Novel benzotriazine dioxide and pharmaceutical composition thereof

Abstract

The present disclosure relates to a novel benzotriazine dioxide and a pharmaceutical composition thereof. The benzotriazine dioxide has a structure of formula (I). The benzotriazine dioxide can be used alone or in combination with other drugs to treat or alleviate benign and malignant tumor disorders in the liver, bile duct, pancreas, stomach, esophagus, kidney, colon, lung, brain (glioma), malignant glioma, breast, ovary, cervical, head and neck, skin, melanoma, prostate, fibrosarcoma, sarcoma, thyroid gland, etc.

Description

FIELD OF THE INVENTION The present disclosure relates to a type of N-benzotriazine dioxides and related derivatives, pharmaceutical compositions, and methods. BACKGROUND OF THE INVENTION The malignant tumor gradually becomes a major disease affecting human life and health, wherein the solid tumor accounts for more than 95%. Chemotherapy and radiation therapy remain important means of tumor treatment, but their therapeutic effects are limited and inevitably produce resistance. A large number of scientific studies have shown that the poor efficacy of chemotherapy and radiotherapy and the development of drug resistance in tumor cells are due to the fact that a portion of tumor cells grow in a hypoxic microenvironment within the tumor. Under hypoxic conditions, chemotherapy and radiotherapy often cannot kill these tumor cells, thereby leading to drug resistance, dissemination, and metastasis of the tumor. Hypoxia is a microenvironment that tumors inevitably experience during their development. The hypoxic microenvironment can directly cause tremendous changes in tumor cells and their surrounding environment, one of the important changes being the induction of neovascularization within the tumor, which provides more oxygen and nutrients to the tumor, thereby leading to tumor cell proliferation, dissemination, and metastasis. It can also lead to altered energy metabolism and biological behaviors such as resistance to conventional chemoradiotherapy. If we can find a drug that can kill tumor cells under hypoxic conditions, combining such a drug that can kill tumor cells under hypoxic conditions with conventional chemotherapeutic drug may maximize the killing and destruction of tumor cells surviving in both aerobic and hypoxic environments within the tumor, thereby enhancing the efficacy of chemotherapeutic medicine against tumors. Currently, research on developing drugs that kill tumors under hypoxia mainly focuses on finding and optimizing hypoxia-activated prodrugs (HAPs) that can kill tumors in the hypoxic microenvironment. Hypoxia-activated prodrugs (HAPs) work by undergoing redox reactions catalyzed by oxidoreductases in tumor cells (or normal cells) under hypoxic conditions (from mild to extreme hypoxia). The direct and indirect results of the redox reaction are the generation of large amounts of free radicals. Free radicals have strong cytotoxic effects, and it is through these free radicals that the killing effect on tumors is achieved. HAP-related drugs have received considerable attention in recent years, and indeed some drugs are in clinical research stages. The key factor for HAP activation under hypoxic conditions is reductases in tumor tissues, including DT-diaphorase, quinone reductase, cytochrome P450 reductase, nitroreductase, and so on. Most of these enzymes are sensitive to oxygen and use nicotinamide adenine dinucleotide (NADH) or nicotinamide adenine dinucleotide phosphate (NADPH) as hydrogen donors to participate in the reduction process of prodrugs. Four classes of chemical groups that have been proven to be activated under hypoxic conditions are: transition metal complexes, quinone compounds, nitrogen oxides (aliphatic nitrogen oxides, aromatic nitrogen oxides), and nitro compounds (nitrobenzene compounds, nitroimidazole compounds). Reduction pathway of tirapazamine in cells Among them, the representative drug of the nitrogen oxide class is tirapazamine (shown above). Between 1997 and 2007, tirapazamine completed multiple Phase I / II / III clinical trials for different clinical indications, with nearly 2,000 people receiving experimental treatment with tirapazamine. Unfortunately, all clinical trials failed to show statistically significant patient benefit. Tirapazamine is a highly specific cytotoxic compound. Under hypoxic conditions, it is reversibly reduced by single-electron reductases (such as cytochrome P450 reductase) to form a radical intermediate. The oxidized hydroxyl radical and benzotriazine radical will abstract an electron from DNA to form a DNA radical (mostly at the C4 position of the ribose ring), thereby causing DNA strand breaks and cell death (as shown above, Int. J. Mol. Sci. 2019, 20, 4602). Preclinical studies have shown that tirapazamine is 15-200 times more active under hypoxia than under aerobic conditions. Nevertheless, tirapazamine still has clinical weaknesses such as poor solubility, rapid in vivo metabolism, poor penetration, inability to achieve sustained therapeutic concentrations in hypoxic regions within tumors, and inability to effectively reach hypoxic regions. Therefore, there is an urgent clinical need to develop a class of small molecule compounds with strong targeting ability, stronger killing ability under hypoxic conditions, novel and unique drug structures, good solubility, and strong drug-likeness. CN114901646A discloses partial work on the structural modification of tirapazamine. However, for in-depth evaluation of drug metabolic stability and hypoxia selectivity, there is a need in the art for a new compound series with greater drug development potential. SUMMARY OF THE INVENTION On the basis of the foregoing, and based on the principles of FBDD and SBDD, combined with physicochemical property analysis and with full consideration of in vitro cellular biological activity, the present disclosure has developed a class of novel compounds, which can be used alone or in combination with other drugs to treat or alleviate benign and malignant tumor including those of the liver, intrahepatic duct, pancreas, stomach, esophagus, kidney, colorectum, lung, brain (glioma), malignant glioma, breast, ovary, cervix, head and neck, skin, melanoma, prostate, fibrosarcoma, sarcoma, thyroid, etc. The present disclosure provides a benzotriazine dioxide having the following formula (I), or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof, The present disclosure also provides a pharmaceutical composition comprising the benzotriazine dioxide or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof and a pharmaceutically acceptable carrier according to the present disclosure. The present disclosure also relates to use of the benzotriazine dioxide or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof, or the pharmaceutical composition according to the present disclosure, in the manufacture of a medicament for treating cancer according to the present disclosure. The present disclosure also relates to a method for treating or alleviating cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of the benzotriazine dioxide or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof according to the present disclosure, or the pharmaceutical composition according to the present disclosure. DETAILED DESCRIPTION OF THE INVENTION The present disclosure is further described in detail below by examples. Through these descriptions, the features and advantages of the present disclosure will become clearer. The word “exemplary” as used herein means “serving as an example, embodiment, or illustration.” Any embodiment described herein as “exemplary” is not necessarily to be construed as preferred or advantageous over other embodiments. In addition, the technical features involved in the different embodiments of the present disclosure described below can be combined with each other as long as they do not conflict with each other. DEFINITIONS Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. Unless otherwise indicated, all patents, patent applications, and publications cited herein are incorporated by reference in their entirety. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient. It should be understood that the above brief description and the following detailed description are exemplary and explanatory only and are not intended to limit the inventive subject matter. In the present disclosure, it must be noted that, unless clearly indicated otherwise in the context, the singular forms used in the specification and claims include the plural forms of the referred-to things. It should also be noted that, unless otherwise indicated, “or” and “and / or” mean “and / or.” In addition, the terms “include” and other forms, such as “comprise / comprises / comprising,” “contain / contains / containing,” and “have / has / having,” are not limiting. Definitions of standard chemical terms can be found in the literature, including Carey and Sundberg, Advanced Organic Chemistry, 4th Ed., Vol. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods within the skill of the art are used, such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacological methods. Unless specific definitions are provided, the nomenclature and laboratory procedures and techniques related to analytical chemistry, organic synthetic chemistry, and medicinal and pharmaceutical chemistry herein are those known to those skilled in the art. Standard techniques can be used for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation, drug delivery, and patient treatment. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). For example, kits with manufacturer’s instructions, methods known in the art, or methods described herein can be used to perform reactions and purification techniques. Generally, the aforementioned techniques and procedures can be performed by conventional methods well known in the art and described in various general or more specific literature, which are cited and discussed in the present disclosure. When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, CH2O is equivalent to OCH2. The term “substituted” means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, provided that the valence of the specific atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced; oxo will not occur on an aromatic group. When any variable (e.g., R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 R, the group may optionally be substituted with up to two R, and each R has independent options. In addition, combinations of substituents and / or variants thereof are permissible only if such combinations result in stable compounds. As used herein, Cm~n means that the moiety has m~n carbon atoms. For example, “C1~8” means that the moiety has 1-8 carbon atoms, i.e., the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms, ... 8 carbon atoms. Thus, for example, “Ci~8 alkyl” means an alkyl group containing 1-8 carbon atoms, i.e., the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, •• • octyl, and the like. Numerical ranges herein, such as “1-8,” refer to each integer in the given range; for example, “1-8 carbon atoms” means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, or 8 carbon atoms. The term “membered” refers to the number of skeletal atoms constituting the ring. For example, pyridine is a six-membered ring, and pyrrole is a five-membered ring. In the present disclosure, each group may have the following definitions: Hydrogen may be represented as -H, and may also be replaced by deuterium, tritium, and other isotopes. Halogen may include fluorine, chlorine, bromine, and iodine. The term “alkyl” as used herein refers to a straight or branched aliphatic group having 112 carbon atoms, preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms, optionally having one, two, or three substituents. Preferred alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. “C0 alkyl” (as in “C0-C3 alkyl”) is a covalent bond. C1~8 alkyl may include methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, heptyl, octyl, and the like. Deuterated C1~8 alkyl means that one or more or even all hydrogen atoms on the C1~8 alkyl are replaced by deuterium, tritium, and other isotopes. The term “alkoxy” as used herein means -O-alkyl, wherein the alkyl is as described herein, including but not limited to -OCH3, -OCF3, -OEt, -OC(CH3)2CH3, and -OCH2CF3. C1~8 alkoxy may be represented as -OC1~8 alkyl, wherein the C1~8 alkyl includes the groups as defined above; for example, C1~8 alkoxy may include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like. C1~8 haloalkyl may be represented as a group obtained by replacing any number of hydrogen atoms in C1~8 alkyl with halogen, wherein the C1~8 alkyl and halogen include the groups as defined above; for example, C1~8 haloalkyl may include -CF3 and the like. Unless otherwise defined, the term “cycloalkyl” as used herein means a non-aromatic saturated or unsaturated monocyclic or polycyclic C3-C12, including but not limited to cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, cyclohexyl, substituted cyclohexyl. C3~8 cycloalkyl may be represented as a non-aromatic saturated carbocycle, including monocyclic (having one ring) and bicyclic (having two rings); for example, C3~8 cycloalkyl may include the following structures and the like: C3~8 cycloalkyl C1~8 alkyl may be represented as C1~8 alkyl substituted with a C3~8 cycloalkyl, wherein C3~8 cycloalkyl and C1~8 alkyl are as defined above; for example, C3~8 cycloalkyl C1~8 alkyl may include cyclopropylmethyl, cyclobutylmethyl, cyclohexylethyl, and the like. “Aryl” refers to a monocyclic or polycyclic aromatic hydrocarbon, including, for example, phenyl, naphthyl, and phenanthryl. C6~20 aryl may include monocyclic aryl, bicyclic aryl, or higher cyclic aryl; for example, it may include phenyl, biphenyl, naphthyl, phenanthryl, anthracenyl, and the like. Unless otherwise indicated, “aryl,” “C6 or C10 aryl,” “C6-10 aryl,” or “aromatic residue” may be unsubstituted or substituted with 1 to 5 groups, preferably 1 to 3 groups, selected from OH, OCH3, Cl, F, Br, I, CN, NO2, NH2, N(CH3)H, N(CH3)2, CF3, OCF3, C(=O)CH3, SCH3, S(=O)CH3, S(=O)2CH3, CH3, CH2CH3, CO2H, and CO2CH3. “Heterocyclyl” or “heterocyclic” group is a ring structure having about 3-12 atoms, wherein the ring structure has one or more heteroatoms selected from N, O, S, and the like. The carbon at one or more positions of the heterocyclyl is optionally substituted. The nitrogen of the heterocyclyl is also independently optionally substituted with alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, or aralkoxycarbonyl. Preferred heterocyclyl groups include, but are not limited to, oxiranyl, thiiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, oxazolidinyl, tetrahydropyrazolyl, pyrrolinyl,     dihydrofuranyl,     dihydrothienyl,     piperidinyl,     tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyranyl, tetrahydropyranyl, dihydrothiopyranyl, azepanyl, oxepanyl, thiepanyl, oxaazabicyclo[2.2.1]heptyl, azaspiro[3.3]heptyl, and the like. In certain preferred embodiments, the heterocyclyl is fused to an aryl, heteroaryl, or cycloalkyl. Examples of such fused heterocycles include, but are not limited to, tetrahydroquinoline and dihydrobenzofuran. The term “heteroaryl” as used herein refers to a group having 5-14 ring atoms, preferably 5, 6, 9, or 10 ring atoms, which has 6, 10, or 14 shared n-electrons in a cyclic arrangement and, in addition to carbon atoms, has 1-3 heteroatoms selected from N, O, and S in each ring. The term “heteroaryl”is also intended to include monocyclic or bicyclic groups. For example, the heteroaryl may be pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, and the like. “Heteroaralkyl” or “heteroarylalkyl” includes a heteroaryl attached to an alkyl via a covalent bond, either of which is independently optionally substituted or unsubstituted. Preferred heteroaralkyl contains C1-C6 alkyl and a heteroaryl having 5, 6, 9, or 10 ring atoms. Examples of preferred heteroaralkyl include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, and thiazolylethyl. For simplicity, reference to “n-m membered” heterocyclyl or heteroaryl means a heterocyclyl or heteroaryl having “n” to “m” ring atoms, wherein “n” and “m” are integers. Thus, for example, 5-6 membered heterocyclyl is a 5- or 6-membered ring having at least one heteroatom, and includes pyrrolidinyl (5-membered ring) and piperidinyl (6-membered ring); 6-membered heteroaryl includes, for example, pyridyl and pyrimidinyl. Hydroxy may be represented as -OH. Mercapto may be represented as -SH. Carboxy may be represented as -COOH. Ester group maybe represented as -COOR’, wherein R’ may be C1~8 alkyl; for example, a C1~8 alkyl-substituted ester group may be represented as -COOC1~8 alkyl, wherein the C1~8 alkyl includes the groups as defined above. Acyl may be represented as -COR’, wherein R’ may be C1~8 alkyl; for example, a C1~8 alkyl-substituted acyl may be represented as -COC1~8 alkyl, wherein the C1~8 alkyl includes the groups as defined above. Amino may be represented as -NH2, -NHR’, or -N(R’)2, wherein R’ may be Ci~8 alkyl; for example, a C1~8 alkyl-substituted amino may be represented as -NHC1~8 alkyl or -N(C1~8 alkyl)2, wherein the C1~8 alkyl includes the groups as defined above. Amido may be represented as -CO-amino, wherein amino is as defined above. Sulfonyl may be represented as -S(O)2R’, wherein R’ may be C1~8 alkyl; for example, a C1~8 alkyl-substituted sulfonyl may be represented as -S(O)2C1~8 alkyl, wherein the C1~8 alkyl includes the groups as defined above. Cyano may be represented as -CN. Oxo may be represented as (=O). In the foregoing definitions, when the number of carbon atoms changes, the above definitions change only according to the number of carbon atoms and do not affect the definition of the group type; for example, “C1~5 alkyl” may include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and the like, i.e., all groups in the foregoing “C1~8 alkyl” definition that have 1-5 carbon atoms. The term “acyloxy” as used herein means -OC(O)alkyl, wherein alkyl is as described herein. Examples of acyloxy substituents used in the present disclosure include -OC(O)CH3,-OC(O)CH(CH3)2, and -OC(O)(CH2)3CH3. The term “N-acylamino” as used herein means N(H)C(O)alkyl, wherein alkyl is as described herein. Examples of N-acylamino substituents used in the present disclosure include -N(H)C(O)CH3, -N(H)C(O)CH(CH3)2, and -N(H)C(O)(CH2)3CH3. The term “aryloxy” as used herein means -O-aryl, wherein the aryl is phenyl, naphthyl, pyridyl, or biphenyl, optionally substituted with one or more substituents selected from alkyl, hydroxyalkyl, alkoxy, trifluoromethyl, acyloxy, amino, N-acylamino, hydroxy, nitro, cyano, halogen, protected hydroxy, and protected amino. The term “heteroatom” as used herein means oxygen, nitrogen, sulfur, silicon, and phosphorus. The term “halogen” as used herein means a substituent selected from bromine, iodine, chlorine, and fluorine. The term “treatment” and derivatives thereof as used herein mean prophylactic and therapeutic treatment. All publications cited in this specification, including but not limited to patents and patent applications, are incorporated herein by reference in their entirety. The term “protected hydroxy” or “protected -OH, -NH2” as used herein means the relevant group in an alcohol, carboxylic acid, amine, or amide, which can be protected by conventional protecting groups in the art. Compounds containing protected hydroxy or amino groups can also be used as pharmaceutically active compounds of the present disclosure. COMPOUNDS The present disclosure provides a benzotriazine dioxide having the following formula (I), or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof: R2, R4, and R5 are selected from the group consisting of hydrogen, halogen, C1-C10 alkyl optionally substituted with R40, C1-C10 alkoxy optionally substituted with R40, C3-C10 cycloalkyl optionally substituted with R40, C6-20 aryl optionally substituted with R40, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with R40, and 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with R40; wherein R40 is each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl; R3 is selected from the group consisting of halogen, C1-C10 alkyl optionally substituted with R50, C1-C10 alkoxy optionally substituted with R50, C3-C10 cycloalkyl optionally substituted with R50, C6-20 aryl optionally substituted with R50, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with R50, and 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with R50; wherein R50 is each independently selected from the group consisting of hydrogen, oxygen, halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl; X is selected from the group consisting of NH, S, Se, CHF, C(=S), S(=O) and S(=O)2; RX is selected from one of the following groups: C1-10 alkyl optionally substituted with RX1, C3-10 cycloalkyl optionally substituted with RX1, R8 R9 >My-Rio \ (formula A), (formula B),          (formula C); wherein RX1 is each independently selected from the group consisting of halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C10 alkyl, C1-C10 haloalkyl, C1-C10 alkoxy, C3-C10 cycloalkyl, C6-20 aryl optionally substituted with RX11, 5- to 10-membered heteroaryl containing a heteroatom selected from the group consisting of O, S, and N and optionally substituted with RX11, 5- to 10-membered heterocyclyl containing a heteroatom selected from the group consisting of O, S, and N and optionally substituted with RX11, and -NR6R7; wherein RX11 is each independently selected from the group consisting of halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl; R6 and R7 are each independently selected from the group consisting of hydrogen, C1-C10 alkyl optionally substituted with RX12, C1-C10 alkoxy optionally substituted with RX12, C3-C10 cycloalkyl optionally substituted with RX12, C6-20 aryl optionally substituted with RX12, 5- to 10membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with RX12, and 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with RX12; wherein RX12 is each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl; or R6 and R7 together with the nitrogen atom to which they are attached form a 5- to 10-membered ring structure; in formula A, R8 and R9 are each independently selected from the group consisting of hydrogen and C1-C6 alkyl, or R8 and R9 together with the C atom to which they are attached form a C3-C6 ring structure; Y is selected from one of the following:   O, S, Se, C(=S),  NR6, ; * represents a site where Y is attached to CR8R9;      represents a site where Y is attached to R10; R10 is selected from the group consisting of hydrogen, C1-C20 alkyl optionally substituted with R30, C1-C20 haloalkyl optionally substituted with R30, C1-C10 alkoxy optionally substituted with R30, C3-C10 cycloalkyl optionally substituted with R30, C2-C20 alkenyl optionally substituted with R30, C6-20 aryl optionally substituted with R30, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with R30, and 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with R30, wherein R30 is each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C6-20 aryl, C6-20 aryloxy, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N, 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N, and C3-C6 cycloalkenyl optionally substituted with R31; wherein R31 is each independently selected from the group consisting of hydrogen, halogen, and C1-C6 alkyl; n is an integer from 1 to 11; in formula B, R20 is selected from the group consisting of hydrogen and -C(=O)R21, wherein R21 is selected from the group consisting of hydrogen, C1-C20 alkyl optionally substituted with R22, C1-C20 haloalkyl optionally substituted with R22, C1-C10 alkoxy optionally substituted with R22, C3-C10 cycloalkyl optionally substituted with R22, C2-C20 alkenyl optionally substituted with R22, C6-20 aryl optionally substituted with R22, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with R22, and 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with R22, wherein R22 is each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C6-20 aryl, C6-20 aryloxy, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N, 5- to 10membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N, and C3-C6 cycloalkenyl optionally substituted with R23; wherein R23 is each independently selected from the group consisting of hydrogen, halogen, and C1-C6 alkyl; m is an integer from 1 to 10; in formula C, k is an integer from 1 to 10. The inventors of the present disclosure have found that by rationally selecting X and the RX group, the resulting compounds and their salts and metabolites have excellent hypoxic activity and good metabolic stability, and also have good water solubility (easy to form salts), and have potential clinical application value in the treatment of solid tumors including liver cancer, cholangiocarcinoma, lung cancer, gastric cancer, and the like. In one embodiment, R2, R4, and R5 are all hydrogen. That is, the 7-position of the benzotriazine ring bears the substituent R3, and the 3-position is connected to -X-RX. In one embodiment, R3 is selected from bromo, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, Me, Et, nPr, iPr, cyclopropyl, nBu, iBu, tBu cyclopropyl, cyclobutyl, cyclopentyl, difluoromethyl, trifluoromethyl, and trifluoroethyl. In one embodiment, R3 is bromo. In one embodiment, R3 is trifluoromethyl. In one embodiment, R3 is trifluoromethoxy. In one embodiment, R3 is methoxy. Depending on the selection of RX, in one embodiment, the benzotriazine dioxide has the following formula II-1, formula II-2, or formula II-3: II-1                         II-2                               II-3 wherein, in formula II-1, formula II-2, and formula II-3, R3 is selected from the group consisting of halogen, C1-C10 alkyl optionally substituted with R50, C1-C10 alkoxy optionally substituted with R50, C3-C10 cycloalkyl optionally substituted with R50, C6-20 aryl optionally substituted with R50, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with R50, and 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with R50; wherein R50 is each independently selected from the group consisting of hydrogen, oxygen, halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl; X is selected from the group consisting of NH and CH2, in formula II-1, R0 is selected from the group consisting of C1-10 alkyl optionally substituted with RX1 and C3-10 cycloalkyl optionally substituted with RX1; wherein RX1 is each independently selected from the group consisting of halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C10 alkyl, C1-C10 haloalkyl, C1-C10 alkoxy, C3-C10 cycloalkyl, C6-20 aryl optionally substituted with RX11, 5- to 10-membered heteroaryl containing a heteroatom selected from the group consisting of O, S, and N and optionally substituted with RX11, 5- to 10-membered heterocyclyl containing heteroatoms selected from the group consisting of O, S, and N and optionally substituted with RX11, and -NR16R17; wherein RX11 is each independently selected from the group consisting of halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl; R16 and R17 are each independently selected from the group consisting of hydrogen, C1-C10 alkyl optionally substituted with RX12, C1-C10 alkoxy optionally substituted with RX12, C3-C10 cycloalkyl optionally substituted with RX12, C6-20 aryl optionally substituted with RX12, 5-to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with RX12, and 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with RX12; wherein RX12 is each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl; or R16 and R17 together with the nitrogen atom to which they are attached form a 5- to 10-membered ring structure; in formula II-2, R8 and R9 are each independently selected from the group consisting of hydrogen and C1-C6 alkyl, or R8 and R9 together with the carbon atom to which they are attached form a C3-C6 ring structure; n is 1, 2, or 3; Y is selected from one of the following: r6 •'V -v O, NR6,      0        0  ; * represents a site where Y is attached to CR8R9;      represents a site where Y is attached to R10; R10 is selected from the group consisting of hydrogen, C1-C20 alkyl optionally substituted with R30, C1-C20 haloalkyl optionally substituted with R30, C1-C10 alkoxy optionally substituted with R30, C3-C10 cycloalkyl optionally substituted with R30, C2-C20 alkenyl optionally substituted with R30, C6-20 aryl optionally substituted with R30, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with R30, and 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with R30, wherein R30 is each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C6-20 aryl, C6-20 aryloxy, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N, 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N, and C3-C6 cycloalkenyl optionally substituted with R31; wherein R31 is each independently selected from the group consisting of hydrogen, halogen, and C1-C6 alkyl; R6 is independently selected from the group consisting of hydrogen, C1-C10 alkyl optionally substituted with RX32, C1-C10 alkoxy optionally substituted with RX32, C3-C10 cycloalkyl optionally substituted with RX32, C6-20 aryl optionally substituted with RX32, 5- to 10membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with RX32, and 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with RX32; wherein RX32 is each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl; in formula II-3, R20 is selected from the group consisting of hydrogen and -C(=O)R21, wherein R21 is selected from the group consisting of hydrogen, C1-C20 alkyl optionally substituted with R22, C1-C20 haloalkyl optionally substituted with R22, C1-C10 alkoxy optionally substituted with R22, C3-C10 cycloalkyl optionally substituted with R22, C2-C20 alkenyl optionally substituted with R22, C6-20 aryl optionally substituted with R22, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with R22, and 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with R22, wherein R22 is each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C6-20 aryl, C6-20 aryloxy, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N, 5- to 10membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N, and C3-C6 cycloalkenyl optionally substituted with R23; wherein R23 is each independently selected from the group consisting of hydrogen, halogen, and C1-C6 alkyl; In one embodiment, the benzotriazine dioxide may have formula II-2: o’ I o                   II-2 wherein R10 is selected from one of the following aromatic cyclic and heterocyclic 10 5 structures: wherein R1 is selected from the group consisting of H, C1-C7 alkyl optionally substituted with R11, C1-C7 cycloalkyl optionally substituted with R11, C1-C7 alkoxy optionally substituted with R11, and C1-C7 acyl optionally substituted with R11, wherein R11 is selected from the group 5 consisting of halogen, hydroxy, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 alkoxy, C1-C7 substituted or unsubstituted alkenyl, C1-C12 substituted or unsubstituted aryl, and C3-C12 substituted or unsubstituted heterocyclyl. In one embodiment, the benzotriazine dioxide may have formula II-2: o’ I o                   II-2 10        R10 is selected from one of the following aromatic rings and heterocyclic structures: wherein R71 is selected from the group consisting of H, C1-C7 alkyl optionally substituted with R12, C1-C7 cycloalkyl optionally substituted with R12, and C1-C7 acyl optionally substituted with R12, wherein R12 is selected from the group consisting of halogen, hydroxy, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 alkoxy, C1-C7 substituted or unsubstituted alkenyl, C1-C12 substituted or unsubstituted aryl, and C3-C12 substituted or unsubstituted heterocyclyl. In one embodiment, the benzotriazine dioxide may have formula II-2: O" I 10 o                   II-2 Y is NR6; R10 is selected from the group consisting of hydrogen and C1-10 alkyl such as methyl; R6 is selected from the group consisting of hydrogen and C1-10 alkyl such as methyl. In one embodiment, the benzotriazine dioxide may have formula II-2: 0 I o                   II-2 Y is       0 R10 is selected from the group consisting of hydrogen and C1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. For the above embodiments of formula II-2, further, X may be NH, R8 and R9 are each independently selected from the group consisting of hydrogen and C1-C6 alkyl such as methyl, or R8 and R9 together with the carbon atom to which they are attached form a C3-C6 ring structure such as a cyclopropyl structure; preferably, R8 and R9 are hydrogen; n is 1, 2, or 3; preferably, n is 2. For formula II-3, when m is 1, it has the following structure II-31: II-31 10 For formula II-3, when m is 2, it has the following structure II-32: For formula II-3, when m is 3, it has the following structure II-33 or II-34: II-33;             -                     II-34. In one embodiment, the benzotriazine dioxide may have the following formula II-3: 15 । O II-3 wherein R20 is selected from one of the following structures: In one embodiment, the benzotriazine dioxide may have the following formula II-3: II-3 wherein R20 is -C(=O)R21, wherein R21 is selected from the group consisting of hydrogen 5 and C1-C20 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. For the above embodiments of formula II-3, further, X may be NH. In one embodiment, the benzotriazine dioxide may have the following formula III-1: 0 I T J RW11 RW13 ^\Lwi / R10 N N Y 0          RW12 o       III-1 10       wherein W1 is O or NR6; RW11, RW12, and RW13 are each independently selected from the group consisting of hydrogen and C1-3 alkyl, or RW12 and RW13 together with the carbon atom to which they are attached form a C3-6 cycloalkyl; R6 is selected from the group consisting of hydrogen and C1-3 alkyl, or when W1 is NR6, 15 RW11 and R6 together with the atoms to which they are attached form a 4- to 6-membered heterocyclyl containing one N atom; R10 is selected from the group consisting of hydrogen, C1-C20 alkyl optionally substituted with R30, C1-C20 haloalkyl optionally substituted with R30, C1-C10 alkoxy optionally substituted with R30, C3-C10 cycloalkyl optionally substituted with R30, C2-C20 alkenyl optionally substituted with R30, C6-20 aryl optionally substituted with R30, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with R30, and 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with R30, wherein R30 is each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C6-20 aryl, C6-20 aryloxy, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N, 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N, and C3-C6 cycloalkenyl optionally substituted with R31; wherein R31 is each independently selected from the group consisting of hydrogen, halogen, and C1-C6 alkyl. In the above embodiments of formula III-1, further, R10 is selected from the group consisting of C1-C20 alkyl optionally substituted with R30, C3-C10 cycloalkyl optionally substituted with R30, C6-20 aryl optionally substituted with R30, and 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with R30; R30 is halogen, hydroxy, or -NH2. In the above embodiments of formula III-1, further, R10 is selected from one of the following: tert-butyl. In the above embodiments of formula III-1, further, RW11, RW12 and RW13 are each independently selected from hydrogen; W1 is O. In the above embodiments of formula III-1, further, RW12 and RW13 are each independently selected from hydrogen; RW11 is hydrogen or C1-3 alkyl; W1 is NR6, wherein R6 is hydrogen or C1-3 alkyl, or RW11 and R6 together with the atoms to which they are attached form a 5- or 6-membered heterocyclic group containing one N atom. In the above embodiments of formula III-1, further, RW12 and RW13 are each independently selected from hydrogen; W1 is NR6, wherein RW11 and R6 together with the atoms to which they are attached form a 5-membered heterocyclic group containing one N atom. In one embodiment, the benzotriazine dioxide may have the following formula III-2: III-2 wherein W2 is O or NRW25, wherein RW25 is hydrogen or C1-3 alkyl; RW21, RW22, and RW23 are each independently selected from the group consisting of hydrogen, hydroxy, and C1-3 alkyl; or when W2 is NRW25, RW21 and RW25 together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl containing one N atom; RW24 is each independently selected from the group consisting of hydrogen, C1-3 alkyl, 5-or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with RW20, C6-20 aryl optionally substituted with RW20, and C6-20 aralkyl optionally substituted with RW20; wherein RW20 is halogen, C1-3 alkyl, or hydroxy. In the above embodiments of formula III-2, further, W2 is O, RW21, RW22, and RW23 are each independently selected from hydrogen. In the above embodiments of formula III-2, further, RW24 is selected from the group consisting of hydrogen, C1-3 alkyl, and phenyl optionally substituted with RW20, wherein RW20 is halogen such as fluorine, C1-3 alkyl, or hydroxy. In the above embodiments of formula III-2, further, RW24 is phenyl or monofluorosubstituted phenyl. In one embodiment, the benzotriazine dioxide may have the following formula III-3: III-3 RW31 and RW32 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, and C1-3 alkyl; RW33 is each independently selected from the group consisting of hydrogen, halogen, C1-3 alkyl, 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with RW30, C6-20 aryl optionally substituted with RW30, and C6-20 aralkyl optionally substituted with RW30; wherein RW30 is halogen, C1-3 alkyl, or hydroxy. In the above embodiments of formula III-3, further, RW31 and RW32 are hydrogen; RW33 is each independently selected from the group consisting of hydrogen, halogen, C1-3 alkyl, and phenyl optionally substituted with RW30, wherein RW30 is halogen such as fluorine, C1-3 alkyl, or hydroxy. In the above embodiments of formula III-3, further, RW33 is phenyl or monofluorosubstituted phenyl. In the above embodiments, R3 may be selected from the group consisting of halogen, C1-6 alkoxy, C1-3 haloalkyl, and C3-6 cycloalkyl, for example, selected from the group consisting of bromo, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, Me, Et, nPr, iPr, cyclopropyl, nBu, iBu, tBu, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethyl, trifluoromethyl, and trifluoroethyl. In the above embodiments, R3 may be bromo, C1-3 haloalkyl such as trifluoromethyl, C1-6 alkoxy such as methoxy, or C1-3 haloalkoxy such as trifluoromethoxy. In the above embodiments, R3 may be halogen, for example, fluorine, chlorine, bromine, or iodine, particularly bromo. In the above embodiments, R3 may be trifluoromethyl. Specifically, the benzotriazine dioxide may be selected from the following compou nds: A-1: 3-((2-(pyridin-3-yloxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4 -dioxide; A-2: 3-(2-(3-fluorophenoxy)ethyl)amino-7-trifluoromethylbenzo[1,2,4]triazine 1,4-diox ide; A-3: 3-(2-(benzyloxy)ethyl)amino)-7-trifluoromethylbenzo[1,2,4]triazine 1,4-dioxide; A-4: 3-((1-methoxy-2-propyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dio xide; A-5: 3-((3-aminotetrahydrofuran)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxid e; B-1: 3-(2,2,2-trifluoroethyl)amino-7-trifluoromethylbenzo[1,2,4]triazine 1,4-dioxide; B-2: 3-((3,3-difluorocyclopentyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide; B-3: 3-((2-(pyridin-3-yl)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dio xide; B-4: 3-((3-fluorophenyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide; B-5: 7-cyclopropyl-3-((2,2,2-trifluoroethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide; B-6: 7-(5-cyclopropyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-3-((2,2,2-trifluoroeth yl)amino)benzo[e][1,2,4]triazine 1,4-dioxide; B-7: 7-(2-chloro-6-methylpyridin-4-yl)-3-((3,3-difluorocyclopentyl)amino)benzo[e][1,2, 4]triazine 1,4-dioxide; B-8: 7-(2-chloro-6-methyl-1-oxidopyridin-4-yl)-3-((3,3-difluorocyclopentyl)amino)benz o[e][1,2,4]triazine 1,4-dioxide; B-9: 7-(2-chloro-6-methylpyridin-4-yl)-3-((2,2,2-trifluoroethyl)amino)benzo[e][1,2,4]tri azine 1,4-dioxide; B-10: 7-(2-chloro-6-1-oxidopyridin-4-yl)-3-((2,2,2-trifluoroethyl)amino)benzo[e][1,2,4] triazine 1,4-dioxide; C-1: 7-bromo-3-((2-ethoxy)amino)benzo[e][1,2,4]triazine 1,4-dioxide; C-2: 3-((2-hydroxyethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide; C-3: 3-((2-hydroxy-2-methylpropyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide; C-4: 3-((1S,4S)-4-hydroxycyclohexyl)amino)-7-trifluoromethylbenzo[e][1,2,4]triazine 1,4-dioxide; C-5: 3-(2-hydroxypropyl)amino-7-trifluoromethylbenzo[1,2,4]triazine 1,4-dioxide; C-6: 7-(5-cyclopropyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-3-((2-hydroxyethyl)a mino)benzo[e][1,2,4]triazine 1,4-dioxide; C-7: 7-bromo-3-((2-(4-fluorophenyl)-2-hydroxyethyl)amino)benzo[e][1,2,4]triazine 1,4 -dioxide; C-8: 7-bromo-3-((2-(isobutyryloxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide; C-9: 7-bromo-3-((2-(hexadecanoyloxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide; C-10: 7-bromo-3-((2-((2-bromohexadecanoyl)oxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide; C-11: 3-((2-(pivaloyloxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-di oxide; C-12: 3-((2-(isobutyryloxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide; C-13: 3-((2-((3-hydroxytetradecanoyl)oxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][1, 2,4]triazine 1,4-dioxide; C-14: 3-((2-(nicotinoyloxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide; C-15: 3-((((2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4, 6,8-tetraenyl)oxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide; C-16: 7-(trifluoromethyl)-3-((2-(propoxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxi de; C-17: 3-((2-((thiophene-3-carbonyl)oxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4] triazine 1,4-dioxide; C-18: 3-((2-(isobutyryloxy)ethyl)amino)-7-(trifluoromethoxy)benzo[e][1,2,4]triazine 1, 4-dioxide; C-19: 3-(2-hydroxyethyl)amino)-7-(trifluoromethoxy)benzo[e][1,2,4]triazine 1,4-dioxid e; C-20: 3-((2-((2-bromohexadecanoyl)oxy)ethyl)amino)-7-(trifluoromethoxy)benzo[e][1, 2,4]triazine 1,4-dioxide; C-21: 6-bromo-3-((2-(isobutyryloxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide; C-22: 8-bromo-3-((2-(isobutyryloxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide; C-23: 7-(5-cyclopropyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-3-((2-(isobutyrylox y)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide; C-24: 7-cyclopropyl-3-((2-(pivaloyloxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxid e; C-25: 3-((2-((thiophene-3-carbonyl)oxy)propyl)amino)-7-(trifluoromethyl)benzo[e][1,2, 4]triazine 1,4-dioxide; C-26: 3-((2-((cyclopropanecarbonyl)oxy)propyl)amino)-7-(trifluoromethyl)benzo[e][1,2, 4]triazine 1,4-dioxide; C-27: 3-((2-(pivaloyloxy)propyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide; C-28: 3-((2-((3-hydroxytetradecanoyl)oxy)propyl)amino)-7-(trifluoromethyl)benzo[e][1, 2,4]triazine 1,4-dioxide; C-29: 3-((2-(pentanoyloxy)ethyl)amino)-7-(thiazol-5-yl)benzo[e][1,2,4]triazine 1,4-dio xide; D-1: 3-((2-aminoethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide; D-2: 3-(pyrrolidin-3-ylamino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide; D-3: 3-(azetidin-3-ylamino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide; D-4: 3-((2-(methylamino)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-di oxide; D-5: 3-((2-pivalamidoethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxi de; D-6: 3-((1-pivaloylpyrrolidin-3-yl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1, 4-dioxide; D-7: 3-((1-pivaloylazetidin-3-yl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide; D-8: 3-((2-(N-methylpivalamido)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazin e 1,4-dioxide; D-9: 3-((2-(N-methylcyclopropanecarboxamido)ethyl)amino)-7-(trifluoromethyl)benzo [e][1,2,4]triazine 1,4-dioxide; D-10: 3-((1-((2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2, 4,6,8-tetraenyl)pyrrolidin-3-yl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide; D-11: 3-(((1-(pivaloyloxy)cyclopropyl)methyl)amino)-7-(trifluoromethyl)benzo[e][1,2, 4]triazine 1,4-dioxide; D-12: 3-((1-((R)-3-hydroxytetradecanoyl)pyrrolidin-3-yl)amino)-7-(trifluoromethyl)ben zo[e][1,2,4]triazine 1,4-dioxide; D-13: 3-((1-(2,2,2-trifluoroacetyl)pyrrolidin-3-yl)amino)-7-(trifluoromethyl)benzo[e][1, 2,4]triazine 1,4-dioxide; D-14: 3-((1-(thiophene-3-carbonyl)pyrrolidin-3-yl)amino)-7-(trifluoromethyl)benzo[e] [1,2,4]triazine 1,4-dioxide; D-15: 3-((2-aminoethyl)amino)-7-bromobenzo[e][1,2,4]triazine 1,4-dioxide; D-16: 3-(((1-aminocyclopropyl)methyl)amino)-7-bromobenzo[e][1,2,4]triazine 1,4-dio xide; D-17: (R)-3-((2-aminopropyl)amino)-7-bromobenzo[e][1,2,4]triazine 1,4-dioxide; D-18: (S)-3-((2-aminopropyl)amino)-7-bromobenzo[e][1,2,4]triazine 1,4-dioxide; D-19: 3-((2-aminoethyl)amino)-7-fluorobenzo[e][1,2,4]triazine 1,4-dioxide; D-20: 3-((2-aminoethyl)amino)-7-chlorobenzo[e][1,2,4]triazine 1,4-dioxide; D-21: 3-((2-aminoethyl)amino)-7-iodobenzo[e][1,2,4]triazine 1,4-dioxide; D-22: 3-((2-aminoethyl)amino)-7-methoxybenzo[e][1,2,4]triazine 1,4-dioxide; D-23: 7-bromo-3-((2-(methylamino)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide; D-1': 3-((2-aminoethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide t rifluoroacetate; D-2': 3-(pyrrolidin-3-ylamino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide tr ifluoroacetate; D-4': 3-((2-(methylamino)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-d ioxide trifluoroacetate; D-16': 3-((2-aminoethyl)amino)-7-bromobenzo[e][1,2,4]triazine 1,4-dioxide trifluoroac etate; D-17': 3-(((1-aminocyclopropyl)methyl)amino)-7-bromobenzo[e][1,2,4]triazine 1,4-dio xide hydrochloride; D-18': (R)-3-((2-aminopropyl)amino)-7-bromobenzo[e][1,2,4]triazine 1,4-dioxide hydr ochloride. PHARMACEUTICALLY ACCEPTABLE SALTS OR ESTERS The conventional phrase “pharmaceutically acceptable salt or ester” as used herein refers to any pharmaceutically acceptable salt or ester that may be prepared from the benzotriazine dioxide compounds of the present disclosure, including salts formed from acidic and basic functional groups such as amino groups of one of the benzotriazine dioxide compounds of the present disclosure. Illustrative salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis(2-hydroxy-3-naphthoate)). The term “pharmaceutically acceptable salt or ester” also includes salts prepared from the benzotriazine dioxide compounds of the present disclosure having acidic functional groups such as carboxylic acid functional groups and pharmaceutically acceptable inorganic or organic bases. Suitable bases include, but are not limited to, alkali metal hydroxides such as sodium, potassium, and lithium hydroxides; alkaline earth metal hydroxides such as calcium and magnesium hydroxides; hydroxides of other metals such as aluminum and zinc; ammonia and organic amines such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributylamine; pyridine; N,N-dimethyl-ethylamine; diethylamine; triethylamine; mono-, di-, or tri(2-hydroxy-lower alkyl)amines such as mono-, di-, or tri(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or tris(hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxy lower alkyl)-amines such as N,N-dimethyl-N-(2-hydroxyethyl)amine, or tri(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and the like. Moreover, when compound (I) and its salts produce tautomers, any tautomer is included in the present disclosure, and compound (I) and its salts may be any of solvates, hydrates, non-solvates, and non-hydrates. In one embodiment, the types of acids used for salt formation include inorganic acids and organic acids. Inorganic acids include, but are not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, and hydrofluoric acid; organic acids include, but are not limited to, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, malic acid, and oxalic acid. The compounds of formula (I) are included in the pharmaceutical compositions of the present disclosure and are used in the methods of the present disclosure. If a -COOH or -OH group is present, pharmaceutically acceptable esters may be used, for example, methyl ester, ethyl ester, pivaloyloxymethyl ester, and the like for -COOH, and acetate, maleate, and the like for -OH; these esters are known in the art to be useful for improving solubility or hydrolysis characteristics, as sustained-release or prodrug dosage forms. THERAPEUTIC / PROPHYLACTIC ADMINISTRATION AND COMPOSITIONS OF THE PRESENT DISCLOSURE Because of their activity, the benzotriazine dioxide compounds of the present disclosure may be advantageously used in veterinary and human medicine. As described above, the benzotriazine dioxide compounds of the present disclosure may be used to treat or prevent diseases in animals in need thereof. When administered to an animal, the benzotriazine dioxide compounds of the present disclosure are administered as a component of a composition comprising a pharmaceutical carrier or excipient. The compositions of the present disclosure comprising the benzotriazine dioxide compounds of the present disclosure may be administered orally. The benzotriazine dioxide compounds of the present disclosure may also be administered by any other convenient route, such as by infusion or bolus injection, absorption through epithelial or mucocutaneous linings (e.g., oral, rectal, and intestinal mucosa, etc.), and may be administered together with other therapeutically active agents. Administration may be systemic or local. Local administration includes, for example, transhepatic arterial administration, direct injection into the liver tumor via a catheter through the tumor-feeding blood vessels of the liver; for example, via the bronchial artery, direct injection into the tumor via a catheter through the tumor-feeding blood vessels of the lung; for example, direct injection into any tumor via a catheter through any tumor-feeding blood vessel; for example, direct injection into the tumor from outside the tumor through the tumor surface, etc. Various delivery systems such as liposome encapsulation, microparticles, microcapsules, capsules, and the like are known and may be used for administration of the benzotriazine dioxide compounds of the present disclosure. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intracerebral, intravaginal, transdermal, rectal, by inhalation, or topical administration, particularly topical administration to the ear, nose, eye, or skin. Also included is local administration, such as transhepatic arterial administration, direct injection into the liver tumor via a catheter through the tumor-feeding blood vessels of the liver; for example, via the bronchial artery, direct injection into the tumor via a catheter through the tumor-feeding blood vessels of the lung; for example, direct injection into any tumor via a catheter through any tumor-feeding blood vessel; for example, direct injection into the tumor from outside the tumor through the tumor surface, etc. The mode of administration is left to the practitioner. In most cases, administration will result in release of the benzotriazine dioxide compounds of the present disclosure into the bloodstream. In specific embodiments, local administration of the benzotriazine dioxide compounds of the present disclosure may be preferred. This may be achieved by non-limiting means such as local infusion during surgery, topical application such as application with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository or enema, or by means of an implant, which is a porous, non-porous, or gelatinous material, including membranes such as sialastic membranes, or fibers. In certain embodiments, it may be preferred to introduce the benzotriazine dioxide compounds of the present disclosure into the central nervous system or gastrointestinal tract by any suitable route, including intraventricular, intrathecal, and epidural injection, and enema. Intraventricular injection may be facilitated by an intraventricular catheter, for example, attached to a reservoir such as an Ommaya reservoir. Pulmonary administration may also be used, for example, by use of an inhaler or nebulizer, and formulation with an aerosol, or by perfusion with a formulation in a fluorocarbon or synthetic pulmonary surfactant. In certain embodiments, the benzotriazine dioxide compounds of the present disclosure may be formulated as suppositories using conventional binders and excipients such as triglycerides. In another embodiment, the benzotriazine dioxide compounds of the present disclosure may be delivered in vesicles, particularly liposomes (see Langer, Sci. 249:1527-1533 (1990); Treat et al., Liposomes in the Therapy of Infectious Disease and Cancer 317-327 and 353-365 (1989)). In yet another embodiment, the benzotriazine dioxide compounds of the present disclosure may be delivered in a controlled-release or sustained-release system (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)). Other controlled- or sustained-release systems discussed in the review by Langer, Sci. 249:1527-1533 (1990) may also be used. In one embodiment, a pump may be used (Langer, Sci. 249:1527- 1533 (1990); Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); and Saudek et al., N. Engl. J. Med. 321:574 (1989)). In another embodiment, polymeric materials may be used (see Medical Applications of Controlled Release (Langer and Wise eds., 1974); Controlled Drug Bioavailability, Drug Product Design and Performance (Smolen and Ball eds., 1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); Levy et al., Sci. 228:190 (1985); During et al., Ann. Neurol. 25:351 (1989); and Howard et al., J. Neurosurg. 71:105 (1989)). In yet another embodiment, a controlled- or sustained-release system may be placed near the target of the benzotriazine dioxide compounds of the present disclosure, such as the spine, brain, or gastrointestinal tract, thus requiring only a fraction of the systemic dose. The compositions of the present disclosure may optionally contain a suitable amount of a pharmaceutically acceptable excipient so as to provide a form suitable for administration to an animal. Such pharmaceutical excipients may be liquids such as water or oils, including those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, mineral oil, sesame oil, and the like. Pharmaceutical excipients may be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, adjuvants, stabilizers, thickeners, lubricants, and coloring agents may be used. In one embodiment, the pharmaceutically acceptable excipient is sterile when administered to an animal. Water is particularly useful as an excipient when the benzotriazine dioxide compounds of the present disclosure are administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions may also be employed as liquid excipients, particularly for injectable solutions. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, and the like. If desired, the compositions of the present disclosure may also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. The compositions of the present disclosure may be in the form of solutions, suspensions, emulsions, tablets, pills, granules, capsules, liquid-containing capsules, powders, sustained- release formulations, suppositories, aerosols, sprays, suspensions, or any other suitable form. In one embodiment, the composition is in the form of a capsule (see, e.g., U.S. Pat. No. 5,698,155). Other examples of suitable pharmaceutical excipients are described in Remington’s Pharmaceutical Sci. 1447-1676 (Alfonso R. Gennaro ed., 19th ed. 1995), which is incorporated herein by reference. In one embodiment, the benzotriazine dioxide compounds of the present disclosure may be formulated according to conventional methods into compositions suitable for oral administration to humans. Compositions for oral delivery may be formulated, for example, as tablets, troches, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or tinctures. Compositions for oral administration may contain one or more agents, for example, sweetening agents such as fructose, aspartame, or saccharin; flavoring agents such as peppermint, wintergreen oil, or cherry; coloring agents; and preservatives, to provide a pharmaceutically palatable preparation. Moreover, when in the form of tablets and pills, the composition may be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing prolonged sustained release. Selectively permeable membranes surrounding an osmotically active driving compound are also suitable for orally administered compositions. In the latter delivery platform, the driving compound absorbs fluid around the capsule and swells to discharge the agent or agent composition through an orifice. In contrast to the peakshaped delivery profile of immediate-release dosage forms, these delivery platforms may provide a substantially zero-order delivery profile. Delayed materials such as glycerol monostearate or glycerol stearate may also be used. Oral compositions may include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. In one embodiment, the excipient is a pharmaceutical grade excipient. In another embodiment, the benzotriazine dioxide compounds of the present disclosure can be formulated into compositions for intravenous administration. Typically, compositions for intravenous administration comprise a sterile isotonic aqueous buffer. If desired, the composition can also contain a solubilizing agent. Compositions for intravenous administration can optionally contain a local anesthetic such as lidocaine to reduce pain at the injection site. Generally, the ingredients are provided separately or mixed together in unit dosage form, for example, as a lyophilized powder or anhydrous concentrate in a sealed container such as an ampoule or sachette indicating the amount of active agent. If the benzotriazine dioxide compounds of the present disclosure are to be administered by infusion, they can be dispersed, for example, using an infusion bottle containing sterile pharmaceutical grade water or saline. If the benzotriazine dioxide compounds of the present disclosure are to be administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration. The benzotriazine dioxide compounds of the present disclosure may be administered by controlled-release or sustained-release means, or by delivery devices well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Pat. Nos. 3845770; 3916899; 3536809; 3598123; 4008719; 5674533; 5059595; 5591767; 5120548; 5073543; 5639476; 5354556; and 5733566, each of which is incorporated herein by reference. These dosage forms may be used to provide controlled or delayed release of one or more active ingredients, for example, using hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof, to provide the desired release profile in varying proportions. Suitable controlled- or sustained-release formulations known to those of ordinary skill in the art for use with the active ingredients of the present disclosure may be readily selected, including those mentioned herein. Thus, the present disclosure includes single unit dosage forms suitable for oral administration, such as but not limited to tablets, capsules, soft gelatin capsules, and caplets suitable for controlled or sustained release. Controlled- or sustained-release pharmaceutical compositions can have the common goal of improving drug therapy over their non-controlled or non-sustained-release counterparts. In one embodiment, a controlled- or sustained-release composition comprises a minimal amount of the benzotriazine dioxide compounds of the present disclosure to cure or control the condition in the shortest time. Advantages of controlled- or sustained-release compositions include extended drug activity, reduced dosage frequency, and improved patient compliance. In addition, controlled- or sustained-release compositions can advantageously affect the time of onset of action or other characteristics such as blood levels of the benzotriazine dioxide compounds of the present disclosure, and thus can reduce the occurrence of adverse side effects. Controlled- or sustained-release compositions can initially release an amount of the benzotriazine dioxide compounds of the present disclosure that promptly produces the desired therapeutic or prophylactic effect, and gradually and continuously release other amounts of the benzotriazine dioxide compounds of the present disclosure to maintain this level of therapeutic or prophylactic effect over a long period of time. To maintain a constant blood concentration of the benzotriazine dioxide compounds of the present disclosure, the benzotriazine dioxide compounds of the present disclosure can be released from the dosage form at a rate that matches the rate at which they are metabolized and excreted from the body. Controlled or sustained release of the active ingredient can be stimulated by various conditions including, but not limited to, changes in pH, changes in temperature, concentration or availability of enzymes, concentration or availability of water, or other physiological conditions or compounds. In another embodiment, the composition is prepared by mixing the benzotriazine dioxide compounds of the present disclosure, or a pharmaceutically acceptable salt or ester thereof, with a pharmaceutical carrier or excipient. The mixing can be accomplished by known methods for mixing a compound (or salt) with a pharmaceutical carrier or excipient. In another embodiment, the benzotriazine dioxide compounds of the present disclosure, or a pharmaceutically acceptable salt or ester thereof, are present in an effective amount. The amount of the benzotriazine dioxide compounds of the present disclosure effective to treat or prevent a condition can be determined according to standard clinical techniques. In addition, in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges. The precise dosage to be employed also depends on the route of administration and the severity of the condition, and can be decided according to the judgment of the practitioner and / or the individual details of the animal. However, a suitable effective dose for humans is about 0.001 mg / kg to 500 mg / kg body weight, although they are usually about 100 mg / kg body weight or less. In one embodiment, the effective dose is about 0.01 mg / kg to 100 mg / kg body weight of the benzotriazine dioxide compounds of the present disclosure, in another embodiment, about 0.02 mg / kg to 50 mg / kg body weight, and in another embodiment, about 0.025 mg / kg to 20 mg / kg body weight. In one embodiment, an effective dose is administered about every 24 hours until the condition is alleviated. In another embodiment, an effective dose is administered about every 12 hours until the condition is alleviated. In another embodiment, an effective dose is administered about every 8 hours until the condition is alleviated. In another embodiment, an effective dose is administered about every 6 hours until the condition is alleviated. In another embodiment, an effective dose is administered about every 4 hours until the condition is alleviated. The effective dose described herein refers to the total amount administered; in other words, if more than one benzotriazine dioxide compound of the present disclosure is administered, the effective dose corresponds to the total amount administered. The benzotriazine dioxide compounds of the present disclosure can kill cancer cells through a hypoxia-selective mechanism to achieve the purpose of curing tumors, and can be used in the treatment of liver cancer, cholangiocarcinoma, lung cancer, gastric cancer, esophageal cancer, colorectal cancer, renal cancer, ovarian cancer, head and neck malignant tumors, fibrosarcoma, sarcoma, prostatic hyperplasia, and the like. Therefore, the present disclosure also relates to use of the benzotriazine dioxide compounds of the present disclosure, or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof, in the manufacture of a medicament for treating cancer. The compounds can be used alone or in combination with other drugs to treat or alleviate benign and malignant tumors including those of the liver, intrahepatic duct, pancreas, stomach, esophagus, kidney, colorectum, lung, brain (glioma), malignant glioma, breast, ovary, cervix, head and neck, skin, melanoma, prostate, fibrosarcoma, sarcoma, thyroid, etc. The present disclosure also relates to a method for treating or alleviating cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of the benzotriazine dioxide compounds of the present disclosure, or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof. When used together with the benzotriazine dioxide compounds of the present disclosure, the phrase “therapeutically effective amount” means an amount effective to treat or prevent a disease. When used together with other therapeutic agents, the phrase “therapeutically effective amount” means an amount that allows the other therapeutic agent to exert a therapeutic effect. The term “effective amount” and derivatives thereof as used herein mean the amount of a drug or agent that, for example, a researcher or clinician seeks to cause a biological or medical response in a tissue, system, animal, or human. In addition, the term “therapeutically effective amount” and derivatives thereof also mean any amount that causes improved treatment, cure, prevention, or amelioration of a disease, disorder, or side effect, or a reduction in the rate of progression of a disease or disorder, compared with a corresponding patient not receiving the amount (drug). The scope of the term also includes an amount effective to enhance normal physiological function. The phrases “treating,” “treatment,” and the like include alleviating or terminating a disease or symptoms thereof. In one embodiment, treatment includes inhibiting, for example, reducing the overall frequency of events of a disease or symptoms thereof. The phrases “preventing,” “prevention,” and the like include avoiding the onset of a disease or symptoms thereof. The term “mammal” includes, but is not limited to, cow, monkey, baboon, chimpanzee, horse, sheep, pig, cat, dog, mouse, rat, rabbit, guinea pig, and human. In one embodiment, the mammal is a mouse, dog, pig, monkey, and human. The benzotriazine dioxide compounds of the present disclosure can effectively inhibit the proliferation, metastasis, differentiation, and the like of tumor cells based on the hypoxic microenvironment, and are mainly used for treating liver cancer, cholangiocarcinoma, pancreatic cancer, lung cancer, gastric cancer, and the like. In one embodiment, the cancer is selected from tumors at the following sites, including liver, intrahepatic duct, pancreas, stomach, esophagus, kidney, colorectum, lung, brain (glioma), malignant glioma, breast, ovary, cervix, head and neck, melanoma, skin, muscle, blood vessels, nerve, ovary, prostate, fibrosarcoma, sarcoma, and thyroid; the cancer includes solid tumors originating from the endoderm, mesoderm, and ectoderm. In one embodiment, the cancer is selected from tumors at the following sites, including liver, intrahepatic duct, pancreas, stomach, esophagus, kidney, colon, lung, brain (glioma), malignant glioma, breast, head and neck, melanoma, ovary, prostate, fibrosarcoma, sarcoma, and thyroid. METHODS FOR PREPARING THE COMPOUNDS OF THE PRESENT DISCLOSURE Compound (I) or a salt thereof and raw material compounds thereof may be prepared according to known methods, for example, the methods shown in the following reaction schemes and the like. Hereinafter, “room temperature” generally means 20-25°C, and each symbol in the chemical structural formulae described in the reaction schemes is as defined above unless otherwise specified. The compounds in the formulae include specific salt forms, and as such salts, for example, those similar to the salts of compound (I) and the like can be mentioned. The intermediates or final products obtained in each step may be used in the next reaction in the form of a mixture or crude product. They can also be purified by conventional methods such as recrystallization, distillation, column chromatography, preparative TLC, and liquidphase preparative column. Throughout this application, the meanings of the following abbreviations are listed below: Me methyl Et ethyl nPr n-propyl iPr isopropyl nBu n-butyl iBu isobutyl tBu tert-butyl Cbz benzyloxycarbonyl Boc tert-butoxycarbonyl; (Boc)2O di-tert-butyl dicarbonate Ph phenyl TEA triethylamine DIPEA N,N-diisopropylethylamine DMAP N,N-dimethyl-4-aminopyridine Pyridine pyridine DCC N,N‘-dicyclohexylcarbodiimide EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride HATU 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate PyBOP       1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate HOBT 1-hydroxybenzotriazole LiOH lithium hydroxide NaOH sodium hydroxide NaIO4 sodium periodate NaBH4 sodium borohydride NaBH3CN sodium cyanoborohydride STAB sodium triacetoxyborohydride KOH potassium hydroxide K2CO3 potassium carbonate K2OsO4 potassium osmate KOAc potassium acetate Cs2CO3 cesium carbonate CuI copper iodide Dioxane (1,4-dioxane) dioxane (1,4-dioxane) THF tetrahydrofuran PE petroleum ether EA ethyl acetate EtOH ethanol MeOH methanol DCM dichloromethane Toluene toluene Hexane n-hexane AcOH acetic acid AcCl acetyl chloride TFA trifluoroacetic acid TFAA trifluoroacetic anhydride Tf2O trifluoromethanesulfonic anhydride DMA N,N-dimethylacetamide DMF N,N-dimethylformamide 2,6-Lutidine 2,6-dimethylpyridine TMSCN trimethylsilyl cyanide m-CPBA m-chloroperbenzoic acid BPO benzoyl peroxide SOCl2 thionyl chloride POCl3 phosphorus oxychloride H2O2 hydrogen peroxide (30%) Pd(dppf)Cl2 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd2(dba)3 tris(dibenzylideneacetone)dipalladium Pd(PPh3)4 tetrakis(triphenylphosphine)palladium Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene DTBPY 4,4'-di-tert-butylbipyridine [Ir(OMe)(cod)]2 methoxy(cyclooctadiene)iridium dimer TBAF tetrabutylammonium fluoride RT room temperature, generally 20-25°C; N2 nitrogen Reflux reflux HPLC high performance liquid chromatography Pre-HPLC preparative high performance liquid chromatography LCMS liquid chromatography-mass spectrometry TLC thin layer chromatography prep-TLC preparative thin layer chromatography SM starting material IM                    intermediate TM                  target molecule tR                     retention time HNMR / CNMR / FNMR      nuclear magnetic resonance hydrogen spectrum, carbon spectrum, fluorine spectrum. Preparative liquid phase conditions: semi-preparative reverse-phase HPLC (column: Welch Ultimate XB-C18 250 x 21.2 mm x 5 pm; mobile phase: 40-64% acetonitrile + 0.1% TFA / water, 8 min). Experimental related reagents, solvents, and instruments: All chemical reagents and solvents were purchased from commercial reagent companies and used without purification unless otherwise specified. All reactions were carried out in dry glass flasks, and the atmosphere was replaced with nitrogen or argon as needed. Nuclear magnetic resonance spectra were measured on a 400M instrument (Bruker AV400, Bruker Corporation, Billerica, MA, USA). Chemical shifts (6) are referenced to tetramethylsilane (TMS), and multiplets are also reported, including s (singlet), d (doublet), dd (doublet of doublets), t (triplet), q (quartet), qui (quintet), spt (septet), m (multiplet). The solvents described in the steps are: acetone, tetrahydrofuran, acetonitrile, dichloromethane, chloroform, toluene, n-hexane, cyclohexane, ethyl formate, ethyl acetate, isopropyl acetate, butyl acetate, trimethyl phosphate, triethyl phosphate, diethyl ether, or isopropyl ether. The acid scavengers in the steps are heterocyclic amines, triethylamine, diisopropylethylamine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, and the like. Specific examples are described below. CLASS I: TERMINAL ARYL ETHERS OR ALKYL ETHERS Example     A-1:     Synthesis     of 3-((2-(pyridin-3-yloxy)ethyl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide N02 nh2cn, hci NH2 Na0H SM1 o IM1 IM-1 was synthesized according to WO2023019912A1, three-step total yield about 15%. IM-1                                          IM-2                                        A-1 RZ1239 At room temperature (25°C), to a solution of 3-chloro-7-(trifluoromethyl)benzo[e] [1,2,4]triazine 1-oxide (IM-1, 150 mg, 0.60 mmol) in DMF (4 mL) were added DIEA (233 mg, 1.81 mmol) and 3-(2-aminoethoxy)pyridine (SM-2, 100 mg, 0.72 mmol). The mixture was stirred at room temperature for 1 hour. LCMS monitored complete conversion of the starting material, and the reaction was stopped. Water (10 mL) was added to the reaction solution, and a yellow solid precipitated. The solid was filtered and dried to give compound IM-2 (165 mg) as a yellow solid in 77.8% yield. Molecular formula:C15H12F3N5O2; molecular weight: 351.28. At room temperature (25°C), to a solution of compound IM-2 (165 mg, 0.47 mmol) in EA (5 mL) were added TFAA (2 mL) and hydrogen peroxide (2 mL). The reaction solution gradually turned red. The reaction solution was heated to 40°C and stirred for 8 hours. LCMS monitored complete conversion of the starting material, and the reaction was stopped. Water (10 mL) was added, and the mixture was extracted with DCM (20 mL*3). The organic layer was concentrated and subjected to silica gel column chromatography (MeOH:DCM=0%-5%) to give 3-((2-(pyridin-3-yloxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (A-1) as a red solid, 37 mg, yield 28%. Molecular formula: C15H12F3N5O3; molecular weight: 367.28; LCMS: (ESI+): m / z 368.1 [M+1]+. Example A-2: Synthesis of 3-(2-(3-fluorophenoxy)ethyl)amino-7-trifluoromethylbenzo[1,2,4]triazine 1,4-dioxide A-2 RZ-1230 At room temperature (25°C), to a solution of IM-1 (150 mg, 0.6 mmol) in DMF (5 mL) were added DIPEA (90 mg, 0.72 mmol) and SM-3 (100 mg, 0.64 mmol). The mixture was stirred at room temperature for 30 minutes. LCMS monitored complete conversion of the starting material. Water (10 mL) was added, and a yellow solid precipitated. The product IM-3 was obtained by filtration and used directly in the next step. At room temperature (25°C), to a solution of IM-3 in EA (10 mL) were added TFAA (2 mL) and hydrogen peroxide (2 mL). The mixture was stirred at room temperature overnight. TLC showed a small amount of starting material remaining. Water (10 mL) was added, and the mixture was extracted with EA (20 mLx3). The organic layer was concentrated with silica gel and purified by column chromatography, eluting with DCM / MeOH=25 / 1 to give the target product 3-(2-(3-fluorophenoxy)ethyl)amino-7-trifluoromethylbenzo[1,2,4]triazine 1,4-dioxide (A-2, 23 mg, 0.06 mmol) as a purple-red solid, two-step yield 10%. Molecular formula: C16H12F4N4O3; molecular weight: 384.29; LCMS: (ESI+): m / z 385.4 [M+1]+. Example A-3: Synthesis of 3-(2-(benzyloxy)ethyl)amino)-7-trifluoromethylbenzo[1,2,4]triazine 1,4-dioxide IM-1                                          IM-4                                       A-3 RZ-1229 At room temperature (25°C), to a solution of IM-1 (150 mg, 0.6 mmol) in DMF (5 m.) were added DIPEA (90 mg, 0.72 mmol) and SM-4 (100 mg, 0.66 mmol). The mixture was stirred at room temperature for 30 minutes. .CMS monitored complete conversion of the starting material. Water (10 m.) was added, and a yellow solid precipitated. The product IM-4 was obtained by filtration and used directly in the next step. At room temperature (25°C), to a solution of IM-4 in EA (10 m.) were added TFAA (2 m.) and hydrogen peroxide (2 m.). The mixture was stirred at room temperature overnight. T.C showed a small amount of starting material remaining. Water (10 m.) was added, and the mixture was extracted with EA (20 m.*3). The organic layer was concentrated with silica gel and purified by column chromatography, eluting with DCM / MeOH=25 / 1 to give the target product 3-(2-(benzyloxy)ethyl)amino)-7-trifluoromethylbenzo[1,2,4]triazine 1,4-dioxide (A-3, 43 mg, 0.11 mmol) as a purple-red solid, two-step yield 18%. Molecular formula: C17H15F3N4O3; molecular weight: 380.33; LCMS: (ESI+): m / z 380.1 [M+1]+. Example A-4: Synthesis of 3-((1-methoxy-2-propyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide IM-1                                           IM-5 0 A-4 RZ1231 At room temperature (25°C), to a solution of 3-chloro-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1-oxide (IM-1, 140 mg, 0.56 mmol) in DMF (5 mL) were added DIEA (217 mg, 1.69 mmol) and 1-methoxypropan-2-amine (SM-5, 50 mg, 0.56 mmol). The mixture was stirred at room temperature for 1 hour. LCMS monitored complete conversion of the starting material, and the reaction was stopped. Water (10 mL) was added, and a yellow solid precipitated. The solid was filtered and dried to give compound IM-5 (130 mg) as a yellow solid in 76% yield. Molecular formula: C12H13F3N4O2; molecular weight: 302.25. At room temperature (25°C), to a solution of compound IM-5 (130 mg, 0.43 mmol) in EA (5 mL) were added TFAA (1 mL) and hydrogen peroxide (1 mL). The reaction solution gradually turned red. The reaction solution was heated to 40°C and stirred for 8 hours. LCMS monitored complete conversion of the starting material, and the reaction was stopped. Water (10 mL) was added, and the mixture was extracted with DCM (20 mL*3). The organic layer was concentrated and subjected to silica gel column chromatography (MeOH:DCM=0%-1%) to give 3-((1-methoxy-2-propyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (A-4, 68 mg) as a red solid in 50% yield. Molecular formula: C12H13F3N4O3; molecular weight: 318.25; LCMS: (ESI+): m / z 319.2 [M+1]+. Example A-5: Synthesis of 3-(3-aminotetrahydrofuran)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4- dioxide IM-1 SM-6 DMF, DIEA IM-6 A-5 RZ 1232 At room temperature (25°C), to a solution of 3-chloro-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1-oxide (IM-1, 150 mg, 0.60 mmol) in DMF (5 mL) were added DIEA (233 mg, 1.81 mmol) and 3-aminotetrahydrofuran (SM-6, 81.5 mg, 0.66 mmol). The mixture was stirred at room temperature for 1 hour. LCMS monitored complete conversion of the starting material, and the reaction was stopped. Water (10 mL) was added, and a yellow solid precipitated. The solid was filtered and dried to give compound IM-6 (175 mg) as a yellow solid in 97% yield. Molecular formula: C12H11F3N4O2; molecular weight: 300.24. At room temperature (25°C), to a solution of compound IM-6 (175 mg, 0.58 mmol) in EA (5 mL) were added TFAA (1 mL) and hydrogen peroxide (1 mL). The reaction solution gradually turned red. The reaction solution was heated to 40°C and stirred for 4 hours. LCMS showed starting material remaining. The mixture was continued stirring at room temperature overnight. LCMS monitored complete conversion of the starting material, and the reaction was stopped. Water (10 mL) was added, and the mixture was extracted with DCM (20 mL*3). The organic layer was concentrated and subjected to silica gel column chromatography (MeOH:DCM     =     0%-1%)     to     give     3-(3-aminotetrahydrofuran)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (A-5, 121 mg) as a red solid in 65% yield. Molecular formula: C12H11F3N4O3; molecular weight: 316.24; LCMS: (ESI+): m / z 317.4 [M+1]+. CLASS II: TERMINAL ARYL, ALKYL, CYCLOALKYL, OR HALOALKYL Example B-1: Synthesis of 3-(2,2,2-trifluoroethyl)amino-7-trifluoromethylbenzo[1,2,4]triazine 1,4- dioxide IM-1                                         IM-7                                 B-1 RZ-1222 At room temperature (25°C), to a solution of 3-chloro-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1-oxide (IM-1, 150 mg, 0.60 mmol) in DMF (5 mL) were added trifluoroethylamine (SM-7, 100 mg, 1.0 mmol) and DIPEA (90 mg, 0.72 mmol). The mixture was stirred at room temperature for 30 minutes. LCMS monitored complete conversion of the starting material. Water (10 mL) was added, and a yellow solid precipitated. The product IM-7 was obtained by filtration and used directly in the next step. Molecular formula: C10H6F6N4O; molecular weight: 312.18. At room temperature, to a solution of IM-7 in EA (10 mL) were added TFAA (2 mL) and hydrogen peroxide (2 mL). The mixture was stirred at room temperature overnight. TLC showed a small amount of starting material remaining. Water (10 mL) was added, and the mixture was extracted with EA (20 mL*3). The organic layer was mixed with silica gel, concentrated, and purified by column chromatography, eluting with DCM / MeOH=25 / 1 to give the target product 3-(2,2,2-trifluoroethyl)amino-7-trifluoromethylbenzo[1,2,4]triazine 1,4-dioxide (B-1, 26 mg) as a red solid, two-step yield 10%. Molecular formula: C10H6F6N4O2; molecular weight: 328.17; LCMS: (ESI+): m / z 329.1 [M+1]+. Example      B-2:      Synthesis      of      3-((3,3-difluorocyclopentyl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide IM-1                                         IM-8                                             B-2, RZ1242 At room temperature (25°C), to a solution of 3-chloro-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1-oxide (IM-1, 150 mg, 0.60 mmol) in DMF (5 mL) were added 3,3-difluorocyclopentylamine (SM-8, 104 mg, 0.66 mmol) and DIEA (232 mg, 1.80 mmol). The mixture was stirred at room temperature for 1 hour. LCMS monitored complete conversion of the starting material, and the reaction was stopped. Water (10 mL) was added, and a yellow solid precipitated. The solid was filtered and dried to give compound IM-8 (180 mg) as a yellow solid in 89% yield. Molecular formula: C13H11F5N4O; molecular weight: 334.24. At room temperature (25°C), to a solution of compound IM-8 (180 mg, 0.54 mmol) in EA (10 mL) were added TFAA (2 mL) and hydrogen peroxide (2 mL). The mixture was heated to 40°C and stirred for 3 hours, then stirred at room temperature overnight. LCMS monitored complete conversion of the starting material. Water (20 mL) was added, and the mixture was extracted with DCM (20 mL*3). The organic layer was concentrated and subjected to silica gel column chromatography (MeOH:DCM=0%-1%) to give 3-((3,3-difluorocyclopentyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (B-2, 160 mg) as a red solid in 85% yield. Molecular formula: C13H11F5N4O2; molecular weight: 350.24; LCMS: (ESI+): m / z 351.3 [M+1]+. Example B-3: Synthesis of 3-((2-(pyridin-3-yl)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide At room temperature (25°C), to a solution of 3-chloro-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1-oxide (IM-1, 150 mg, 0.60 mmol) in DMF (4 mL) were added DIEA (233 mg, 1.81 mmol) and 3-(2-aminoethyl)pyridine (SM-9, 88 mg, 0.72 mmol). The mixture was stirred at room temperature for 1 hour. LCMS monitored complete conversion of the starting material, and the reaction was stopped. Water (10 mL) was added, and a yellow solid precipitated. The solid was filtered and dried to give compound IM-9 (160 mg) as a yellow solid in 79% yield. Molecular formula:C15H12F3N5O; molecular weight: 335.28. At room temperature (25°C), to a solution of compound IM-9 (160 mg, 0.48 mmol) in EA (5 mL) were added TFAA (2 mL) and hydrogen peroxide (2 mL). The reaction solution gradually turned red. The reaction solution was heated to 40°C and stirred for 8 hours. LCMS monitored complete conversion of the starting material, and the reaction was stopped. Water (10 mL) was added, and the mixture was extracted with DCM (20 mL*3). The organic layer was concentrated and subjected to silica gel column chromatography (MeOH:DCM=0%-5%) to give 3-((2-(pyridin-3-yl)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (B-3, 47 mg) as a red solid in 28% yield. Molecular formula: C15H12F3N5O2; molecular weight: 351.28; LCMS: (ESI+): m / z 352.2 [M+1]+. Example B-4: Synthesis of 3-((3-fluorophenyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4- dioxide At room temperature (25°C), to a solution of 3-chloro-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1-oxide (IM-1, 200 mg, 0.80 mmol) in DMF (4 mL) were added DIEA (310 mg, 2.41 mmol) and 2-(3-fluorophenyl)ethylamine (SM-10, 134 mg, 0.96 mmol). The mixture was stirred at room temperature for 1 hour. LCMS monitored complete conversion of the starting material, and the reaction was stopped. Water (10 mL) was added, and a yellow solid precipitated. The solid was filtered and dried to give compound IM-10 (250 mg) as a yellow solid in 88.6% yield. Molecular formula: C16H12F4N4O; molecular weight: 352.29. At room temperature (25°C), to a solution of compound IM-10 (250 mg, 0.71 mmol) in EA (5 mL) were added TFAA (2 mL) and hydrogen peroxide (2 mL). The reaction solution gradually turned red. The reaction solution was heated to 40°C and stirred for 8 hours. LCMS monitored complete conversion of the starting material, and the reaction was stopped. Water (10 mL) was added, and the mixture was extracted with DCM (20 mL*3). The organic layer was concentrated and subjected to silica gel column chromatography (MeOH:DCM = 0%-1%) to give 3-((3-fluorophenyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (B-4, 178 mg) as a red solid in 68% yield. Molecular formula: C16H12F4N4O2; molecular weight: 368.29;LCMS: (ESI+): m / z 369.3 [M+1]+. Example B-5: Synthesis of 7-cyclopropyl-3-((2,2,2-trifluoroethyl)amino)benzo[e][1,2,4]triazine 1,4- dioxide IM-13 was synthesized according to WO2023019912A1. At room temperature (25°C), to a solution of 7-bromo-3-chlorobenzo[e][1,2,4]triazine 1-oxide (IM-13, 500 mg, 1.92 mmol) in DMF (10 mL) were added trifluoroethylamine (SM-7, 285 mg, 2.88 mmol) and DIEA (744 mg, 5.76 mmol). The mixture was stirred at 50°C for 6 hours. LCMS monitored complete conversion of the starting material, and the reaction was stopped. Water (20 mL) was added, and a yellow solid precipitated. The solid was filtered and dried to give compound IM-11 (530 mg) as a yellow solid in 85.4% yield. Molecular formula: C9H6BrF3N4O; molecular weight: 323.07. At room temperature (25°C), to a solution of compound IM-11 (100 mg, 0.31 mmol) in EA (10 mL) were added cyclopropylboronic acid (52 mg, 0.62 mmol), potassium carbonate (128 mg, 0.93 mmol), water (0.5 mL), and Pd(dppf)Cl2 (25 mg, 0.03 mmol). Under nitrogen protection, the mixture was heated to 80°C under reflux and stirred. After 2 hours, LCMS monitored complete conversion of the starting material. Water (20 mL) was added, and the mixture was extracted with DCM (20 mL*3). The organic layer was concentrated and subjected to silica gel column chromatography (EA:PE = 0%-30%) to give compound IM-12 (50 mg) as a yellow solid in 56.8% yield. Molecular formula: C12H11F3N4O; molecular weight: 284.24. At room temperature (25°C), to a solution of compound IM-12 (50 mg, 0.17 mmol) in EA (5 mL) were added TFAA (1 mL) and hydrogen peroxide (1 mL). The mixture was heated to 40°C and stirred for 8 hours. LCMS monitored complete conversion of the starting material. Water (20 mL) was added, and the mixture was extracted with DCM (20 mLv3). The organic layer was concentrated and subjected to silica gel column chromatography (MeOH:DCM=0%-1%) to give 7-cyclopropyl-3-((2,2,2-trifluoroethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide (B-5, 5 mg) as a red solid in 9.4% yield. Molecular formula: C12H11F3N4O2; molecular weight: 300.24; LCMS: (ESI+): m / z 301.2 [M+1]+. Example B-6: Synthesis of 7-(5-cyclopropyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-3-((2,2,2-trifluoroethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide At room temperature (25°C), to a solution of compound IM-11 (350 mg, 1.08 mmol) in EA (10 mL) were added TFAA (2 mL) and hydrogen peroxide (2 mL). The mixture was stirred at room temperature for 60 hours. LCMS monitored complete conversion of the starting material. Water (20 mL) was added, and the mixture was extracted with DCM (20 mL*3). The organic layer was concentrated and subjected to silica gel column chromatography (MeOH:DCM=0%-1%) to give compound IM-14 (235 mg) as a red-brown solid in 64% yield. Molecular formula: C9H6BrF3N4O2; molecular weight: 339.07. IM-15 was synthesized according to WO2023019912A1. At room temperature (25°C), to a solution of compound IM-14 (100 mg, 0.29 mmol) in DMF (4 mL) were added IM-15 (258 mg, 0.88 mmol), potassium carbonate (122 mg, 0.88 mmol), water (0.5 mL), and Pd2(dba)3 (27 mg, 0.03 mmol). The mixture was heated to 35°C under nitrogen protection and stirred. After 1 hour, LCMS monitored complete conversion of the starting material. Water (10 mL) was added, and a brown solid precipitated. The solid was collected by filtration, and the organic layer was concentrated and subjected to silica gel column chromatography     (MeOH:DCM=0%-2%)    to    give    7-(5-cyclopropyl-4,5,6,7- tetrahydrothieno[3,2-c]pyridin-2-yl)-3-((2,2,2-trifluoroethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide (B-6, 22 mg) as a red-brown solid in 17% yield. Molecular formula: C19H18F3N5O2S; molecular weight: 437.44; LCMS: (ESI+): m / z 438.3 [M+1]+. Example B-7:     Synthesis     of    7-(2-chloro-6-methylpyridin-4-yl)-3-((3,3- difluorocyclopentyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide Example B-8:   Synthesis of  7-(2-chloro-6-methyl-1-oxidopyridin-4-yl)-3-((3,3- difluorocyclopentyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide SM-8 IM-13 IM-15 K2CO3, Pd(dppf)CI2 TFAA, H2O2 EA B-7 RZ1268 At room temperature (25°C), to a solution of 7-bromo-3-chlorobenzo[e][1,2,4]triazine 1-oxide (200 mg, 0.77 mmol) in DMF (5 mL) were added DIEA (298 mg, 2.3 mmol) and 3,3-difluorocyclopentylamine (SM-8, 120 mg, 0.77 mmol). The mixture was stirred at room temperature for 1 hour. LCMS monitored complete conversion of the starting material. Water (10 mL) was added, and a yellow solid precipitated. The solid was filtered and dried to give compound IM-15 (200 mg) in 75% yield. At room temperature (25°C), to a solution of compound IM-15 (200 mg, 0.58 mmol) in EA (6 mL) were added SM-13 (220 mg, 0.87 mmol), potassium carbonate (60 mg, 1.74 mmol), water (0.5 mL), and Pd(dppf)Cl2 (20 mg). Under nitrogen protection, the mixture was heated to 80°C and stirred for 2 hours. LCMS monitored complete conversion of the starting material, and the reaction was stopped. The reaction solution was cooled to room temperature, filtered through Celite, and the filtrate was collected, concentrated, and subjected to silica gel chromatography (PE / EA=2 / 1) to give compound IM-16 (200 mg) as a yellow solid in 88% yield. At room temperature (25°C), to a solution of compound IM-16 (200 mg, 0.51 mmol) in EA (6 mL) were slowly added TFAA (2 mL) and hydrogen peroxide (2 mL). The mixture was heated to 40°C and stirred for 3.5 hours, and the reaction solution gradually turned red. LCMS monitored that the starting material was substantially completely converted, and a trioxide product was also formed. The reaction was stopped. Water (20 mL) was added, and the mixture was extracted with DCM (20 mL*3). The organic layer was concentrated and subjected to silica gel column chromatography (DCM / MeOH=100 / 1) to give (B-7, 110 mg) as a red solid in 53% yield. Molecular formula: C18H16ClF2N5O2; molecular weight: 407.81; LCMS: (ESI+): m / z 408.1 [M+1]+. DCM / MeOH = 30 / 1 gave (B-8, 70 mg) as a red solid in 32% yield. Molecular formula: C18H16ClF2N5O3; molecular weight: 423.80; LCMS: (ESI+): m / z 424.1 [M+1]+. Example    B-9:    Synthesis    of    7-(2-chloro-6-methylpyridin-4-yl)-3-((2,2,2- trifluoroethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide Example    B-10:    Synthesis    of    7-(2-chloro-6-1-oxidopyridin-4-yl)-3-((2,2,2- trifluoroethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide B-10 RZ 1264 At room temperature (25°C), to a solution of compound IM-11 (200 mg, 0.62 mmol) in EA (6 mL) were added SM-13 (312 mg, 1.24 mmol), potassium carbonate (256 mg, 1.86 mmol), water (0.5 mL), and Pd(dppf)Cl2 (22 mg, 0.03 mmol). Under nitrogen protection, the mixture was heated to 80°C and stirred for 2 hours. LCMS monitored complete conversion of the starting material, and the reaction was stopped. The reaction solution was cooled to room temperature, filtered through Celite, and the filtrate was collected, concentrated, and subjected to silica gel chromatography (EA:PE = 0%-30%) to give compound IM-17 (180 mg) as a yellow solid in 78.9% yield. Molecular formula: C15H11ClF3N5O; molecular weight: 369.73. At room temperature (25°C), to a solution of compound IM-17 (180 mg, 0.49 mmol) in EA (6 mL) were slowly added TFAA (2 mL) and hydrogen peroxide (2 mL). The mixture was heated to 40°C and stirred for 3.5 hours, and the reaction solution gradually turned red. LCMS monitored that the starting material was substantially completely converted, and a trioxide product was also formed. The reaction was stopped. Water (20 mL) was added, and the mixture was extracted with DCM (20 mL*3). The organic layer was concentrated and subjected to silica gel column chromatography (MeOH:DCM = 0%-1%) to give 7-(2-chloro-6-methylpyridin-4-yl)-3-((2,2,2-trifluoroethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide (B-9, 33 mg) as a red solid in 17.6% yield. Molecular formula: C15H11ClF3N5O2; molecular weight: 385.73; LCMS:  (ES+): m / z 386.4[M+1]+. Silica gel column chromatography (MeOH:DCM=1%-30%) gave 7-(2-chloro-6-methyl-1-oxidopyridin-4-yl)-3-((2,2,2-trifluoroethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide (B-10, 26 mg) as a red solid in 13.3% yield. Molecular formula: C15H11ClF3N5O3; molecular weight: 401.73; LCMS: (ES+): m / z 402.3[M+1]+. CLASS III: TERMINAL OH, OCOR Example C-1: Synthesis of 7-bromo-3-((2-ethoxy)amino)benzo[e][1,2,4]triazine 1,4- dioxide At room temperature (25°C), to a solution of 7-bromo-3-chlorobenzo[e][1,2,4]triazine 1-oxide (IM-13, 6 g, 23.07 mmol) in DMF (30 mL) were added DIEA (8.9 g, 69.23 mmol) and ethanolamine (2.81 g, 46.15 mmol). The mixture was stirred at room temperature for 1 hour. LCMS monitored complete conversion of the starting material. Water (40 mL) was added, and a yellow solid precipitated. The solid was filtered, dried, and collected to give compound IM-18 (6 g) as a yellow solid in 92% yield. Molecular formula: C9H9BrN4O2; molecular weight: 285.10. At room temperature (25°C), to a suspension of compound IM-18 (1.5 g, 5.26 mmol) in EA (20 mL) were added TFAA (2 mL) and hydrogen peroxide (2 mL). The mixture was stirred at room temperature for 60 h. LCMS showed some starting material remaining, and the reaction was stopped. The reaction solution was filtered, and water (30 mL) was added to the filtrate. The mixture was extracted with DCM (50 mL*3). The organic layer was concentrated and combined with the filter cake, and subjected to silica gel column chromatography (MeOH:DCM=0%-3%) to give 7-bromo-3-((2-ethoxy)amino)benzo[e][1,2,4]triazine 1,4-dioxide (C-1, 1.26 g) as a red solid in 79% yield. Molecular formula: C9H9BrN4O3; molecular weight: 301.10; LCMS: (ESI+): m / z 302.3 [M+1]+. Example       C-2:       Synthesis       of 3-((2-hydroxyethyl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide F3C IM-1 ?         / -\ 0H N HjN -^ +' N ------------- T DMF, DIEA N^CI At room temperature (25°C), to a solution of compound IM-1 (280 mg, 1.12 mmol) in DMF (4 mL) were added DIEA (435 mg, 3.37 mmol) and ethanolamine (137 mg, 2.25 mmol). The mixture was stirred at room temperature for 30 minutes. LCMS monitored complete conversion of the starting material. Water (10 mL) was added, and a yellow solid precipitated. The solid was filtered and dried to give compound IM-19 (250 mg) as a yellow solid in 81% yield. Molecular formula: C10H9F3N4O2; molecular weight: 274.20. At room temperature (25°C), to a solution of compound IM-19 (250 mg) in EA (5 mL) were added TFAA (2 mL) and hydrogen peroxide (2 mL). The mixture was stirred at room temperature for 16 hours. LCMS monitored complete conversion of the starting material. Water (10 mL) was added, and the mixture was extracted with DCM (20 mL*3). The organic layer was concentrated and subjected to silica gel column chromatography (MeOH:DCM=0%-4%) to give 3-((2-hydroxyethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (C-2, 66 mg) as a red solid in 25% yield. Molecular formula: C10H9F3N4O3; molecular weight: 290.20; LCMS: (ESI+): m / z 291.3 [M+1]+. Example     C-3:     Synthesis     of     3-((2-hydroxy-2-methylpropyl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide IM-1                                        IM-20                                           C-3 RZ1224 At room temperature (25°C), to a solution of 3-chloro-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1-oxide (IM-1, 600 mg, 2.41 mmol) in DMF (8 mL) were added DIEA (932 mg, 7.23 mmol) and 1-amino-2-methylpropanol (429 mg, 4.82 mmol). The mixture was stirred at room temperature for 1 hour. LCMS monitored complete conversion of the starting material, and the reaction was stopped. Water (20 mL) was added, and a yellow solid precipitated. The solid was filtered and dried to give compound IM-20 (650 mg) as a yellow solid in 89% yield. Molecular formula: C12H13F3N4O2; molecular weight: 302.25. At room temperature (25°C), to a solution of compound IM-20 (100 mg, 0.33 mmol) in EA (5 mL) were added TFAA (1 mL) and hydrogen peroxide (1 mL). The reaction solution gradually turned red. The reaction solution was heated to 40°C and stirred for 4 hours. LCMS showed starting material remaining. The mixture was continued stirring at room temperature overnight. LCMS showed less starting material remaining, and the reaction was stopped. Water (10 mL) was added, and the mixture was extracted with DCM (20 mL*3). The organic layer was concentrated and subjected to silica gel column chromatography (MeOH:DCM = 0%-2%) to give 3-((2-hydroxy-2-methylpropyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (C-3, 21 mg) as a red solid in 26% yield. Molecular formula: C12H13F3N4O3; molecular weight: 318.25; LCMS: (ESI+): m / z 319.2 [M+1]+. Example C-4:    Synthesis of 3-((1S,4S)-4-hydroxycyclohexyl)amino)-7- trifluoromethylbenzo[e][1,2,4]triazine 1,4-dioxide At room temperature, to a solution of IM-1 (150 mg, 0.6 mmol) in DMF (5 mL) were added DIPEA (90 mg, 0.72 mmol) and 4-hydroxycyclohexylamine (115 mg, 1.0 mmol). The mixture was stirred at room temperature for 30 minutes. LCMS monitored complete conversion of the starting material. Water (10 mL) was added, and a yellow solid precipitated. The product IM-21 was obtained by filtration and used directly in the next step. At room temperature, to a solution of IM-21 in EA (10 mL) were added TFAA (1.5 mL) and hydrogen peroxide (1.5 mL). The mixture was stirred at room temperature overnight. TLC showed a small amount of starting material remaining. Water (10 mL) was added, and the mixture was extracted with EA (20 mL*3). The organic layer was mixed with silica gel, concentrated, and purified by column chromatography, eluting with DCM / MeOH = 25 / 1 to give       the       target       product       3-((1S,4S)-4-hydroxycyclohexyl)amino)-7- trifluoromethylbenzo[e][1,2,4]triazine 1,4-dioxide (C-4, 65 mg) as a red solid, two-step yield 31%. Molecular formula: C14H15F3N4O3; molecular weight: 344.29; LCMS: (ESI+): m / z 345.3 [M+1]+. Example       C-5:       Synthesis of       3-(2-hydroxypropyl)amino-7- trifluoromethylbenzo[1,2,4]triazine 1,4-dioxide IM-1                                             IM-22 C-5, RZ-1227 At room temperature, to a solution of IM-1 (150 mg, 0.6 mmol) in DMF (5 mL) were added DIPEA (90 mg, 0.72 mmol) and 2-methylethanolamine (100 mg, 1.3 mmol). The mixture was stirred at room temperature for 30 minutes. LCMS monitored complete conversion of the starting material. Water (10 mL) was added; no yellow solid precipitated. The mixture was extracted with EA and dried to give product IM-22, which was used directly in the next step. At room temperature, to a solution of IM-22 in EA (10 mL) were added TFAA (1.5 mL) and hydrogen peroxide (1.5 mL). The mixture was stirred at room temperature overnight. TLC showed a small amount of starting material remaining. Water (10 mL) was added, and the mixture was extracted with EA (20 mL*3). The organic layer was mixed with silica gel, concentrated, and purified by column chromatography, eluting with DCM / MeOH = 25 / 1 to give the target product 3-(2-hydroxypropyl)amino-7-trifluoromethylbenzo[1,2,4]triazine 1,4-dioxide (C-5, 45 mg) as a purple-red solid, two-step yield 24%. Molecular formula: C11H11F3N4O3; molecular weight: 304.23; LCMS: (ESI+): m / z 305.3 [M+1]+. Example C-6:   7-(5-cyclopropyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-3-((2- hydroxyethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide At room temperature (25°C), to a suspension of 7-bromo-3-((2-hydroxyethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide (C-1, 900 mg, 2.99 mmol) in DMF (10 mL) were added 5-cyclopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine (IM-15, 1.8 g, 5.90 mmol), potassium carbonate (1.2 g, 8.97 mmol), water (2 mL), and Pd2(dba)3 (200 mg, 0.22 mmol). The mixture was heated to 35°C under nitrogen protection and stirred for 1 hour. LCMS monitored complete conversion of the starting material, and the reaction was stopped. Water (20 mL) was added, and a dark brown solid precipitated. The solid was filtered. The filter cake was triturated with DCM / MeOH = 6 / 1, and the solid was collected and dried to give a red solid (C-6, 580 mg) in 48.5% yield. Molecular formula: C19H21N5O3S; molecular weight: 399.47;LCMS: (ESI+): m / z 400.2 [M+1]+. Example      C-7:       Synthesis      of      7-bromo-3-((2-(4-fluorophenyl)-2- hydroxyethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide At room temperature (25°C), to a solution of 2-amino-1-(4-fluorophenyl)ethan-1-one hydrochloride (300 mg, 1.58 mmol) in MeOH (5 mL) was added NaBH4 (90 mg, 2.37 mmol). The mixture was stirred for 2 hours. Water (25 mL) was added to the reaction, and the mixture was extracted with DCM / MeOH=10 / 1. The organic layer was concentrated to give crude 2-amino-1-(4-fluorophenyl)ethan-1-ol (145 mg) as a white solid, which was used directly in the next step. Molecular formula: C8H10FNO; molecular weight: 155.17. To a solution of IM-13 (240 mg, 0.93 mmol) and 2-amino-1-(4-fluorophenyl)ethan-1-ol (145 mg, 0.93 mmol) in DMF (8 mL) was added DIEA (480 mg, 3.72 mmol). The mixture was stirred for 20 hours. Water (15 mL) was added to the reaction, and the mixture was filtered. The filter cake was dried to give yellow solid IM-23 (180 mg), which was used directly in the next step. At room temperature (25°C), to a solution of compound IM-23 (180 mg, 0.47 mmol) in DCM (5 mL) were added TFAA (3 mL) and hydrogen peroxide (3 mL). The mixture was stirred for 20 hours. Water (10 mL) was added, and the mixture was extracted with DCM (20 mL*3). The organic layer was concentrated and purified by preparative HPLC to give 7-bromo-3-((2-(4-fluorophenyl)-2-hydroxyethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide (C-7, 9.5 mg) as a red solid in 5.1% yield. Molecular formula: C15H12BrFN4O3; molecular weight: 395.19; 1H NMR (400 MHz, DMSO-d6, ppm): d 8.36 (s, 1H), 8.13 (t, J = 6.0 Hz, 1H), 8.05 (s, 2H), 7.43 (dd, J = 8.4 Hz, 5.6 Hz, 2H), 7.16 (t, J = 8.8 Hz, 2H), 5.72 (d, J = 4.4 Hz, 1H), 4.89 (dd, J = 10.4 Hz, 5.6 Hz, 1H), 3.55 (t, J = 6.0 Hz, 2H); LCMS: (ESI+): m / z 395.0 [M+1]+. Example C-8: Synthesis of 7-bromo-3-((2-(isobutyryloxy)ethyl)amino)benzo[e][1,2,4]triazine  1,4- dioxide At room temperature (25°C), compound IM-18 (300 mg, 1.05 mmol) and isobutyric acid (370 mg, 4.21 mmol) were added to a flask, and SOCI2 (1 mL) was slowly added to the suspension. The reaction solution was heated to 90°C under reflux and stirred. The reaction solution changed from a yellow suspension to a red suspension. After 3 hours, LCMS monitored the formation of the target product and no remaining starting material. The reaction solution was cooled to room temperature, water was added, and a yellow solid precipitated. The solid was filtered to give compound IM-24 (310 mg) as a yellow solid in 83% yield. Molecular formula: C13H15BrN4O3; molecular weight: 355.19. Compound IM-24 (310 mg, 0.87 mmol) and isopropyl acetate (5 mL) were added to a flask, and AcOH (1 mL), TFAA (2 mL), and hydrogen peroxide (2 mL) were added sequentially at room temperature. The mixture was stirred at 35°C for 4 hours, then stirred at room temperature for 64 hours. LCMS showed no remaining starting material. Water (10 mL) was added, and the mixture was extracted with DCM (20 mL*3). The organic layer was concentrated and subjected to silica gel column chromatography (MeOH:DCM=0%-1%) to give 7-bromo-3-((2-(isobutyryloxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide (C-8, 35 mg) as a red solid in 11% yield. Molecular formula: C13H15BrN4O4; molecular weight: 371.19; LCMS: (ESI+): m / z 374.2 [M+1]+. Example C-9: Synthesis of 7-bromo-3-((2-(hexadecanoyloxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide C-1 EDCI, DMAP, DCM C15H C-9 At room temperature (25°C), to a suspension of 7-bromo-3-((2- hydroxyethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide (C-1, 200 mg, 0.66 mmol) in DCM (6 mL) were added n-hexadecanoic acid (256 mg, 0.99 mmol), EDCI (152 mg, 0.79 mmol), and DMAP (122 mg, 0.99 mmol). The mixture was stirred at room temperature overnight. TLC showed a small amount of starting material remaining and formation of a product spot. The reaction solution was concentrated and subjected to silica gel column chromatography (EA:PE = 0%-100%) to give 7-bromo-3-((2-(hexadecanoyloxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide (C-9, 110 mg) as a red solid in 30.7% yield. Molecular formula: C25H39BrN4O4; molecular weight: 539.51; LCMS: (ESI+): m / z 541.2[M+1]+. Example C-10: 7-bromo-3-((2-((2-bromohexadecanoyl)oxy)ethyl)amino)benzo[e][1,2,4]triazine     1,4- dioxide Br O EDCI, DMAP C-10 At room temperature (25°C), to a solution of 7-bromo-3-((2- hydroxyethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide (C-1, 100 mg, 0.33 mmol) in DCM (6 mL) were added 2-bromohexadecanoic acid (166 mg, 0.50 mmol), EDCI (76 mg, 0.40 mmol), and DMAP (36 mg, 0.40 mmol). The mixture was stirred at room temperature for 16 hours. TLC showed a small amount of starting material remaining, and the reaction was stopped. The reaction solution was concentrated and purified by Prep-TLC (PE / EA = 1 / 1) to give 7-bromo-3-((2-((2-bromohexadecanoyl)oxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide (C-10, 20 mg) as a red solid in 9.7% yield. Molecular formula: C25H38Br2N4O4; molecular weight: 618.40; LCMS: (ESI+): m / z 620.4 [M+1]+. (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide TFAA, H2O2 EA 0 C-11, RZ1228 At room temperature (25°C), to a solution of  3-((2-hydroxyethyl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1-oxide (IM-19, 300 mg, 1.09 mmol) in DMF (5 mL) were added DIEA (424 mg, 3.28 mmol) and pivaloyl chloride (394 mg, 3.28 mmol). The mixture was heated to 45°C and stirred for 2 hours. LCMS monitored complete conversion of the starting material, and the reaction was stopped. Water (20 mL) was added, and the mixture was extracted with EA (20 mL*3). The organic layer was washed with water and concentrated, and subjected to silica gel column chromatography (EA:PE=0%-15%) to give compound IM-25 (147 mg) as a yellow solid in 37.5% yield. Molecular formula: C15H17F3N4O3; molecular weight: 358.32. At room temperature (25°C), to a solution of compound IM-25 (147 mg, 0.41 mmol) in EA (5 mL) were added TFAA (1 mL) and hydrogen peroxide (1 mL). The reaction solution gradually turned red. The reaction solution was heated to 40°C and stirred for 8 hours. LCMS monitored complete conversion of the starting material, and the reaction was stopped. Water (20 mL) was added, and the mixture was extracted with DCM (20 mL*3). The organic layer was concentrated and subjected to silica gel column chromatography (MeOH:DCM = 0%-1%) to give 3-((2-(pivaloyloxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (C-11, 40 mg) as a red solid in 26% yield. Molecular formula: C15H17F3N4O4; molecular weight: 374.32; LCMS: (ESI+): m / z 375.3 [M+1]+. Example     C-12:     Synthesis     of 3-((2-(isobutyryloxy)ethyl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide TFAA, H2O2 EA O’ C-12, RZ1225 At room temperature (25°C), to a solution of 3-((2-hydroxyethyl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1-oxide (IM-19, 150 mg, 0.55 mmol) in DMF (5 mL) were added DIEA (212 mg, 1.64 mmol) and isobutyryl chloride (174 mg, 1.64 mmol). The mixture was heated to 45°C and stirred for 2 hours. LCMS monitored complete conversion of the starting material. The reaction was stopped, water (20 mL) was added, and the mixture was extracted with EA (20 mL*3). The organic layer was washed with water and concentrated to give compound IM-26 (100 mg) as a yellow solid, which was used directly in the next reaction. At room temperature (25°C), to a solution of compound IM-26 (100 mg, 0.29 mmol) in EA (5 mL) were added TFAA (1 mL) and hydrogen peroxide (1 mL). The reaction solution gradually turned red. The reaction solution was heated to 40°C and stirred for 8 hours. LCMS monitored complete conversion of the starting material, and the reaction was stopped. Water (20 mL) was added, and the mixture was extracted with DCM (20 mL*3). The organic layer was concentrated and subjected to silica gel column chromatography (MeOH:DCM=0%-1%) to give 3-((2-(isobutyryloxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (C-12, 40 mg) as a red solid in 38% yield. Molecular formula: C14H15F3N4O4; molecular weight: 360.29; LCMS: (ESI+): m / z 361.5 [M+1]+. Example C-13: Synthesis of 3-((2-((3-hydroxytetradecanoyl)oxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide C-2, RZ-1218                                     C-13, RZ-1233 C-2 (100 mg, 0.2 mmol), 3-hydroxymyristic acid (140 mg, 0.6 mmol), EDCI (57 mg, 0.3 mmol), DMAP (5 mg, 0.01 mmol), and DCM (4 mL) were mixed and stirred at room temperature for 4 h. TLC showed a small amount of starting material remaining. The reaction solution was dried and subjected to column chromatography, eluting with DCM / MeOH=100 / 1 to give the target product   3-((2-((3-hydroxytetradecanoyl)oxy)ethyl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (C-13, 52 mg, 0.03 mmol) as a red solid, two-step yield 16%. Molecular formula: C24H35F3N4O5; molecular weight: 516.56; LCMS: (ESI+): m / z 517.7 [M+1]+. Example     C-14: Synthesis      of      3-((2-(nicotinoyloxy)ethyl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide 0“ C-2, RZ-1218 C-14, RZ-1234 C-2 (20 mg, 0.07 mmol), nicotinic acid (30 mg, 0.07 mmol), EDCI (20 mg, 0.1 mmol), DMAP (1 mg, 0.0035 mmol), and DCM (4 mL) were mixed and stirred at room temperature for 4 h. TLC showed a small amount of starting material remaining. The reaction solution was dried and subjected to column chromatography, eluting with DCM / MeOH = 50 / 1 to give the target product 3-((2-(nicotinoyloxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (C-14, 14.6 mg, 0.04 mmol) as a red solid in 54% yield. Molecular formula: C16H12F3N5O4; molecular weight: 395.30; LCMS: (ESI+): m / z 396.5 [M+1]+. Example C-15:     Synthesis of    3-((((2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6- trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenyl)oxy)ethyl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide SM-14 C-2                                                                                          C-15, RZ-1235 C-2 (20 mg, 0.07 mmol), SM-14 (30 mg, 0.07 mmol), EDCI (20 mg, 0.1 mmol), DMAP (1 mg, 0.0035 mmol), and DCM (4 mL) were mixed and stirred at room temperature for 12 h. TLC showed a small amount of starting material remaining. The reaction solution was dried and subjected to column chromatography, eluting with DCM / MeOH=100 / 1 to give the target product 3-((((2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenyl)oxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (C-15, 3 mg) as a red solid in 5% yield. Molecular formula: C30H35F3N4O4; molecular weight: 572.63; LCMS: (ESI+): m / z 573.5 [M+1]+. Example C-16: Synthesis of 7-(trifluoromethyl)-3-((2-(propoxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4- dioxide C-16, RZ-1237 At room temperature (25°C), to C-2 (150 mg, 0.55 mmol) were added N-Boc valine (130 mg, 0.60 mmol), EDCI (110 mg, 0.6 mmol), DMAP (5 mg, 0.025 mmol), and DCM (4 mL). The mixture was stirred at room temperature overnight. TLC showed a small amount of starting material remaining. The reaction solution was dried and subjected to column chromatography, eluting with DCM / MeOH=100 / 1 to give IM-27, which was concentrated to an oil and used directly in the next step. At room temperature, to a solution of IM-27 in EA (10 mL) were added TFAA (2 mL) and hydrogen peroxide (2 mL). The mixture was stirred at room temperature overnight. TLC showed a small amount of starting material remaining. Water (10 mL) was added, and the mixture was extracted with EA (20 mL*3). The organic layer was mixed with silica gel, concentrated, and purified by column chromatography, eluting with DCM / MeOH = 10 / 1 to give the target product 7-(trifluoromethyl)-3-((2-(propoxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide (C-16, 38 mg) as a red solid, hygroscopic, two-step yield 17%. Molecular formula: C15H18F3N5O4; molecular weight: 389.34; LCMS: (ESI+): m / z 390.4 [M+1]+. Example C-17:   Synthesis of  3-((2-((thiophene-3-carbonyl)oxy)ethyl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide C-17, RZ1243 At room temperature (25°C), to a solution of 3-((2-hydroxyethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (C-2, 50 mg, 0.17 mmol) in DCM (5 mL) were added 3-thiophenecarboxylic acid (27 mg, 0.20 mmol), EDCI (50 mg, 0.25 mmol), and DMAP (31 mg, 0.25 mmol). The mixture was stirred at room temperature for 4.5 hours. LCMS monitored complete conversion of the starting material, and the reaction was stopped. Water (10 mL) was added, and the mixture was extracted with DCM (20 mL*3). The organic layers were combined and concentrated, and subjected to silica gel column chromatography (DCM:MeOH=0%-1%) to give    3-((2-((thiophene-3-carbonyl)oxy)ethyl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (C-17, 27 mg) as a red solid in 39% yield. Molecular formula: C15H11F3N4O4S; molecular weight: 400.33; LCMS: (ESI+): m / z 401.1 [M+1]+. Example      C-18:      Synthesis      of      3-((2-(isobutyryloxy)ethyl)amino)-7- (trifluoromethoxy)benzo[e][1,2,4]triazine 1,4-dioxide Example       C-19:       Synthesis       of       3-((2-hydroxyethyl)amino)-7- (trifluoromethoxy)benzo[e][1,2,4]triazine 1,4-dioxide C-19 C-18 IM-28 was synthesized according to WO2023019912A1. At room temperature (25°C), to a solution of 3-chloro-7- (trifluoromethoxy)benzo[e][1,2,4]triazine 1-oxide (IM-28, 820 mg, 3.09 mmol) in DMF (4 mL) were added DIEA (1.20 g, 9.28 mmol) and ethanolamine (377 mg, 6.18 mmol). The mixture was stirred at room temperature for 30 minutes. LCMS monitored complete conversion of the starting material, and the reaction was stopped. Water (20 mL) was added, and a yellow solid precipitated. The solid was filtered and dried to give compound IM-29 (850 mg) in 95% yield. Molecular formula: C10H9F3N4O3; molecular weight: 290.20. At room temperature (25°C), to a solution of compound IM-29 (850 mg, 2.93 mmol) in DCM (8 mL) were added DIEA (1.13 g, 8.79 mmol) and isobutyryl chloride (928 mg, 8.79 mmol). The mixture was stirred at room temperature for 4 hours. LCMS monitored complete conversion of the starting material, and the reaction was stopped. Water (20 mL) was added, and the mixture was extracted with DCM (20 mL*3). The organic layers were combined and concentrated to give compound IM-30 (940 mg), which was used directly in the next reaction. At room temperature (25°C), to a solution of compound IM-30 (940 mg, 2.61 mmol) in EA (10 mL) were added TFAA (3 mL) and hydrogen peroxide (3 mL). The mixture was stirred at room temperature for 16 hours. LCMS monitored that the starting material had substantially reacted completely, and the reaction was stopped. Water (20 mL) was added, and the mixture was extracted with DCM (20 mL*3). The organic layer was concentrated and subjected to silica gel    column    chromatography    (DCM:MeOH=0%-1%) to    give    3-((2- (isobutyryloxy)ethyl)amino)-7-(trifluoromethoxy)benzo[e][1,2,4]triazine 1,4-dioxide (C-18, 700 mg) as a red solid in 71% yield. Molecular formula: C14H15F3N4O5; molecular weight: 376.29; LCMS: (ESI+): (ESI+): m / z 377.4 [M+1]+. At room temperature (25°C), to a solution of compound C-18 (150 mg, 0.40 mmol) in methanol (10 mL) was added lithium hydroxide hydrate (50 mg, 1.20 mmol). The mixture was stirred at room temperature for 1 hour. LCMS monitored complete conversion of the starting material, and the reaction was stopped. Water (20 mL) was added, and the mixture was extracted with DCM (20 mL*3). The organic layer was concentrated to give 3-((2-hydroxyethyl)amino)-7-(trifluoromethoxy)benzo[e][1,2,4]triazine 1,4-dioxide (C-19, 120 mg) as a red solid in 98% yield. Molecular formula: C10H9F3N4O4; molecular weight: 306.20; LCMS: (ESI+): m / z 3707.2 [M+1]+. Example C-20:  Synthesis of  3-((2-((2-bromohexadecanoyl)oxy)ethyl)amino)-7- (trifluoromethoxy)benzo[e][1,2,4]triazine 1,4-dioxide Br C-!9                                                              C-20 At room temperature (25°C), to a solution of 3-((2-hydroxyethyl)amino)-7-(trifluoromethoxy)benzo[e][1,2,4]triazine 1,4-dioxide (C-19, 50 mg, 0.16 mmol) in DCM (5 mL) were added 2-bromohexadecanoic acid (83 mg, 0.24 mmol), EDCI (38 mg, 0.19 mmol), and DMAP (18 mg, 0.19 mmol). The mixture was stirred at room temperature for 1 hour. TLC showed starting material remaining and formation of a new spot. The mixture was continued stirring overnight. TLC still showed a small amount of starting material remaining, and the reaction was stopped. The reaction solution was concentrated and purified by Prep-TLC (PE / EA     =1 / 1)     to     give     3-((2-((2-bromohexadecanoyl)oxy)ethyl)amino)-7- (trifluoromethoxy)benzo[e][1,2,4]triazine 1,4-dioxide (C-20, 20 mg) as a red solid in 19% yield. Molecular formula: C26H38BrF3N4O5; molecular weight: 623.50; LCMS:  (ESI+): m / z 623.4 [M+1]+. Example C-21: 6-bromo-3-((2-(isobutyryloxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide IM-31 was synthesized according to WO2023019912A1, starting from 2-nitro-5- bromoaniline. At room temperature (25°C), to a solution of 6-bromo-3-chlorobenzo[e][1,2,4]triazine 1-oxide (IM-31, 250 mg, 0.96 mmol) in DMF (5 mL) were added DIEA (372 mg, 2.88 mmol) and ethanolamine (88 mg, 1.44 mmol). The mixture was stirred at room temperature for 1 hour. LCMS monitored complete conversion of the starting material, and the reaction was stopped. Water (20 mL) was added, and a yellow solid precipitated. The solid was filtered and dried to give compound IM-32 (140 mg) as a yellow solid in 51% yield. Molecular formula: C9H9BrN4O2; molecular weight: 285.10. At room temperature (25°C), to a solution of compound IM-32 (140 mg, 0.49 mmol) in dichloromethane (5 mL) were added DIEA (325 mg, 1.47 mmol) and isobutyryl chloride (78 mg, 0.74 mmol). The mixture was heated to 50°C and stirred for 1 hour. LCMS monitored that the starting material had substantially reacted completely, and the reaction was stopped. Water (20 mL) was added, and the mixture was extracted with dichloromethane (20 mL*3). The organic layer was concentrated to give compound IM-33 (100 mg) as a yellow solid, which was used directly in the next reaction. At room temperature (25°C), to a solution of compound IM-33 (100 mg, 0.28 mmol) in EA (6 mL) were added TFAA (1 mL) and hydrogen peroxide (1 mL). The mixture was heated to 35°C and stirred for 8 hours. LCMS monitored complete conversion of the starting material, and the reaction was stopped. Water (20 mL) was added, and the mixture was extracted with dichloromethane (20 mL*3). The organic layer was concentrated and subjected to silica gel column chromatography (DCM:MeOH=0%-1%) to give    6-bromo-3-((2- (isobutyryloxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide (C-21, 20 mg) as a red solid in 19% yield. Molecular formula: C13H15BrN4O4; molecular weight: 371.19; LCMS: (ESI+): m / z 372.4 [M+1]+. Example C-22: Synthesis of 8-bromo-3-((2-(isobutyryloxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4- dioxide The synthesis of C-22 refers to C-21. Example C-23: Synthesis of 7-(5-cyclopropyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-3-((2- At room temperature (25°C), to a solution of 7-bromo-3-((2- (isobutyryloxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide (C-8, 180 mg, 0.48 mmol) in DMF (4 mL) were added 5-cyclopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (IM-15, 250 mg, 0.81 mmol), potassium carbonate (200 mg, 1.44 mmol), water (0.3 mL), and Pd2(dba)3 (30 mg, 0.03 mmol). The atmosphere was replaced with nitrogen, and the mixture was heated to 35°C and stirred for 1 hour. LCMS monitored that the starting material had substantially completely converted, and the reaction was stopped. Water (10 mL) was added, and the mixture was stirred at room temperature for 30 minutes. A dark red solid precipitated. The solid was collected by filtration and subjected to silica gel column chromatography (MeOH:DCM=0%-2%) to give 7-(5-cyclopropyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-3-((2-(isobutyryloxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide (C-23, 130 mg) as a red solid in 45% yield. Molecular formula: C23H27N5O4S; molecular weight: 469.56; LCMS: (ESI+): m / z 470.4 [M+1]+. Example C-24: Synthesis of 7-cyclopropyl-3-((2-(pivaloyloxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4- dioxide C-24, RZ 1258 At room temperature (25°C), to a solution of 7-bromo-3-((2- hydroxyethyl)amino)benzo[e][1,2,4]triazine 1-oxide (IM-18, 500 mg, 1.75 mmol) in DMF (6 mL) were added DIEA (679 mg, 5.26 mmol), DMAP (321 mg, 2.62 mmol), and pivaloyl chloride (252 mg, 2.1 mmol). The mixture was stirred at room temperature for 3 hours. LCMS monitored that the starting material had substantially reacted completely. Water (20 mL) was added, and a yellow solid precipitated. The solid was filtered and dried to give compound IM- 34 (600 mg) as a yellow solid in 92.7% yield. Molecular formula: C14H17BrN4O3; molecular weight: 369.21. At room temperature (25°C), to a solution of compound IM-34 (200 mg, 0.54 mmol) in EA (10 mL) were added cyclopropylboronic acid (92 mg, 1.08 mmol), potassium carbonate (224 mg, 1.62 mmol), water (1 mL), and Pd(dppf)Cl2 (40 mg, 0.05 mmol). Under nitrogen protection, the mixture was heated to 80°C and stirred for 2 hours. LCMS monitored complete conversion of the starting material, and the reaction was stopped. The reaction solution was filtered through Celite, concentrated, and subjected to silica gel column chromatography (EA:PE = 0%-20%) to give compound IM-35 (160 mg) as a yellow solid in 89% yield. Molecular formula: C17H22N4O3; molecular weight: 330.38. At room temperature (25°C), to a solution of compound IM-35 (160 mg, 0.48 mmol) in EA (6 mL) were added TFAA (2 mL) and hydrogen peroxide (2 mL). The mixture was heated to 40°C and stirred for 3.5 hours. LCMS monitored complete reaction of the starting material, and the reaction was stopped. Water (20 mL) was added, and the mixture was extracted with DCM (20 mL*3). The organic layer was concentrated and subjected to silica gel column chromatography     (MeOH:DCM=0%-1%)     to     give     7-cyclopropyl-3-((2- (pivaloyloxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide (C-24, 84 mg) as a red solid in 50% yield. Molecular formula:C17H22N4O4; molecular weight: 346.38; LCMS: (ESI+): m / z 347.4 [M+1]+. Example C-25: Synthesis of  3-((2-((thiophene-3-carbonyl)oxy)propyl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide o IM-22                                                         IM-36 C-25, RZ-1255 At room temperature (25°C), to a flask containing IM-22 (90 mg, 0.3 mmol), 2-thiophenecarboxylic acid (76 mg, 0.6 mmol), EDCI (57 mg, 0.3 mmol), and DMAP (3 mg, 0.015 mmol) was added DCM (4 mL). The mixture was stirred at room temperature for 12 h. TLC showed a small amount of starting material remaining. The reaction solution was dried to give product IM-36, which was used directly in the next step. At room temperature, to a solution of IM-36 in EA (10 mL) were added TFAA (2 mL) and hydrogen peroxide (2 mL). The mixture was stirred at room temperature overnight. TLC showed a small amount of starting material remaining. Water (10 mL) was added, and the mixture was extracted with EA (20 mL*3). The organic layer was mixed with silica gel, concentrated, and purified by column chromatography, eluting with DCM / MeOH = 100 / 1 to give     the     target     product     3-((2-((thiophene-3-carbonyl)oxy)propyl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (C-25, 81 mg) as a red solid, two-step yield 65%. Molecular formula: C16H13F3N4O4S; molecular weight: 414.36; LCMS: (ESI+): m / z 415.5 [M+1]+. Example C-26: Synthesis of 3-((2-((cyclopropanecarbonyl)oxy)propyl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide EDCI, DMAP, DCM IM-22 IM-37 TFAA,H2O2 DCM C-26, RZ-1256 At room temperature (25°C), to a flask containing IM-22 (90 mg, 0.3 mmol), cyclopropanecarboxylic acid (51 mg, 0.6 mmol), EDCI (57 mg, 0.3 mmol), and DMAP (3 mg, 0.015 mmol) was added DCM (4 mL). The mixture was stirred at room temperature for 12 h. TLC showed a small amount of starting material remaining. The reaction solution was dried to give product IM-37, which was used directly in the next step. At room temperature, to a solution of IM-37 in EA (10 mL) were added TFAA (2 mL) and hydrogen peroxide (2 mL). The mixture was stirred at room temperature overnight. TLC showed a small amount of starting material remaining. Water (10 mL) was added, and the mixture was extracted with EA (20 mL*3). The organic layer was mixed with silica gel, concentrated, and purified by column chromatography, eluting with DCM / MeOH=100 / 1 to give     the     target product     3-((2-((cyclopropanecarbonyl)oxy)propyl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (C-26, 42 mg) as a red solid, two-step yield 37%. Molecular formula: C16H13F3N4O4S; molecular weight: 372.30; LCMS: (ESI+): m / z 373.5 [M+1]+. Example C-27: 3-((2-(pivaloyloxy)propyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide IM-22                                                   IM-50                                                            C-27, RZ1271 At room temperature (25°C), to a solution of compound IM-22 (220 mg, 0.76 mmol) in DMF (5 mL) were added pivaloyl chloride (136 mg, 1.14 mmol), DIEA (294 mg, 2.28 mmol), and DMAP (139 mg, 1.14 mmol). The mixture was stirred at room temperature for 16 hours. LCMS monitored complete reaction. Water (10 mL) was added, and a yellow solid precipitated. The solid was filtered and dried to give compound IM-50 (280 mg) in 98% yield. Molecular formula: C16H19F3N4O3; molecular weight: 372.34. At room temperature (25°C), to a solution of compound IM-50 (280 mg) in EA (6 mL) were slowly added TFAA (2 mL) and hydrogen peroxide (2 mL). The mixture was heated to 40°C and stirred for 3.5 hours, then stirred at room temperature for 16 hours. LCMS monitored that the starting material had substantially completely converted. Water (20 mL) was added, and the mixture was extracted with DCM (20 mL*3). The organic layer was concentrated and subjected to silica gel column chromatography (MeOH:DCM=0%-1%) to give (C-27, 208 mg) as a red solid in 71% yield. Molecular formula: C16H19F3N4O4 molecular weight: 388.34; LCMS:  (ES+): m / z 389.4 [M+1]+. Example C-28: Synthesis of 3-((2-((3-hydroxytetradecanoyl)oxy)propyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide C-28, RZ1272 At room temperature (25°C), to a flask containing IM-22 (288 mg, 1.0 mmol), 3-hydroxymyristic acid (240 mg, 1.1 mmol), EDCI (200 mg, 1.2 mmol), and DMAP (6 mg, 0.05 mmol) was added DCM (4 mL). The mixture was stirred at room temperature for 24 h. TLC showed a small amount of starting material remaining. Water (10 mL) was added, and the mixture was extracted with DCM (20 mL*3). The solution was dried to give 3-((2-((3-hydroxytetradecanoyl)oxy)propyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1-oxide, which was used directly in the next step. At room temperature, to a solution of 3-((2-((3-hydroxytetradecanoyl)oxy)propyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1-oxide in EA (10 mL) were added TFAA (2 mL) and hydrogen peroxide (2 mL). The mixture was stirred at room temperature overnight. TLC showed a small amount of starting material remaining. Water (10 mL) was added, and the mixture was extracted with EA (20 mL*3). The organic layer was mixed with silica gel, concentrated, and purified by column chromatography, eluting with DCM / MeOH = 40 / 1 to give the target product    3-((2-((3-hydroxytetradecanoyl)oxy)propyl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (C-28, 55 mg) as a red solid, two-step yield 10%. Molecular formula: C25H37F3N4O5; molecular weight: 530.59; LCMS: (ESI+): m / z 531.6 [M+1]+. Example C-29: Synthesis of 3-((2-(pentanoyloxy)ethyl)amino)-7-(thiazol-5-yl)benzo[e][1,2,4]triazine 1,4-dioxide IM-18 K2CO3, h2o Pd(dppf)CI2 dioxane TFAA, H2O2 EA RZ1279 At room temperature (15°C), to a solution of IM-18 (150 mg, 1 eq) in DMF (10 mL) were added pivaloyl chloride (76 mg, 1.2 eq), DMAP (77 mg, 1.2 eq), and DIEA (203 mg, 3 eq). The mixture was stirred at room temperature for 1 hour. LCMS monitored complete conversion of the starting material. Water (30 mL) was added, and a yellow solid precipitated. The solid was filtered and dried to give 156 mg of a yellow solid, which was used in the next step. At room temperature (15°C), to a solution of the above product (150 mg) in dioxane (20 mL) were added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (86 mg), potassium carbonate (168 mg), water, and Pd(dppf)Cl2 (10 mg). Under nitrogen protection, the mixture was heated to 120°C and stirred for 3 hours. LCMS monitored complete conversion of the starting material, and the reaction was stopped. The reaction solution was filtered, water was added to the filtrate, and the mixture was extracted with EA. The organic layer was concentrated and the crude product was subjected to silica gel column chromatography, eluting with EA / PE=100% to give product IM-56, 100 mg, as a yellow solid, which was used in the next step. At room temperature (15°C), to a solution of the above product (100 mg) in EA (20 mL) were added TFAA and hydrogen peroxide (2 mL each). The mixture was stirred at room temperature for 4.5 hours. LCMS showed less starting material remaining, and the reaction was stopped. Water was added to the reaction solution, silica gel was added, and the mixture was subjected to column chromatography, eluting with MeOH / DCM=25% to give 3-((2-(pentanoyloxy)ethyl)amino)-7-(thiazol-5-yl)benzo[e][1,2,4]triazine 1,4-dioxide (C-29, 20 mg) as a red solid in 19% yield. Molecular formula: C17H19N5O4S; molecular weight: 389.43; LCMS: (ESI+): m / z 390.4 [M+1]+. CLASS IV: TERMINAL AMINE OR SUBSTITUTED AMINE Example D-1: Synthesis of 3-((2-aminoethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide IM-1                                          IM-38                                  IM-39                                           D-1.RZ-1244 At room temperature (25°C), to a solution of IM-1 (200 mg, 0.8 mmol) in DMF (5 mL) were added DIPEA (104 mg, 0.8 mmol) and N-tert-butoxycarbonyl ethylenediamine (160 mg, 1 mmol). The mixture was stirred at room temperature for 3 h. LCMS monitored complete conversion of the starting material. Water (10 mL) was added, and a yellow solid precipitated. The product IM-38 was obtained by filtration and used directly in the next step. At room temperature, to a solution of IM-38 in EA (10 mL) were added TFAA (2 mL) and hydrogen peroxide (2 mL). The mixture was stirred at room temperature overnight. TLC showed a small amount of starting material remaining. A small amount of aqueous sodium bicarbonate was added to adjust the pH to weakly basic, and the mixture was extracted with EA (20 mLx3) and dried to give IM-39, which was used directly in the next step. The concentrated IM-39 from the previous step was dissolved in about 10 mL of DCM, and 2 mL of TFA was added. The mixture was stirred at room temperature overnight. TLC showed no remaining starting material. The reaction solution was dried and subjected to column chromatography, eluting with DCM / MeOH = 5 / 1, and then with 0.1% triethylamine, to give the target product 3-((2-aminoethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4- dioxide (D-1, 132 mg) as a red solid, three-step yield 57%. Molecular formula: C10H10F3N5O2; molecular weight: 289.22; LCMS: (ES+): m / z 290.2 [M+1]+. Example D-2: Synthesis of 3-(pyrrolidin-3-ylamino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4- dioxide IM-1                                      IM-40                                                   IM-41                                        D-2, RZ-1245 At room temperature (25°C), to a solution of IM-1 (200 mg, 0.8 mmol) in DMF (5 mL) were added DIPEA (104 mg, 0.8 mmol) and tert-butyl 3-aminopyrrolidine-1-carboxylate (186 mg, 1.05 mmol). The mixture was stirred at room temperature for 3 h. LCMS monitored complete conversion of the starting material. Water (10 mL) was added; no precipitate formed. The mixture was extracted with EA and dried to give product IM-40, which was used directly in the next step. At room temperature, to a solution of IM-40 in EA (10 mL) were added TFAA (2 mL) and hydrogen peroxide (2 mL). The mixture was stirred at room temperature overnight. TLC showed a small amount of starting material remaining. The mixture was extracted with EA (20 mL*3) and dried to give IM-41, which was used in the next step. The dried solution IM-41 from the previous step was dissolved in 10 mL of DCM, and 2 mL of TFA was added. The mixture was stirred at room temperature overnight. TLC showed no remaining starting material. The reaction solution was dried and subjected to column chromatography, eluting with DCM / MeOH = 10 / 1, and then with 0.1% triethylamine, to give the target product 3-(pyrrolidin-3-ylamino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (D-2, 93 mg) as a red solid, three-step yield 36%. Molecular formula: C12H12F3N5O2; molecular weight: 315.26; LCMS: (ES+): m / z 316.3 [M+1]+. Example D-3: Synthesis of 3-(azetidin-3-ylamino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide IM-1 IM-42 IM-43 D-3, RZ-1250 At room temperature (25°C), to a solution of IM-1 (200 mg, 0.8 mmol) in DMF (5 mL) were added DIPEA (104 mg, 0.8 mmol) and tert-butyl 3-aminoazetidine-1-carboxylate (186 mg, 1.08 mmol). The mixture was stirred at room temperature for 3 h. LCMS monitored complete conversion of the starting material. Water (10 mL) was added, and a precipitate formed. The product IM-42 was obtained by filtration and drying and used directly in the next step. At room temperature, to a solution of IM-42 in EA (10 mL) were added TFAA (2 mL) and hydrogen peroxide (2 mL). The mixture was stirred at room temperature overnight. TLC showed a small amount of starting material remaining. The mixture was extracted with EA (20 mL*3) and dried to give IM-43, which was used directly in the next step. The dried solution IM-43 from the previous step was dissolved in 10 mL of DCM, and 2 mL of TFA was added. The mixture was stirred at room temperature overnight. TLC showed no remaining starting material. The reaction solution was dried and subjected to column chromatography, eluting with DCM / MeOH=10 / 1, and then with 0.1% triethylamine, to give the target product 3-(azetidin-3-ylamino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (D-3, 20 mg) as a red solid, three-step yield 8%. Molecular formula: C11H10F3N5O2; molecular weight: 301.23; LCMS: (ES+): m / z 302.2 [M+1]+. Example D-4: Synthesis of 3-((2-(methylamino)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide D-4,RZ 1248 At room temperature (25°C), to a solution of 3-chloro-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1-oxide (IM-1, 200 mg, 0.80 mmol) in DMF (5 mL) were added N-methyl-N-tert-butoxycarbonyl-1,2-ethylenediamine (169 mg, 0.96 mmol) and DIEA (310 mg, 2.4 mmol). The mixture was stirred at room temperature for 1 hour. LCMS monitored complete conversion of the starting material, and the reaction was stopped. Water (10 mL) was added, and a yellow solid precipitated. The solid was filtered and dried to give compound IM-44 (250 mg) as a yellow solid in 80% yield. Molecular formula: C16H20F3N5O3; molecular weight: 387.36. At room temperature (25°C), to a solution of compound IM-44 (250 mg, 0.64 mmol) in EA (10 mL) were added TFAA (2 mL) and hydrogen peroxide (2 mL). The mixture was heated to 40°C and stirred for 8 hours. LCMS monitored complete conversion of the starting material. Water (20 mL) was added, and the mixture was extracted with DCM (20 mLx3). The organic layer was concentrated to give compound IM-45. Compound IM-45 was dissolved in DCM (10 mL), TFA (3 mL) was added, and the mixture was stirred at room temperature for 3 hours. LCMS monitored complete conversion of the starting material. The reaction solution was concentrated and subjected to silica gel column chromatography (MeOH:DCM=0%-20%) to give 3-((2-(methylamino)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (D-4, 70 mg) as a red solid in 35% yield. Molecular formula:C11H12F3N5O2; molecular weight: 303.24; LCMS: (ESI+): m / z 304.2[M+1]+. Example D-5: Synthesis of 3-((2-pivalamidoethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide D-1 (95 mg, 0.32 mmol) was weighed, and EDCI (64 mg, 0.32 mmol), pivalic acid (30 mg, 0.34 mmol), DMAP (6 mg, 0.016 mmol), and DCM (10 mL) were added. The mixture was stirred at room temperature overnight. LCMS showed consumption of the starting material. The reaction solution was dried and subjected to column chromatography, eluting with DCM / MeOH = 20 / 1 to give the target product 3-((2-pivalamidoethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (D-5, 27.5 mg) as a red solid in 22% yield. Molecular formula: C15H18F3N5O3; molecular weight: 373.34; LCMS: (ES+): m / z 400.4 [M+1]+. Example     D-6:     Synthesis     of     3-((1-pivaloylpyrrolidin-3-yl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide D-2, RZ-1245                                    D.6 rz-1247 D-2 (51 mg, 0.16 mmol) was weighed, and EDCI (32 mg, 0.16 mmol), pivalic acid (13 mg, 0.16 mmol), DMAP (3 mg, 0.008 mmol), and DCM (10 mL) were added. The mixture was stirred at room temperature overnight. LCMS showed consumption of the starting material. The reaction solution was dried and subjected to column chromatography, eluting with DCM / MeOH     =     20 / 1     to     give     3-((1-pivaloylpyrrolidin-3-yl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (D-6, 24 mg, 0.06 mmol) as a red solid in 37% yield. Molecular formula: C17H20F3N5O3; molecular weight: 399.37; LCMS: (ES+): m / z 400.4 [M+1]+. Example D-7: Synthesis                   of (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide O” f3c^^ Ak, >p<p+'N   r-~.NH   EDCI,DMAP,DCM ° ”          I Cl^p\ D-3, RZ-1250 3-((1-pivaloylazetidin-3-yl)amino)-7- F3C^^^N      8 — *N' “N 6- H D-7, RZ-1251 D-3 (78 mg, 0.25 mmol) was taken, and EDCI (50 mg, 0.25 mmol), pivalic acid (20 mg, 0.25 mmol), DMAP (5 mg, 0.0125 mmol), and DCM (10 mL) were added. The mixture was stirred at room temperature overnight. LCMS showed consumption of the starting material. The reaction solution was dried and subjected to column chromatography, eluting with DCM / MeOH =20 / 1 to give the target product 3-((1-pivaloylazetidin-3-yl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (D-7, 10 mg) as a red solid in 10% yield. Molecular formula: C16H18F3N5O3; molecular weight: 385.35; LCMS: (ES+): m / z 386.4 [M+1]+. Example D-8:    Synthesis of    3-((2-(N-methylpivalamido)ethyl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide D-4, RZ1248                                                  D-8RZ1249 At room temperature (25°C), to a solution of D-4 (50 mg, 0.17 mmol) in DCM (5 mL) were added pivalic acid (25 mg, 0.25 mmol), EDCI (47 mg, 0.25 mmol), and DMAP (30 mg, 0.25 mmol). The mixture was stirred at room temperature for 8 hours. LCMS monitored complete conversion of the starting material. Water (20 mL) was added, and the mixture was extracted with DCM (20 mLx3). The organic layer was concentrated and subjected to silica gel column     chromatography     (MeOH:DCM=0%-2%)     to     give     3-((2-(N- methylpivalamido)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (D-8, 22 mg) as a red solid in 34% yield. Molecular formula: C16H20F3N5O3; molecular weight: 387.36; LCMS: (ES+): m / z 388.5 [M+1]+. Example D-9: Synthesis of 3-((2-(N-methylcyclopropanecarboxamido)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide $                HCI in dioxane F3C.     / N.ki       ----------► F3C^^ ^Ti             ' N                ।                                          ||       | H JI T            dcm         Hl AA~         N' Boc H IM-44 o’ TFAA, H2O2      F3C^^nJn EA 0         0 _                                              o’ ° 0 , “ Til   1 A 1       H EDCI, DMAP, DCM    '' A' nX'-n^'.^N- A ' H A H                                         IM-47 IM-46 A D-9 RZ 1252 At room temperature (25°C), to a solution of    3-((2-((tert- butoxycarbonyl)(methyl)amino)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1-oxide (IM-44, 640 mg, 1.65 mmol) in DCM (5 mL) was slowly added a solution of hydrogen chloride in dioxane (4 M, 3 mL). The mixture was stirred at room temperature for 1 hour. A yellow solid precipitated. LCMS monitored complete conversion of the starting material. The reaction solution was concentrated to give crude compound IM-46 as a yellow solid, which was used directly in the next step. At room temperature (25°C), to a suspension of compound IM-46 (200 mg, 0.70 mmol) in DCM (6 mL) were added cyclopropanecarboxylic acid (120 mg, 0.14 mmol), EDCI (199 mg, 1.04 mmol), and DMAP (127 mg, 1.04 mmol). The mixture was stirred at room temperature for 16 hours. LCMS monitored complete conversion of the starting material. Water (20 mL) was added, and the mixture was extracted with DCM (20 mL*3). The organic layer was concentrated to give crude compound IM-47 (210 mg) as a yellow oil, which was used directly in the next step. At room temperature (25°C), to a solution of compound IM-47 (210 mg, 0.59 mmol) in EA (6 mL) were slowly added TFAA (2 mL) and hydrogen peroxide (2 mL). The mixture was heated to 40°C and stirred for 3.5 hours, and the reaction solution gradually turned red. LCMS monitored that the starting material had substantially completely converted. Water (20 mL) was added, and the mixture was extracted with DCM (20 mL*3). The organic layer was concentrated and subjected to silica gel column chromatography (MeOH:DCM=0%-2%) to give                            3-((2-(N-methylcyclopropanecarboxamido)ethyl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (D-9, 116 mg) as a red solid in 53% yield. Molecular formula: C15H16F3N5O3; molecular weight: 371.31; LCMS: (ESI+): m / z 372.6[M+1]+. Example D-10:    Synthesis of    3-((1-((2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6- trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenyl)pyrrolidin-3-yl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide D-2 (51 mg, 0.25 mmol) was weighed, and EDCI (50 mg, 0.25 mmol), retinoic acid (65 mg, 0.3 mmol), DMAP (3 mg, 0.0125 mmol), and DCM (10 mL) were added. The mixture was stirred at room temperature overnight. LCMS showed consumption of the starting material. The reaction solution was dried and subjected to column chromatography, eluting with DCM / MeOH = 50 / 1 to give 3-((1-((2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenyl)pyrrolidin-3-yl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (D-10, 68 mg) as a red solid in 45% yield. Molecular formula: C32H38F3N5O3; molecular weight: 597.68; LCMS: (ES+): m / z 598.7 [M+1]+. Example D-11:  Synthesis of 3-(((1-(pivaloyloxy)cyclopropyl)methyl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide D-11 RZ1270 At room temperature (25°C), to a solution of 3-chloro-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1-oxide (IM-1, 200 mg, 0.80 mmol) in DMF (5 mL) were added DIEA (310 mg, 2.41 mmol) and 1-(aminomethyl)cyclopropanol (70 mg, 0.80 mmol). The mixture was stirred at room temperature for 1 hour. LCMS monitored complete conversion of the starting material. Water (10 mL) was added, and a yellow solid precipitated. The solid was filtered and dried to give compound IM-48 (220 mg) as a yellow solid in 91% yield. Molecular formula: C12H11F3N4O2; molecular weight: 300.24. At room temperature (25°C), to a solution of compound IM-48 (200 mg, 0.67 mmol) in DMF (5 mL) were added pivaloyl chloride (120 mg, 1.00 mmol), DIEA (258 mg, 2.00 mmol), and DMAP (122 mg, 1.00 mmol). The mixture was stirred at room temperature for 16 hours. LCMS showed some starting material remaining, and the reaction was stopped. Water (10 mL) was added, and the mixture was extracted with EA (20 mLx3). The organic layer was concentrated to give crude IM-49, which was used directly in the next reaction. At room temperature (25°C), to a solution of compound IM-49 (200 mg) in EA (6 mL) were slowly added TFAA (2 mL) and hydrogen peroxide (2 mL). The mixture was heated to 40°C and stirred for 3.5 hours, then stirred at room temperature for 16 hours. LCMS monitored that the starting material had substantially completely converted. Water (20 mL) was added, and the mixture was extracted with DCM (20 mLx3). The organic layer was concentrated and subjected to silica gel column chromatography (PE / EA=1 / 1) to give 3-(((1-(pivaloyloxy)cyclopropyl)methyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine      1,4- dioxide (D-11, 26 mg) as a red solid in 12.5% yield. Molecular formula: C17H19F3N4O4; molecular weight: 400.35; LCMS: (ES+): m / z 401.1[M+1]+. Example D-12: Synthesis of 3-((1-((R)-3-hydroxytetradecanoyl)pyrrolidin-3-yl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide IM-50                                                   IM-51                                       D-12RZ1274 At room temperature (25°C), to a flask containing IM-50 (299 mg, 1.0 mmol), R-3-hydroxymyristic acid (240 mg, 1.1 mmol), EDCI (200 mg, 1.2 mmol), and HOBT (150 mg, 1.1 mmol) was added DCM (4 mL). The mixture was stirred at room temperature for 24 h. TLC showed a small amount of starting material remaining. Water (10 mL) was added, and the mixture was extracted with DCM (20 mLx3). The solution was dried to give IM-51, which was used directly in the next step. At room temperature, to a solution of IM-51 in DCM (10 mL) were added TFAA (2 mL) and hydrogen peroxide (2 mL). The mixture was stirred at room temperature overnight. TLC showed a small amount of starting material remaining. Water (10 mL) was added, and the mixture was extracted with DCM (20 mLx3). The organic layer was mixed with silica gel, concentrated, and purified by column chromatography, eluting with DCM / MeOH=40 / 1 to give 3-((1-((R)-3-hydroxytetradecanoyl)pyrrolidin-3-yl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (D-12, 242 mg) as a red solid, two-step yield 42%. Molecular formula: C26H38F3N5O4; molecular weight: 541.6; LCMS: (ESI+): m / z 542.6[M+1]+. Example D-13: Synthesis of 3-((1-(2,2,2-trifluoroacetyl)pyrrolidin-3-yl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide IM-50 D13 RZ-1275 At room temperature (25°C), to a flask containing IM-50 (299 mg, 1.0 mmol) was added 15 mL of DCM, and TFAA (2 mL) and hydrogen peroxide (2 mL) were added. The mixture was stirred at room temperature overnight. TLC showed a small amount of starting material remaining. Water (10 mL) was added, and the mixture was extracted with DCM (20 mL*3). The organic layer was mixed with silica gel, concentrated, and purified by column chromatography, eluting with DCM / MeOH =   100 / 1 to give 3-((1-(2,2,2- trifluoroacetyl)pyrrolidin-3-yl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (D-13, 300 mg) as a red solid in 76% yield. Molecular formula: C14H11F6N5O3; molecular weight: 411.2; LCMS: (ESI+): m / z 412.5 [M+1]+. Example D-14: Synthesis of 3-((1-(thiophene-3-carbonyl)pyrrolidin-3-yl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide D2 O । D14 RZ-1301 At room temperature (25°C), to a flask containing 3-thiophenecarboxylic acid (45 mg, 0.35 mmol), D2 (110 mg, 0.35 mmol), EDCI (80 mg, 0.42 mmol), HOBT (57 mg, 0.42 mmol), and TEA (43 mg, 0.42 mmol) was added DCM (4 mL). The mixture was stirred at room temperature overnight. LCMS detected the reaction; no starting material remained, and the reaction was stopped. Water (10 mL) was added, and the mixture was extracted with DCM (20 mLx3). The organic layer was mixed with silica gel, concentrated, and purified by column chromatography, eluting with DCM / MeOH =  50 / 1 to give 3-((1-(thiophene-3- carbonyl)pyrrolidin-3-yl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (D-14, 20 mg) as a red solid in 13% yield. Molecular formula: C17H14F3N5O3S; molecular weight: 425.38; LCMS: (ESI+): m / z 426.3 [M+1]+. Example D-15: Synthesis of 3-((2-aminoethyl)amino)-7-bromobenzo[e][1,2,4]triazine 1,4-dioxide o DMF, DIPEA,RT IM-13 D-15 RZ-1348 D-15 was synthesized analogously to Example D-1 to give 3-((2-aminoethyl)amino)-7- bromobenzo[e][1,2,4]triazine 1,4-dioxide (D-15) as a red solid. Molecular formula: C9H10BrN5O2; molecular weight: 300.16; LCMS: (ES+): m / z 301.2 [M+1]+. Example D-16:    Synthesis of 3-(((1-aminocyclopropyl)methyl)amino)-7- bromobenzo[e][1,2,4]triazine 1,4-dioxide At room temperature (25°C), to a reaction flask were added IM-13 (104 mg, 0.4 mmol), 1-aminomethyl-1-(Boc-amino)cyclopropane (83 mg, 0.45 mmol), DIPEA (78 mg, 0.6 mmol), and DMF (5 mL). The mixture was stirred at room temperature for 2 h. TLC showed that the starting material was substantially not remaining. Water (10 mL) was added, and a precipitate formed. The solid was filtered and dried to give 148 mg of IM-71, which was used directly in the next step. At room temperature, to a reaction flask containing 140 mg of IM-71 was added EA (10 mL). The solution was ultrasonically dissolved, with some undissolved material. TFAA (1.5 mL) and H2O2 (1.5 mL) were added dropwise. The mixture was stirred at 30°C overnight. TLC showed that IM-71 was substantially not remaining, and the reaction was stopped. The reaction solution was dried, EA (10 mL) was added, and the mixture was extracted, dried over anhydrous sodium sulfate, and the organic phase was dried to give 110 mg of IM-72, which was used directly in the next step. At room temperature, to a reaction flask containing 110 mg of IM-72 was added DCM (10 mL), and 1.2 mL of HCl / dioxane (4 M) was added dropwise. The mixture was stirred at room temperature for 4 h. TLC showed that IM-72 was substantially not remaining, and a solid precipitated. The reaction was stopped, and the solid was filtered and dried to give 3-(((1-aminocyclopropyl)methyl)amino)-7-bromobenzo[e][1,2,4]triazine 1,4-dioxide (D-16, 73 mg) as a brick-red solid, three-step yield 50%. Molecular formula: C11H12BrN5O2; molecular weight: 326.1; LCMS: (ESI+): m / z 326.1,328.1[M+1]+. Example D-17: Synthesis of (R)-3-((2-aminopropyl)amino)-7-bromobenzo[e][1,2,4]triazine 1,4-dioxide NHBoc DIPEA, DMF O’ IM-73 TFAA,H2O2 EA, RT O IM-74 HCI,dioxane DCM,RT D17 RZ-1363(R) At room temperature (25°C), to a reaction flask were added IM-13 (130 mg, 0.5 mmol), (R)-(1-aminopropan-2-yl)carbamic acid tert-butyl ester (96 mg, 0.55 mmol), DIPEA (78 mg, 0.6 mmol), and DMF (5 mL). The mixture was stirred at room temperature for 2 h. TLC showed that the starting material was substantially not remaining. Water (10 mL) was added, and a precipitate formed. The solid was filtered and dried to give 160 mg of IM-73, which was used directly in the next step. At room temperature, to a reaction flask containing 150 mg of IM-73 was added EA (10 mL). The solution was ultrasonically dissolved, with some undissolved material. TFAA (2 mL) and H2O2 (2 mL) were added dropwise. The mixture was stirred at 30°C overnight. TLC showed that much IM-73 remained. Additional TFAA (1 mL) and H2O2 (1 mL) were added, and the reaction was continued for 3 h. TLC still showed IM-73 remaining, and the reaction was stopped. The reaction solution was dried, EA (10 mL) was added, and the mixture was extracted, dried over anhydrous sodium sulfate, and the organic phase was dried and subjected to column chromatography, eluting with DCM / MeOH = 50 / 1 to give 60 mg of IM-74, which was used in the next step. At room temperature, to a reaction flask containing 55 mg of IM-74 was added DCM (10 mL), and 1.5 mL of HCl / dioxane (4 M) was added dropwise. The mixture was stirred at room temperature for 4 h. TLC showed that IM-74 was substantially not remaining, and a solid precipitated. The reaction was stopped, and the solid was filtered and dried to give (R)-3-((2-aminopropyl)amino)-7-bromobenzo[e][1,2,4]triazine 1,4-dioxide (D-17, 30 mg) as a brick-red solid, three-step yield 17%. Molecular formula: C10H12BrN5O2; molecular weight: 314.1; LCMS: (ESI+): m / z 314.1,316.1[M+1]+. Example D-18: Synthesis of (S)-3-((2-aminopropyl)amino)-7-bromobenzo[e][1,2,4]triazine 1,4-dioxide IM-13                                                                               D18 RZ-1363(S) At room temperature (25°C), to a reaction flask were added IM-13 (130 mg, 0.5 mmol), (S)-(1-aminopropan-2-yl)carbamic acid tert-butyl ester (96 mg, 0.55 mmol), DIPEA (78 mg, 0.6 mmol), and DMF (5 mL). The mixture was stirred at room temperature for 2 h. TLC showed that the starting material was substantially not remaining. Water (10 mL) was added, and a precipitate formed. The solid was filtered and dried to give 240 mg of IM-75, which was used directly in the next step. At room temperature, to a reaction flask containing 230 mg of IM-75 was added DCM (10 mL). The solution was ultrasonically dissolved, with some undissolved material. TFAA (3 mL) and H2O2 (3 mL) were added dropwise. The mixture was stirred at 30°C overnight. TLC showed that less IM-75 remained, and the reaction was stopped. The reaction solution was dried and subjected to column chromatography, eluting with DCM / MeOH = 10 / 1 to give (S)-3-((2-aminopropyl)amino)-7-bromobenzo[e][1,2,4]triazine 1,4-dioxide (D-18, 110 mg) as a brick-red solid, two-step yield 33%. Molecular formula: C10H12BrN5O2; molecular weight: 314.1; LCMS: (ESI+): m / z 314.1,316.1[M+1]+. Example D-19: Synthesis of 3-((2-aminoethyl)amino)-7-fluorobenzo[e][1,2,4]triazine 1,4-dioxide IM-76                                  IM-77                                D19RZ1364 IM-76 was synthesized according to WO2023019912A1. At room temperature (15°C), to a solution of IM-76 (200 mg, 1 eq) in DMF (10 mL) were added mono-Boc ethylenediamine (241 mg, 1.5 eq) and DIEA (389 mg, 3 eq). The mixture was stirred at room temperature for 1 hour. LCMS monitored complete conversion of the starting material. Water (30 mL) was added, and a yellow solid precipitated. The solid was filtered and dried to give 280 mg of IM-77 as a yellow solid, which was used in the next step. At room temperature (15°C), to 280 mg of IM-77 was added DCM (10 mL), and TFAA and hydrogen peroxide (2 mL each) were added. The mixture was heated to 40°C and stirred for 5 hours. LCMS showed less starting material remaining, and the reaction was stopped. The reaction solution was concentrated and subjected to silica gel column chromatography, eluting with MeOH / DCM = 17% to collect the product, which was concentrated to give 3-((2-aminoethyl)amino)-7-fluorobenzo[e][1,2,4]triazine 1,4-dioxide (D-19, 78 mg) as a red solid in 25% yield. Molecular formula: C9H10FN5O2; molecular weight: 239.2; LCMS: (ESI+): m / z 240.1[M+1]+. Example D-20: Synthesis of 3-((2-aminoethyl)amino)-7-chlorobenzo[e][1,2,4]triazine 1,4-dioxide O                           9                                O H2N      Boc~                H TFAA, H2O2 CI^^N.N DIEA, DMF ' ^^NAN^N'Boc DCM * M^N^NH2 H                                   O_ H IM-78                                  IM-79                                 D20RZ1365 IM-78 was synthesized according to WO2023019912A1. At room temperature (15°C), to a solution of IM-78 (200 mg, 1 eq) in DMF (10 mL) were added mono-Boc ethylenediamine (241 mg, 1.5 eq) and DIEA (389 mg, 3 eq). The mixture was stirred at room temperature for 1 hour. LCMS monitored complete conversion of the starting material. Water (30 mL) was added, and a yellow solid precipitated. The solid was filtered and dried to give 250 mg of IM-79 as a yellow solid, which was used in the next step. At room temperature (15°C), to 250 mg of IM-79 was added DCM (10 mL), and TFAA and hydrogen peroxide (2 mL each) were added. The mixture was heated to 40°C and stirred for 6 hours. LCMS showed less starting material remaining, and the reaction was stopped. The reaction solution was concentrated and subjected to silica gel column chromatography, eluting with MeOH / DCM = 17% to collect the product, which was concentrated to give 3-((2-aminoethyl)amino)-7-chlorobenzo[e][1,2,4]triazine 1,4-dioxide (D-20, 129 mg) as a red solid in 47% yield. Molecular formula: C9H10ClN5O2; molecular weight: 255.7; LCMS: (ESI+): m / z 256.1,258.1[M+1]+. Example D-21: Synthesis of 3-((2-aminoethyl)amino)-7-iodobenzo[e][1,2,4]triazine 1,4-dioxide IM-80 was synthesized according to WO2023019912A1. At room temperature (15°C), to a solution of IM-80 (200 mg, 1 eq) in DMF (10 mL) were added mono-Boc ethylenediamine (156 mg, 1.5 eq) and DIEA (252 mg, 3 eq). The mixture was stirred at room temperature for 1 hour. LCMS monitored complete conversion of the starting material. Water (30 mL) was added, and a yellow solid precipitated. The solid was filtered and dried to give 260 mg of IM-81 as a yellow solid, which was used in the next step. At room temperature (15°C), to 250 mg of IM-81 was added DCM (10 mL), and TFAA and hydrogen peroxide (2 mL each) were added. The mixture was heated to 40°C and stirred for 6 hours. LCMS showed less starting material remaining, and the reaction was stopped. The reaction solution was concentrated and subjected to silica gel column chromatography, eluting with MeOH / DCM=17% to collect the product, which was concentrated to give 3-((2-aminoethyl)amino)-7-iodobenzo[e][1,2,4]triazine 1,4-dioxide (D-21, 159 mg) as a red solid in 57% yield. Molecular formula: C9H10IN5O2; molecular weight: 347.1; LCMS: (ESI+): m / z 348.0 [M+1]+. Example D-22: Synthesis of 3-((2-aminoethyl)amino)-7-methoxybenzo[e][1,2,4]triazine 1,4-dioxide O                           9                                0 MeO^ / ^N.^ H2N      Boc MeO^. N..n h TFAA, H2O2 MeO^^N.-N DIEA, DMF *                            DCM ' H                                   O_ H IM-82                                  IM-83                                 D22RZ1367 IM-82 was synthesized according to WO2023019912A1. At room temperature (15°C), to a solution of IM-82 (200 mg, 1 eq) in DMF (10 mL) were added mono-Boc ethylenediamine (227 mg, 1.5 eq) and DIEA (366 mg, 3 eq). The mixture was stirred at room temperature for 1 hour. LCMS monitored complete conversion of the starting material. Water (30 mL) was added, and a yellow solid precipitated. The solid was filtered and dried to give 280 mg of IM-83 as a yellow solid, which was used in the next step. At room temperature (15°C), to 280 mg of IM-83 was added DCM (10 mL), and TFAA and hydrogen peroxide (2 mL each) were added. The mixture was heated to 40°C and stirred for 10 hours. LCMS showed less starting material remaining, and the reaction was stopped. The reaction solution was concentrated and subjected to silica gel column chromatography, eluting with MeOH / DCM=17% to collect the product, which was concentrated to give 3-((2-aminoethyl)amino)-7-methoxybenzo[e][1,2,4]triazine 1,4-dioxide (D-22, 80 mg) as a red solid in 26% yield. Molecular formula: C10H13N5O3; molecular weight: 251.3; LCMS: (ESI+): m / z 252.1 [M+1]+. Example D-23: Synthesis of  7-bromo-3-((2-(methylamino)ethyl)amino)benzo[e][1,2,4]triazine  1,4- dioxide trifluoroacetate TFAA,H2O2 DCM,RT D23 RZ-1370 At room temperature (25°C), to a reaction flask were added IM-13 (130 mg, 0.50 mmol), N-Boc-N-methylethylenediamine (71 mg, 0.55 mmol), DIPEA (104 mg, 0.80 mmol), and DMF (5 mL). The mixture was stirred at room temperature for 2 h. TLC showed that the starting material was substantially not remaining. Water (10 mL) was added, and a precipitate formed. The solid was filtered and dried to give 139 mg of IM-84, which was used directly in the next step. At room temperature, to a reaction flask containing 130 mg of IM-84 was added DCM (10 mL). The solution was ultrasonically dissolved, with some undissolved material. TFAA (3 mL) and H2O2 (3 mL) were added dropwise. The mixture was stirred at 30°C overnight. TLC showed that less IM-84 remained, and the reaction was stopped. The reaction solution was dried and subjected to column chromatography, eluting with DCM / MeOH = 5 / 1 to give 7-bromo-3-((2-(methylamino)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide (D-23, 40 mg) as a red solid in 19% yield. Molecular weight: C10H12BrN5O2; molecular formula: 314.1; LCMS: (ESI+): m / z 314.1,316.1[M+1]+. I. TEST FOR IN VITRO BIOLOGICAL ACTIVITY AND ANTITUMOR ACTIVITY Background: Hypoxia is a prominent feature of the tumor microenvironment. Regulating cell activity under hypoxic conditions is a major approach to inhibiting tumor growth, proliferation, and differentiation. Therefore, screening for drug molecules with hypoxic activity that release free radicals through bioreductive enzymes to act on DNA and thereby kill tumor cells is of great clinical application significance. In vitro cell test method: The CTG method was used to detect the effects of different compounds on HT29 cell (human colon cancer cell) activity under anaerobic conditions. Introduction to CTG test principle: CTG (full name CellTiter-Glo) Luminescent Cell Viability Assay is a rapid, highly sensitive luminescent detection method for cell viability based on ATP detection. The detection principle is as follows: Lysed cells Ultra-GloTM HO      S X N N / COOH /         rLuciferase    o                 o -< j + atp+02    M2+    - tvwy + AMP+PPi+CO2 + S                      Mg                 N    S Living cells contain ATP, and the luciferase reaction depends on ATP in living cells. CellTiter-Glo® 3D detection reagent contains Ultra-GloTM recombinant luciferase and luciferin, and can be directly added to cultured cells for detection. The detection reagent can automatically lyse cells to release ATP from living cells and protect ATP from degradation. ATP in living cells participates in the luciferase reaction, and the light generated by the reaction is proportional to the number of living cells in the microtissue. CellTiter-Glo® luminescent cell viability detection is a homogeneous detection method for detecting the number of living cells in a culture by quantitatively measuring ATP (a key indicator of living cell metabolism), and the amount of ATP is directly proportional to the number of cells in the culture. The CellTiter-Glo® detection kit produces a “glow-type” luminescent signal, with a half-life generally greater than 5 hours, depending on cell type and medium. Because the signal half-life is long, continuous detection can be performed flexibly without a reagent autosampler. Specific experimental protocol: A series of concentrations of compounds and 2000 HT29 cells were co-incubated under anaerobic and aerobic conditions for 3 days. CTG reagent was added, and the fluorescence value was read using a microplate reader. The compound activity curve was drawn using GraphPad Prism 5.0 software. The EC50 value was obtained from the viability curve. Detailed information: 1. Ce 11 information Cell name Growth characterist ics Passage number Cell number / w ell Complete medium Cell source HT29 Adherent P156 2000 DMEM / F12+10% FBS+1%Pen / Strep Beijing Xiehe Cell Resource Center 2. Reagents and consumables Fetal bovine serum FBS (Hyclone, Cat# SH30406.05) DME / F12 1:1 (1X) medium (Hyclone, Cat# SH30023.01) Cell Titer-Glo (CTG) Luminescent Cell Viability Assay (Promega, Cat# G7571) 96-well cell culture plate (Corning, Cat# 3603) PBS (Hyclone, Cat# SH30256.01) Trypsin 0.25% (Hyclone, Cat# SH30042.01) Pen / Strep, 10,000 units / ml (Hyclone, Cat# SV30010) DMSO (SIGMA, D4540-100ML) Anaerobic incubator: purchased from Gene Science. Setting mode: 0% O2, 5% CO2, 95% N2, 94-97% humidity. 3. Experimental procedure 3.1 Cell culture and plating HT29 cells were cultured in DME / F12+10%FBS+1%Pen / Strep complete medium, maintaining T75 flask density at 2*105 to 1*106 viable cells / mL. Cells were collected, old medium was discarded, cells were washed once with sterile PBS, trypsin was added to digest cells, and complete medium was added and pipetted repeatedly to obtain single cells. After trypan blue staining and counting, subsequent experiments were performed when cell viability was greater than 95%. Complete medium was used to adjust the cell density to 2.0*104viable cells / mL. 100 pL of cell suspension was added to each well of a 96-well cell culture plate, with a cell density of 2*103 viable cells / well. The plate was placed in an incubator for 24 h. 3.2 Compound dilution a) Preparation of 4* compound starting concentration and 3-fold gradient dilution: The test compound was subjected to 3-fold gradient dilution with complete medium containing 2% (4* final concentration) DMSO, for 10 gradient concentration points. b) 50 pL of complete medium was added to a cell plate containing 100 pL of cells, and then 50 pL of 4*concentration compound (3-fold gradient dilution) solution was added to the designed cell plate containing a total of 150 pL, with two replicate wells per concentration, so that each well finally contained 200 pL of culture medium. The final DMSO concentration in complete medium was 0.5%. DMSO wells were used as 100% growth control, and complete medium without cells was used as 0% control. c) After adding the compound, the cell culture plate was placed in an anaerobic incubator and incubated for 3 days (72 hours). 3.3 CTG detection a) CTG Buffer was thawed at room temperature and added to the CTG substrate bottle to completely dissolve it, thereby preparing CTG reagent. b) CTG reagent was added in an amount equal to the cell suspension. c) The cell plate was placed on a shaker in the dark and mixed for 10 min to induce cell lysis. d) The lysed cells were placed in the dark at room temperature for 30 min to stabilize the fluorescence signal, and finally the luminescence value was read. e) The fluorescence value was read using a microplate reader (i3X, Molecular Device). 7. Data processing: The raw data were analyzed using GraphPad Prism 5.0 software, and the dose-response curve was fitted using nonlinear S-curve regression to calculate the EC50 value. The effects of the example compounds on HT29 cell activity under anaerobic / aerobic conditions are shown in Table 1 below. Among them, the anaerobic state is represented by “*” or “>6 liML” representing the EC50 value range, as follows: “*” represents 4-6lM / L; “**” represents 2-4lM / L; “***” represents 1-2lM / L; “****” represents <1lM / L. The aerobic state is represented by “+” representing the EC50 value range, i.e.: “+” represents <40lM / L; “++” represents 40-60lM / L; “+++” represents 60-80lM / L; “++++” represents >80lM / L; “ / ” represents not tested. Selectivity refers to the ratio of the aerobic EC50 value to the anaerobic EC50 value; the larger the value, the better the selectivity. Compound Activity Table (EC50)   Table 1 Selectivity No. Structure Anaerobic Aerobic TPZ o’ 1 ifY++x '"'nh2 0 * ++++ >20 A-1 1239 o rt OTZ+ ZtO, yi * IZ o d *** ++ >20 A-2 1230 b o ZI , , O-Z+ +2^0 O o *** +++ >30 A-3 1229 o —N N       Bn 6’ H *** +++ >30 A-4 1231 / o ZI , + , o o LL? **** +++ >25 A-5 1232 0 F3COi x> N N 6 H **** +++ >30 B-1 1222 o < ZI , , O-Z+ -Z-O o LL? **** ++ >20 B-2 1242 0 f3c^n;n N       F 0 H *** +++ >30 B-3 1238 ZI , + w , lO±Z +^0 a o LL? *** +++ >30 B-4 1236 O            F F3C.                     X. Y^TJ  A o H **** + >20 B-5 1257 A        0 / \            1+ / N. TXJ 6’ H ** + >20 B-6 1241 d ( Yi      °" \— / /            i+ S [|           N YY Y n ^CFo 6’ H ** + >20 B-7 1268 nA)     0 Cl ii N yvf ^Y- Y" N Y / > 6’ H **** ++ >30 B-8 1269 o’ 1                                 '+ As, X         _ c|YY N YV-f YY+^k N Y / 'f 6’ H **** ++ >30 B-9 1263 N il            0 1                                 l+ ci                  N'N N N CF3 o H **** ++ >30 B-10 1264 CO o ( ZI , + H , lO±Z +Z1O '° o **** ++ >30 C-1 1070 □0 d IO-Z+ +Z-OI Yz IZ I *** + >30 C-2 1218 0 F3C^AN L Y\+Y   ^OH N N 6’ H *** + >30 C-3 1224 I o ZI , H . O-Z + + Z-O 0 o LL° *** ++ >30 C-4 1226 o Q O?Z+ +Z-O 1        ____ h           I IZ b b *** ++ >30 C-5 1227 b rt O?Z+ +Z-O 1            ______ > /                 I IZ -7 o I *** ++ >30 C-6 1216 OT^ IZ o *** ++ >30 C-7 1058 6 Hr.,        N.                  T YY'I jfT 0 H OH *** ++ >30 C-8 1195 o’ XXjA o          o **** + >30 C-9 1219 00 OTZ^b^Z-O M p cn I co ** ++ >30 C-10 1220 CD rf IO-Z+ ZrO, M' IZ o / —? p I co ** ++ >30 C-11 1228 0 F3C      / N'M “yk 0         0 **** + >30 C-12 1225 0“ F3C^^ b'N^N^Y^ 0          0 **** + >30 C-13 1233 o’ f3cYV^n 1- H              II 1 o          0 CnHzs *** ++ >30 C-14 1234 o ZI . . O-Z + + Z-O o LL? *** ++ >30 C-15 1235 o o H o 1           1           1 *** ++ >30 C-16 1237 o I O-Z + + Z-O 1 IZ u. *** ++ >30 C-17 1243 o Q O z + zTO, IZ ( o Is 0) *** ++ >30 C-18 o F3C ^iV+'i1         1 0          0 ** +++ >30 C-19 I o ZI , , O-Z+ +Z-O O o \ o ** +++ >30 C-20 1221 0 1+ znk f3c p r 'n            Br kA^N^ / °Y^C14H29 0         O ** +++ >30 C-21 1220 0 JQ-X ,^o i 0 H      0 ** +++ >30 C-22 1199 IO-Z+ +Z-OI ^z' IZ O O=^ ** +++ >25 C-23 1212 o ZI , + w, lo±z +Z-O / . w ** +++ >30 C-24 1258 A        0 / \          1+ 0          0 ** +++ >25 C-25 1256 o p I O-Z + + Z-O ^z'   1 IZ 4 o o=( o US ** +++ >30 C-26 1256 o f3cv^An O         1    0 *** ++ >30 C-27 1271 O+ F3C. ^Y-V'iA O'          1     0 *** ++ >30 C-28 1272 o’ 0       1   0 OH *** ++ >30 C-29 1279 N-     o 0          0 *** ++ >30 D-1 1244 CXI I z ZI Z—( 1     ' / V O-z + +z-O i 0 o *** ++ >30 D-2 1245 I Q ZI । H . O-Z+ +Z-O 0 o LL? *** ++ >30 D-3 1250 I ZT 1                                                           . o-z+ +z-o 0 o **** ++ >30 D-4 1248 o 1             H N N o H **** ++ >30 D-5 1246 Y xz ZI 1 O-z + + z-O i 0 o LL? **** + >30 D-6 1247 O 0 O-Z+ +Z-O 1 \\ z'        1 >—z IZ £ *** + >25 D-7 1261 ?        o f3C.       -K           II 6- H **** + >30 D-8 1249 d 0          0 *** + >25 D-9 1252 o F3C^^nL o          o *** + >25 D-10 1259 IJT Jj II °r z 0 o *** + >25 D-11 1270 0 1+ F3(0        .Nx                \ / 3       '7        v [1 A + J . 0-- / ^ N   N 0<   W - H △ 0 *** ++ >30 D-12 1274 co cxi Ls KJ , , O-Z+ +Z—O 0 CO LL O *** + >25 D-13 1275 O co 0 O-z+ +z-O ' %£ ' "o °^o co **** ++ >25 D-14 1301 q O-Z+ Z-O| 0 CO o *** ++ >25 D-15 1348 CM I z ZI । , o-z+ +z-O p CD *** ++ >30 D-16 1362 0 TXa ^nh2 *** ++ >30 D-17 1363(R) d O-Z + + Z-O 1 1 IZ III" z I bo **** ++ >25 D-18 1363(S) 0 Br\     / N, VV+ N / ^s)NH2 N N T 2 6- H * **** ++ >25 D-19 1364 CM I . । O-Z+ + Z-O 0 LL *** ++ >30 D-20 1365 o 0 O-Z + + Z-O । ^z z bo ** + >25 D-21 1366 0 O-Z + +Z-O 1 1 ^z T bo ** + >30 D-22 1367 0 MeO^^^N M fl ** + >25 D-23 1370 CO d O-Z+ +z-O *** ++ >25 The data in Table 1 above show that the activities of most of the example compounds of the present disclosure are superior to tirapazamine, and their EC50 values under anaerobic conditions are less than 4 gM, with good selectivity. In particular, the following compounds have anaerobic activity EC50 values less than 1 gM: A-4 / A-5 / B-1 / B-4 / B-7 / B-8 / B-9 / B-10 / C- 5   8 / C-11 / C-12 / D-3 / D-4 / D-5 / D-7. These compounds will provide a reliable basis for further confirmation of in vivo activity. II. METABOLIC STABILITY AND PHARMACOKINETIC ANALYSIS o                                    o ।                                                                                                                                                                                         । X = ORn NR2R3                        Z = OR1; OCORi, NHCORt, or aryl / heteroaryl Y = Br, Ar, alkyl, or substituted alkyl            Y = Br, Ar, alkyl, or substituted alkyl Cpd A                                     Cpd B Cpd A is a terminal carboxylic acid ester or acylate; Cpd B is a terminal alcohol ester, amine acylate, or alkyl / aryl compound. Drug metabolism impact: Cpd A has an ester group, is metabolized relatively quickly, and after metabolism gives COOH, which has no hypoxic or aerobic activity. Taking compound A-7 in CN114901646A as an example, the half-life is about 40 min, and after metabolism it gives a carboxylic acid with an EC50 value >100 pM / L and no activity; the half-life of Cpd B analogs is significantly prolonged, and the metabolite alcohol or amine still has strong activity. 10 The protocol for selecting some compounds for metabolic stability analysis is as follows: 1. Specific description Species / Sex SD rat / male Route                  of administration / Dose IV-2mg / kg Feeding mode Fasted overnight Number of animals 3 SD rats / group, one group per compound Dosage Form / Solvent 10%NMP+20%PEG400+70%(30% Solutol in water ) as a red clear solution Anticoagulant EDTA-K2 Blood collection method Blood collection from the saphenous vein Sample volume 20 pL plasma / time point Blood collection time points 0.833, 0.25, 0.5, 1, 2, 4, 6, 8, 24 (hours) Sample collection Blood samples will be placed on ice until centrifugation to obtain plasma samples. Sample storage -80oC (except for analysis) Sample detection LCMS-MS to measure concentration at each time point. 2. Research methods 2.1 In vivo experiment a) SD rats were fasted overnight with free access to water. b) After administration, the animals’ status was observed and abnormal manifestations were recorded. c) Plasma samples were centrifuged at 4°C at 3500 rpm for 10 min. After separation, the samples were transferred to EP tubes and immediately stored at -80°C until analysis. 2.2 Sample bioanalysis acceptable criteria 2.2.1 Calibration curve The calibration curve should use at least six non-zero concentration points, excluding blank samples (matrix samples without analyte and internal standard) and zero samples (matrix samples containing internal standard). The concentration accuracy should be within ±15%, except that the lower limit of quantification (LLOQ) should be within ±20%. 2.2.2 Lower limit acceptable criteria The lower limit of quantification (LLOQ) is defined as the lowest concentration of the standard curve, and the relative error should not exceed 20%. 2.2.3 Upper limit acceptable criteria The upper limit of quantification (ULOQ) is defined as the highest concentration measurable by the standard curve, and the accuracy relative error should not exceed 15%. 2.2.4 Reagent blank, single blank, double blank acceptable criteria In sample analysis, each batch should contain at least one reagent blank and double blank (without internal standard) to demonstrate that there are no substances that interfere with the detection of the analyte or internal standard. After the reagent blank, double blank and blank samples should be analyzed to eliminate possible carryover interference. Include at least one blank biological matrix spiked with internal standard and analyze according to the method to demonstrate that the internal standard does not interfere with the detection of the analyte. The animal matrix must have no interfering peaks (at the LLOQ, the analyte response should be <20%). 2.2.5 Quality control (QC) sample acceptable criteria The accuracy values of QC samples should be within ±15% of the nominal value. At least 4 of 6 (67%) QC samples and at least 50% of each concentration level should meet this standard. If this standard is not met, the analysis operation should be stopped and the sample analysis study should be re-performed. The minimum number of QC samples should be at least 5% of the number of unknown samples. 2.2.6 Internal standard acceptable criteria The coefficient of variation (CV value) of the internal standard was calculated for each data set. If the incubation and analysis operations are normal, the CV value should not exceed 15%. 3. Data analysis, pharmacokinetic parameter calculation, and reporting The internal standard method was used to establish the standard curve, with the theoretical standard curve concentration as the abscissa and the peak area ratio (test compound peak area / internal standard peak area) as the ordinate. Linear regression method was used (weighting factor 1 / X2), R2>0.9900. Unknown samples were calculated from the standard curve. The pharmacokinetic parameters were calculated by non-compartmental analysis model using WinNonlin 8.2 software and presented in the report, including T1 / 2, Tmax, Cmax, AUC, etc. Instrument: API-4000 Qtrap-Shimadzu Controller-CBM20A Liquid phase conditions: mobile phase A: 0.1% formic acid aqueous solution; mobile phase B: 0.1% formic acid acetonitrile solution Column: Waters Xbridge C18 3.5 pm 2.1 x 50 mm Elution program:_______________________________ Step Total time (min) Flow rate (ml / min) A% B% 1 0.01 0.45 98 2 2 0.30 0.45 98 2 3 1.20 0.45 2 98 4 2.50 0.45 2 98 5 2.51 0.45 98 2 6 3.50 0.45 98 2 Sample preparation: a) Transfer 50 pL of plasma sample to a 96-well plate; b) Add 500 pL of acetonitrile to precipitate proteins; c) Centrifuge for 20 min (4°C, 4000 rpm); d) Transfer 300 pL of supernatant to a new 96-well plate and mix with 300 pL of 0.1% formic acid aqueous solution; e) LC-MS / MS injection volume is 5 pL. The test compound results are as follows: o                           o C-8, RZ-1195 O l+ C-11, RZ-1228 The pharmacokinetics are shown in Table 2 below. 5                                  Table 2: Pharmacokinetic data A-7* RZ-1230 RZ-1236 RZ-1247 RZ-1195 RZ-1228 C0 (ng / mL) 996 2351 743 4896 1667 94.7 T1 / 2 (hr) 0.66 1.25 1.3 7.56 2.3 3.2 AUC0-t (ngAr / mL) 78.7 328 233 4063 273 467 AUCo-, (ng^hr / mL) 79.6 332 245 4096 278 403 Vz (L / kg) 5.99 7.47 15.3 7.51 1.36 37 CL (mL / min / kg) 455 101 136 10.7 121 3420 Vss (L / kg) 2.04 1.56 11 0.77 1.04 23.6 *Synthesized according to Example A-7 of CN11490164A. The results show that, compared with the known compound A-7, some compounds of the present disclosure have significantly higher half-lives and higher AUCo-, upon IV administration, indicating better pharmacokinetic properties. 10 III. SOLUBILITY-RELATED DRUG-LIKENESS ANALYSIS Some compounds of the present disclosure, such as D-1 to D-4 and D-16 to D-24, readily form salts and can form salts with some acids such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, formic acid, acetic acid, and the like. Hydrochloric acid or trifluoroacetic acid was used to prepare salts of these compounds, and the solubility of these salts in pure water (mg / mL) was tested at room temperature. The results are listed in Table 3. As a comparison, hydrochloric acid and trifluoroacetic acid were also used to prepare the salts of known compound A-7 and tirapazamine. However, experiments showed that the known compound A-7, like tirapazamine, does not form salts with acid radicals. Therefore, the solubility of the known compound A-7 and tirapazamine in pure water (mg / mL) was directly measured at room temperature. The results are listed in Table 3. Table 3: Solubility data of compound salts Compoun d D-1 D-2 D-4 D-16 D-17 D-18 Tirapaz amine A-7 Salt form Trifluoroa cetate salt Trifluoroac etate salt Trifluoroac etate salt Trifluoroac etate salt Hydrochl oride salt Hydrochl oride salt N / A N / A Solubility in    pure water (mg / mL) >19 >18 >18 >20 >23 >20 <2 <0.5 The results show that the water solubility of the corresponding salts of the compounds of the present disclosure is much greater than that of tirapazamine (tirapazamine does not readily form salts, water solubility less than 2 mg / mL) and the known compound A-7 (the known compound A-7 also does not readily form salts, water solubility less than 0.5 mg / mL), which is favorable for the development of various formulation processes. In summary, the compounds of the present disclosure have excellent hypoxic activity, good metabolic stability, and certain water solubility, and have potential clinical application value in the treatment of solid tumors including liver cancer, cholangiocarcinoma, lung cancer, gastric cancer, and the like. Mode of drug use: oral, IV, or intratumoral administration. The present disclosure has been described above in conjunction with preferred embodiments, but these embodiments are merely exemplary and serve only an illustrative purpose. On this basis, various replacements and improvements can be made to the present disclosure, and these all fall within the protection scope of the present disclosure.

Claims

1. A benzotriazine dioxide having the following formula (I) or a pharmaceutically acceptable salt or ester, hydrate, solvate or prodrug thereof,R5 0R2, R4, and R5 are selected from the group consisting of hydrogen, halogen, C1-C10 alkyl optionally substituted with R40, C1-C10 alkoxy optionally substituted with R40, C3-C10 cycloalkyl optionally substituted with R40, C6-20 aryl optionally substituted with R40, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with R40, and 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with R40; wherein R40 is each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl;R3 is selected from the group consisting of halogen, C1-C10 alkyl optionally substituted with R50, C1-C10 alkoxy optionally substituted with R50, C3-C10 cycloalkyl optionally substituted with R50, C6-20 aryl optionally substituted with R50, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with R50, and 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with R50; wherein R50 is each independently selected from the group consisting of hydrogen, oxygen, halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl;X is selected from the group consisting of NH, S, Se, CHF, C(=S), S(=O) and S(=O)2;RX is selected from one of the following groups: C1-10 alkyl optionally substituted with RX1,R8 R9 ..........  . . ■„ jAy-RwC3-10 cycloalkyl optionally substituted with R, '(formula C);1— N"R20s(formula A),        m (formulawherein RX1 is each independently selected from the group consisting of halogen, cyano,hydroxy, mercapto, nitro, amino, C1-C10 alkyl, C1-C10 haloalkyl, C1-C10 alkoxy, C3-C10 cycloalkyl, C6-20 aryl optionally substituted with RX11, 5- to 10-membered heteroaryl containing a heteroatom selected from the group consisting of O, S, and N and optionally substituted with RX11, 5- to 10membered heterocyclyl containing a heteroatom selected from the group consisting of O, S, and N and optionally substituted with RX11, and -NR6R7; wherein RX11 is each independently selected from the group consisting of halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl;R6 and R7 are each independently selected from the group consisting of hydrogen, C1-C10 alkyl optionally substituted with RX12, C1-C10 alkoxy optionally substituted with RX12, C3-C10 cycloalkyl optionally substituted with RX12, C6-20 aryl optionally substituted with RX12, 5- to 10membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with RX12, and 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with RX12; wherein RX12 is each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl; or R6 and R7 together with the nitrogen atom to which they are attached form a 5- to 10-membered ring structure;in formula A, R8 and R9 are each independently selected from the group consisting of hydrogen and C1-C6 alkyl, or R8 and R9 together with the C atom to which they are attached form a C3-C6 ring structure;Y is selected from one of the following:   O, S, Se, C(=S),  NR6,;* represents a site where Y is attached to CR8R9;      represents a site where Y is attachedto R10;R10 is selected from the group consisting of hydrogen, C1-C20 alkyl optionally substituted with R30, C1-C20 haloalkyl optionally substituted with R30, C1-C10 alkoxy optionally substituted with R30, C3-C10 cycloalkyl optionally substituted with R30, C2-C20 alkenyl optionally substituted with R30, C6-20 aryl optionally substituted with R30, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with R30, and 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with R30, wherein R30 is each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C6-20 aryl, C6-20 aryloxy, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N, 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N, and C3-C6 cycloalkenyl optionally substituted with R31; wherein R31 is each independently selected from the group consisting of hydrogen, halogen, and C1-C6 alkyl;n is an integer from 1 to 11;in formula B, R20 is selected from the group consisting of hydrogen and -C(=O)R21, wherein R21 is selected from the group consisting of hydrogen, C1-C20 alkyl optionally substituted with R22, C1-C20 haloalkyl optionally substituted with R22, C1-C10 alkoxy optionally substituted with R22, C3-C10 cycloalkyl optionally substituted with R22, C2-C20 alkenyl optionally substituted with R22, C6-20 aryl optionally substituted with R22, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with R22, and 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with R22, wherein R22 is each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C6-20 aryl, C6-20 aryloxy, 5- to 10membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N, 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N, and C3-C6 cycloalkenyl optionally substituted with R23; wherein R23 is each independently selected from the group consisting of hydrogen, halogen, and C1-C6 alkyl;m is an integer from 1 to 10;in formula C, k is an integer from 1 to 10.

2. The benzotriazine dioxide or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof according to claim 1, wherein R2, R4, and R5 are all hydrogen.

3. The benzotriazine dioxide or a pharmaceutically acceptable salt or ester, hydrate, solvate or prodrug thereof according to claim 1, wherein the benzotriazine dioxide has the following formula II-1, formula II-2, or formula II-3II-1II-2                             II-3wherein, in formula II-1, formula II-2, and formula II-3, R3 is selected from the group consisting of halogen, C1-C10 alkyl optionally substituted with R50, C1-C10 alkoxy optionally substituted with R50, C3-C10 cycloalkyl optionally substituted with R50, C6-20 aryl optionally substituted with R50, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with R50, and 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with R50; wherein R50 is each independently selected from the group consisting of hydrogen, oxygen, halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl;X is selected from the group consisting of NH and CH2,in formula II-1, R0 is selected from the group consisting of C1-10 alkyl optionally substituted with RX1 and C3-10 cycloalkyl optionally substituted with RX1;wherein RX1 is each independently selected from the group consisting of halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C10 alkyl, C1-C10 haloalkyl, C1-C10 alkoxy, C3-C10 cycloalkyl, C6-20 aryl optionally substituted with RX11, 5- to 10-membered heteroaryl containing a heteroatom selected from the group consisting of O, S, and N and optionally substituted with RX11, 5- to 10membered heterocyclyl containing heteroatoms selected from the group consisting of O, S, and N and optionally substituted with RX11, and -NR16R17; wherein RX11 is each independently selected from the group consisting of halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl;R16 and R17 are each independently selected from the group consisting of hydrogen, C1-C10 alkyl optionally substituted with RX12, C1-C10 alkoxy optionally substituted with RX12, C3-C10cycloalkyl optionally substituted with RX12, C6-20 aryl optionally substituted with RX12, 5- to 10membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with RX12, and 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with RX12; wherein RX12 is each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl; or R16 and R17 together with the nitrogen atom to which they are attached form a 5- to 10-membered ring structure;in formula II-2, R8 and R9 are each independently selected from the group consisting of hydrogen and C1-C6 alkyl, or R8 and R9 together with the carbon atom to which they are attached form a C3-C6 ring structure;n is 1, 2, or 3;Y is selected from one of the following:r6* Y * YO, NR6,      0        0  ;* represents a site where Y is attached to CR8R9;      represents a site where Y is attachedto R10;R10 is selected from the group consisting of hydrogen, C1-C20 alkyl optionally substituted with R30, C1-C20 haloalkyl optionally substituted with R30, C1-C10 alkoxy optionally substituted with R30, C3-C10 cycloalkyl optionally substituted with R30, C2-C20 alkenyl optionally substituted with R30, C6-20 aryl optionally substituted with R30, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with R30, and 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with R30, wherein R30 is each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C6-20 aryl, C6-20 aryloxy, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N, 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N, and C3-C6 cycloalkenyl optionally substituted with R31; wherein R31 is each independently selected from the group consisting of hydrogen, halogen, and C1-C6 alkyl;R6 is independently selected from the group consisting of hydrogen, C1-C10 alkyl optionally substituted with RX32, C1-C10 alkoxy optionally substituted with RX32, C3-C10 cycloalkyl optionally substituted with RX32, C6-20 aryl optionally substituted with RX32, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with RX32, and 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with RX32; wherein RX32 is each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl;in formula II-3, R20 is selected from the group consisting of hydrogen and -C(=O)R21, wherein R21 is selected from the group consisting of hydrogen, C1-C20 alkyl optionally substituted with R22, C1-C20 haloalkyl optionally substituted with R22, C1-C10 alkoxy optionally substituted with R22, C3-C10 cycloalkyl optionally substituted with R22, C2-C20 alkenyl optionally substituted with R22, C6-20 aryl optionally substituted with R22, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with R22, and 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with R22, wherein R22 is each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C6-20 aryl, C6-20 aryloxy, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N, 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N, and C3-C6 cycloalkenyl optionally substituted with R23; wherein R23 is each independently selected from the group consisting of hydrogen, halogen, and C1-C6 alkyl;m is 1, 2, or 3.

4. The benzotriazine dioxide or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof according to claim 3, wherein the benzotriazine dioxide has formula II-2:o’Io                   II-2wherein R10 is selected from one of the following aromatic cyclic and heterocyclic structures:wherein R1 is selected from the group consisting of H, C1-C7 alkyl optionally substituted with R11, C1-C7 cycloalkyl optionally substituted with R11, C1-C7 alkoxy optionally substituted with R11, and C1-C7 acyl optionally substituted with R11, wherein R11 is selected from the group consisting of halogen, hydroxy, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 alkoxy, C1-C7 substituted or unsubstituted alkenyl, C1-C12 substituted or unsubstituted aryl, and C3-C12 substituted or unsubstituted heterocyclyl.

5. The benzotriazine dioxide or a pharmaceutically acceptable salt or ester, hydrate, solvate or prodrug thereof according to claim 1, wherein the benzotriazine dioxide has the formula II-2II-2R10 is selected from one of the following aromatic rings and heterocyclic structures:wherein R71 is selected from the group consisting of H, C1-C7 alkyl optionally substituted with R12, C1-C7 cycloalkyl optionally substituted with R12, and C1-C7 acyl optionally substituted with R12, wherein R12 is selected from the group consisting of halogen, hydroxy, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 alkoxy, C1-C7 substituted or unsubstituted alkenyl, C1-C12 substituted orunsubstituted aryl, and C3-C12 substituted or unsubstituted heterocyclyl.

6. The benzotriazine dioxide or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof according to claim 3, wherein the benzotriazine dioxide has formula II-2:0 Io                   II-2Y is NR6;R10 is selected from the group consisting of hydrogen and C1-10 alkyl such as methyl;R6 is selected from the group consisting of hydrogen and C1-10 alkyl such as methyl.

7. The benzotriazine dioxide or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof according to claim 3, wherein the benzotriazine dioxide has formula II-2:0 i0II-2Y isR10 is selected from the group consisting of hydrogen and C1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

8. The benzotriazine dioxide or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof according to any one of claims 3 to 7, whereinX is NH,R8 and R9 are each independently selected from the group consisting of hydrogen and C1-C6 alkyl such as methyl, or R8 and R9 together with the carbon atom to which they are attached form a C3-C6 ring structure such as a cyclopropyl structure; preferably, R8 and R9 are hydrogen;n is 1, 2, or 3; preferably, n is 2.

9. The benzotriazine dioxide or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof according to claim 1, wherein the benzotriazine dioxide has the following formula II-3:II-3wherein R20 is selected from one of the following structures:

10. The benzotriazine dioxide or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof according to claim 1, wherein the benzotriazine dioxide has the following formula II-3:II-3wherein R20 is -C(=O)R21, wherein R21 is selected from the group consisting of hydrogen andC1-C20 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,and hexyl.

11. The benzotriazine dioxide or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof according to any one of claims 9 to 10, wherein X is NH.

12. The benzotriazine dioxide or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof according to claim 1, wherein the benzotriazine dioxide has the following formula III-1:0 I R3        hkT J RW11 RW13 XJ / Wt _R10 N   N  T  n'-    H       ।       II0          RW12 0       III—1wherein W1 is O or NR6;RW11, RW12, and RW13 are each independently selected from the group consisting of hydrogen and C1-3 alkyl, or RW12 and RW13 together with the carbon atom to which they are attached form a C3-6 cycloalkyl;R6 is selected from the group consisting of hydrogen and C1-3 alkyl, or when W1 is NR6, RW11 and R6 together with the atoms to which they are attached form a 4- to 6-membered heterocyclyl containing one N atom;R10 is selected from the group consisting of hydrogen, C1-C20 alkyl optionally substituted with R30, C1-C20 haloalkyl optionally substituted with R30, C1-C10 alkoxy optionally substituted with R30, C3-C10 cycloalkyl optionally substituted with R30, C2-C20 alkenyl optionally substituted with R30, C6-20 aryl optionally substituted with R30, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with R30, and 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with R30, wherein R30 is each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C6-20 aryl, C6-20 aryloxy, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N, 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N, and C3-C6 cycloalkenyl optionally substituted with R31; wherein R31 is each independently selected from the group consisting of hydrogen, halogen, and C1-C6 alkyl.

13. The benzotriazine dioxide or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof according to claim 12, whereinR10 is selected from the group consisting of C1-C20 alkyl optionally substituted with R30, C3-C10 cycloalkyl optionally substituted with R30, C6-20 aryl optionally substituted with R30, and 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with R30;R30 is halogen, hydroxy, or -NH2.

14. The benzotriazine dioxide or a pharmaceutically acceptable salt or ester, hydrate, solvate,or prodrug thereof according to claim 13, wherein R10 is selected from one of the following:C-11 H23BrC14H29, cyclopropyl.

15. The benzotriazine dioxide or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof according to claim 13, wherein R10 is C1-6 alkyl, such as isopropyl or tert-butyl.

16. The benzotriazine dioxide or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof according to any one of claims 12 to 15, whereinRW11, RW12 and RW13 are each independently selected from hydrogen;W1 is O.

17. The benzotriazine dioxide or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof according to any one of claims 12 to 15, whereinRW12 and RW13 are each independently selected from hydrogen;RW11 is hydrogen or C1-3 alkyl;W1 is NR6, wherein R6 is hydrogen or C1-3 alkyl, or RW11 and R6 together with the atoms to which they are attached form a 5- or 6-membered heterocyclic group containing one N atom.

18. The benzotriazine dioxide or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof according to any one of claims 12 to 15, whereinRW12 and RW13 are each independently selected from hydrogen;W1 is NR6, wherein RW11 and R6 together with the atoms to which they are attached form a 5-membered heterocyclic group containing one N atom.

19. The benzotriazine dioxide or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof according to claim 1, wherein the benzotriazine dioxide has the following formula III-2:r3III-2wherein W2 is O or NRW25, wherein RW25 is hydrogen or C1-3 alkyl;RW21, RW22, and RW23 are each independently selected from the group consisting of hydrogen, hydroxy, and C1-3 alkyl;or when W2 is NRW25, RW21 and RW25 together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl containing one N atom;RW24 is each independently selected from the group consisting of hydrogen, C1-3 alkyl, 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with RW20, C6-20 aryl optionally substituted with RW20, and C6-20 aralkyl optionally substituted with RW20;wherein RW20 is halogen, C1-3 alkyl, or hydroxy.

20. The benzotriazine dioxide or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof according to claim 19, whereinW2 is O,RW21, RW22, and RW23 are each independently selected from hydrogen.

21. The benzotriazine dioxide or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof according to claim 19 or 20, whereinRW24 is selected from the group consisting of hydrogen, C1-3 alkyl, and phenyl optionally substituted with RW20, wherein RW20 is halogen such as fluorine, C1-3 alkyl, or hydroxy.

22. The benzotriazine dioxide or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof according to claim 21, whereinRW24 is phenyl or monofluoro-substituted phenyl.

23. The benzotriazine dioxide or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof according to claim 1, wherein the benzotriazine dioxide has the following formula III-3:III-3RW31 and RW32 are each independently selected from the group consisting of hydrogen,halogen, hydroxy, and C1-3 alkyl;RW33 is each independently selected from the group consisting of hydrogen, halogen, C1-3 alkyl, 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, and N and optionally substituted with RW30, C6-20 aryl optionally substituted with RW30, and C6-20 aralkyl optionally substituted with RW30;wherein RW30 is halogen, C1-3 alkyl, or hydroxy.

24. The benzotriazine dioxide or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof according to claim 23, whereinRW31 and RW32 are hydrogen;RW33 is each independently selected from the group consisting of hydrogen, halogen, C1-3 alkyl, and phenyl optionally substituted with RW30, wherein RW30 is halogen such as fluorine, C1-3 alkyl, or hydroxy.

25. The benzotriazine dioxide or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof according to claim 24, whereinRW33 is phenyl or monofluoro-substituted phenyl.

26. The benzotriazine dioxide or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof according to any one of claims 1 to 25, wherein R3 is selected from the group consisting of halogen, C1-6 alkoxy, C1-3 haloalkyl, and C3-6 cycloalkyl, for example, selected from the group consisting of bromo, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, Me, Et, nPr, iPr, cyclopropyl, nBu, iBu, tBu, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethyl, trifluoromethyl, and trifluoroethyl.

27. The benzotriazine dioxide or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof according to claim 26, wherein R3 is bromo, C1-3 haloalkyl such as trifluoromethyl, C1-6 alkoxy such as methoxy, or C1-3 haloalkoxy such as trifluoromethoxy.

28. The benzotriazine dioxide or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof according to claim 26, wherein R3 is bromo.

29. The benzotriazine dioxide or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof according to claim 26, wherein R3 is trifluoromethyl.

30. The benzotriazine dioxide or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof according to claim 1, wherein the benzotriazine dioxide is selected from the following compounds:A-1: 3-((2-(pyridin-3-yloxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-di oxide;A-2: 3-(2-(3-fluorophenoxy)ethyl)amino-7-trifluoromethylbenzo[1,2,4]triazine 1,4-dioxid e;A-3: 3-(2-(benzyloxy)ethyl)amino)-7-trifluoromethylbenzo[1,2,4]triazine 1,4-dioxide;A-4: 3-((1-methoxy-2-propyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxid e;A-5: 3-((3-aminotetrahydrofuran)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide;B-1: 3-(2,2,2-trifluoroethyl)amino-7-trifluoromethylbenzo[1,2,4]triazine 1,4-dioxide;B-2: 3-((3,3-difluorocyclopentyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dio xide;B-3: 3-((2-(pyridin-3-yl)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxi de;B-4: 3-((3-fluorophenyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide;B-5: 7-cyclopropyl-3-((2,2,2-trifluoroethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide;B-6: 7-(5-cyclopropyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-3-((2,2,2-trifluoroethyl) amino)benzo[e][1,2,4]triazine 1,4-dioxide;B-7: 7-(2-chloro-6-methylpyridin-4-yl)-3-((3,3-difluorocyclopentyl)amino)benzo[e][1,2,4]t riazine 1,4-dioxide;B-8: 7-(2-chloro-6-methyl-1-oxidopyridin-4-yl)-3-((3,3-difluorocyclopentyl)amino)benzo [e][1,2,4]triazine 1,4-dioxide;B-9: 7-(2-chloro-6-methylpyridin-4-yl)-3-((2,2,2-trifluoroethyl)amino)benzo[e][1,2,4]triazi ne 1,4-dioxide;B-10: 7-(2-chloro-6-1-oxidopyridin-4-yl)-3-((2,2,2-trifluoroethyl)amino)benzo[e][1,2,4]tria zine 1,4-dioxide;C-1: 7-bromo-3-((2-ethoxy)amino)benzo[e][1,2,4]triazine 1,4-dioxide;C-2: 3-((2-hydroxyethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide;C-3: 3-((2-hydroxy-2-methylpropyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide;C-4: 3-((1S,4S)-4-hydroxycyclohexyl)amino)-7-trifluoromethylbenzo[e][1,2,4]triazine 1,4 -dioxide;C-5: 3-(2-hydroxypropyl)amino-7-trifluoromethylbenzo[1,2,4]triazine 1,4-dioxide;C-6: 7-(5-cyclopropyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-3-((2-hydroxyethyl)ami no)benzo[e][1,2,4]triazine 1,4-dioxide;C-7: 7-bromo-3-((2-(4-fluorophenyl)-2-hydroxyethyl)amino)benzo[e][1,2,4]triazine 1,4-di oxide;C-8: 7-bromo-3-((2-(isobutyryloxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide;C-9: 7-bromo-3-((2-(hexadecanoyloxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide;C-10: 7-bromo-3-((2-((2-bromohexadecanoyl)oxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4 -dioxide;C-11: 3-((2-(pivaloyloxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxi de;C-12: 3-((2-(isobutyryloxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dio xide;C-13: 3-((2-((3-hydroxytetradecanoyl)oxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4] triazine 1,4-dioxide;C-14: 3-((2-(nicotinoyloxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dio xide;C-15: 3-((((2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenyl)oxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide;C-16: 7-(trifluoromethyl)-3-((2-(propoxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide;C-17: 3-((2-((thiophene-3-carbonyl)oxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]tri azine 1,4-dioxide;C-18: 3-((2-(isobutyryloxy)ethyl)amino)-7-(trifluoromethoxy)benzo[e][1,2,4]triazine 1,4-d ioxide;C-19: 3-(2-hydroxyethyl)amino)-7-(trifluoromethoxy)benzo[e][1,2,4]triazine 1,4-dioxide;C-20: 3-((2-((2-bromohexadecanoyl)oxy)ethyl)amino)-7-(trifluoromethoxy)benzo[e][1,2,4] triazine 1,4-dioxide;C-21: 6-bromo-3-((2-(isobutyryloxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide;C-22: 8-bromo-3-((2-(isobutyryloxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide;C-23: 7-(5-cyclopropyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-3-((2-(isobutyryloxy)e thyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide;C-24: 7-cyclopropyl-3-((2-(pivaloyloxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide;C-25: 3-((2-((thiophene-3-carbonyl)oxy)propyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]t riazine 1,4-dioxide;C-26: 3-((2-((cyclopropanecarbonyl)oxy)propyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4] triazine 1,4-dioxide;C-27: 3-((2-(pivaloyloxy)propyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dio xide;C-28: 3-((2-((3-hydroxytetradecanoyl)oxy)propyl)amino)-7-(trifluoromethyl)benzo[e][1,2, 4]triazine 1,4-dioxide;C-29: 3-((2-(pentanoyloxy)ethyl)amino)-7-(thiazol-5-yl)benzo[e][1,2,4]triazine 1,4-dioxid e;D-1: 3-((2-aminoethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide;D-2: 3-(pyrrolidin-3-ylamino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide;D-3: 3-(azetidin-3-ylamino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide;D-4: 3-((2-(methylamino)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-diox ide;D-5: 3-((2-pivalamidoethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide;D-6: 3-((1-pivaloylpyrrolidin-3-yl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-d ioxide;D-7: 3-((1-pivaloylazetidin-3-yl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dio xide;D-8: 3-((2-(N-methylpivalamido)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide;D-9: 3-((2-(N-methylcyclopropanecarboxamido)ethyl)amino)-7-(trifluoromethyl)benzo[e] [1,2,4]triazine 1,4-dioxide;D-10: 3-((1-((2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6, 8-tetraenyl)pyrrolidin-3-yl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide;D-11: 3-(((1-(pivaloyloxy)cyclopropyl)methyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]tr iazine 1,4-dioxide;D-12: 3-((1-((R)-3-hydroxytetradecanoyl)pyrrolidin-3-yl)amino)-7-(trifluoromethyl)benzo [e][1,2,4]triazine 1,4-dioxide;D-13: 3-((1-(2,2,2-trifluoroacetyl)pyrrolidin-3-yl)amino)-7-(trifluoromethyl)benzo[e][1,2,4] triazine 1,4-dioxide;D-14: 3-((1-(thiophene-3-carbonyl)pyrrolidin-3-yl)amino)-7-(trifluoromethyl)benzo[e][1,2, 4]triazine 1,4-dioxide;D-15: 3-((2-aminoethyl)amino)-7-bromobenzo[e][1,2,4]triazine 1,4-dioxide;D-16: 3-(((1-aminocyclopropyl)methyl)amino)-7-bromobenzo[e][1,2,4]triazine 1,4-dioxid e;D-17: (R)-3-((2-aminopropyl)amino)-7-bromobenzo[e][1,2,4]triazine 1,4-dioxide;D-18: (S)-3-((2-aminopropyl)amino)-7-bromobenzo[e][1,2,4]triazine 1,4-dioxide;D-19: 3-((2-aminoethyl)amino)-7-fluorobenzo[e][1,2,4]triazine 1,4-dioxide;D-20: 3-((2-aminoethyl)amino)-7-chlorobenzo[e][1,2,4]triazine 1,4-dioxide;D-21: 3-((2-aminoethyl)amino)-7-iodobenzo[e][1,2,4]triazine 1,4-dioxide;D-22: 3-((2-aminoethyl)amino)-7-methoxybenzo[e][1,2,4]triazine 1,4-dioxide;D-23: 7-bromo-3-((2-(methylamino)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide;D-1': 3-((2-aminoethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide trifl uoroacetate;D-2': 3-(pyrrolidin-3-ylamino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide trifl uoroacetate;D-4': 3-((2-(methylamino)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-diox ide trifluoroacetate;D-16': 3-((2-aminoethyl)amino)-7-bromobenzo[e][1,2,4]triazine 1,4-dioxide trifluoroaceta te;D-17': 3-(((1-aminocyclopropyl)methyl)amino)-7-bromobenzo[e][1,2,4]triazine 1,4-dioxid e hydrochloride;D-18': (R)-3-((2-aminopropyl)amino)-7-bromobenzo[e][1,2,4]triazine 1,4-dioxide hydroc hloride.

31. A pharmaceutical composition, comprising the benzotriazine dioxide or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof according to any one of claims 1 to 30, and a pharmaceutically acceptable carrier.

32. Use of the benzotriazine dioxide or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof according to any one of claims 1 to 30, or the pharmaceutical composition according to claim 31, in the manufacture of a medicament for treating cancer.

33. A method for treating or alleviating cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of the benzotriazine dioxide or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof according to any one of claims 1 to 30, or the pharmaceutical composition according to claim 31.

34. The method according to claim 33, wherein the mammal is a mouse, dog, pig, monkey, and human.

35. The method according to claim 33, wherein the cancer is selected from tumors at the following sites, including liver, intrahepatic duct, pancreas, stomach, esophagus, kidney, colorectum, lung, brain (glioma), malignant glioma, breast, ovary, cervix, head and neck, melanoma, skin, muscle, blood vessels, nerves, ovary, prostate, sarcoma, and thyroid, the cancer includes solid tumors originating from the endoderm, mesoderm, and ectoderm.

36. The method according to claim 35, wherein the cancer is selected from tumors at the following sites: liver, intrahepatic duct, pancreas, stomach, esophagus, kidney, colorectum, lung, brain (glioma), malignant glioma, breast, head and neck, melanoma, ovary, prostate, sarcoma, and thyroid.