD2) and isotopomers (e.g., isomers having the same number of each isotopic atom but different positions).

[0070] It should be understood that any aspect / embodiment described as a compound, pharmaceutically acceptable salt, hydrate, solvate, tautomer, racemic mixture, scalemic mixture, enantiomer, diastereomer, isotopomer, isotopic variant, prodrug, or a combination thereof refers to any one of the compound, its pharmaceutically acceptable salt, its hydrate, its solvate, its tautomer, racemic mixture, its scalemic mixture, its enantiomer, its diastereomer, its isotopomer, its isotopic variant, or its prodrug, and (or alternatively) various combinations thereof.

[0071] For specific compound terms, generally, when referring to a particular element (e.g., hydrogen or H), it is meant to include all isotopes of that element where applicable.

[0072] When the term "alkyl" is used alone or in combination with other terms (such as "haloalkyl" and "alkylamino"), it encompasses straight-chain or branched-chain carbon groups having, for example, from 1 to about 20 carbon atoms, or in certain embodiments from 1 to about 12 carbon atoms. In other embodiments, alkyl is "lower alkyl" having 1 to about 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, isopentyl, hexyl, and the like. In more specific embodiments, lower alkyl has 1 to 4 carbon atoms.

[0073] The term "alkenyl" encompasses straight-chain or branched-chain groups of carbon atoms having at least one carbon-carbon double bond. The term "alkenyl" can encompass conjugated and non-conjugated carbon-carbon double bonds or combinations thereof. Alkenyl, for example but not limited to, can contain from 2 to about 20 carbon atoms, or in certain embodiments, from 2 to about 12 carbon atoms. In various embodiments, alkenyl is a "lower alkenyl" having from 2 to about 4 carbon atoms. Examples of alkenyl include but are not limited to vinyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. The terms "alkenyl" and "lower alkenyl" encompass groups having "cis" and "trans" orientations, or "E" and "Z" orientations.

[0074] The term "alkoxy" encompasses straight-chain or branched-chain oxygen-containing groups, each having an alkyl moiety, for example but not limited to, from 1 to about 10 carbon atoms. In various embodiments, alkoxy is a "lower alkoxy" having from 1 to 6 carbon atoms. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, and tert-butoxy. In certain embodiments, the lower alkoxy has from 1 to 3 carbon atoms. "Alkoxy" can be further substituted by one or more halogen atoms (such as fluorine, chlorine, or bromine) to form "haloalkoxy". In other embodiments, the lower haloalkoxy has from 1 to 3 carbon atoms. Examples of such groups include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy, and fluoropropoxy.

[0075] The term "alkylamino" refers to an amino group substituted by one alkyl and two alkyls, including the terms "N-alkylamino" and "N,N-dialkylamino". In various embodiments, alkylamino refers to "lower alkylamino", which has an alkyl of 1 to 6 carbon atoms attached to one nitrogen atom or two. In other embodiments, the lower alkylamino has from 1 to 3 carbon atoms. Suitable "alkylamino" can be monoalkylamino or dialkylamino, such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, etc.

[0076] The term "alkylaminoalkyl" encompasses aminoalkyl in which the nitrogen atom is independently substituted by an alkyl. In some embodiments, alkylaminoalkyl is "lower alkylaminoalkyl" having an alkyl of 1 to 6 carbon atoms. In other embodiments, the lower alkylaminoalkyl has an alkyl of 1 to 3 carbon atoms. Suitable alkylaminoalkyl can be monoalkyl-substituted or dialkyl-substituted, such as N-methylaminomethyl, N,N-dimethylaminoethyl, N,N-diethylaminomethyl, etc.

[0077] The term "alkylaminoalkylamino" denotes an alkylamino substituted by one or two alkylamino. In various embodiments, there is C1-C3 alkylamino-C1-C3 alkylamino.

[0078] The term "alkylcarbonyl" means a carbonyl group substituted with an alkyl group. In certain embodiments, "lower alkylcarbonyl" refers to a lower alkyl as described above attached to a carbonyl group.

[0079] When the term "alkylene" is used alone or in combination with other terms (such as "haloalkylene"), it encompasses straight-chain or branched-chain groups of carbon atoms having, for example, from 1 to about 20 carbon atoms, or in certain embodiments, from 1 to about 12 carbon atoms. In other embodiments, alkylene is "lower alkylene" having 1 to about 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, isopentylene, hexylene, and the like. In more specific embodiments, lower alkylene has 1 to 4 carbon atoms.

[0080] The term "alkylthio" encompasses straight-chain or branched-chain alkyl groups having 1 to 10 carbon atoms attached to a divalent sulfur atom. In certain embodiments, lower alkylthio has 1 to 3 carbon atoms. An example of "alkylthio" is methylthio, (CH3S-).

[0081] The term "alkynyl" means a straight-chain or branched-chain group of carbon atoms having at least one carbon-carbon triple bond. The term "alkynyl" may contain conjugated and non-conjugated carbon-carbon triple bonds or combinations thereof. Alkynyl, for example but not limited to, may contain from 2 to about 20 carbon atoms, or in certain embodiments, from 2 to about 12 carbon atoms. In various embodiments, alkynyl is "lower alkynyl" having 2 to about 10 carbon atoms. Some examples are lower alkynyl having 2 to about 4 carbon atoms. Examples of such groups include propargyl, butynyl, and the like.

[0082] The term "aminoalkyl" encompasses straight-chain or branched-chain alkyl groups having 1 to about 10 carbon atoms, any of which may be substituted with one or more amino groups. In various embodiments, aminoalkyl is "lower aminoalkyl" having 1 to 6 carbon atoms and one or more amino groups. Examples of such groups include aminomethyl, aminoethyl, aminopropyl, aminobutyl, and aminohexyl.

[0083] The term "aralkyloxy" encompasses an aralkyl group containing oxygen attached to another group through an oxygen atom. In certain embodiments, aralkyloxy refers to "lower aralkyloxy" as described above having an optionally substituted phenyl group attached to a lower alkoxy group.

[0084] The term "aralkyl" encompasses an aryl-substituted alkyl. In various embodiments, the aralkyl is a "lower aralkyl" formed by linking an aryl to an alkyl having 1 to 6 carbon atoms. In other embodiments, the lower aralkyl phenyl is linked to an alkyl moiety having 1 to 3 carbon atoms. Examples of such groups include benzyl, diphenylmethyl, and phenethyl. The aryl in the aralkyl may also be substituted with halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy.

[0085] The term "aralkylamino" refers to an amino group substituted with one or two aralkyl groups. In other embodiments, there is phenyl-C1-C3 alkylamino, such as N-benzylamino. The "aralkylamino" may be further substituted on the aromatic ring portion of the group.

[0086] The term "aromatic group" or "aryl" refers to an aromatic group having one or more rings, where these rings may be linked together in a pendent manner or may be fused. In specific embodiments, the aromatic group has one, two, or three rings. The ring of a monocyclic aromatic group may contain 4 to 10 carbon atoms, typically 4 to 7 carbon atoms, and more typically 4 to 6 carbon atoms. A typical polycyclic aromatic group has two or three rings. The rings of a polycyclic aromatic group having two rings usually have 8 to 12 carbon atoms, preferably 8 to 10 carbon atoms. Examples of aromatic groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl, or acenaphthylenyl.

[0087] The term "arylamino" refers to an amino group substituted with one or two aryl groups, such as N-phenylamino. The "arylamino" may be further substituted on the aromatic ring portion of the group.

[0088] The term "arylalkenyl" encompasses an aryl-substituted alkenyl. In various embodiments, the arylalkenyl refers to a "lower arylalkenyl" formed by linking an aryl to an alkenyl having 2 to 6 carbon atoms. Examples of such groups include phenylvinyl. The aryl in the arylalkenyl may also be substituted with halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy.

[0089] The term "arylalkynyl" encompasses an aryl-substituted alkynyl. In various embodiments, the arylalkynyl refers to a "lower arylalkynyl" formed by linking an aryl to an alkynyl having 2 to 6 carbon atoms. Examples of such groups include phenylethynyl. The aryl in the arylalkynyl may also be substituted with halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy. The terms "benzyl" and "phenylmethyl" may be used interchangeably.

[0090] The term "aryloxy" encompasses an optionally substituted aryl as defined above linked to an oxygen atom. Examples of such groups include phenoxy.

[0091] The term "arylthio" encompasses an aryl group having 6 to 10 carbon atoms attached to a divalent sulfur atom. An example of "arylthio" is phenylthio. The term "aralkylthio" encompasses an aralkyl group as described above attached to a divalent sulfur atom. In certain embodiments, there is phenyl-C1-C3-alkylthio. An example of "aralkylthio" is benzylthio.

[0092] The term "carbocyclic group" refers to a saturated or unsaturated carbocyclic hydrocarbon ring. The carbocyclic group is not aromatic. The carbocyclic group can be monocyclic or polycyclic. The polycyclic carbocyclic group can be a fused-ring, spiro-ring or bridged-ring system. The ring of the monocyclic carbocyclic group can contain 4 to 10 carbon atoms, usually 4 to 7 carbon atoms, more usually 5 to 6 carbon atoms. The ring of the bicyclic carbocyclic group can contain 8 to 12 carbon atoms, usually 9 to 10 carbon atoms.

[0093] The term "carbonyl", whether used alone or in combination with other terms, such as "aminocarbonyl", means -(C=O)-.

[0094] The term "carboxy" or "carboxyl group", whether used alone or in combination with other terms, such as "carboxyalkyl", means -(C=O)-O-.

[0095] The term "cycloalkyl" includes saturated carbocyclic groups. In certain embodiments, the cycloalkyl contains a C3-C6 ring. In multiple embodiments, there are compounds containing cyclopentyl, cyclopropyl and cyclohexyl.

[0096] The term "cycloalkenyl" includes a carbocyclic group having one or more carbon-carbon double bonds; the carbon-carbon double bonds are conjugated or non-conjugated or a combination thereof. The term "cycloalkenyl" includes "cycloalkenyl" and "cycloalkyldienyl" compounds. In certain embodiments, the cycloalkenyl contains a C3-C6 ring. Examples include cyclopentenyl, cyclopentadienyl, cyclohexenyl and cycloheptadienyl. "Cycloalkenyl" can be substituted with 1 to 3 substituents, such as lower alkyl, hydroxy, halogen, haloalkyl, nitro, cyano, alkoxy, lower alkylamino, etc.

[0097] The term "fused" means that two adjacent rings share two or more carbon atoms / member atoms, for example, the ring is a "fused ring".

[0098] The term "halogen" refers to a halogen such as a fluorine, chlorine, bromine or iodine atom.

[0099] The term "haloalkyl" encompasses groups in which any one or more of the alkyl carbon atoms are substituted by a halogen as defined above. Specifically encompassed are monohaloalkyl, dihaloalkyl, and polyhaloalkyl groups, including perhaloalkyl groups. For example, a monohaloalkyl group can have an iodine, bromine, chlorine, or fluorine atom within the group. Dihaloalkyl and polyhaloalkyl groups can have two or more of the same halogen atoms, or a combination of different halogen groups. "Lower haloalkyl" encompasses groups having 1-6 carbon atoms. In some embodiments, the lower haloalkyl has 1-3 carbon atoms. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl.

[0100] The term "heteroaromatic group" or "heteroaryl" refers to an aromatic group having one or more rings, which can be linked together in a pendant fashion or fused together, wherein the aromatic group contains at least one heteroatom. The ring of a monocyclic heteroaromatic group can contain 4 to 10 member atoms, typically 4 to 7 member atoms, and more typically 4 to 6 member atoms. A typical polycyclic heteroaromatic group has two or three rings. The rings of a polycyclic aromatic group having two rings typically contain 8 to 12 member atoms, and more typically 8 to 10 member atoms. Examples of heteroaromatic 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, benzothiazole, quinoline, isoquinoline, quinazoline, quinoxaline, etc.

[0101] The term "heteroarylamino" refers to an amino group substituted by one or two heteroaryl groups, such as N-thienylamino. "Heteroarylamino" can be further substituted on the heteroaromatic ring portion of the group.

[0102] The term "heteroatom" refers to an atom other than carbon. Generally, the heteroatom is selected from the group consisting of sulfur, phosphorus, nitrogen, and oxygen atoms. A group containing more than one heteroatom can contain different heteroatoms.

[0103] The term "heterocyclic group" is a saturated or unsaturated ring structure containing carbon atoms and one or more heteroatoms in the ring. The heterocyclic group is not aromatic. The heterocyclic group can be monocyclic or polycyclic. A polycyclic heterocyclic group can be a fused ring, spiro ring, or bridged ring system. The ring of a monocyclic heterocyclic group can contain 4 to 10 member atoms (i.e., including carbon atoms and at least one heteroatom), typically 4 to 7, and more typically 5 to 6. The rings of a bicyclic heterocyclic group can contain 8 to 18 member atoms, typically 9 or 10. Representative heterocyclic groups include, for example, pyrrolidine, imidazolidine, pyrazolidine, piperidine, 1,4-dioxane, morpholine, thiomorpholine, piperazine, 3-pyrroline, etc.

[0104] The term "heterogeneous group" refers to a saturated or unsaturated chain containing carbon atoms and at least one heteroatom (such as an ether group, an ether moiety, etc.). The heterogeneous group typically has from 1 to 25 member atoms. More typically, the chain contains from 1 to 12 member atoms, from 1 to 10 member atoms, and most typically from 1 to 6 member atoms. The chain can be straight-chain or branched-chain. A typical branched-chain heterogeneous group has one or two branches, more typically one branch. Usually, the heterogeneous group is saturated. An unsaturated heterogeneous group can have one or more double bonds, one or more triple bonds, or both. A typical unsaturated heterogeneous group has one or two double bonds or one triple bond. More typically, the unsaturated heterogeneous group has one double bond.

[0105] The term "hydrocarbyl" or "hydrocarbyl group" refers to a chain containing from 1 to 25 carbon atoms, typically from 1 to 12 carbon atoms, more typically from 1 to 10 carbon atoms, and most typically from 1 to 8 carbon atoms. The hydrocarbyl can have a straight-chain or branched-chain structure. A typical hydrocarbyl contains one or two branches, usually one branch. Usually, the hydrocarbyl is saturated. An unsaturated hydrocarbyl can contain one or more double bonds, one or more triple bonds, or a combination thereof. A typical unsaturated hydrocarbyl contains one or two double bonds or one triple bond; more typically, the unsaturated hydrocarbyl contains one double bond.

[0106] The term "hydroxyalkyl" encompasses straight-chain or branched-chain alkyls, for example but not limited to from 1 to about 10 carbon atoms, where any one of the carbon atoms can be substituted with one or more hydroxyl groups. In various embodiments, hydroxyalkyl refers to "lower hydroxyalkyl" having from 1 to 6 carbon atoms and one or more hydroxyl groups. Examples of such groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, and hydroxyhexyl.

[0107] The terms "suitable substituent", "substituent" or "substituted" when used with the 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 should be understood that the substituents and substitution patterns on the compounds of the present invention can be selected by those of ordinary skill in the art to provide compounds that are chemically stable and readily synthesized by techniques known in the art and the methods described hereinafter. If a substituent itself is substituted by more than one group, it should be understood that these multiple groups can be located on the same carbon / member atom or on different carbon / member atoms, as long as a stable structure can be formed. Illustrative examples of some suitable substituents include halogen, haloalkyl, perfluoroalkyl, perfluoroalkoxy, alkyl, alkenyl, alkynyl, hydroxy, oxo, mercapto, alkylthio, alkoxy, cycloalkyl, heterocyclic group, hydroxyalkyl, benzyl, carbonyl, aryl or heteroaryl, aryloxy or heteroaryloxy, aralkyl or heteroaralkyl, aralkoxy or heteroaralkoxy, HO-(C=O)-, amido, amino, alkylamino and dialkylamino, cyano, nitro, carbamoyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylcarbonyl, aryloxycarbonyl, alkylsulfonyl and arylsulfonyl. Typical substituents include halogen groups, hydroxy, cyano, amino, hydrocarbon groups (including alkyl such as methyl), substituted hydrocarbon groups (such as benzyl), and heteroatom-containing groups (including alkoxy such as methoxy), aromatic groups or substituted aromatic groups.

[0108] When the term "unsaturated" is used in connection with any group, the group can be fully unsaturated or partially unsaturated. However, when the word "unsaturated" is used in connection with a specific group as defined herein, the term retains the limitations of that specific group. For example, based on the definition of "carbocyclic group" herein, an unsaturated "carbocyclic group" does not include aromatic groups.

[0109] Pharmaceutically acceptable salts of the compounds described herein include conventional non-toxic salts formed by the compounds with, for example, non-toxic inorganic acids or organic acids. For example, such conventional non-toxic salts include non-toxic salts formed by inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc.); and salts prepared by 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, p-aminobenzoic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, etc.).

[0110] The pharmaceutically acceptable salts of the compounds described herein can be synthesized from the compounds containing basic or acidic moieties described herein by conventional chemical methods. Generally, the salts of basic compounds can be prepared by ion exchange chromatography or by reacting the free base with a stoichiometric or excess amount of the desired inorganic or organic acid for salt formation in a suitable solvent or various solvent combinations. Similarly, the salts of acidic compounds can be prepared by reacting with suitable inorganic or organic bases.

[0111] The compounds described herein can include pharmaceutically acceptable salts, hydrates, solvates, metabolites, and prodrugs of the compounds described herein, as well as any suitable combinations thereof.

[0112] The compounds described herein are 1H-pyrazole analogs, and provide compositions containing at least one analog, methods of administering the same, and uses thereof.

[0113] 1H-pyrazole analogs of formula I

[0114] In one embodiment, the 1H-pyrazole analog is represented by a compound having the structure of formula I:

[0115]

[0116] its pharmaceutically acceptable salts, its hydrates, its solvates, its tautomers, its geometric isomers, its enantiomers, its diastereomers, its N-oxides, its metabolites, its isotopomers, its isotopic variants, its prodrugs, or combinations thereof,

[0117] wherein:

[0118] X1 is selected from -BR 8 R 9 or -BR 10 R 11 R 12 ;

[0119] R 1 to R 7 、R 10 、R 11 and R 12 are each independently selected from H, halogen groups, hydroxy, cyano, nitro, mercapto, sulfonyl, sulfate, substituted or unsubstituted amino, substituted or unsubstituted hydrocarbon groups, substituted or unsubstituted heteroatom-containing groups, -BR 13 R 14 、-BR 15 R 16 R 17 、substituted or unsubstituted carbocyclic groups, substituted or unsubstituted heterocyclic groups, substituted or unsubstituted aromatic groups, or substituted or unsubstituted heteroaromatic groups, where R 13 to R17 Each independently selected from H, a halogen group, a hydroxyl group, a cyano group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heteroatom-containing 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 together form a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group; and

[0120] R 8 and R 9 Each independently selected from H, a halogen group, a hydroxyl group, a cyano group, a nitro group, a mercapto group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heteroatom-containing 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.

[0121] More embodiments of the compound having the structure of formula I are outlined in i) to iii) below, and these embodiments can be in any suitable permutation and combination. For one or more embodiments, it should be understood that one or more atoms can be isotopes. In certain embodiments, it should be understood that one or more H can be replaced by D (deuterium).

[0122] i) Embodiments of X1

[0123] a) X1 is selected from -BR 8 R 9

[0124] R 8 and R 9 Embodiments where no ring is formed together:

[0125] In a plurality of embodiments, R 8 and R 9 Each independently selected from H, a halogen group, a hydroxyl group, a cyano group, a nitro group, a mercapto group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heteroatom-containing 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 other embodiments, R 8 and R 9Each independently selected from H, a halogen 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.

[0127] In other embodiments, R 8 and R 9 Each independently selected from H, a halogen 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.

[0128] In another embodiment, R 8 and R 9 Each independently selected from H, a halogen 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 alkyl heteroalkyl 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 -O-C(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.

[0129] In another embodiment, R 8 and R 9Each independently selected from H, a halogen 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 C1-C6 alkyl -C(O)O- group, a substituted or unsubstituted C1-C6 alkyl -O-C(O)- group, a substituted or unsubstituted C1-C6 alkyl -O-C(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.

[0130] In another embodiment, R 8 and R 9 Each independently selected from H, a halogen 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 -C(O)O- group, a substituted or unsubstituted C1-C6 alkyl -O-C(O)- group, a substituted or unsubstituted C1-C6 alkyl -O-C(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 alkyl heteroaryl group, a substituted or unsubstituted pyridyl group or a substituted or unsubstituted pyrrolyl group.

[0131] In another embodiment, R 8 and R 9Each independently selected from H, a halogen group, a hydroxyl group, a substituted or unsubstituted haloalkyl group, a substituted or unsubstituted hydroxyalkyl group, a substituted or unsubstituted cyanoalkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted alkylcycloalkyl group, a substituted or unsubstituted alkylcycloalkenyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted alkylheterocycloalkyl group, a substituted or unsubstituted heterocycloalkenyl group, a substituted or unsubstituted alkylheterocycloalkenyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkylaryl group, a substituted or unsubstituted alkylheteroaryl group, alkylene-O-alkyl, alkylene-O-cycloalkyl, alkylene-O-heterocycloalkyl, alkylene-O-alkylene-cycloalkyl or alkylene-O-alkylene-heterocycloalkyl.

[0132] In another embodiment, R 8 and R 9 are each independently selected from a halogen group, a hydroxyl group or an alkoxy group. In a specific embodiment, R 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. In other embodiments, R 8 and R 9 are each independently selected from a fluoro group, a hydroxyl group or an alkoxy group.

[0133] In another embodiment, R 8 and R 9 are each independently selected from a halogen group or a hydroxyl group. In a specific embodiment, R 8 and R 9 are each independently selected from a fluoro group, a chloro group, a bromo group or a hydroxyl group. In other embodiments, R 8 and R 9 are each independently selected from a fluoro group or a hydroxyl group.

[0134] R 8 and R 9 Embodiments in which a ring is formed together:

[0135] In a plurality of embodiments, R 8 and R 9 together form a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group.

[0136] In a plurality of embodiments, R 8 and R 9 together form a substituted or unsubstituted heterocyclic group. In a plurality of embodiments, R 8 and R 9 together form a substituted or unsubstituted -O(C2-C8 alkylene)O- ring. In an embodiment, R 8 and R9 together form a substituted or unsubstituted -O(C2-C4 alkylene)O- ring. In other embodiments, R 8 and R 9 together form a substituted or unsubstituted -O(C 2- alkylene)O- ring. In other embodiments, R 8 and R 9 together form a substituted or unsubstituted -O(C 3- alkylene)O- ring. In other embodiments, R 8 and R 9 together form a substituted or unsubstituted -O(C 4- alkylene)O- ring. In embodiments, R 8 and R 9 together form -OCR1R2CR3R4O-, where R1, R2, R3, and R4 are each independently selected from any of the groups listed herein as R 1 through R 7 , R 10 , R 11 , and R 12 . In embodiments, R 8 and R 9 together form -OCH2CH2O-, –OC(CH3)2CH2O-, or –OC(CH3)2C(CH3)2O-.

[0137] In various embodiments, R 8 and R 9 together form a substituted or unsubstituted -O(C1-C2 alkylene)NH(C1-C2 alkylene)O- ring. In various embodiments, R 8 and R 9 together form a substituted or unsubstituted -O(C1-C2 alkylene)N(alkyl)(C1-C2 alkylene)O- ring. In other embodiments, R 8 and R 9 together form a substituted or unsubstituted -O(C2 alkylene)NH(C2 alkylene)O- ring. In various embodiments, R 8 and R 9 together form a substituted or unsubstituted -O(C2 alkylene)N(alkyl)(C2 alkylene)O- ring. In other embodiments, R 8 and R 9Together 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-.

[0138] b) X1 is selected from -BR 10 R 11 R 12

[0139] In multiple embodiments, R 10 、R 11 and R 12 are each independently selected from H, a halogen group, a hydroxyl group, a cyano group, a nitro group, a mercapto group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heteroatom-containing 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.

[0140] In other embodiments, R 10 、R 11 and R 12 are each independently selected from H, a halogen 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.

[0141] In other embodiments, R 10 、R 11 and R 12 are each independently selected from H, a halogen 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.

[0142] In another embodiment, R 10 、R 11 and R 12Each independently selected from H, a halogen 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 alkyl heteroalkyl 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 - O - C(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.

[0143] In another embodiment, R 10 , R 11 and R 12 Each independently selected from H, a halogen 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 C1 - C6 alkyl - C(O)O - group, a substituted or unsubstituted C1 - C6 alkyl - O - C(O) - group, a substituted or unsubstituted C1 - C6 alkyl - O - C(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.

[0144] In another embodiment, R 10 , R 11 and R 12 Each independently selected from H, a halogen 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 - C(O)O - group, a substituted or unsubstituted C1 - C6 alkyl - O - C(O) - group, a substituted or unsubstituted C1 - C6 alkyl - O - C(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 alkyl heteroaryl group, a substituted or unsubstituted pyridyl group or a substituted or unsubstituted pyrrolyl group.

[0145] In another embodiment, R 10 , R 11 and R 12 are each independently selected from H, a halogen group, a hydroxyl group, a substituted or unsubstituted haloalkyl group, a substituted or unsubstituted hydroxyalkyl group, a substituted or unsubstituted cyanoalkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted alkylcycloalkyl group, a substituted or unsubstituted alkylcycloalkenyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted alkylheterocycloalkyl group, a substituted or unsubstituted heterocycloalkenyl group, a substituted or unsubstituted alkylheterocycloalkenyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkylaryl group, a substituted or unsubstituted alkylheteroaryl group, an alkylene-O-alkyl group, an alkylene-O-cycloalkyl group, an alkylene-O-heterocycloalkyl group, an alkylene-O-alkylene-cycloalkyl group or an alkylene-O-alkylene-heterocycloalkyl group.

[0146] In another embodiment, R 10 , R 11 and R 12 are each independently selected from a halogen group, a hydroxyl group or an alkoxy group. In a specific embodiment, R 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. In other embodiments, R 10 , R 11 and R 12 are each independently selected from a fluoro group, a hydroxyl group or an alkoxy group.

[0147] In another embodiment, R 10 , R 11 and R 12 are each independently selected from a halogen group or a hydroxyl group. In a specific embodiment, R 10 , R 11 and R 12 are each independently selected from a fluoro group, a chloro group, a bromo group or a hydroxyl group. In other embodiments, R 10 , R 11 and R 12 are each independently selected from a fluoro group or a hydroxyl group.

[0148] ii) Embodiments of R 1 and R 2

[0149] In a plurality of embodiments, R 1 and R 2Each independently selected from H, a halogen group, a hydroxyl group, a cyano group, a nitro group, a mercapto group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heteroatom-containing 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.

[0150] In a further embodiment, R 1 and R 2 Each independently selected from H, a halogen 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.

[0151] In yet another embodiment, R 1 and R 2 Each independently selected from H, a halogen 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.

[0152] In another embodiment, R 1 and R 2 Each independently selected from H, a halogen 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.

[0153] In another embodiment, R 1 and R 2 Each independently selected from H, a halogen 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 pyridyl group, or a substituted or unsubstituted pyrrolyl group.

[0154] In another embodiment, R 1 and R 2Each independently selected from H, a halogen group, a substituted or unsubstituted haloalkyl, a substituted or unsubstituted hydroxyalkyl, a substituted or unsubstituted cyanoalkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted alkylcycloalkyl, a substituted or unsubstituted alkylcycloalkenyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted alkylheterocycloalkyl, a substituted or unsubstituted heterocycloalkenyl, a substituted or unsubstituted alkylheterocycloalkenyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted alkylaryl, a substituted or unsubstituted alkylheteroaryl, an alkylene-O-alkyl, an alkylene-O-cycloalkyl, an alkylene-O-heterocycloalkyl, an alkylene-O-alkylene-cycloalkyl or an alkylene-O-alkylene-heterocycloalkyl.

[0155] In another embodiment, R 1 is H or a substituted or unsubstituted alkyl, and R 2 is selected from H, a halogen group, a hydroxy group, a cyano group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heteroatom-containing 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.

[0156] In a further embodiment, R 1 is H or a substituted or unsubstituted alkyl, and R 2 is selected from H, a halogen group, a hydroxy group, a cyano group, a substituted or unsubstituted amino group, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, 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.

[0157] In yet another embodiment, R 1 is H or a substituted or unsubstituted alkyl, and R 2 is selected from H, a halogen group, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group or a substituted or unsubstituted heteroaromatic group.

[0158] In another embodiment, R 1 is H or a substituted or unsubstituted C1-C6 alkyl, R 2Selected from H, a halogen 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.

[0159] In another embodiment, R 1 is H or a substituted or unsubstituted C1-C6 alkyl group, and R 2 is selected from H, a halogen 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 pyridyl group, or a substituted or unsubstituted pyrrolyl group.

[0160] In another embodiment, R 1 is H, -CH3, -CH2CH3 or –CH2CH2CH3, and R 2 is selected from H, F, Cl, CN, -CH3, -CH2F, -CHF2 or -CF3.

[0161] iii) Embodiments of R 3 to R 7

[0162] In an embodiment, R 3 to R 7 are each independently selected from H, a halogen group, a hydroxyl group, a cyano group, a nitro group, a mercapto group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heteroatom-containing 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, wherein R 13 to R 17 are each independently selected from H, a halogen group, a hydroxyl group, a cyano group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heteroatom-containing 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 together form a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group.

[0163] In multiple embodiments, R 3 to R 7 are each independently selected from H, a halogen 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 heteroatom-containing 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, wherein R 13 to R 17 are each independently selected from H, a halogen group, a hydroxyl group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heteroatom-containing 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 together form a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group.

[0164] In multiple embodiments, R 3 to R 7 are each independently selected from H, a halogen group, a cyano group, a nitro group, a sulfate group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heteroatom-containing 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.

[0165] In multiple embodiments, R 3 to R 7 are each independently selected from H, a halogen 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 alkyl borate 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.

[0166] In yet another embodiment, R 3 to R 7Each independently selected from H, a halogen 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 boric acid group, a substituted or unsubstituted alkyl borate 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.

[0167] In another embodiment, R 3 to R 7 Each independently selected from H, a halogen group, a cyano group, a nitro group, a sulfate group, a substituted or unsubstituted alkyl group, a haloalkyl group, a substituted or unsubstituted alkyl heteroalkyl 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 -O-C(O)- group, -C(O)OH, a boric acid group, a substituted or unsubstituted alkyl borate 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.

[0168] In another embodiment, R 3 to R 7 Each independently selected from H, a halogen 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 -C(O)O- group, a substituted or unsubstituted C1-C6 alkyl -O-C(O)- group, a substituted or unsubstituted C1-C6 alkyl -O-C(O)-C1-C6 alkylene group, -C(O)OH, a boric acid group, a substituted or unsubstituted C1-C6 alkyl borate 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.

[0169] In another embodiment, R 3 to R 7Each independently selected from H, a halogen 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 alkyl - O - C(O) - group, a substituted or unsubstituted C1-C6 alkyl - O - C(O) - C1-C6 alkylene group, -C(O)OH, a boric acid group, a substituted or unsubstituted C1-C6 alkyl borate 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 alkyl heteroaryl group, a substituted or unsubstituted pyridyl group or a substituted or unsubstituted pyrrolyl group.

[0170] In another embodiment, R 3 to R 7 Each independently selected from H, a halogen group, a substituted or unsubstituted haloalkyl group, a substituted or unsubstituted hydroxyalkyl group, a substituted or unsubstituted cyanoalkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted alkyl cycloalkyl group, a substituted or unsubstituted alkyl cycloalkenyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted alkyl heterocycloalkyl group, a substituted or unsubstituted heterocycloalkenyl group, a substituted or unsubstituted alkyl heterocycloalkenyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkyl aryl group, a substituted or unsubstituted alkyl heteroaryl group, alkylene - O - alkyl, alkylene - O - cycloalkyl, alkylene - O - heterocycloalkyl, alkylene - O - alkylene - cycloalkyl or alkylene - O - alkylene - heterocycloalkyl.

[0171] In another embodiment, R 3 , R 4 , R 6 and R 7 Each independently selected from H or a substituted or unsubstituted alkyl group, and R 5 is selected from H, a halogen group, a hydroxy group, a cyano group, a nitro group, a mercapto group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heteroatom-containing group, -BR 13 R 14 , -BR 15 R 16 R 17 is selected from 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, where R13 to R 17 each independently selected from H, a halogen group, a hydroxyl group, a cyano group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heteroatom-containing 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 together form a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group.

[0172] In another embodiment, R 3 , R 4 , R 6 and R 7 each independently selected from H or a substituted or unsubstituted alkyl group, and R 5 is selected from H, a halogen group, a cyano group, a nitro group, a sulfate group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heteroatom-containing 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.

[0173] In yet another embodiment, R 3 , R 4 , R 6 and R 7 each independently selected from H or a substituted or unsubstituted alkyl group, and R 5 is selected from H, a halogen 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 boric acid group, a substituted or unsubstituted alkyl borate 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.

[0174] In yet another embodiment, R 3 , R 4 , R 6 and R 7 each independently selected from H or a substituted or unsubstituted alkyl group, and R 5 is selected from H, a halogen 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 boric acid group, a substituted or unsubstituted alkyl borate 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.

[0175] 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, and R 5 is selected from H, a halogen group, a cyano group, a nitro group, a sulfate group, a substituted or unsubstituted alkyl group, a haloalkyl group, a substituted or unsubstituted alkyl heteroalkyl 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 -O-C(O)- group, -C(O)OH, a boric acid group, a substituted or unsubstituted alkyl borate 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.

[0176] 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, and R 5 is selected from H, a halogen 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 -C(O)O- group, a substituted or unsubstituted C1-C6 alkyl -O-C(O)- group, a substituted or unsubstituted C1-C6 alkyl -O-C(O)-C1-C6 alkylene group, -C(O)OH, a boric acid group, a substituted or unsubstituted C1-C6 alkyl borate 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.

[0177] 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, and R 5Selected from H, a halogen 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 alkyl-O-C(O)- group, a substituted or unsubstituted C1-C6 alkyl-O-C(O)-C1-C6 alkylene group, -C(O)OH, a boric acid group, a substituted or unsubstituted C1-C6 alkyl borate 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 alkyl heteroaryl group, a substituted or unsubstituted pyridyl group or a substituted or unsubstituted pyrrolyl group.

[0178] 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, and R 5 is selected from H, a halogen group, a substituted or unsubstituted haloalkyl group, a substituted or unsubstituted hydroxyalkyl group, a substituted or unsubstituted cyanoalkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted alkyl cycloalkyl group, a substituted or unsubstituted alkyl cycloalkenyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted alkyl heterocycloalkyl group, a substituted or unsubstituted heterocycloalkenyl group, a substituted or unsubstituted alkyl heterocycloalkenyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkyl aryl group, a substituted or unsubstituted alkyl heteroaryl group, alkylene-O-alkyl, alkylene-O-cycloalkyl, alkylene-O-heterocycloalkyl, alkylene-O-alkylene-cycloalkyl or alkylene-O-alkylene-heterocycloalkyl.

[0179] In another embodiment, R 3 、R 4 、R 6 and R 7 are each independently selected from H, -CH3, -CH2CH3 or -CH2CH2CH3, and R 5 is selected from H, F, Cl, CN, -CH3, -CH2F, -CHF2 or -CF3.

[0180] In various embodiments, the compound of formula I may be selected from:

[0181]

[0182] Its pharmaceutically acceptable salts, its hydrates, its solvates, its tautomers, its geometric isomers, its enantiomers, its diastereoisomers, its N-oxides, its metabolites, its isotopomers, its isotopic variants, its prodrugs or combinations thereof. X1 and R 2 to R 5 Each independently selected from any one of the groups listed in i) to iii) above.

[0183] In various embodiments, the compound of formula I may be selected from:

[0184]

[0185] Its pharmaceutically acceptable salts, its hydrates, its solvates, its tautomers, its geometric isomers, its enantiomers, its diastereoisomers, its N-oxides, its metabolites, its isotopomers, its isotopic variants, its prodrugs or combinations thereof. R1 to R4 and R 2 to R 5 Each independently selected from any one of the groups listed in i) to iii) above.

[0186] In various embodiments, the compound of formula I may be selected from:

[0187]

[0188] Its pharmaceutically acceptable salts, its hydrates, its solvates, its tautomers, its geometric isomers, its enantiomers, its diastereoisomers, its N-oxides, its metabolites, its isotopomers, its isotopic variants, its prodrugs or combinations thereof. X + is any suitable counterion (such as Na, K, etc.), and R 3 to R 5 Each independently selected from any one of the groups listed in i) to iii) above. In other embodiments, R 3 to R 5 Each independently selected from H, F, Cl, CN, -CH3, -CH2F, -CHF2 or -CF3.

[0189] In various embodiments, the compound of formula I may be selected from:

[0190]

[0191] Its pharmaceutically acceptable salts, its hydrates, its solvates, its tautomers, its geometric isomers, its enantiomers, its diastereoisomers, its N-oxides, its metabolites, its isotopomers, its isotopic variants, its prodrugs or combinations thereof. X +is any suitable counterion (e.g., Na, K, etc.), and R 3 to R 5 each independently selected from any one of the groups listed in i) to iii) above. In other embodiments, R 3 to R 5 each independently selected from H, F, Cl, CN, -CH3, -CH2F, -CHF2 or -CF3.

[0192] In various embodiments, it should be understood that the compounds described herein can be a single compound itself or a combination of its compounds, including compounds having the structure of Formula I, their pharmaceutically acceptable salts, their hydrates, their solvates, their tautomers, their enantiomers, their diastereomers, their isotopomers, their isotopic variants, their prodrugs. For example, it can be its pharmaceutically acceptable salt alone, or various combinations with other compounds described herein. In multiple embodiments, the compound can be a racemic mixture or a non-racemic mixture.

[0193] The compounds of Formula I, including their pharmaceutically acceptable salts, their hydrates, their solvates, their tautomers, their enantiomers, their diastereomers, their isotopomers, their isotopic variants, their prodrugs or their combinations, can be prepared by using reactions and standard operations known in the literature or exemplified herein [46-48]. An example of the synthetic steps for preparing the compounds of Formula I is shown below:

[0194]

[0195] Another specific example is as follows:

[0196]

[0197] Methods and uses of 1H-pyrazole analogs and their compositions

[0198] In multiple embodiments, the 1H-pyrazole analogs described herein can act as metal chelators. In this way, the 1H-pyrazole analogs may be able to reduce heavy metal-induced genotoxicity. In multiple embodiments, the heavy metals can be selected from arsenic trioxide, bismuth subcitrate colloid, cadmium chloride, mercury chloride and / or lead chloride. Since low-dose 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. In this regard, without being bound by theory, the 1H-pyrazole analogs described herein can form reversible complexes with metal enzymes due to their Lewis acid properties and empty p orbitals, and thus can form stable complexes with metals such as copper and zinc in the scaffold of protein SOD1 (associated with neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS)), making it more stable.

[0199] In other embodiments, the 1H-pyrazole analogs described herein can act as antioxidants. In this way, the 1H-pyrazole analogs described herein are capable of reducing oxidative stress. This can serve to, for example, alleviate symptoms associated with diseases, disorders, and / or conditions associated with oxidative stress (described below).

[0200] Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species (hereinafter referred to as ROS) / reactive nitrogen species (hereinafter referred to as RNS) and antioxidants, which imbalance promotes the overproduction of free radicals. This process leads to the oxidation of biomolecules, which in turn results in the loss of their biological functions and / or homeostatic imbalance, manifested as potential oxidative damage to cells and tissues. The accumulation of ROS / RNS can lead to a variety of harmful effects, such as lipid peroxidation, protein oxidation, and DNA damage (including base damage and strand breaks). In addition, some reactive oxygen species act as cellular messengers in redox signaling. Thus, oxidative stress disrupts the normal signal transduction mechanisms of cells.

[0201] "ROS" and "RNS" are terms that collectively refer to free radicals and other non-radical reactive derivatives (also referred to as oxidants). Free radicals are less stable than non-radical species, but they are generally more reactive. Molecules with one or more unpaired electrons in their outer shell are called free radicals. Free radicals are formed from molecules in the following ways: bond cleavage such that each fragment retains an electron, free radical cleavage to produce another free radical, and redox reactions.

[0202] Oxidative stress can be reduced by the 1H-pyrazole analogs described herein through a variety of 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 may be capable of scavenging ROS and / or RNS. In some embodiments, the scavenging of ROS and / or RNS can be the elimination of ROS and / or RNS. In other embodiments, the scavenging of ROS and / or RNS can be a reduction in the amount of ROS and / or RNS. Those skilled in the art can understand the scavenging mechanism. For example, it can be achieved by providing a hydrogen atom to ROS and converting ROS into other more stable molecules (such as water). 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.

[0203] In multiple embodiments, ROS and / or RNS include free radicals and / or oxidants. The free radicals and / or oxidants include, but are not limited to, hydroxyl radical (HO·), superoxide anion radical (O2·-), nitric oxide radical (NO·), nitrogen dioxide radical (NO2·), peroxyl radical (ROO·) and lipid peroxyl radical (LOO·), hydrogen peroxide (H2O2), ozone (O3), singlet oxygen ( 1 O2), hypochlorous acid (HOCl), hydroperoxide nucleophile (-OOH), nitrous acid (HNO2), dinitrogen trioxide (N2O3), and lipid peroxide (LOOH). It is understood that hydrogen peroxide (H2O2), ozone (O3), singlet oxygen ( 1 O2), nitrous acid (HNO2), peroxynitrite (ONOO - ), dinitrogen trioxide (N2O3), and lipid peroxide (LOOH) are not free radicals and are generally referred to as oxidants, but can easily initiate free radical reactions in living organisms.

[0204] In typical embodiments, the free radical and / or oxidant is hydrogen peroxide (H2O2). In specific embodiments, the 1H-pyrazole analogs described herein are capable of reacting with hydrogen peroxide to reduce the amount of ROS / oxidative stress in vitro; in other specific embodiments, the 1H-pyrazole analogs described herein are capable of reacting with hydrogen peroxide to reduce the amount of ROS / oxidative stress in vivo.

[0205] In multiple embodiments, the 1H-pyrazole analogs described herein can react with hydrogen peroxide to generate edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one; EDR; Figure 1 ). Thus, in multiple embodiments, the 1H-pyrazole analogs described herein can act as prodrugs of EDR. EDR can be generated in vitro or in vivo in this manner. Regarding the prodrug function of the 1H-pyrazole analogs, in specific embodiments, derivatization of the carbon-5 of EDR to generate the 1H-pyrazole analogs described herein ( Figure 2 ) enables the 1H-pyrazole analogs to be activated by ROS (such as H2O2) and release EDR / scavenge ROS ( Figure 3 ). In these embodiments, the reaction with H2O2 or ROS in vivo can insert an oxygen atom at the carbon-5 of EDR, forming a new C-O bond in the 1H-pyrazole analogs described herein. After hydrolysis, enolic EDR can be produced, such that the 1H-pyrazole analogs can serve as prodrugs to directly generate EDR intracellularly and / or at the site of oxidative stress ( Figure 3 ). These properties may contribute to the use of the 1H-pyrazole analogs described herein as therapeutic agents for preventing and / or treating diseases, disorders, and / or conditions associated with oxidative stress (as described below).

[0206] Without being bound by theory, 1H-pyrazole analogs (i.e., B 5 -EDR analogs), as prodrugs of EDR, can not only directly generate EDR intracellularly, but also 1H-pyrazole analogs can relieve oxidative stress by, for example, reacting with H2O2 / ROS. In this way, 1H-pyrazole analogs can treat and / or relieve some symptoms caused by diseases, disorders, and / or conditions related to oxidative stress (described in more detail below) by, for example, targeting and / or eliminating molecules (such as H2O2 / ROS) involved in the oxidative stress pathway. In other embodiments, the 1H-pyrazole analogs described herein are prodrugs of antioxidants and EDR.

[0207] EDR has a low molecular weight (molecular weight of about 174.2 g / mol), is a class IV amphiphilic molecule in the biopharmaceutics classification system (BCS), and due to its poor water solubility (about 1.85 mg / ml), permeability (Peff = about 3.18 ± 0.0706*10 -7 cm / s), short half-life (about 0.1 to about 5.16 hours), and a pKa value of about 7 [3,22]. EDR is a redox regulator in cellular processes and acts by reducing ROS / RNS free radicals (i.e., superoxide anion, hydroxyl radical, singlet oxygen, peroxyl radical, hydrogen peroxide, peroxynitrite) to their stable configuration state. Since EDR is an amphoteric molecule, it can reduce both water-soluble and lipid-soluble free radicals by donating an electron to complete its octet and stabilize its electrons. This mechanism is called the single electron transfer process (SET)

[18] . In addition, EDR is a substrate of the P-glycoprotein (Pgp) efflux pump and is metabolized systemically by the CYP3A4 enzyme. It also undergoes extensive phase II metabolism, glucuronidation (about 68% to about 83%) by uridine glucuronosyltransferase (UGT), and sulfation (about 5% to about 13%) by sulfotransferase, forming pharmacologically inactive glucuronide and sulfate conjugates, which may result in high passive permeability and low therapeutic concentrations reaching the target side [3,23].

[0208] EDR exists as a solid in the form of a keto tautomer, while its enol tautomer 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 depends on the pH value. When the pH value of the solution rises above 8, EDR acts as an acid and provides hydronium ions, forming its conjugate base, the EDR anion. Under physiological conditions (pH value of approximately 7.4), approximately 71.5% of EDR exists in the anionic form, and the remaining approximately 28.5% exists in the neutral form

[18] . The anion can reduce free radicals or even molecular oxygen through a single-electron transfer process to form a stable EDR radical, which is stabilized by three resonance structures (enol form, keto form, and amine form), and then forms an inactive EDR trimer under anaerobic conditions, presenting as a yellow precipitate

[24] . EDR decomposes to generate oxidatively stable products such as OPB, 4-OxoEDR, EDR peroxyl radical, BPOH, and phenylhydrazine

[25] . The low oral bioavailability of EDR is due to its low water solubility, low permeability, poor stability, and extensive pre-systemic metabolism. Therefore, analogs of EDR (which can serve as its prodrugs) can improve these properties because, compared with EDR, these compounds do not exist as keto-enol tautomers.

[0209] EDR diffuses into most organs and regulates the redox cycle, including highly metabolic organs such as the brain and heart [19,20]. Therefore, EDR is the first neuroprotective drug produced in Japan for the treatment of ischemic stroke [3] and has been approved in multiple jurisdictions for the treatment of ALS (for example, approved by the FDA in May 2017 for the treatment of ALS [1], and approved by Health Canada in October 2018 [2]). As a free radical scavenger (antioxidant), EDR reduces cellular oxidative stress, which is the proposed MoA to help patients recover from stroke. In randomized clinical trials, it was found that for patients in the early stage of the disease, when the drug was administered for 6 months or longer, EDR delayed the progression of ALS [4]. Although the effect of EDR is limited, it is still one of the only therapies clinically proven to improve patient prognosis. In addition, the exact cellular and molecular targets of EDR are not yet known, but the antioxidant pathway is considered a possible mechanism. However, EDR has limitations in patient compliance, pharmacokinetics, oral bioavailability, and may be unstable as an intravenous (i.v.) aqueous formulation. The recommended intravenous (i.v.) dose of edaravone for ALS is 60 mg administered over 60 minutes for 14 days, followed by a 14-day drug withdrawal [1], and there are problems with drug administration in elderly patients. For these patients, the oral route is highly preferred due to its convenience of administration, flexible dosing, reduction of long-term hospitalization, cost-effectiveness, and improvement of quality of life. In a specific embodiment, the 1H-pyrazole analogs described herein may be able to circumvent some of the above limitations of EDR.

[0210] In multiple embodiments, the 1H-pyrazole analogs described herein can be used for preventing and / or treating diseases, disorders, and / or conditions associated with oxidative stress. In other words, the 1H-pyrazole analogs described herein can be used for preventing, stabilizing, reducing the severity, slowing the progression, and / or treating diseases, disorders, and / or conditions associated with oxidative stress. In multiple embodiments, the 1H-pyrazole analogs described herein can be used for reducing oxidative stress and / or neurotoxicity, thereby producing, for example, a neuroprotective effect and slowing the progression of, for example, diseases, disorders, and / or conditions associated with oxidative stress. For example, in multiple embodiments, the 1H-pyrazole analogs described herein can be used for reducing oxidative stress and / or neurotoxicity, thereby producing a neuroprotective effect and slowing the progression of, for example, neurodegenerative diseases, disorders, and / or conditions associated with oxidative stress. In multiple embodiments, the oxidative stress is caused by the ROS and / or reactive nitrogen species (RNS) described herein.

[0211] In multiple embodiments, the diseases, conditions, and / or disorders associated with oxidative stress are 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 system 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 diseases, conditions, and / or disorders associated with oxidative stress include neurodegenerative diseases, disorders, and / or conditions. In other exemplary embodiments, the neurodegenerative diseases, disorders, and / or conditions are associated with motor dysfunction, and in further exemplary embodiments, the neurodegenerative diseases, disorders, and / or conditions are associated with cognitive impairment.

[0212] 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 stroke, cerebral ischemic injury, stroke, and / or spinocerebellar degeneration. Neurodegenerative diseases, disorders, and / or conditions associated with cognitive impairment include, but are not limited to, Alzheimer's disease, dementia, and / or Huntington's disease. In typical embodiments, the disease, disorder, and / or condition associated with oxidative stress is a neurodegenerative disease, disorder, and / or condition associated with motor dysfunction; in other typical embodiments, the neurodegenerative disease, disorder, and / or condition associated with motor dysfunction is ALS. In some embodiments, ALS is familial ALS; in other embodiments, ALS is sporadic ALS. In further embodiments, ALS is caused by a mutation in the superoxide dismutase 1 (SOD1) gene or the TARDBP gene.

[0213] ALS, also known as Lou Gehrig's disease, is an idiopathic, fatal, neuromuscular disease of the motor neuron system that results in impaired voluntary skeletal muscle function and ultimately death due to respiratory failure. Voluntary muscles become weak and immobile; however, the sensory system and intelligence are largely unaffected. In short, ALS is defined as a neurodegenerative disease, and a large number of studies have shown that the misfolding and / or aggregation of specific proteins are hallmarks of the disease; ROS and RNS are facilitators of this pathophysiology [3]. Abnormalities in the normal cellular redox cycle lead to the production of highly toxic ROS / RNS species, which results in neuronal death. The oxidative cellular environment promotes the formation of abnormal disulfide bonds and the peroxynitrite nitration of tyrosine residues in proteins, leading to abnormal protein aggregation or abnormal enzyme activity [5]. The occurrence and progression of ALS involve multiple factors, but oxidative stress caused by free radicals may be involved in the oxidation of hallmark proteins in neurodegenerative disorders, leading to the accumulation of misfolded proteins, which causes cell dysfunction and cell death [6].

[0214] ALS is mainly divided into two types: sporadic (S) ALS (accounting for 85 - 90% of cases) and familial (F) ALS (accounting for 10 - 15% of cases). Approximately 20% of FALS cases are found to be caused by mutations in the superoxide dismutase 1 (SOD1) gene [7], and the pathophysiology of FALS and SALS has similar pathological and clinical mechanisms. The disease is thought to be caused by mutations in only one gene - SOD1 - and more than 100 mutations in the SOD1 gene have been found in patients with ALS [8]. A large amount of evidence indicates that mutant SOD1 proteins acquire toxic functions, leading to neuronal degeneration, and transgenic mice overexpressing mutant SOD1-G93A and SOD1-G37R have been generated for ALS animal models. Oxidative stress-induced misfolding of SOD1 is a pathological marker of ALS-related SOD1 mutations [9]. The research results show that pathological concentrations of mild oxidants, such as hydrogen peroxide (H2O2) (which is an uncharged, non-ionizing free radical initiator), are involved in regulating the aggregation and toxicity of wild-type and mutant SOD1, leading to motor neuron death [10–12]. Pathological concentrations of H2O2 can induce the fibrillation and misfolding of SOD1 enzyme by oxidative modification of the amino acid Cys-111. Oxidized SOD1 may cause protein misfolding and produce toxicity, leading to motor neuron death [13,14].

[0215] Hydrogen peroxide (H2O2) is a molecule with paradoxical redox properties, which can initiate cell signaling or cell death depending on its concentration in living cells. At physiological concentrations of approximately 1 to 10 nM, it generates oxidative eustress and can initiate cellular processes such as proliferation and changes in cell shape / size. Higher concentrations above approximately 100 nM disrupt redox signaling, leading to oxidative distress and resulting in the oxidation of biomolecules

[15] . SOD1 regulates the level of H2O2 in normal physiological processes. It converts highly reactive and toxic superoxide into hydrogen peroxide, which is relatively less reactive, uncharged, and freely diffusible. Although the concentration of SOD1 in cells is low, its pathological concentration is approximately 10 μM to approximately 100 μM and can increase to approximately 150 μM under conditions of high oxidative stress

[16] . At concentrations of H2O2 from approximately 20 nM to approximately 200 nM, the SOD1 protein undergoes fibrillation, with the amino acid Cys-111 being oxidized to form unstable and short-lived cysteine sulfenic acid (C-SOH), gradually forming amyloid fibrils rich in β-sheet conformations in neuronal cells. The sulfenic acid-modified SOD1 oligomers can cause the redistribution of TDP-43 from the nucleus to the cytoplasm, thereby inducing the formation of SOD1 / TDP-43 amyloid fibrils, a phenomenon observed during the progression of ALS

[17] . Therefore, H2O2 may cause misfolding and toxicity of SOD1 in the nuclei of motor neurons, leading to their death

[13] . Thus, reducing oxidative stress and / or SOD1 oxidation / misfolding may be a therapeutic strategy for treating ALS.

[0216] In multiple embodiments, the 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 onset, and / or preventing recurrence, and can refer to treating the symptoms caused by the above disease, disorder, and / or condition. In multiple embodiments, the treatment of a symptom includes, for example, inhibiting the progression of the symptom, alleviating the symptom, curing the symptom, preventing the occurrence of the symptom, and / or preventing the recurrence of the symptom. Symptoms are, for example, dysfunctions caused by a disease, disorder, and / or condition associated with an oxidative stress disease, such as motor dysfunction or cognitive impairment in a neurodegenerative disease, disorder, and / or condition. For example, in multiple embodiments, the use of the 1H-pyrazole analogs described herein may help alleviate the decline in motor function associated with ALS (e.g., the 1H-pyrazole analogs described herein may increase the motor function of a subject with ALS).

[0217] In multiple embodiments, the 1H-pyrazole analogs described herein can affect the therapeutic index of ALS. In multiple embodiments, the 1H-pyrazole analogs described herein can improve the therapeutic index of ALS as compared to edaravone (EDR). The therapeutic index can measure a variety of different symptoms of ALS, such as muscle weakness, muscle atrophy (wasting), weight loss (cachexia), fasciculations, muscle cramps, bradykinesia, poor balance, ataxia, altered voice quality, dysarthria, dysphagia, incomplete eyelid closure, drooling, pseudobulbar affect, and / or premature death. In multiple embodiments, when comparing subjects receiving the 1H-pyrazole analogs described herein to subjects receiving EDR, the improved therapeutic index includes improvement of one or more of the symptoms listed above. In some embodiments, the improved therapeutic index is measured by an increase in survival / life span of subjects receiving the 1H-pyrazole analogs as compared to subjects receiving edaravone (EDR). In other embodiments, the improved therapeutic index is measured by enhanced motor function of subjects receiving the 1H-pyrazole analogs as compared to subjects treated with edaravone (EDR). In further embodiments, the improved therapeutic index is measured by a lower percentage of weight loss in subjects receiving the 1H-pyrazole analogs as compared to subjects receiving edaravone (EDR).

[0218] In some embodiments, treating and / or preventing ALS with the 1H-pyrazole analogs described herein improves or eliminates one or more of the following ALS symptoms: muscle weakness, muscle atrophy (wasting), fasciculations, muscle cramps, bradykinesia, poor balance, ataxia, altered voice quality, dysarthria, dysphagia, incomplete eyelid closure, drooling, pseudobulbar affect, and premature death. In other embodiments, treating with the 1H-pyrazole analogs described herein can prevent or delay the onset of one or more of the above symptoms.

[0219] In some embodiments, improvement of the therapeutic index can be determined by detecting improvement of a subject's symptoms as compared to one or more of the following: (1) a baseline measurement or symptom level detected prior to or at the start of treatment; (2) a measurement or symptom level from control subjects or a group of control subjects, where the control subjects exhibit one or more ALS symptoms and (i) have not been administered the 1H-pyrazole analogs described herein, or (ii) have been administered a control analog; or (3) a standard.

[0220] In other embodiments, the 1H-pyrazole analogs described herein may have improved pharmacokinetics compared to edaravone (EDR). Since pharmacokinetics may be controlled by the 1H-pyrazole analogs being prodrugs, the 1H-pyrazole analogs may have better drug-like properties compared to, for example, EDR, such as higher lipophilicity, higher membrane permeability, lower Pgp recognition rate, and longer half-life. In this way, a subject receiving the 1H-pyrazole analogs described herein may benefit from a higher in vivo bioavailability of the 1H-pyrazole analogs described herein compared to EDR (e.g., the 1H-pyrazole analogs described herein have a longer half-life and / or are more resistant to in vivo degradation). The increased bioavailability of the 1H-pyrazole analogs described herein can contribute to, for example, increased heavy metal chelation, increased ROS and / RNS scavenging, reduced oxidative damage / oxidative stress, thereby enhancing the therapeutic effect of diseases, disorders, and / or conditions associated with oxidative stress. Additionally, based on the ability of the 1H-pyrazole analogs described herein to possess the multiple functions described herein, in multiple embodiments, the 1H-pyrazole analogs described herein can be used as therapeutic agents for the prevention and / or treatment of diseases, conditions, and / or disorders associated with oxidative stress, such as an in vivo therapeutic agent for ALS.

[0221] In other embodiments, the muscle diseases, disorders, and / or conditions include muscular dystrophy. In multiple embodiments, the vascular diseases, disorders, and / or conditions include cerebral infarction. In other embodiments, the systemic inflammatory diseases, disorders, and / or conditions include multiple sclerosis and / or systemic scleroderma. In multiple embodiments, the local inflammatory diseases, disorders, and / or conditions include stomatitis.

[0222] 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; (v) kidney diseases, disorders and / or conditions, including but not limited to nephrotoxicity (drug-induced nephropathy), acute kidney injury (AKI), chronic kidney disease (CKD), diabetic nephropathy and / or end-stage renal disease (ESRD); (vi) liver diseases, disorders and / or conditions, including but not limited to hepatotoxicity, viral hepatitis, cirrhosis; (vii) digestive system diseases, disorders and / or conditions, including but not limited to inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, gastritis, pancreatitis and / or peptic ulcer; (viii) viral infectious diseases, disorders and / or conditions, including but not limited to blood-borne hepatitis viruses (types B, C and D), human immunodeficiency virus (HIV), influenza A, Epstein-Barr virus and / or respiratory syncytial virus; (ix) cancers, including but not limited to prostate cancer, breast cancer, lung cancer, colorectal cancer, bladder cancer, ovarian cancer, skin cancer, gastric cancer and / or liver cancer; and (x) sepsis / septic shock. Subjects having any of the above oxidative stress-related diseases, disorders and / or conditions can be identified by any diagnostic or prognostic assay known in the art or a combination thereof.

[0223] 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 treated and / or prevented by administering or delivering the 1H-pyrazole analogs described herein. In various embodiments, the method includes administering a 1H-pyrazole analog to a subject in need thereof.

[0224] The subjects described herein generally refer to subjects suffering from one or more oxidative stress diseases, conditions, and / or disorders, and / or at risk of suffering from one or more oxidative stress diseases, conditions, and / or disorders. In this way, the uses and methods described herein, for example, can be used to prevent the occurrence of oxidative stress diseases, conditions, and / or disorders when providing (e.g., administering) 1H-pyrazole analogs to subjects at risk of developing the oxidative stress diseases, disorders, and / or conditions described herein. Alternatively, the uses and methods described herein, for example, can be used to treat oxidative stress-related diseases, conditions, and / or disorders when providing (e.g., administering) 1H-pyrazole analogs to subjects suffering from oxidative stress-related diseases, conditions, and / or disorders. For the purposes of this disclosure, a subject can suffer from a single oxidative stress-related disease, condition, and / or disorder, or a series of oxidative stress-related diseases, conditions, and / or disorders, which can be treated by the uses and methods described herein.

[0225] In other embodiments, the 1H-pyrazole analogs described herein can be used to prepare a medicament, which is generally used to prevent and / or treat oxidative stress-related diseases, conditions, and / or disorders described herein. In a typical embodiment, the 1H-pyrazole analog is used as a medicament for administration to a subject in need (e.g., a mammal, typically a human).

[0226] The 1H-pyrazole analog can be administered to a mammal, typically a human. When administered in the form of a pharmaceutical composition, the 1H-pyrazole analog can be used in combination with a pharmaceutically acceptable carrier or diluent, optionally with a pharmaceutically acceptable adjuvant (e.g., alum). Accordingly, the 1H-pyrazole analog can be appropriately formulated into a pharmaceutical composition and administered to a human subject in a biocompatible form suitable for in vivo administration.

[0227] Accordingly, in various embodiments, the pharmaceutical composition comprises a 1H-pyrazole analogue blended with a suitable diluent or carrier. Compositions containing a 1H-pyrazole analogue can be prepared by methods known for preparing pharmaceutically acceptable compositions that can be administered to a subject such that an effective amount of the 1H-pyrazole analogue is admixed with a pharmaceutically acceptable carrier to form a mixture. Suitable carriers are described, for example, in Remington's Pharmaceutical Sciences (2003 - 20th edition), published in 1999, in The United States Pharmacopeia: The National Formulary (USP 24NF19), and in the Handbook of Pharmaceutical Additives (compiled by Michael and Irene Ash, Gower Publishing Limited, Aldershot, England (1995)), the entire contents of these references being incorporated herein by reference. On this basis, the composition may comprise a solution of the 1H-pyrazole analogue with one or more pharmaceutically acceptable carriers or diluents and be contained in a buffered solution having a suitable pH and isotonic with physiological fluids. Solutions of the 1H-pyrazole analogue can be prepared by appropriately mixing it with suitable excipients in water. Under conventional storage and use conditions, these formulations may 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.

[0228] The 1H-pyrazole analogue can be administered alone or in combination with other components / ingredients / active substances. For example, the 1H-pyrazole analogue can be administered in the form of a pharmaceutical composition. Those skilled in the art will understand that the 1H-pyrazole analogue and / or its composition can be administered to a subject in various forms depending on the chosen route of administration. The 1H-pyrazole analogue and its pharmaceutical composition can be administered, for example, orally, parenterally (e.g., by intravenous, intraperitoneal, subcutaneous, intramuscular, transdermal, nasal, intrapulmonary, intrathecal, rectal, and topical routes of administration), buccally, sublingually, by patch, pump, or transdermally. In a typical embodiment, the 1H-pyrazole analogue described herein is administered or intended to be administered using an oral or intravenous route of administration.

[0229] If the 1H-pyrazole analog is administered orally, the selected compound can be administered in the form of, for example, a swallowable powder (such as a pure powder), tablet or capsule, or as an aqueous solution or suspension. Examples can include: swallowable tablets, oral tablets, lozenges, capsules, elixirs, suspensions, syrups, cachets, etc. For tablet dosage forms, depending on the dose, the 1H-pyrazole analog can account for 1 wt% to 99 wt% of the dosage form, more commonly 5 wt% to 60 wt% of the dosage form. In addition, common carriers include lactose and corn starch, and lubricants are usually added, such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. In addition, tablets usually contain disintegrants. 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. Available diluents include lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, glucose, sucrose, sorbitol, microcrystalline cellulose, starch, and dibasic calcium phosphate dihydrate. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose, and hydroxypropylmethylcellulose. Other conventional ingredients include antioxidants, colorants, flavorants, preservatives, and taste-masking agents. The tablet mixture can be directly compressed or formed into tablets by roller compaction. The tablet mixture or a portion of the mixture can also be wet granulated, dry granulated, or melt granulated, melt solidified, or extruded before tableting. The final preparation can contain one or more layers, can be coated or uncoated; or encapsulated. The formulation of tablets has been discussed in detail in "Pharmaceutical Dosage Forms: Tablets, Vol. 1", by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0 8247 6918X), the entire disclosure of which is incorporated herein by reference.

[0230] When preparing an aqueous suspension for oral administration, the active ingredient can be mixed with an emulsifier and a suspending agent. If desired, certain sweetening agents and / or flavorants can be added. The 1H-pyrazole analog can be administered orally, for example, mixed with an inert diluent or with an absorbable edible carrier, or encapsulated in a hard gelatin capsule or a soft gelatin capsule, or compressed into tablets, or directly added to food. For oral therapeutic administration, the 1H-pyrazole analog can be mixed with excipients and used in the form of swallowable tablets, oral tablets, lozenges, capsules, elixirs, suspensions, syrups, cachets, etc.

[0231] If the 1H-pyrazole analog is administered parenterally, the parenteral administration can be by continuous infusion, bolus injection, or intermittent bolus injection and can be completed over a selected period of time. Examples of devices suitable for parenteral administration include needle (including micro-needle) syringes, needle-free syringes, and infusion techniques. For intramuscular, intraperitoneal, subcutaneous, and intravenous use, a sterile solution of the active ingredient is generally prepared, and the pH of the solution is appropriately adjusted and buffered. For intravenous use, the total concentration of the solute can be controlled to render the formulation isotonic. Thus, in various embodiments, one or more 1H-pyrazole analogs described herein can be formulated in an isotonic medium and administered intravenously.

[0232] Pharmaceutical dosage forms suitable for injectable use can include sterile aqueous solutions or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In various embodiments, the dosage form is sterile and the fluid is readily aspirated and injected with a syringe. Using standard pharmaceutical techniques known to those of skill in the art, a parenteral administration kit for immediate reconstitution under sterile conditions (e.g., by lyophilization) can be readily prepared.

[0233] 1H-pyrazole analogs (including their pharmaceutical compositions) suitable for nasal administration can be conveniently formulated as aerosols, drops, gels, and powder sprays. Aerosol formulations generally contain a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent, and are usually present in a sealed container in sterile form, either as a single dose or in multiple doses, which can be in the form of a cartridge or a refill for use with an atomizing device (e.g., a nebulizer) (e.g., to generate a misty dispersion of the 1H-pyrazole analog, such as in an aqueous carrier (e.g., saline)). Alternatively, the sealed container can be a unitary dispensing device, such as a single-dose nasal inhaler or an aerosol dispenser equipped with a metering valve, which is intended to be discarded after use. When the dosage form contains an aerosol dispenser, it will contain a propellant, which can be a compressed gas (e.g., compressed air) or an organic propellant (e.g., a chlorofluorocarbon). The aerosol dosage form can also be in the form of a pump nebulizer.

[0234] 1H-pyrazole analogs (including their pharmaceutical compositions) suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, in which the active ingredient is formulated with a carrier (e.g., sugar, gum acacia, tragacanth, or gelatin and glycerol). Compositions for rectal administration are generally in the form of suppositories, which contain a conventional suppository base, such as cocoa butter. In various embodiments, a delivery system can be used to deliver the 1H-pyrazole analog (e.g., a formulation or a pharmaceutical composition). It is understood that the delivery system itself can include a device, such as an implantable device.

[0235] 1H-pyrazole analogs can be combined with soluble macromolecules (such as cyclodextrins and their suitable analogs or polyethylene glycol-containing polymers) to enhance their solubility, dissolution rate, taste masking effect, bioavailability, and / or stability, and thus be used for any of the above-mentioned modes of administration. Regardless of the selected route of administration, 1H-pyrazole analogs (which can be used in the form of suitable hydrates) and / or their pharmaceutical compositions can be formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

[0236] The actual dosage level of the analogs may vary so as to obtain a dosage that is effective for a particular patient, composition, and mode of administration to achieve the desired therapeutic response. To this end, the dosage of the 1H-pyrazole analogs can depend on the pharmacokinetic and pharmacodynamic properties of the 1H-pyrazole analogs and their mode and route of administration; the release rate of the 1H-pyrazole analogs, the age, gender, health status, medical condition, nature and degree of symptoms, and body weight of the recipient; the renal and hepatic functions of the patient; the frequency of treatment and the type of concurrent treatment (if any), and the clearance rate of the 1H-pyrazole analogs in the subject being treated and the desired effect. The selected dosage level may also depend on other factors, including the activity of the specific 1H-pyrazole analogs and their pharmaceutical compositions described herein, the time of administration, the excretion or metabolic rate of the specific 1H-pyrazole analogs used, the rate and extent of absorption, the duration of treatment, other drugs that may be administered to the patient, compounds and / or materials used in combination with the specific 1H-pyrazole analogs, and other factors well known in the medical field. Those skilled in the art can determine the appropriate dosage based on the above factors.

[0237] A physician or veterinarian with ordinary skill in the art can readily determine and prescribe an effective dosage of the 1H-pyrazole analogs or their pharmaceutical compositions. For example, a physician or veterinarian can start with a dosage of the 1H-pyrazole analogs used in the pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. Generally, the appropriate daily dosage of the 1H-pyrazole analogs is the amount of the compound that is the lowest dosage effective in producing a therapeutic effect. This effective dosage generally depends on the above factors.

[0238] The 1H-pyrazole analogs can initially be administered at a suitable dosage and adjusted as needed according to the clinical response. For short-term in vitro cell treatment (such as 30 minutes to 1 hour or longer), higher dosages of the 1H-pyrazole analogs can be used than for long-term in vivo treatment.

[0239] In some embodiments, the 1H-pyrazole analog can be administered in an amount of from about 0.001 mg / kg body weight to about 1000 mg / kg body weight per day; for example, from about 0.01 mg / kg body weight to about 500 mg / kg body weight per day; from about 0.01 mg / kg body weight to about 250 mg / kg body weight per day; or from 0.01 mg / kg body weight to about 100 mg / kg body weight per day, as well as any intermediate range or specific amount, such as from 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 / kg, about 50 mg / kg, about 75 mg / kg, about 100 mg / kg, about 150 mg / 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 to 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 / kg, about 50 mg / kg, about 75 mg / kg, about 100 mg / kg, about 150 mg / 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 body weight per day, per hour, per week or per dose.

[0240] As a typical specific example, for the dose of each administration of the pharmaceutical composition, taking the dose of the 1H-pyrazole analog for an adult as a reference, the lower limit is, for example, about 40 mg or about 70 mg, and the upper limit is, for example, about 400 mg, about 140 mg, about 120 mg or about 105 mg. The range is, for example, from about 40 mg to about 400 mg, preferably from about 40 mg to about 140 mg, more preferably from about 40 mg to about 120 mg, even more preferably from about 40 mg to about 105 mg. The dose is particularly preferably about 40 mg, about 50 mg, about 60 mg or about 70 mg, especially preferably about 45 mg or about 55 mg, and most preferably about 50 mg. If intravenous administration is desired, in a typical embodiment, the dose range during a constant rate infusion is from about 0.01 mg / kg / minute to about 10 mg / kg / minute.

[0241] If formulated in a fixed dose, such combination products employ the 1H-pyrazole analog within the above dosage ranges, and other pharmaceutically active ingredients within their approved dosage ranges. When combination formulations are not applicable, the 1H-pyrazole analog may also be used sequentially with known pharmaceutically acceptable drugs.

[0242] The therapeutically effective amount of the compound generally up to the maximum tolerated dose, but may vary widely. Of course, the precise dose used by the attending physician will vary depending on the 1H-pyrazole analog, the route of administration, the physical condition of the patient (e.g., age, weight, individual patient response, and the severity of the patient's symptoms), and other factors. The daily dose may be administered as a single dose, or may be divided into multiple doses, such as two, three, or four times a day. Alternatively, the dose may be provided weekly, biweekly, or monthly. In some embodiments, a reduced dose compared to the conventional therapeutic dose of known agents may be used.

[0243] It should be understood that the 1H-pyrazole analog may also be used in combination with and / or co-administered with other therapeutic agents selected for their specific effectiveness against the diseases, disorders, and / or conditions associated with oxidative stress described herein. In other words, the 1H-pyrazole analog may be used in combination with and / or co-administered with therapeutic agents to treat and / or prevent the diseases, disorders, and / or conditions associated with oxidative stress described herein. As an example of a therapeutic agent that may be used in combination with the 1H-pyrazole analog described herein to treat and / or prevent ALS, such therapeutic agents include, but are not limited to, riluzole (Rilutek TM ), edaravone (Radicava TM ), mecasermin, baclofen (Lioresal TM ), diazepam (Valium TM ), dantrolene (Dantrium TM ), non-steroidal anti-inflammatory drugs, anticonvulsant drugs (e.g., carbamazepine (Tegretol) or phenytoin (Dilantin TM ), amitriptyline (Elavil TM ), nortriptyline (Pamelor TM ), and lorazepam (Ativan TM)。In some embodiments, the additional therapy includes co - administration of elamipretide (also known as SS - 31 or Bendavia). In these embodiments, the therapeutic agent co - administered with the 1H - pyrazole analogs described herein can produce a synergistic therapeutic effect. For example, such a combination has a greater - than - additive effect in preventing and / or treating ALS. Thus, when used in combination with the 1H - pyrazole analogs described herein, lower doses of one or more of any individual therapeutic agent can be used to treat or prevent ALS, thereby enhancing the therapeutic effect and reducing side effects. The combination of the 1H - pyrazole analogs described herein with the therapeutic agent can be administered simultaneously or sequentially in any order. In multiple embodiments, the 1H - pyrazole analogs and the therapeutic agent act additively or synergistically to prevent and / or treat oxidative stress diseases, disorders, and / or conditions.

[0244] Additional embodiments include:

[0245] Embodiment 1. A compound having the structure of Formula I:

[0246]

[0247] Its pharmaceutically acceptable salts, its hydrates, its solvates, its tautomers, its geometric isomers, its enantiomers, its diastereomers, its N - oxides, its metabolites, its isotopomers, its isotopic variants, its prodrugs, or combinations thereof,

[0248] Wherein:

[0249] X1 is selected from - BR 8 R 9 or - BR 10 R 11 R 12 ;

[0250] R 1 to R 7 、R 10 、R 11 and R 12 are each independently selected from H, a halogen 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 heteroatom - containing 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, where R 13 to R 17each independently selected from H, a halogen group, a hydroxyl group, a cyano group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heteroatom-containing 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 together form a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group; and

[0251] R 8 and R 9 each independently selected from H, a halogen group, a hydroxyl group, a cyano group, a nitro group, a mercapto group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heteroatom-containing 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.

[0252] Embodiment 2. The compound according to Embodiment 1, wherein X1 is -BR 8 R 9 .

[0253] Embodiment 3. The compound according to Embodiment 1 or 2, wherein R 8 and R 9 each independently selected from H, a halogen group, a hydroxyl group, a cyano group, a nitro group, a mercapto group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heteroatom-containing 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.

[0254] Embodiment 4. The compound according to any one of Embodiments 1 to 3, wherein R 8 and R 9 each independently selected from H, a halogen 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.

[0255] Embodiment 5. The compound according to any one of Embodiments 1 to 4, wherein R 8 and R 9Each independently selected from H, a halogen 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 C1-C6 alkyl-C(O)O- group, a substituted or unsubstituted C1-C6 alkyl-O-C(O)- group, a substituted or unsubstituted C1-C6 alkyl-O-C(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.

[0256] Embodiment 6. The compound according to any one of Embodiments 1 to 5, wherein R 8 and R 9 Each independently selected from a fluoro group, a chloro group, a bromo group, a hydroxyl group or an alkoxy group.

[0257] Embodiment 7. The compound according to Embodiment 1 or 2, wherein R 8 and R 9 Together form a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group.

[0258] Embodiment 8. The compound according to any one of Embodiments 1, 2 and 7, wherein R 8 and R 9 Together form a substituted or unsubstituted heterocyclic group.

[0259] Embodiment 9. The compound according to any one of Embodiments 1, 2, 7 and 8, wherein R 8 and R 9 Together form a substituted or unsubstituted -O(C2-C8 alkylene)O- ring.

[0260] Embodiment 10. The compound according to any one of Embodiments 1, 2 and 7 to 9, wherein R 8 and R 9 Together form -OCH2CH2O-, -OC(CH 3)2 CH2O-, or –OC(CH3)2C(CH3)2O-.

[0261] Embodiment 11. The compound according to any one of Embodiments 1, 2, 7 and 8, wherein R 8 and R 9Together form a substituted or unsubstituted -O(C1-C2 alkylene)NH(C1-C2 alkylene)O- ring.

[0262] Embodiment 12. The compound according to any one of Embodiments 1, 2, and 7 to 9, wherein 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-.

[0263] Embodiment 13. The compound according to Embodiment 1, wherein X1 is -BR 10 R 11 R 12 .

[0264] Embodiment 14. The compound according to Embodiment 1 or 13, wherein R 10 , R 11 and R 12 Are each independently selected from H, a halogen 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 heteroatom-containing 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.

[0265] Embodiment 15. The compound according to any one of Embodiments 1, 13, and 14, wherein R 10 , R 11 and R 12 Are each independently selected from H, a halogen 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.

[0266] Embodiment 16. The compound according to any one of Embodiments 1 and 13 to 15, wherein R 10 , R 11 and R 12Each independently selected from H, a halogen 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 C1-C6 alkyl-C(O)O- group, a substituted or unsubstituted C1-C6 alkyl-O-C(O)- group, a substituted or unsubstituted C1-C6 alkyl-O-C(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.

[0267] Embodiment 17. The compound according to any one of Embodiments 1 and 13 to 16, wherein R 10 , R 11 and R 12 are each independently selected from a fluorine group, a chlorine group, a bromine group, a hydroxyl group or an alkoxy group.

[0268] Embodiment 18. The compound according to any one of Embodiments 1 to 17, wherein R 1 and R 2 are each independently selected from H, a halogen group, a hydroxyl group, a cyano group, a nitro group, a mercapto group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heteroatom-containing 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.

[0269] Embodiment 19. The compound according to any one of Embodiments 1 to 18, wherein R 1 and R 2 are each independently selected from H, a halogen 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.

[0270] Embodiment 20. The compound according to any one of Embodiments 1 to 19, wherein R 1 and R 2Each independently selected from H, a halogen 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.

[0271] Embodiment 21. The compound according to any one of Embodiments 1 to 20, wherein R 1 is H or a substituted or unsubstituted alkyl group, and R 2 is selected from H, a halogen group, a hydroxyl group, a cyano group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heteroatom-containing 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.

[0272] Embodiment 22. The compound according to any one of Embodiments 1 to 21, wherein R 1 is H, -CH3, -CH2CH3 or -CH2CH2CH3, and R 2 is selected from H, F, Cl, CN, -CH3, -CH2F, -CHF2 or -CF3.

[0273] Embodiment 23. The compound according to any one of Embodiments 1 to 22, wherein R 3 to R 7 are each independently selected from H, a halogen group, a hydroxyl group, a cyano group, a nitro group, a mercapto group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heteroatom-containing 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, wherein R 13 to R 17 are each independently selected from H, a halogen group, a hydroxyl group, a cyano group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heteroatom-containing 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 together form a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group.

[0274] Embodiment 24. The compound according to any one of Embodiments 1 to 23, wherein R 3 to R 7 are each independently selected from H, a halogen group, a cyano group, a nitro group, a sulfate group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heteroatom-containing 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.

[0275] Embodiment 25. The compound according to any one of Embodiments 1 to 24, wherein R 3 to R 7 are each independently selected from H, a halogen 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 boric acid group, a substituted or unsubstituted alkyl borate 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.

[0276] Embodiment 26. The compound according to any one of Embodiments 1 to 25, wherein R 3 to R 7 are each independently selected from H, a halogen 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 alkyl-O-C(O)- group, a substituted or unsubstituted C1-C6 alkyl-O-C(O)-C1-C6 alkylene group, -C(O)OH, a boric acid group, a substituted or unsubstituted C1-C6 alkyl borate 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 alkyl heteroaryl group, a substituted or unsubstituted pyridyl group, or a substituted or unsubstituted pyrrolyl group.

[0277] Embodiment 27. The compound according to any one of Embodiments 1 to 26, wherein R 3 , R 4 , R 6 and R 7 are each independently selected from H, -CH3, -CH2CH3 or -CH2CH2CH 3， and R 5Selected from H, F, Cl, CN, -CH3, -CH2F, -CHF2 or -CF3.

[0278] Embodiment 28. The compound according to any one of Embodiments 1 to 27, wherein the compound is selected from:

[0279]

[0280] Its pharmaceutically acceptable salts, its hydrates, its solvates, its tautomers, its geometric isomers, its enantiomers, its diastereoisomers, its N-oxides, its metabolites, its isotopomers, its isotopic variants, its prodrugs or combinations thereof.

[0281] Embodiment 29. The compound according to any one of Embodiments 1 to 28, wherein the compound is selected from:

[0282]

[0283] Its pharmaceutically acceptable salts, its hydrates, its solvates, its tautomers, its geometric isomers, its enantiomers, its diastereoisomers, its N-oxides, its metabolites, its isotopomers, its isotopic variants, its prodrugs or combinations thereof, wherein R1 to R4 are each independently selected from any one of the groups of R 3 to R 7 in the group.

[0284] Embodiment 30. The compound according to any one of Embodiments 1 to 29, wherein the compound is selected from:

[0285]

[0286] Its pharmaceutically acceptable salts, its hydrates, its solvates, its tautomers, its geometric isomers, its enantiomers, its diastereoisomers, its N-oxides, its metabolites, its isotopomers, its isotopic variants, its prodrugs or combinations thereof, wherein X + is any suitable counterion.

[0287] Embodiment 31. The compound according to any one of Embodiments 1 to 30, wherein the compound is selected from:

[0288]

[0289] Its pharmaceutically acceptable salts, its hydrates, its solvates, its tautomers, its geometric isomers, its enantiomers, its diastereoisomers, its N-oxides, its metabolites, its isotopomers, its isotopic variants, its prodrugs or combinations thereof, wherein X + is any suitable counterion.

[0290] Embodiment 32. The compound according to any one of Embodiments 1 to 31, wherein the compound is a racemic mixture.

[0291] Embodiment 33. The compound according to any one of Embodiments 1 to 32, wherein the compound is a non-racemic mixture.

[0292] Embodiment 34. The compound according to any one of Embodiments 1 to 33, wherein the compound is a pharmaceutically acceptable salt.

[0293] Embodiment 35. The compound according to any one of Embodiments 1 to 34, wherein the compound can act as a metal chelator.

[0294] Embodiment 36. The compound according to any one of Embodiments 1 to 35, wherein the compound can act as an antioxidant.

[0295] Embodiment 37. The compound according to any one of Embodiments 1 to 36, wherein the compound reduces oxidative stress.

[0296] Embodiment 38. The compound according to any one of Embodiments 1 to 37, wherein the compound reduces oxidative damage / oxidative stress by scavenging reactive oxygen species (ROS) and / or reactive nitrogen species (RNS).

[0297] Embodiment 39. The compound according to any one of Embodiments 1 to 38, wherein the compound can reduce reactive oxygen species (ROS) and / or reactive nitrogen species (RNS) in vitro.

[0298] Embodiment 40. The compound according to any one of Embodiments 1 to 39, wherein the compound can reduce reactive oxygen species (ROS) and / or reactive nitrogen species (RNS) in vivo.

[0299] Embodiment 41. The compound according to any one of Embodiments 38 to 40, wherein the ROS and / or RNS include free radicals and / or oxidants.

[0300] Embodiment 42. The compound according to Embodiment 41, wherein the free radicals and / or oxidants are selected from hydroxyl radical (HO·), superoxide anion radical (O2·-), nitric oxide radical (NO·), nitrogen dioxide radical (NO2·), peroxyl radical (ROO·) and lipid peroxyl radical (LOO·), hydrogen peroxide (H2O2), ozone (O3), singlet oxygen ( 1O2), hypochlorous acid (HOCl), hydroperoxide nucleophiles (-OOH), nitrous acid (HNO2), dinitrogen trioxide (N2O3), and lipid peroxides (LOOH).

[0301] Embodiment 43. The compound according to Embodiment 41, wherein the radical and / or oxidant is hydrogen peroxide (H2O2).

[0302] Embodiment 44. The compound according to any one of Embodiments 1 to 43, wherein the compound can react with hydrogen peroxide in vivo to produce edaravone (EDR).

[0303] Embodiment 45. The compound according to any one of Embodiments 1 to 44, wherein the compound can react with hydrogen peroxide in vitro to produce edaravone (EDR).

[0304] Embodiment 46. The compound according to any one of Embodiments 1 to 45, wherein the compound is a prodrug of edaravone (EDR).

[0305] Embodiment 47. The compound according to any one of Embodiments 1 to 46, wherein the compound is an antioxidant and a prodrug of edaravone (EDR).

[0306] Embodiment 48. The compound according to any one of Embodiments 1 to 47, wherein the compound is a therapeutic agent for the in vivo treatment of amyotrophic lateral sclerosis (ALS).

[0307] Embodiment 49. The compound according to any one of Embodiments 1 to 48, wherein the compound is a therapeutic agent for preventing and / or treating diseases, conditions, and / or disorders associated with oxidative stress.

[0308] Embodiment 50. A pharmaceutical composition comprising the compound according to any one of Embodiments 1 to 49.

[0309] Embodiment 51. A pharmaceutical composition comprising the compound according to any one of Embodiments 1 to 49 and at least one pharmaceutically acceptable carrier and / or diluent.

[0310] Embodiment 52. The compound according to any one of Embodiments 1 to 49 or the composition according to Embodiment 50 or 51, for preventing and / or treating diseases, conditions, and / or disorders associated with oxidative stress.

[0311] Embodiment 53. The compound or composition according to Embodiment 52, wherein the oxidative stress is caused by reactive oxygen species (ROS) and / or reactive nitrogen species (RNS).

[0312] Embodiment 54. The compound or composition according to Embodiment 53, wherein the ROS and / or RNS include free radicals and / or oxidants.

[0313] Embodiment 55. The compound or composition according to any one of Embodiments 52 to 54, wherein the free radical and / or oxidant is selected from the group consisting of hydroxyl radical (HO·), superoxide anion radical (O2·-), nitric oxide radical (NO·), nitrogen dioxide radical (NO2·), peroxyl radical (ROO·) and lipid peroxyl radical (LOO·), hydrogen peroxide (H2O2), ozone (O3), singlet oxygen ( 1 O2), hypochlorous acid (HOCl), hydroperoxide nucleophile (-OOH), nitrous acid (HNO2), dinitrogen trioxide (N2O3) and lipid peroxide (LOOH).

[0314] Embodiment 56. The compound or composition according to Embodiment 54, wherein the free radical and / or oxidant is hydrogen peroxide (H2O2).

[0315] Embodiment 57. The compound or composition according to any one of Embodiments 52 to 56, wherein the diseases, disorders and / or conditions associated with oxidative stress are 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 system diseases, disorders and / or conditions, aging, disorders and / or conditions, viral infectious diseases, disorders and / or conditions, cancer and sepsis / septic shock.

[0316] Embodiment 58. The compound or composition according to Embodiment 57, wherein the neurodegenerative diseases, disorders and / or conditions are associated with motor dysfunction.

[0317] Embodiment 59. The compound or composition according to Embodiment 58, wherein the neurodegenerative diseases, disorders and / or conditions associated with motor dysfunction are amyotrophic lateral sclerosis (ALS).

[0318] Embodiment 60. The compound or composition according to Embodiment 59, wherein the ALS is familial ALS.

[0319] Embodiment 61. The compound or composition according to Embodiment 59, wherein the ALS is sporadic ALS.

[0320] Embodiment 62. The 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.

[0321] Embodiment 63. The compound or composition according to any one of Embodiments 59 to 62, wherein the compound or composition delays the onset of ALS.

[0322] Embodiment 64. The compound or composition according to any one of Embodiments 52 to 63, wherein the compound or composition has an improved ALS treatment index compared to edaravone (EDR).

[0323] Embodiment 65. The compound or composition according to Embodiment 64, wherein the treatment index is a measure of one or more of the following symptoms: muscle weakness, muscle atrophy (wasting), weight loss (cachexia), fasciculations, muscle cramps, bradykinesia, poor balance, ataxia, altered voice quality, dysarthria, dysphagia, incomplete eyelid closure, drooling, pseudobulbar affect, and / or premature death.

[0324] Embodiment 66. The compound or composition according to Embodiment 64 or 65, wherein the improved treatment index is measured by an increase in the survival / lifespan of the subjects receiving the compound or composition compared to the subjects receiving edaravone (EDR).

[0325] Embodiment 67. The compound or composition according to any one of Embodiments 64 to 66, wherein the improved treatment index is measured by enhanced motor function of the subjects receiving the compound or composition compared to the subjects receiving edaravone (EDR).

[0326] Embodiment 68. The compound or composition according to any one of Embodiments 64 to 67, wherein the improved treatment index is measured by a lower percentage of weight loss (cachexia) in the subjects receiving the compound or composition compared to the subjects receiving edaravone (EDR).

[0327] Embodiment 69. The compound or composition according to any one of Embodiments 52 to 68, wherein the compound or composition has improved pharmacokinetics compared to edaravone (EDR).

[0328] Embodiment 70. The compound or composition according to Embodiment 69, wherein the improved pharmacokinetics includes an increase in the bioavailability of the compound or composition compared to edaravone (EDR).

[0329] Embodiment 71. A method for preventing and / or treating a disease, disorder, and / or condition associated with oxidative stress, comprising administering to a mammal 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.

[0330] Embodiment 72. The method according to Embodiment 71, wherein the oxidative stress is caused by reactive oxygen species (ROS) and / or reactive nitrogen species (RNS).

[0331] Embodiment 73. The method according to Embodiment 72, wherein the ROS and / or RNS include free radicals and / or oxidants.

[0332] Embodiment 74. The method according to Embodiment 73, wherein the free radicals and / or oxidants are selected from hydroxyl radical (HO·), superoxide anion radical (O2·-), nitric oxide radical (NO·), nitrogen dioxide radical (NO2·), peroxyl radical (ROO·) and lipid peroxyl radical (LOO·), hydrogen peroxide (H2O2), ozone (O3), singlet oxygen ( 1 O2), hypochlorous acid (HOCl), hydroperoxide nucleophile (-OOH), nitrous acid (HNO2), dinitrogen trioxide (N2O3), and lipid peroxide (LOOH).

[0333] Embodiment 75. The method according to Embodiment 73, wherein the free radicals and / or oxidants are hydrogen peroxide (H2O2).

[0334] Embodiment 76. The method according to any one of Embodiments 71 to 75, wherein the disease, disorder, and / or condition 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 system diseases, disorders, and / or conditions, aging, disorders, and / or conditions, viral infectious diseases, disorders, and / or conditions, cancer, and sepsis / septic shock.

[0335] Embodiment 77. The method according to Embodiment 76, wherein the neurodegenerative disease, disorder, and / or condition is associated with motor dysfunction.

[0336] Embodiment 78. The method according to embodiment 77, wherein the neurodegenerative disease, disorder, and / or condition associated with motor dysfunction is amyotrophic lateral sclerosis (ALS).

[0337] Embodiment 79. The method according to embodiment 78, wherein the ALS is familial ALS.

[0338] Embodiment 80. The method according to embodiment 78, wherein the ALS is sporadic ALS.

[0339] Embodiment 81. The method according to 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.

[0340] Embodiment 82. The method according to any one of embodiments 78 to 81, wherein the compound or composition delays the onset of ALS.

[0341] Embodiment 83. The method according to any one of embodiments 71 to 82, wherein the compound or composition has an improved ALS treatment index compared to edaravone (EDR).

[0342] Embodiment 84. The method according to embodiment 83, wherein the treatment index is a measure of one or more of the following symptoms: muscle weakness, muscle atrophy (wasting), weight loss (cachexia), fasciculations, muscle cramps, bradykinesia, poor balance, ataxia, altered voice quality, dysarthria, dysphagia, incomplete eyelid closure, drooling, pseudobulbar affect, and / or premature death.

[0343] Embodiment 85. The method according to embodiment 83 or 84, wherein the improved treatment index is measured by an increase in survival / life span of the subjects receiving the compound or composition compared to the subjects receiving edaravone (EDR).

[0344] Embodiment 86. The method according to any one of embodiments 83 to 85, wherein the improved treatment index is measured by enhanced motor function of the subjects receiving the compound or composition compared to the subjects receiving edaravone (EDR).

[0345] Embodiment 87. The method according to any one of embodiments 83 to 86, wherein the improved treatment index is measured by a lower percentage of weight loss (cachexia) of the subjects receiving the compound or composition compared to the subjects receiving edaravone (EDR).

[0346] Embodiment 88. The method according to any one of embodiments 71 to 87, wherein the compound or composition has improved pharmacokinetics compared to edaravone (EDR).

[0347] Embodiment 89. The method according to embodiment 88, wherein the improved pharmacokinetics comprises an increase in the bioavailability of the compound or composition compared to edaravone (EDR).

[0348] Embodiment 90. The method according to any one of embodiments 71 to 89, wherein the mammal is a human.

[0349] Embodiment 91. The method according to any one of embodiments 71 to 90, wherein the compound or composition is administered orally and / or intravenously.

[0350] 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 a disease, disorder and / or condition associated with oxidative stress.

[0351] 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).

[0352] Embodiment 94. The use according to embodiment 93, wherein the ROS and / or RNS comprise free radicals and / or oxidants.

[0353] Embodiment 95. The use according to embodiment 94, wherein the free radicals and / or oxidants are selected from hydroxyl radical (HO·), superoxide anion radical (O2·-), nitric oxide radical (NO·), nitrogen dioxide radical (NO2·), peroxyl radical (ROO·) and lipid peroxyl radical (LOO·), hydrogen peroxide (H2O2), ozone (O3), singlet oxygen ( 1 O2), hypochlorous acid (HOCl), hydroperoxide nucleophile (-OOH), nitrous acid (HNO2), dinitrogen trioxide (N2O3) and lipid peroxide (LOOH).

[0354] Embodiment 96. The use according to embodiment 94, wherein the free radicals and / or oxidants are hydrogen peroxide (H2O2).

[0355] Embodiment 97. The use according to any one of Embodiments 92 to 96, wherein the diseases, disorders and / or conditions related to oxidative stress are 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 system diseases, disorders and / or conditions, aging, disorders and / or conditions, viral infectious diseases, disorders and / or conditions, cancer and sepsis / septic shock.

[0356] Embodiment 98. The use according to Embodiment 97, wherein the neurodegenerative diseases, disorders and / or conditions are related to motor dysfunction.

[0357] Embodiment 99. The use according to Embodiment 98, wherein the neurodegenerative diseases, disorders and / or conditions related to motor dysfunction are amyotrophic lateral sclerosis (ALS).

[0358] Embodiment 100. The use according to Embodiment 99, wherein the ALS is familial ALS.

[0359] Embodiment 101. The use according to Embodiment 99, wherein the ALS is sporadic ALS.

[0360] Embodiment 102. The 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.

[0361] Embodiment 103. The use according to any one of Embodiments 99 to 102, wherein the compound or composition delays the onset of ALS.

[0362] Embodiment 104. The use according to any one of Embodiments 92 to 103, wherein the compound or composition has an improved ALS treatment index compared to edaravone (EDR).

[0363] Embodiment 105. The use according to Embodiment 104, wherein the treatment index is a measure of one or more of the following symptoms: muscle weakness, muscle atrophy (wasting), weight loss (cachexia), fasciculations, muscle cramps, bradykinesia, poor balance, ataxia, change in voice quality, dysarthria, dysphagia, incomplete eyelid closure, drooling, pseudobulbar affect and / or premature death.

[0364] Embodiment 106. The use according to Embodiment 104 or 105, wherein the improved therapeutic index is measured by the extension of the survival / lifespan of the subject receiving the compound or composition compared to the subject receiving edaravone (EDR).

[0365] Embodiment 107. The use according to any one of Embodiments 104 to 106, wherein the improved therapeutic index is measured by the enhancement of the motor function of the subject receiving the compound or composition compared to the subject receiving edaravone (EDR).

[0366] Embodiment 108. The use according to any one of Embodiments 104 to 107, wherein the improved therapeutic index is measured by a lower percentage of weight loss (cachexia) of the subject receiving the compound or composition compared to the subject receiving edaravone (EDR).

[0367] 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).

[0368] Embodiment 110. The use according to Embodiment 109, wherein the improved pharmacokinetics includes an increase in the bioavailability of the compound or composition compared to edaravone (EDR).

[0369] Embodiment 111. The use according to any one of Embodiments 92 to 110, wherein the mammal is a human.

[0370] Embodiment 112. The use according to any one of Embodiments 92 to 111, wherein the compound or composition is administered orally and / or intravenously.

[0371] The present invention has been generally described above. A more complete understanding can be obtained by referring to the following specific embodiments. These embodiments are for illustrative purposes only and do not constitute a limitation unless otherwise specified. Therefore, the present invention should not be construed as being limited to the following embodiments, but should be understood to cover any and all variations that are obvious in light of the teachings provided herein.

[0372] Without further elaboration, it is believed that one skilled in the art can, using the foregoing description and the following exemplary embodiments, make and use the compounds of the present disclosure and practice the claimed methods. Accordingly, the following working examples specifically point out typical aspects and should not be construed as any limitation to the present disclosure.

[0373] Examples

[0374] Example 1Synthesis, Characterization, and Development of Boron-Based EDR Analogs

[0375] B 5 -EDR analogs can be used as prodrugs through oxidative transformation.

[0376] Methods: B 5 -EDR analogs were synthesized and the in vitro conversion of B 5 -EDR analogs to EDR as prodrugs was evaluated.

[0377] The synthesized compounds are as follows:

[0378]

[0379] Experiments

[0380] General Instructions: 1 1H and 13 13C nuclear magnetic resonance (NMR) spectra were recorded on Bruker 400 MHz and 300 MHz spectrometers (Billerica, MA, USA), using DMSO-d6 (CAS-2206-27-1), acetone-d6 (CAS-666-52-4), chloroform-d6 (CAS-865-49-6), methanol-d6 (CAS-811-98-3) (Acros organics, Switzerland) as solvents and tetramethylsilane (TMS) as the internal standard. 2.5 M hexane solution of n-butyllithium, product of Acros organics, Germany (CAS-109-72-8); 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS-61676-62-8), purchased from Sigma-Aldrich, St. Louis, MO, USA; 3-methyl-1-phenyl-1H-pyrazole (Catalog No.: AK139802), purchased from Ark Pharm, Inc., Arlington Heights, IL, USA; 3-(trifluoromethyl)-1-phenyl-1H-pyrazole (CAS-99498-65-4), AKScientific Ahern Ave, city CA, USA; cuprous oxide (CAS-1317-39-1), purchased from Sigma-Aldrich, St. Louis, MO, USA; potassium bifluoride (CAS-7789-29-9), purchased from Sigma-Aldrich, St. Louis, MO, USA. Reactions were monitored by TLC (Sigma, Silica gel 60F 254 ) and the crude reaction mixtures were purified by silica gel column chromatography on Purification was carried out on an Rf 200 purification system (Teledyne Isco, USA). Unless otherwise stated, organic solvents were purchased from BDH, VWR Analytical. Unless otherwise stated, all chemicals were used without further purification.

[0381] Scheme I: N - arylpyrazole boronic acid pinacol ester is synthesized from commercially available N - arylated substituted pyrazole starting materials through a two - step in - situ synthesis process. Scheme II: Potassium N - arylpyrazole trifluoroborate is synthesized from N - arylpyrazole boronic acid pinacol ester.

[0382] This synthetic route involves the synthesis of N-arylpyrazole boronic acid pinacol ester from commercially available N-arylated substituted pyrazoles as starting materials through a two-step in-situ synthesis process. The first step involves lithiation of the C-5 position of N-arylated substituted pyrazole with n-butyllithium (n-BuLi) via the directed ortho-metallation (DOM) mechanism. The second step involves electrophilic substitution of the lithium at the C-5 position with isopropoxy 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (PINBOP). Subsequently, acidic workup is carried out to obtain N-arylpyrazole boronic acid pinacol ester as our proposed first EDR (B 5 -EDR) prodrug.

[0383]

[0384] Scheme I. Synthesis of N-arylpyrazole boronic acid pinacol ester from commercially available N-arylated substituted pyrazoles.

[0385] The 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 according to the reported procedure below with minor modifications, Scheme I

[46] .

[0386] Under argon at -78 °C, n-butyllithium (2.5 M hexane solution, 1.5 cm 3 , 3.793 mmol) was added dropwise to a solution of N-arylated substituted pyrazole (500 mg, 0.471 cm 3 , 3.161 mmol) in anhydrous THF (22 cm 3 ). 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 warmed to room temperature (r.t., RT) 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 diatomaceous earth and washed with EtOAc (100 cm 3) Washing. The organic solvent was removed under vacuum to obtain the crude product. The expected product was confirmed by TLC (20% EtOAc / hexane). Then, the crude product was purified by silica gel column chromatography on a Rf 200 purification system (Teledyne Isco, USA) with ethyl acetate and hexane (0% to 10%). The residual solvent was evaporated under vacuum to obtain a light brown crystalline solid (815 mg, 90%).

[0387] Compound (NS-1-2) was synthesized according to the following reaction procedure, and its structure was characterized by 1 H and 13 C NMR.

[0388] 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1-phenyl-1H-pyrazole (NS-1-2): A prodrug of edaravone. Crystalline solid (815 mg, 90%); 1H NMR (400 MHz, CDCl3-d6) δ 7.52 - 7.49 (2H, m, J = 12 Hz), δ 7.40 - 7.36 (2H, m, J = 16 Hz), 7.33 - 7.29 (1H, m, J = 16 Hz), δ 6.66 (1H, S), δ 2.35 (3H, S) δ 1.26 (12H, S); 13C NMR (300 MHz, DMSO-d6) δ 147.4, 139.4, 127.0, 125.7, 122.4, 115.9, 82.7, 22.9, 11.4 (C ipso to B not detected).

[0389]

[0390] The representative experimental procedure for the synthesis of 3-trifluoromethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1-phenyl-1H-pyrazole was carried out according to the following reported procedure with minor modifications, Scheme I

[46] .

[0391] Under argon at -78 °C, n-butyllithium (2.5 M hexane solution, 1.4 cm 3 , 3.5 mmol, 1 equiv) was added dropwise to N-arylated substituted pyrazole (617 mg, 0.61 cm 3 , 2.9 mmol) in anhydrous THF (20 cm 3) In a solution. 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 warmed to room temperature over 1 hour, and then acetic acid (180 μL, 3.2 mmol) was added. The mixture was filtered through a pad of diatomaceous earth and washed with EtOAc (100 cm 3 ). The organic solvents were removed in vacuo to give the crude product. The expected product was confirmed by TLC (5% EtOAc / hexane). Subsequently, purification of the crude product was carried out by silica gel column chromatography on a Rf 200 purification system (Teledyne Isco, USA) using ethyl acetate and hexane (0% to 10%). The residual solvent was evaporated in vacuo to give a light brown crystalline solid product (815 mg, 90%).

[0392] Compound (NS-1-12) was synthesized according to the following reaction procedure, and its structure was characterized by 1 H and 13 C NMR.

[0393] 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 (C ipso to B not detected).

[0394]

[0395] Scheme III: 4 - fluoro - N - arylpyrazole boronic acid pinacol ester is synthesized from 4 - fluoro - N - arylated substituted pyrazole starting materials through a two - step in - situ synthesis process.

[0396] The synthetic route involves the synthesis of potassium N-arylpyrazole trifluoroborate from N-arylated substituted pyrazole boronic acid pinacol esters. It is a three-step synthesis, including a lithiation reaction in the first step, a boronation reaction in the second step to give N-arylated pyrazole boronic acid pinacol esters, and then conversion of the pinacol borate ester to the corresponding trifluoroborate ester with aqueous potassium hydrogen fluoride

[47] .

[0397]

[0398] Scheme II: Synthesis of potassium N-arylpyrazole trifluoroborate from N-arylated substituted pyrazole pinacol borate.

[0399] The representative procedure for the synthesis of potassium N-arylpyrazole trifluoroborate from N-arylated substituted pyrazole pinacol borate was carried out according to the procedure reported below with slight modification

[47] .

[0400] To a stirred solution of borate 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. New spots appeared on the TLC after 1 hour and 2.5 hours, and the reaction was complete. The crude reaction mixture obtained was filtered through an 11 cm whatman filter paper, and the filter paper was thoroughly washed with hot acetone to filter out all the products from the crude reaction mixture. The residue left on the filter paper was a white amorphous solid, which was dissolved in ethyl acetate and TLC was observed under UV. There was no spot corresponding to the product. The filtrate was concentrated in vacuo to remove all volatile substances. The resulting waxy syrup was redissolved in 50% aqueous MeOH (4 mL) and all volatile substances were evaporated again on a rotary evaporator (5 - 1 mbar / 45 - 50 °C; the undesirable bumping of the mixture can be significantly reduced by adjusting the rotation speed). This evaporation - dissolution cycle was repeated until the 1 1H NMR analysis showed that the pinacol content was less than 1 mol%. The evaporation - dissolution cycle was optimized for the synthesis of the prodrug. For the synthesis of the prodrug, the optimized cycle was 10. The final concentrated residue was an amorphous solid, which was finally dried overnight on a desiccator to give a white amorphous solid product (815 mg, 90%). Some minor product losses were mainly related to the evaporation / drying / material transfer operations. All compounds (NS-1-21, NS-1-19) were synthesized according to this reaction procedure. Their structures were characterized by 1 1H and 13 13C NMR.

[0401] Potassium trifluoro(3-methyl-1-phenyl-1H-pyrazol-5-yl)borate (NS-1-21): A prodrug of edaravone.

[0402] 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 (C ipso to B not detected).

[0403]

[0404] Potassium trifluoro(3-trifluoromethyl-1-phenyl-1H-pyrazol-5-yl)borate (NS-1-19):

[0405] 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 (C ipso to B not detected).

[0406]

[0407] Figure 3 Figure 4A

[0408] This synthetic route involves the synthesis of 4-fluoro-N-arylated pyrazole boronic acid pinacol ester from a 4-fluoro-N-arylated substituted pyrazole starting material through a two-step in-situ synthesis process. The first step involves the N-arylation of pyrazole with arylboronic acid in methanol at room temperature using heterogeneous copper(I) oxide under base-free conditions. The second step involves the lithiation of the C-5 position of the N-arylated substituted pyrazole with n-butyllithium (n-BuLi) through a direct ortho-metalation (DOM) mechanism. The second step involves the electrophilic substitution of the lithium at the C-5 position with isopropoxy 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (PINBOP). Then an acidic workup is carried out to obtain 4-fluoro-N-arylated pyrazole boronic acid pinacol ester

[48] .

[0409]

[0410] Figure III: Synthesis of 4-fluoro-N-arylpyrazole boronic acid pinacol ester from 4-fluoro-N-arylated substituted pyrazole starting materials.

[0411] The 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 according to the procedure reported below with minor modifications [46,48].

[0412] The first step involves N-arylation of pyrazole with arylboronic acid under ambient conditions. 1 mol% Cu2O (10 mmol, 1.02 equiv) was added to a mixture of pyrazole (10 mmol, 1 equiv) and arylboronic acid (10 mmol, 1.2 equiv) in methanol (3 ml / mol) at room temperature, and the mixture was stirred for 5 h under an air atmosphere. The progress of the reaction was monitored by TLC. After completion of the reaction, the crude reaction mixture was concentrated under reduced pressure to obtain the crude product. Then, the crude product was purified by silica gel column chromatography on an Rf200 purification system (Teledyne Isco, USA) using ethyl acetate and hexane (0%-2%). The residual solvent was evaporated in vacuo to obtain a light green waxy syrup, which was allowed to stand in an ice bath for 20 min to precipitate green crystals, giving the product in light green crystalline form (2096 mg, 90.8%). Compound (NS-1-22) was synthesized according to this reaction procedure. Its structure was characterized by 1 H and 13 13C NMR.

[0413] In the second step, under argon at -78 °C, n-butyllithium (2.5 M hexane solution, 1.4 cm 3 , 3.5 mmol, 1 equiv) was added dropwise to a solution of N-arylated substituted pyrazole (667 mg, 2.9 mmol, 1 equiv) in anhydrous THF (20 cm 3 ). The reaction mixture was stirred at -78 °C for 45 min. At -78 °C, 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, and the mixture was stirred for 1.5 h. The mixture was warmed to room temperature over 1 h and acetic acid (180 μL, 3.2 mmol) was added. The mixture was filtered through a pad of diatomaceous earth and washed with EtOAc (100 cm 3 ). The organic solvents were removed in vacuo to obtain the crude product. The expected product was confirmed by TLC (20% EtOAc / Hex). Then, the crude product was purified by silica gel column chromatography on an The crude product was purified with ethyl acetate and hexane (0% to 5%) on an Rf 200 purification system (Teledyne Isco, USA). The residual solvent was evaporated under vacuum to obtain a crude product in the form of a waxy syrup. The syrup was dissolved in pure hexane and left to stand overnight at -80 °C. After 12 hours, the hexane was removed using a rotary evaporator, and the product was isolated at room temperature as crystals (556 mg, 53.8%). Compound (NS-1-23) was synthesized according to this reaction procedure. Its structure was characterized by 1 H and 13 CNMR.

[0414] 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 (C ipso to B not detected); F19 NMR (300 MHz, DMSO-d6) δ -60.32.

[0415]

[0416] The C-5 position of the EDR pyrazole skeleton was modified using the "boron prodrug method", Figure 5 .

[0417] Results: As shown in Example 2 -B, these analogues were almost quantitatively converted to EDR in vitro using hydrogen peroxide. In fact, B 5 -EDR was successfully converted to EDR in 95% yield using H2O2. Therefore, the synthesized B 5 -EDR compounds can act as EDR prodrugs under oxidative conditions. In addition, Figure 7A shows a variety of synthesized B 5 -EDR analogues.

[0418] Figure 6A : Testing the ability of boron-based EDR analogues as redox regulators

[0419] B 5-EDR analogs can act as independent redox regulators through the antioxidant action of boron and as neuroprotective agents in a manner similar to EDR, including having a neurotoxicity / cell viability profile similar to that of EDR.

[0420] Methods: The in vitro properties and antioxidant capacity of synthetic B 5 -EDR analogs were evaluated in cell-based assays. B 5 -EDR analogs were synthesized as described in Example 1 and the neurotoxicity / neuroprotective effects of B Figures 7A - 7C -EDR analogs, EDR, and H2O2 were evaluated in (i) primary cortical neuronal cells (Figure 6) (ii) neuroblastoma-spinal cord hybrid NSC-34 cells ( 5 -C and 8A-B); the neurotoxicity / neuroprotective effects were compared to control / EDR by WST-8 assay (a neurotoxicity marker). A detailed description of the methods employed in each of these assays is provided below.

[0421] (i) Method for neurotoxicity / cell viability analysis of primary cortical neuronal cells ( Figures 8A - 8B -B): Briefly, the cerebral cortex was isolated from fetal mice at approximately 17 to 18 days of gestation. After removing the meninges and blood vessels, the tissue was digested with trypsin at approximately 37 °C for approximately 15 minutes and then incubated with DNase at approximately 37 °C for approximately 15 minutes, and the reaction was terminated 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 the cells were triturated by gently pipetting. The neuronal cells contained in the supernatant were transferred to poly-D-lysine-coated plastic culture plates and adjusted to approximately 10 6cells / ml and cultured in Neurobasal medium containing GS21 supplement (Sigma - Aldrich Canada), 1X GlutaMax (Life Technologies Inc,), and approximately 1% penicillin - streptomycin at approximately 37°C and approximately 5% CO2. Inoculated into 96 - well plates at approximately 100k cells / 100μL / well and cultured for 2 Div. At 2 Div, neurons were treated with different concentrations of EDR (1, 10, and 25 μM) and EDR analogs NS - 1 - 2, NS - 1 - 12, NS - 1 - 13, NS - 1 - 19, and NS - 1 - 21 (1 μM, 10 μM, and 25 μM) and incubated until 8 Div. At 8 Div, approximately 10 μL of WST reagent was added to each well and incubated for approximately 2 hours. After incubation for approximately 2 hours, the absorbance of the soluble colored formazan dye at approximately 450 nM was measured colorimetrically using a microplate reader (Biotek instruments), with the blank as the background control. Cell viability was determined by comparing the absorbance of compound - treated cells with that of control cells. Data represent two independent experiments with six measurements or dose tests each time.

[0422] (ii) (NSC - 34) cell neurotoxicity / cell viability analysis method ( Figure 6A ): Briefly, NSC - 34 cells were inoculated into 96 - well plates at approximately 20,000 (20k) cells / well and cultured in complete medium for approximately 20 hours to reach approximately 70% to approximately 75% confluence. The complete medium consisted of high - glucose Dulbecco's modified eagle medium (DMEM) (ThermoFisher Scientific), supplemented with approximately 10% fetal bovine serum of American origin (Thermo Fisher Scientific), GlutaMAX - 1, approximately 200 mM (100X) (Thermo Fisher Scientific), approximately 1% of 100 mM sodium pyruvate, and approximately 1% 10,000 U / mL penicillin - streptomycin solution (Thermo Fisher Scientific). All cells were cultured in an incubator at approximately 37°C and approximately 5% CO2. Inoculated into 96 - well plates at approximately 20,000 cells / 100μL / well and cultured for approximately 20 hours, repeated three times. Cells were treated with different concentrations of the compound 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 incubation for approximately 2.5 hours, the absorbance of the soluble colored formazan dye at approximately 450 nM was measured colorimetrically using a microplate reader (Biotek instruments), with the blank as the 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 measured three times.

[0423] (iii) (NSC-34) cell neuroprotective effect / cell viability analysis method ( Figure 6B ): Briefly, NSC-34 cells were seeded at approximately 20,000 cells / well in a 96-well plate and cultured in complete medium for approximately 20 hours to reach a confluence of approximately 70% to approximately 75%. The complete medium consisted of high-glucose Dulbecco's modified eagle medium (DMEM) (ThermoFisher Scientific), supplemented with approximately 10% fetal bovine serum of US origin (Thermo Fisher Scientific), GlutaMAX-1, approximately 200 mM (100X) (Thermo Fisher Scientific), approximately 1% 100 mM sodium pyruvate, and approximately 1% of 10,000 U / mL penicillin-streptomycin solution (Thermo Fisher Scientific). All cells were cultured in an incubator at approximately 37 °C and approximately 5% CO2. Approximately 20,000 cells / 100 μL / well were seeded in a 96-well plate, cultured for approximately 20 hours, and repeated three times. Approximately 20 hours later, the medium was changed, and the cells were pretreated or prophylactically treated with different doses of EDR analogs and EDR for approximately 1 hour. Approximately 1 hour later, the cells were treated with 250 μM H2O2 for approximately 2 hours. Approximately 3 hours in total, approximately 10 μL of WST-8 reagent was added to each well, and the absorbance readings were recorded at 450 nm after approximately 2.5 hours. All experiments were repeated at least three times and measured three times.

[0424] Results:

[0425] (i) Neurotoxicity / cell viability analysis of primary cortical neurons: As Figure 7A shown, the cell viability results of the two test analogs (NS-1-2 and NS-1-12) were similar to those of EDR, and there seemed to be no decrease in cell viability at concentrations of 1 μM and 10 μM. Only at much higher concentrations of 25 μM did all compounds, including EDR, show a decrease in cell viability. Therefore, based on these results, B 5 -EDR analogs do not seem to reduce cell viability more severely than EDR. As Figure 7AAs shown, compared with the control, lower 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 good cell viability of approximately 100% on PCNC. In addition, the cell viability of the analogs was similar to that of EDR. Furthermore, compared with the control (DMSO), higher concentrations (25 μM) of EDR and EDR analogs showed a decrease in PCNC cell viability of approximately (70 ± 10%).

[0426] (ii) Neurotoxicity / cell viability analysis of (NSC-34) cells: As Figure 7B shown, pre-treatment with both EDR and NS-1-2 protected NSC-34 cells from loss of cell viability caused by 250 μM H2O2 and had a neuroprotective effect against H2O2-induced oxidative stress. In this experiment, it was found that both EDR and NS-1-2 had neuroprotective effects in PCNC and NSC-34 cells ( Figures 8A - 8B showing NSC-34 in). As Example 3 shown, compared with the control group, the synthesized EDR analogs showed higher viability and no cytotoxicity and neurotoxicity. In addition, all the tested compounds showed a viability of approximately 90%-100% at almost every concentration (1 μM to 100 μM). Also, very similar to the above PCNC study, the tested compounds showed the same viability compared to the EDR group. Finally, the application of 1 μM to 100 μM of EDR and EDR analogs did not show neurotoxicity and cytotoxicity to NSC-34 motor neuron cells. Based on these viability results, the neuroprotective effects of the EDR analogs were evaluated in the experiments described in (iii). The results of these experiments are shown below.

[0427] (iii) Neuroprotective effect / cell viability analysis in (NSC-34) cells: As Example 4 shown, EDR showed significant dose-dependent H2O2 scavenging. In addition, the results also showed that all five EDR analogs (NS-1-2); (NS-1-13); (NS-1-21); (NS-1-19); (NS-1-12) showed almost equal viability to EDR at a dose of 50 μM (which was statistically significant). In addition, at a lower dose of 25 μM, all five tested EDR analogs (NS-1-2); (NS-1-13); (NS-1-21); (NS-1-19); (NS-1-12) showed better neuroprotective effects than EDR in scavenging the neurotoxic effects of H2O2. This indicates that the EDR analogs are more effective in scavenging H2O2 at lower doses than EDR.

[0428] In addition, four EDR analogs (NS-1-2); (NS-1-13); (NS-1-21); (NS-1-19) showed better neuroprotective effects in scavenging the neurotoxic effects of H2O2 compared to EDR at a lower dose of 1 μM; this again indicates that EDR analogs are more effective than EDR in scavenging the neurotoxic effects of H2O2 at lower doses. Finally, compared to EDR, these analogs had higher neuroprotective effects at lower doses of 1 μM and 25 μM, equivalent neuroprotective effects at 50 μM, and higher doses (i.e., 100 μM) showed a reduced survival rate (10 - 15%).

[0429] Acute toxicity determination of WG37R mice: : Evaluation of the Therapeutic Index and Pharmacokinetic Properties of Boron-Based EDR Analogs

[0430] The synthesized B 5 -EDR analogs can also be used as dual-action therapeutic agents, generating a therapeutic index similar to or better than that of EDR and better pharmacokinetic properties through the advantages of the boron function and by acting as a prodrug of EDR.

[0431] Methods: To evaluate B 5-Pharmacokinetics and biodistribution of EDR analogues compared to EDR. The preliminary study focused on acute administration by single intravenous injection to rats using the most promising lead compounds. Using a population PK approach, the novel compounds were administered to rats by tail vein injection (n = 2 per time point), and the rats were sacrificed at 10 minutes, 20 minutes, 30 minutes, 60 minutes, 120 minutes, and 4 hours, 8 hours, 12 hours, and 24 hours, respectively. Blood was drawn at sacrifice, the blood was purified by liquid-liquid extraction, and the compound concentration was determined by liquid chromatography / mass spectrometry (LC / MS) to construct the concentration-time curve of the group of drugs. Pharmacokinetic models were used to determine the parameters of AUC, Cmax, Kel, and Tpeak. Organs including the brain, heart, kidney, liver, pancreas, spleen, and stomach were collected, and the organ samples were homogenized (added to a Tris-HCl mixture containing protease inhibitors at a ratio of 1:3), subjected to liquid-liquid extraction, and then the level of the compound in the organs was analyzed by LC / MS. This will ensure that there is no preferential regionalization of the drug. Gross dissection and detailed microscopy were also performed to generally obtain basic safety pharmacology / toxicology data. Another group of rats was administered by oral gavage and further analyzed to determine oral pharmacokinetic and biodistribution data. A method for detecting EDR in vivo (rats and SOD1-G37R) was also developed as a proof-of-concept for the biomarker of the B5-EDR compound as a prodrug of EDR, including kinetics. After the rat PK study, a similar experiment was conducted on SOD1-G37R mice by single intraperitoneal injection for acute administration. In addition, the activities of UGT and CYP enzymes on the novel compounds were evaluated using a reaction phenotyping method of substrate consumption. Under specific mass spectrometry conditions, the selected B 5- The metabolic profiles of the EDR analogs were determined to identify possible metabolic pathways. Briefly, the novel B5-EDR analogs were placed into tubes containing buffer, recombinant active hepatic UGTs (UGT1A1, 1A3, 1A4, 1A6, 1A9, 2B4, 2B7, 2B15, 2B17) and CYP (1A2, 2C9, 2C19, 2D6, 3A4) isoforms, as well as the co-activator UDPGA or NADPH as needed. The supernatants were analyzed by mass spectrometry, and the loss of the compound was compared to an initial spiked tube incubated under the same conditions but without the cofactor. A positive control was used for each selective / specific substrate; for example, bilirubin was the positive control for UGT1A1. If no compound loss was observed, the compound was determined to be a "non-substrate". If metabolism was observed, kinetic curves (e.g., Michaelis-Menten kinetics or Sigmoidal kinetics) were determined. The Km and Vmax parameters were determined, which can be used to estimate the intrinsic clearance. The intrinsic clearance is typically used for CYP isoforms to obtain a good indicator of the in vivo clearance. Additional experiments were conducted to detect the 5 - p-glycoprotein liabilities of the B-EDR analogs

[42]

[43] , including studies to evaluate their blood-brain barrier permeability

[44]

[45] .

[0432] Figure 9 : In vivo studies of B5-EDR analogs in a mouse ALS model

[0433] The synthesized B 5 - EDR analogs can be used as candidate drugs for the development of effective therapies for ALS patients. Therefore, efficacy and acute toxicity evaluations were conducted on a mouse ALS model.

[0434] Methods: B 5-EDR analogs were synthesized as described in Example 1. The specific method used in this example is as follows. All statistical analyses were performed using GraphPad Prism 8 software (version 9.5.1 (733)) (GraphPad Software, La Jolla, CA). Statistical significance was analyzed using a two-tailed unpaired t-test, which was used for body weight assessment, disease onset, survival, and body weight loss comparisons. Kaplan-Meier survival analysis and Log-rank test were also used for survival analysis. For these in vivo studies, disease onset or symptom onset was defined by two criteria. The first criterion was defined as a 10% decrease in the highest body weight recorded during the age of the mice after the treatment study before the appearance of symptoms. A 10% body weight loss was usually accompanied by the appearance of myasthenia symptoms. The second criterion was disease onset, which was retrospectively defined as the age at which the mice reached their peak body weight. Starting at 90 days of age, well before the clinical onset of the disease, trained staff evaluated and monitored the body weight and myasthenia of the mice daily. According to the general consensus in the ALS scientific community, disease onset was defined as the time when the mice reached their peak body weight before muscle atrophy and body weight loss caused by denervation.

[0435] (i) Mouse and tissue preparation:

[0436] Transgenic mice carrying the human G37R mutant SOD1 [B6.Cg Tg(SOD1*G37R)42Dpr / J] were obtained from The Jackson Laboratory (Bar Harbor, ME, USA). These mice were crossed with female mice on a C57BL / 6 background for at least four generations. The colony was maintained by the Central Animal Care Services (CACS) at the University of Manitoba. The use of mice complied with the Guide of Care and Use of Experimental Animals of the Canadian Council on Animal Care. Transgenic offspring were genotyped by PCR of DNA obtained from ear biopsy samples using the protocol provided by The Jackson Laboratory, as described below (ia).

[0437] (ia) DNA isolation and genotyping

[0438] The ear samples were lysed overnight at approximately 55 °C in approximately 300 μL of TNES buffer (approximately 1 M Tris, pH approximately 8.5, approximately 0.5 M EDTA, approximately 10% SDS, approximately 5 M NaCl, distilled water) and approximately 20 μg / μL proteinase K (Sigma). Approximately equal volume of phenol / chloroform (approximately 1:1) was added to the mixture and gently mixed. Then it was centrifuged at approximately 14500 rpm for approximately 15 minutes to separate the debris from the sample, and the supernatant containing DNA was collected. Cold 95% ethanol (47, -20 °C) of approximately equal volume was used to precipitate the DNA, and it was centrifuged at approximately 14500 rpm for approximately 10 minutes to pellet the DNA. The supernatant was discarded, and the pellet was washed with approximately 70% ethanol. Centrifugation was repeated to discard the ethanol. The tube was placed in the fume hood for approximately 1 hour to evaporate the residual ethanol. Then the DNA was resuspended in approximately 30 μL of distilled water and stored at approximately 4 °C until genotyping by PCR. The isolated DNA was used to determine the genotypes of the offspring. Approximately 450 mice from this breeding line were genotyped. 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 MgCl2, approximately 0.25 μL of approximately 10 mM dNTP, 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 above reaction PCR conditions included: initial denaturation at approximately 95 °C for 3 minutes; followed by approximately 35 cycles as follows: a denaturation step at approximately 95 °C for approximately 30 seconds, an annealing step at approximately 55 °C for approximately 30 seconds and an extension step at approximately 73 °C for approximately 45 seconds. Then, a final extension step was carried out at approximately 72 °C for approximately 10 minutes. The PCR products mixed with gel red were separated on approximately 1% agarose gel. Then the gel was visualized on a G:BOX imager using GeneSys imaging software (Syngene, UK).

[0439] (ii) Grouping arrangement, drug preparation, compound storage and administration, Grouping arrangement for acute toxicity determination of WG37R mice:

[0440] WG37R mice were randomly divided into 2 groups: For the first set of experiments, a total of 6 animals (3 females and 3 males) per group were used for the study. Group 1: Sham-treatment group 1 (1:20 DMSO / PBS); Group 2: NS-1-2 (10 mg / kg body weight). According to the requirements of acute toxicity studies, 6 - 10 animals should be used to evaluate the effect of a substance. However, since the new analog is structurally similar to edaravone and the single-dose safety profile is 450 mg / kg, it is expected that the edaravone analog will not cause death at a dose of 10 mg / kg body weight / day. Considering the above facts, for this acute study, the minimum number of animals was 6 per group. During the 14-day acute toxicity assessment, morphological changes, histological changes, and mean body weight assessment of the entire group of animals in the WG37R control group (N = 6; 1:20, DMSO:PBS) and the WG37R treatment group (N = 6; NS-1-2; 10 mg / kg body weight) were evaluated by a single intraperitoneal injection in 2-month-old mice (for more details, see (iia) below).

[0441] (ii) Grouping arrangement, drug preparation, compound storage and administration, Grouping arrangement for the chronic toxicity determination of WG37R mice:

[0442] WG37R mice were randomly divided into 2 groups: For the second set of experiments, a total of 6 animals (3 females and 3 males) per group were used for the study. Group 3: Sham-treatment group 1 (1:20 DMSO / PBS); Group 4: NS-1-2 (10 mg / kg body weight). According to the requirements of acute toxicity studies, 6 - 10 animals should be used to evaluate the effect of a substance. However, since the new analog is structurally similar to edaravone and the single-dose safety profile is 450 mg / kg, it is expected that the edaravone analog will not cause death at a dose of 10 mg / kg body weight / day. Considering the above facts, for this acute study, the minimum number of animals was recommended to be 6 per group. During the 120-day chronic toxicity assessment, morphological changes, histological changes, and mean body weight assessment of the entire group of animals in the WG37R control group (N = 5; 1:20, DMSO:PBS) and the WG37R treatment group (N = 6; NS-1-2; 10 mg / kg body weight) were evaluated by 120 daily intraperitoneal injections in 3-month-old mice. Only one male mouse in Group 3 (control group) died accidentally, probably due to an accidental error in injection (discussed with the Central Animal Care Service, veterinarian, and staff). Intraperitoneal injection may be difficult due to the aggressiveness of mice (especially male mice during body restraint). Overall, 1440 (12 X 120) daily intraperitoneal injections were recommended for chronic toxicity assessment (for more details, see (iia) below).

[0443] (iia) Formulation, storage, and route of administration for acute and chronic toxicity assays:

[0444] For intraperitoneal administration, the NS-1-2 test substance was suspended in approximately 1:20 DMSO / PBS with a pH of approximately 7.4. Edaravone was dissolved in approximately 1 mL of approximately 1 mol / L NaOH solution, adjusted to a pH of approximately 7.4 with the addition of approximately 1 mol / L HCl, and then diluted with saline. An aliquot of approximately 400 μL was taken from the final reconstituted solution and stored at approximately -80 °C until further use. For the acute toxicity experiment, the NS-1-2 was administered as a single intraperitoneal injection of approximately 10 mg / kg body weight to Group 2 (2-month-old WG37R mouse model). The WG37R mice in Group 1 were injected with an equal volume of approximately 1:20 DMSO:PBS. For the chronic toxicity experiment, the NS-1-2 was administered intraperitoneally 120 times at a daily dose of approximately 10 mg / kg body weight to Group 4 (3-month-old WG37R mouse model) for 120 days until 7 months of age. The WG37R mice in Group 3 received an injection of an equal volume of approximately 1:20 DMSO:PBS.

[0445] (iib) Hematoxylin and eosin (H&E) staining and microscopy

[0446] Wild-type (WT) G37R mice at 2 months of age received a single intraperitoneal injection of Sham (vehicle) suspended in (approx. 1:20; DMSO:PBS) at a volume of approximately 0.2 ml, and a single intraperitoneal injection of NS-1-2 at a dose of approximately 10 mg / kg body weight (approx. 0.2 ml) suspended in approximately 1:20 DMSO:PBS. Mice were observed for 2 weeks. At the end of the experiment, mice were first deeply anesthetized with approximately 20% v / v isoflurane / propylene glycol mixture (approx. 1 ml of the mixture per approximately 500 ml of bell jar space, University of Manitoba Animal Care SOP A003), then bled by cutting the right atrium of the animal, and then perfused intracardially with approximately 0.9% NaCl. During perfusion, prolonged anesthesia was maintained using a syringe barrel nasal cone. After cardiac perfusion, the mice were perfused 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 solution at approximately 4 °C for approximately 48 hours. Only the spinal cord was processed after approximately 24 hours to remove the vertebral column and fixed again for approximately 24 hours. Samples were processed and embedded in paraffin blocks at the Histomorphology and Ultrastructural Imaging platform of the Department of Human Anatomy and Cell Science, University of Manitoba. Briefly, the embedded tissues were cut into approximately 5 μm thick sections, placed on super frost plus slides, and dried overnight at approximately 37 °C. The slides were dewaxed in approximately two changes of xylene and rehydrated in decreasing alcohols (approx. two changes of approximately 100% ethanol and approx. two changes of approximately 95% ethanol) and tap water. They were stained with Harris Haematoxylin, then differentiated with acidic alcohol. After rinsing with tap water, the nuclei were blued with saturated lithium carbonate. After that, the slides were rinsed with tap water and counterstained with eosin. After eosin staining, the slides were dehydrated in increasing alcohols, cleared with xylene, and a coverslip was placed over the sections with paramount mounting medium.

[0447] The mounted slides were then visualized and images were acquired using an Axioskop 2 mot plus microscope and AxioVision software version 4.8 (Carl Zeiss, Inc., Thornwood, NY).

[0448] Similar to the acute toxicity experiment, animals assigned to the chronic toxicity group were subjected to hematoxylin and eosin (H&E) staining and microscopic examination (data not shown here).

[0449] (iii) In the SOD1-G37R mouse model of ALS, the grouping arrangement was carried out to determine the therapeutic effects (reducing weight loss (cachexia), delaying disease onset, and prolonging survival) of the B 5 -EDR analog compared directly with the control group / sham-treatment group.

[0450] For these experiments, a set of experiments was conducted on two groups of mice:

[0451] Group 1: Sham-treatment group (1:20 DMSO / PBS); and

[0452] Group 2: NS-1-2 treatment group (1:20 DMSO / PBS) (10 mg / kg body weight / day).

[0453] In these experiments, age-matched Het G37R (42 line) mice were administered a vehicle (1:20, DMSO:PBS) or treatment (NS-1-2; 10 mg / kg body weight) daily from 90 days of age until 210 days of age, and several important humane endpoint indicators were monitored daily, including: a) the mouse was unable to right itself within 15 seconds, b) a 25% decrease in body weight relative to the highest recorded weight, c) complete paralysis of one or more hind limbs, d) loss of bladder function, e) eye crusting / loss of vision, and / or f) penile prolapse.

[0454] For the weight loss experiment, the weight loss was based on the highest recorded weight (humane endpoint).

[0455] For the disease onset experiment, the onset of symptoms was evaluated (i.e., a 10% weight loss based on the highest recorded weight accompanied by muscle weakness, the time to peak body weight (days)), and was assessed and monitored daily by trained staff starting from 90 days of age, that is, several important humane endpoint indicators were also monitored daily before the appearance of disease symptoms, including a) the mouse was unable to right itself within 15 seconds, b) a 25% decrease in body weight relative to the highest recorded weight, c) complete paralysis of one or more hind limbs, d) loss of bladder function, e) eye crusting / loss of vision, f) penile prolapse. A one-tailed (unpaired t-test) was performed to analyze the age at which (10%) weight loss was reached.

[0456] In addition, to reduce pain / inflammation, the injection sites were alternated between the left and right sides of the animals. To observe the treatment effects in these experiments, the sample size used per group was 12. The mean deviation of the oxidized SOD1 level was 20%. The oxidized SOD1 in the treated group was reduced by at least 30%, the signal-to-noise ratio (S / N ratio) was 1.5, the power was 0.9, the significance level was 0.05, and the required sample size was 12. If fewer samples were used, the data would not be statistically significant. This study will include two additional groups: a sham-treatment group (1M NaOH) and edaravone (10 mg / kg body weight / day) in 1M NaOH. When these groups are added to the experimental protocol, a total of 12 animals (6 males and 6 females) will be used per group. Thus, a total of 48 mice will be used for all experiments.

[0457] Results:

[0458] Figure 10

[0459] (i) Morphological changes: Mice were observed for 2 weeks after receiving a single intraperitoneal injection of NS-1-2 (10 mg / kg body weight, approximately 0.2 mls) suspended in (approximately 1:20; DMSO:PBS) at 2 months of age. From the first day of treatment until day 14, various important humane endpoints such as body weight, appearance, physical condition, and general behavior were monitored daily (for examples of humane endpoints and method (iii) above, see Figure 11 ). During the 2-week monitoring period, no treatment-related acute deaths occurred. Overall daily observations showed normal appearance, normal general behavior, and good physical condition. In addition, a single dose of NS-1-2 at 10 mg / kg body weight did not change the skin, hair color, eyes, mucous membranes, secretions, and excretions, locomotor activity, or autonomic activity of the mice tested (data not shown).

[0460] The chronic toxicity study started at 3 months of age and continued until 7 months of age, with daily administration for 120 days. These experimental results were similar to those of the above acute toxicity study, with 6 animals in each group. Wild-type G37R mice seemed to tolerate daily intraperitoneal injection of NS-1-2 (10 mg / kg / day) for 120 days (a total of 120 intraperitoneal injections, with a total dose of 1200 mg within 120 days). During the 4-month monitoring period, no deaths related to chronic treatment occurred. Daily overall observations showed normal appearance, normal general behavior, and good physical condition. In addition, 120 administrations of NS-1-2 at 10 mg / kg body weight did not change the appearance, fur color, eyes, mucous membranes, secretions, and excretions, locomotor activity, or spontaneous activity of the test mice (data not shown). Daily chronic intraperitoneal injection of NS-1-2 (10 mg / kg / day) for 120 days was tolerated by wild-type G37R mice. In addition, compared with mice treated with the vehicle (1:20, DMSO:PBS), mice treated with NS-1-2 did not show any clinical toxicity symptoms, including decreased average body weight, hunched posture, orbital constriction, piloerection, and reduced activity.

[0461] (ii) Body weight assessment (acute toxicity assessment): As Figure 12 shown, in the wild-type G37R model, acute treatment with the EDR analogue NS-1-2 at a dose of 10 mg / kg body weight did not cause any abnormal changes in the body weight of mice. In addition, there was no significant difference in body weight changes between the control group and the treatment group, further demonstrating its non-toxicity.

[0462] (ii) Body weight assessment (chronic toxicity assessment): As Figure 13 shown, in the wild-type G37R model, chronic treatment with the EDR analogue NS-1-2 at a dose of 10 mg / kg body weight for 120 days did not cause any abnormal changes in the body weight of mice. In addition, there was no significant difference in body weight changes between the control group and the treatment group, further demonstrating its non-toxicity.

[0463] (iii) Histological analysis: As Figure 14As shown, male G37RWT mice received a single intraperitoneal (IP) injection of NS-1-2 at a dose of 10 mg / kg body weight starting from 60 days of age, and there were no significant differences in the stained tissue samples compared to the control group of mice. In addition, no signs of obvious degeneration, inflammation, and necrosis were found in any of the tissues examined. Particularly for the liver, both the control male mice and the treated male mice (NS-1-2) showed a normal lobular structure with a central vein and radial hepatic cords. Normal hepatocytes were observed in the liver tissues of both the control group and the NS-1-2 treatment group, and no signs of inflammatory response were found. For the kidneys, both the control male mice and the treated male mice (NS-1-2) showed a normal glomerular structure, and no pathological changes were observed between the two groups. For the spleen, both the control male mice and the treated male mice (NS-1-2) showed a normal microstructure of white pulp and red pulp, without morphological changes. For the heart, both the control male mice and the treated male mice (NS-1-2) had a normal myocardial morphology. For the lungs, both the control male mice and the treated male mice (NS-1-2) showed a normal lung structure, and no changes in the alveolar structure were seen. For the muscle, both the control male mice and the treated male mice (NS-1-2) showed a normal uniform distribution of polygonal muscle fibers and peripheral nuclei. No fiber degeneration was seen, and both groups were morphologically normal. For the spinal cord, both the control male mice and the treated male mice (NS-1-2) presented a normal morphology with a central canal, neurons, and glial cells. For the brain, both the control male mice and the treated male mice (NS-1-2) presented a normal hippocampal morphology and showed a regular structure in the CA3 region, where the neurons in the pyramidal cell layer (P) were found to be of uniform size and evenly arranged.

[0464] Similarly, as Figure 15As shown, female G37RWT mice received a single intraperitoneal (IP) injection of NS-1-2 at a dose of 10 mg / kg body weight starting at 60 days of age, and there were no significant differences compared to control mice in stained tissue samples. In addition, no signs of significant degeneration, inflammation, or necrosis were found in any of the tissues examined. Specifically for the liver, both control female mice and treated female mice (NS-1-2) showed a normal lobular structure with a central vein and radial hepatic cords. Normal hepatocytes were observed in the liver tissues of both the control and NS-1-2 treated groups, and no signs of inflammatory response were found. For the kidneys, both control female mice and treated female mice (NS-1-2) showed a normal glomerular structure, and no pathological changes were observed in either group. For the spleen, both control female mice and treated female mice (NS-1-2) showed a normal white pulp and red pulp microstructure with no morphological changes. For the heart, both control female mice and treated female mice (NS-1-2) had a normal myocardial morphology. For the lungs, both control female mice and treated female mice (NS-1-2) showed a normal lung structure with no changes in the alveolar structure. For the muscle, both control female mice and treated female mice (NS-1-2) showed a normal uniform distribution of polygonal muscle fibers and peripheral nuclei. No fiber degeneration was seen, and both groups were morphologically normal. For the spinal cord, both control female mice and treated female mice (NS-1-2) presented a normal morphology with a central canal, neurons, and glial cells. For the brain, both control female mice and treated female mice (NS-1-2) presented a normal hippocampal morphology and showed a regular structure in the CA3 region, where pyramidal cell layer neurons (P) were found to be of uniform size and evenly arranged.

[0465] B 5 -Determination of the therapeutic effect of EDR analogs:

[0466] (i) Survival time: The survival time of mice receiving the EDR analog was also evaluated. It was found that starting at 90 days of age, daily intraperitoneal injections were given until 210 days of age, and the survival time of treated Het G37R (42 line) mice (n = 10 / treatment group) was extended compared to the untreated group (N = 10 / control group). As ii) Body weight loss: shown, the mean survival time was extended from 183.4 days in untreated mice (n = 10 / control group) to 196.7 days in treated mice (n = 10 / treatment group). Using a two-tailed unpaired t-test, this value was statistically significant (P = 0.0276).

[0467] Given the 13.3-day or nearly two-week difference in survival time, it seems that the B 5 -EDR compound NS-1-2 could be an effective therapeutic agent for the G37R mouse model. In addition, as Figure 16As shown, the survival rate (humanitarian endpoint) of HetG37R (Line 42) ALS model mice was examined using the Kaplan-Meier Log-rank (Mantel-cox) test. It was found that mice were intraperitoneally injected (IP, IJ) daily from 90 days of age until 210 days of age, which extended the median survival time from 185 days in untreated mice (n = 10 / control group) to 199.5 days in treated mice (n = 10 / treatment group). This was statistically significant (Log-rank (Mantel-cox) test: P = 0.0107). In addition, the Kaplan-Meier survival curve showed that long-term treatment with NS-1-2 extended the survival age or lifespan of mutant G37R ALS mice by 14.5 days compared to control mutant G37R ALS mice. The survival period data are also presented in tabular form below (Table 1).

[0468] ( (iii) Disease onset (age at which body weight drops by 10% (accompanied by muscle weakness)): As a representative of ALS progression, the change in body weight loss of mice was also evaluated. As Figure 17 shown, daily intraperitoneal injection (IP, IJ) of NS-1-2 treatment from 90 days of age until 210 days of age significantly prevented the percentage of mean body weight loss (humanitarian endpoint) or the percentage of body weight loss due to ALS-induced cachexia (humanitarian endpoint), from 26.76% in untreated mice (n = 10 / control) to 17.55% in treated mice (n = 10 / treatment). Therefore, these results showed that six out of ten animals in the control group had a body weight loss > 25% at the humanitarian endpoint, and the remaining four out of ten animals had a body weight loss > 23.5%, while in the treatment group, no animal had a body weight loss > 25%, nor did any treated animal have a body weight loss > 23.5%, indicating that the treatment group resisted body weight changes; this is a typical feature of ALS progression. In addition, body weight loss is considered a predictor of shortened survival. The body weight loss data are also presented in tabular form below (Table 1).

[0469] (iv) Disease onset (age (days) at which peak body weight is reached): The onset of the disease in mice was also evaluated by measuring the age at which body weight loss reached 10% (accompanied by muscle weakness) based on the highest recorded body weight. As Figure 18As shown, from 90 days of age until 210 days of age, mice were intraperitoneally injected (IP, IJ) daily to delay disease onset, with the mean age (10% body weight loss) increasing from 164.9 days in mice (n = 10 / control) to 188.1 days in mice (n = 10 / treatment). Additionally, compared to the untreated control group, the disease onset in the NS-1-2 treatment group was delayed by approximately 23.2 days. Using a two-tailed unpaired t-test, this was statistically significant (P = 0.0018). Thus, directly compared to the control group, the EDR analog NS-1-2 can delay disease onset. The disease onset data are also presented in tabular form below (Table 1).

[0470] Figure 19 Disease onset was retrospectively defined as the age at which mice reached peak body weight. As ​ shown, from 90 days of age until 210 days of age, daily intraperitoneal injection (IP, IJ) delayed disease onset, with the mean age (time to reach peak body weight) increasing from 131.4 days in mice (n = 10 / control group) to 155 days in mice (n = 10 / treatment group). Additionally, compared to the untreated control group, the disease onset in the NS-1-2 treatment group was delayed by approximately 23.6 days. This was statistically significant (P = 0.0011). Thus, directly compared to the control group, the EDR analog NS-1-2 can delay disease onset. Additionally, as ​ shown, using the Kaplan-Meier Log-rank (Mantel-cox) test to analyze the probability of disease onset (age at which mice reached peak body weight) in Het G37R (Line42) ALS model mice, it was found that from 90 days of age until 210 days of age, daily intraperitoneal injection (IP, IJ) in mice extended the median survival from 131 days in untreated mice (n = 10 / control) to 151 days in treated mice (n = 10 / treatment). This was statistically significant (Log-rank (Mantel-cox) test: P = 0.0013). Additionally, the Kaplan-Meier survival curve showed that compared to control mutant G37R ALS mice, treatment with NS-1-2 extended the disease onset time in mutant G37R ALS mice by 20 days.

[0471] The disease onset data are also presented in tabular form below (Table 1).

[0472] Table 1 below compiles the data provided for outcomes (i)-(iv) in the above treatment effect studies.

[0473] Table 1: B 5 - Comparison of treatment effects between the EDR analog (NS-1-2) and the control group / sham treatment group

[0474]

[0475] The examples provided herein demonstrate that boron-based EDR analogs can have neuroprotective capabilities and limited neurotoxicity. The examples also show that, compared to control / sham-treated mice, in the ALS SOD1-G37R mouse model, mice treated with an EDR analog (such as NS-1-2) had reduced weight loss (cachexia), delayed onset, and extended survival. Thus, in summary, these results indicate that B 5 -EDR analogs are non-acutely toxic, and these tolerable B 5 -EDR analogs may be useful for treating and / or preventing oxidative stress-related (neurodegenerative) diseases, disorders, and / or conditions, such as ALS. In this regard, B 5 -EDR analogs can be standalone compounds that can function as described and exemplified herein, and / or B 5 -EDR analogs can be prodrugs of EDR and can confer improved pharmacokinetic properties to EDR, thereby resulting in improved drug-like properties, such as a longer half-life and good oral formulation.

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Claims

1. A compound having the structure of formula I: its pharmaceutically acceptable salts, its hydrates, its solvates, its tautomers, its geometric isomers, its enantiomers, its diastereomers, its N-oxides, its metabolites, its isotopomers, its isotopic variants, its prodrugs or combinations thereof, wherein: X1 is selected from -BR 8 R 9 or -BR 10 R 11 R 12 ; R 1 to R 7 、R 10 、R 11 and R 12 are each independently selected from H, a halogen group, a hydroxyl group, a cyano group, a nitro group, a mercapto group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heteroatom-containing 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, wherein R 13 to R 17 are each independently selected from H, a halogen group, a hydroxyl group, a cyano group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heteroatom-containing 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 together form a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group; and R 8 and R 9 each independently selected from H, a halogen group, a hydroxyl group, a cyano group, a nitro group, a mercapto group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heteroatom-containing 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.

2. The compound according to claim 1, wherein X1 is -BR 8 R 9 .

3. The compound according to claim 1 or 2, wherein R 8 and R 9 are each independently selected from H, a halogen group, a hydroxyl group, a cyano group, a nitro group, a mercapto group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heteroatom-containing 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. The compound according to any one of claims 1 to 3, wherein R 8 and R 9 are each independently selected from H, a halogen 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.

5. A compound according to any one of claims 1 to 4, wherein R 8 and R 9 are each independently selected from H, a halogen 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 C1-C6 alkyl - C(O)O- group, a substituted or unsubstituted C1-C6 alkyl - O - C(O)- group, a substituted or unsubstituted C1-C6 alkyl - O - C(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.

6. The compound according to any one of claims 1 to 5, wherein R 8 and R 9 are each independently selected from fluoro, chloro, bromo, hydroxy or alkoxy.

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

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

9. A compound according to any one of claims 1, 2, 7 and 8, wherein R 8 and R 9 together form a substituted or unsubstituted -O(C2-C8 alkylene)O- ring.

10. A compound according to any one of claims 1, 2 and 7 to 9, wherein R 8 and R 9 together form -OCH2CH2O-, -OC(CH 3)2 CH2O-, or –OC(CH3)2C(CH3)2O-.

11. A compound according to any one of claims 1, 2, 7 and 8, wherein R 8 and R 9 together form a substituted or unsubstituted -O(C1-C2 alkylene)NH(C1-C2 alkylene)O- ring.

12. A compound according to any one of claims 1, 2 and 7 to 9, wherein 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-.

13. The compound according to claim 1, wherein X1 is -BR 10 R 11 R 12 .

14. The compound according to claim 1 or 13, wherein R 10 , R 11 and R 12 are each independently selected from H, a halogen 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 heteroatom-containing 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. The compound according to any one of claims 1, 13, and 14, wherein R 10 , R 11 , and R 12 are each independently selected from H, a halogen 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. The compound according to any one of claims 1 and 13 to 15, wherein R 10 , R 11 and R 12 are each independently selected from H, a halogen 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 C1-C6 alkyl-C(O)O- group, a substituted or unsubstituted C1-C6 alkyl-O-C(O)- group, a substituted or unsubstituted C1-C6 alkyl-O-C(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.

17. A compound according to any one of claims 1 and 13 to 16, wherein R 10 , R 11 and R 12 are each independently selected from fluoro, chloro, bromo, hydroxy or alkoxy.

18. The compound according to any one of claims 1 to 17, wherein R 1 and R 2 are each independently selected from H, a halogen group, a hydroxyl group, a cyano group, a nitro group, a mercapto group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heteroatom-containing 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. The compound according to any one of claims 1 to 18, wherein R 1 and R 2 are each independently selected from H, a halogen 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. The compound according to any one of claims 1 to 19, wherein R 1 and R 2 are each independently selected from H, a halogen 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.

21. The compound according to any one of claims 1 to 20, wherein R 1 is H or substituted or unsubstituted alkyl, and R 2 is selected from H, a halogen group, a hydroxyl group, a cyano group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heteroatom-containing 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. The compound according to any one of claims 1 to 21, wherein R 1 is H, -CH3, -CH2CH3 or -CH2CH2CH3, and R 2 is selected from H, F, Cl, CN, -CH3, -CH2F, -CHF2 or -CF3.

23. The compound according to any one of claims 1 to 22, wherein R 3 to R 7 are each independently selected from H, a halogen group, a hydroxyl group, a cyano group, a nitro group, a mercapto group, a sulfonyl group, a sulfate group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heteroatom-containing 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, wherein R 13 to R 17 are each independently selected from H, a halogen group, a hydroxyl group, a cyano group, a substituted or unsubstituted amino group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heteroatom-containing 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 together form a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group.

24. The compound according to any one of claims 1 to 23, wherein R 3 to R 7 are each independently selected from H, a halogen group, a cyano group, a nitro group, a sulfate group, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heteroatom-containing 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. The compound according to any one of claims 1 to 24, wherein R 3 to R 7 are each independently selected from H, a halogen 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 boric acid group, a substituted or unsubstituted alkyl borate 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. The compound according to any one of claims 1 to 25, wherein R 3 to R 7 are each independently selected from H, a halogen 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 alkyl-O-C(O)- group, a substituted or unsubstituted C1-C6 alkyl-O-C(O)-C1-C6 alkylene group, -C(O)OH, a boric acid group, a substituted or unsubstituted C1-C6 alkyl borate 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 alkyl heteroaryl group, a substituted or unsubstituted pyridyl group or a substituted or unsubstituted pyrrolyl group.

27. The compound according to any one of claims 1 to 26, wherein R 3 , R 4 , R 6 and R 7 are each independently selected from H, -CH3, -CH2CH3 or -CH2CH2CH 3， and R 5 is selected from H, F, Cl, CN, -CH3, -CH2F, -CHF2 or -CF3.

28. The compound according to any one of claims 1 to 27, wherein the compound is selected from: its pharmaceutically acceptable salts, its hydrates, its solvates, its tautomers, its geometric isomers, its enantiomers, its diastereomers, its N-oxides, its metabolites, its isotopomers, its isotopic variants, its prodrugs or combinations thereof.

29. The compound according to any one of claims 1 to 28, wherein the compound is selected from: Its pharmaceutically acceptable salts, hydrates, solvates, tautomers, geometric isomers, enantiomers, diastereoisomers, N-oxides, metabolites, isotopomers, isotopic variants, prodrugs or combinations thereof, wherein each of R1 to R4 is independently selected from any one of the groups of R 3 to R 7 in the group.

30. The compound according to any one of claims 1 to 29, wherein the compound is selected from: Its pharmaceutically acceptable salts, its hydrates, its solvates, its tautomers, its geometric isomers, its enantiomers, its diastereoisomers, its N-oxides, its metabolites, its isotopomers, its isotopic variants, its prodrugs or combinations thereof, wherein X + is any suitable counterion.

31. The compound according to any one of claims 1 to 30, wherein the compound is selected from: Its pharmaceutically acceptable salts, its hydrates, its solvates, its tautomers, its geometric isomers, its enantiomers, its diastereoisomers, its N-oxides, its metabolites, its isotopomers, its isotopic variants, its prodrugs or combinations thereof, wherein X + is any suitable counterion.

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

33. The compound according to any one of claims 1 to 32, wherein the compound is a non-racemic mixture.

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

35. The compound according to any one of claims 1 to 34, wherein the compound can act as a metal chelator.

36. The compound according to any one of claims 1 to 35, wherein the compound can act as an antioxidant.

37. The compound according to any one of claims 1 to 36, wherein the compound reduces oxidative stress.

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

39. The compound according to any one of claims 1 to 38, wherein the compound can reduce reactive oxygen species (ROS) and / or reactive nitrogen species (RNS) in vitro.

40. The compound according to any one of claims 1 to 39, wherein the compound can reduce reactive oxygen species (ROS) and / or reactive nitrogen species (RNS) in vivo.

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

42. The compound according to claim 41, wherein the radical and / or the oxidant is selected from the group consisting of hydroxyl radical (HO·), superoxide anion radical (O2·-), nitric oxide radical (NO·), nitrogen dioxide radical (NO2·), peroxyl radical (ROO·) and lipid peroxyl radical (LOO·), hydrogen peroxide (H2O2), ozone (O3), singlet oxygen ( 1 O2), hypochlorous acid (HOCl), hydroperoxide nucleophile (-OOH), nitrous acid (HNO2), dinitrogen trioxide (N2O3) and lipid peroxide (LOOH).

43. The compound according to claim 41, wherein the free radical and / or oxidant is hydrogen peroxide (H2O2).

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

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

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

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

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

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

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

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

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

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

54. The compound or composition according to claim 53, wherein the ROS and / or RNS include free radicals and / or oxidants.

55. A compound or composition according to any one of claims 52 to 54, wherein the radical and / or the oxidizing agent is selected from hydroxyl radical (HO·), superoxide anion radical (O2·-), nitric oxide radical (NO·), nitrogen dioxide radical (NO2·), peroxyl radical (ROO·) and lipid peroxyl radical (LOO·), hydrogen peroxide (H2O2), ozone (O3), singlet oxygen ( 1 O2), hypochlorous acid (HOCl), hydroperoxide nucleophile (-OOH), nitrous acid (HNO2), dinitrogen trioxide (N2O3) and lipid peroxide (LOOH).

56. The compound or composition according to claim 54, wherein the free radical and / or oxidant is hydrogen peroxide (H2O2).

57. The compound or composition according to any one of claims 52 to 56, wherein the diseases, disorders and / or conditions associated with oxidative stress are 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 system diseases, disorders and / or conditions, aging, disorders and / or conditions, viral infectious diseases, disorders and / or conditions, cancer and sepsis / septic shock.

58. The compound or composition according to claim 57, wherein the neurodegenerative diseases, disorders and / or conditions are related to motor dysfunction.

59. The compound or composition according to claim 58, wherein the neurodegenerative diseases, disorders and / or conditions related to motor dysfunction are amyotrophic lateral sclerosis (ALS).

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

61. The compound or composition according to claim 59, wherein the ALS is sporadic ALS.

62. A compound or composition according to 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. A compound or composition according to any one of claims 59 to 62, wherein the compound or composition delays the onset of ALS.

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

65. The compound or composition according to claim 64, wherein the therapeutic index is a measure of one or more of the following symptoms: muscle weakness, muscle atrophy (wasting), weight loss (cachexia), fasciculations, muscle cramps, slowness of movement, poor balance, ataxia, change in voice quality, dysarthria, dysphagia, incomplete eyelid closure, drooling, pseudobulbar affect, and / or premature death.

66. The compound or composition according to claim 64 or 65, wherein the improved therapeutic index is measured by an increase in survival / life span of a subject receiving the compound or composition compared to a subject receiving edaravone (EDR).

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

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

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

70. The compound or composition according to claim 69, wherein the improved pharmacokinetics includes an increase in bioavailability of the compound or composition compared to edaravone (EDR).

71. A method of preventing and / or treating a disease, disorder, and / or condition 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. The method according to claim 71, wherein the oxidative stress is caused by reactive oxygen species (ROS) and / or reactive nitrogen species (RNS).

73. The method according to claim 72, wherein the ROS and / or RNS include free radicals and / or oxidants.

74. The method according to claim 73, wherein the free radical and / or the oxidant are selected from hydroxyl radical (HO·), superoxide anion radical (O2·-), nitric oxide radical (NO·), nitrogen dioxide radical (NO2·), peroxy radical (ROO·) and lipid peroxy radical (LOO·), hydrogen peroxide (H2O2), ozone (O3), singlet oxygen ( 1 O2), hypochlorous acid (HOCl), hydroperoxide nucleophile (-OOH), nitrous acid (HNO2), dinitrogen trioxide (N2O3) and lipid peroxide (LOOH).

75. The method according to claim 73, wherein the free radical and / or oxidant is hydrogen peroxide (H2O2).

76. The method according to any one of claims 71 to 75, wherein the diseases, disorders and / or conditions related to oxidative stress are selected from neurodegenerative diseases, disorders and / or conditions, muscular 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 system diseases, disorders and / or conditions, aging, disorders and / or conditions, viral infectious diseases, disorders and / or conditions, cancer, and sepsis / septic shock.

77. The method according to claim 76, wherein the neurodegenerative diseases, disorders and / or conditions are related to motor dysfunction.

78. The method according to claim 77, wherein the neurodegenerative diseases, disorders and / or conditions related to motor dysfunction are amyotrophic lateral sclerosis (ALS).

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

80. The method according to claim 78, wherein the ALS is sporadic ALS.

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

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

84. The method according to claim 83, wherein the therapeutic index is a measure of one or more of the following symptoms: muscle weakness, muscle atrophy (wasting), weight loss (cachexia), fasciculations, muscle cramps, bradykinesia, poor balance, ataxia, change in voice quality, dysarthria, dysphagia, incomplete eyelid closure, drooling, pseudobulbar affect, and / or premature death.

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

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

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

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

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

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

91. The method according to 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 a disease, disorder and / or condition associated with oxidative stress.

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

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

95. The use according to claim 94, wherein the free radical and / or oxidant is selected from hydroxyl radical (HO·), superoxide anion radical (O2·-), nitric oxide radical (NO·), nitrogen dioxide radical (NO2·), peroxyl radical (ROO·) and lipid peroxyl radical (LOO·), hydrogen peroxide (H2O2), ozone (O3), singlet oxygen ( 1 O2), hypochlorous acid (HOCl), hydroperoxide nucleophile (-OOH), nitrous acid (HNO2), dinitrogen trioxide (N2O3) and lipid peroxide (LOOH).

96. The use according to claim 94, wherein the free radical and / or oxidant is hydrogen peroxide (H2O2).

97. The use according to any one of claims 92 to 96, wherein the disease, disorder and / or condition 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 system diseases, disorders and / or conditions, aging, disorders and / or conditions, viral infectious diseases, disorders and / or conditions, cancer and sepsis / septic shock.

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

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

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

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

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

105. Use according to claim 104, wherein the therapeutic index is a measure of one or more of the following symptoms: muscle weakness, muscle atrophy (wasting), weight loss (cachexia), fasciculations, muscle cramps, bradykinesia, poor balance, ataxia, altered voice quality, dysarthria, dysphagia, incomplete eyelid closure, drooling, pseudobulbar affect, and / or premature death.

106. Use according to claim 104 or 105, wherein the improved therapeutic index is measured by an increase in survival / lifespan of a subject receiving the compound or composition compared to a subject receiving edaravone (EDR).

107. Use according to any one of claims 104 to 106, wherein the improved therapeutic index is measured by an enhancement of motor function of a subject receiving the compound or composition compared to a subject receiving edaravone (EDR).

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

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

110. Use according to claim 109, wherein the improved pharmacokinetics includes an increase in bioavailability of the compound or composition compared to edaravone (EDR).

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

112. 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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