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

Novel benzotriazine dioxide and pharmaceutical compositions thereof TECHNICAL FIELD

[0001] The present disclosure relates to a class of N-benzotriazine dioxide and related derivatives, pharmaceutical compositions, and methods. BACKGROUND

[0002] Malignant tumors have gradually become an important disease affecting human life and health, among which solid tumors account for more than 95%. Chemotherapy and radiotherapy of tumors are still important means of tumor treatment, but their therapeutic effect is limited, and drug resistance is inevitable. A large number of scientific researches show that the poor effect of tumor cells on chemotherapy and radiotherapy and the generation of drug resistance are due to the fact that a part of tumor cells grow in a hypoxic microenvironment inside the tumor. In a low-oxygen environment, chemotherapy and radiotherapy often cannot kill these tumor cells, thereby leading to tumor drug resistance, diffusion and metastasis. Hypoxia is often a microenvironment that must be experienced during tumor development, and a hypoxic microenvironment can directly cause great changes in tumor cells and their environment. One important change is to cause tumor angiogenesis, providing more oxygen and nutrients for tumors, thereby leading to tumor cell proliferation, diffusion and metastasis, and also leading to changes in energy metabolism and drug resistance to traditional chemotherapy and radiotherapy. If we can find a drug that can kill tumor cells in a hypoxic environment, and use such a drug in combination with ordinary chemotherapy drugs in a hypoxic environment, it is possible to kill tumor cells in an aerobic environment and a hypoxic environment as much as possible, thereby increasing the efficacy of chemotherapy drugs on tumors.

[0003] Currently, the research on developing drugs for killing tumors in hypoxia mainly focuses on finding and optimizing hypoxia-activated prodrugs (HAP) that can kill tumors in a hypoxic microenvironment. Hypoxia-activated prodrugs (HAP) are oxidized and reduced by oxidoreductases in tumor cells (or normal cells) under hypoxic conditions (from mild to extreme hypoxia). The direct and indirect results of the oxidation-reduction reaction are the generation of a large number of free radicals, which have strong cytotoxic effects, and then the free radicals achieve the killing effect on tumors.

[0004] HAP-related drugs have gained more attention in recent years, and there are some drugs in clinical research stage. The key factor for the activation of HAP under hypoxic conditions is the reductase in tumor tissue, including DT-diaphorase, quinone reductase, cytochrome P450 reductase, nitroreductase, etc. Most of the enzymes are sensitive to oxygen components, using nicotinamide adenine dinucleotide (NADH) or nicotinamide adenine dinucleotide phosphate (NADPH) as hydrogen donor, and are involved in the reduction process of prodrugs. Four types of hypoxia-activated chemical groups that have been proven are: over metal complex, quinone compound, nitroxide compound (aliphatic nitroxide compound, aromatic nitroxide compound), nitro compound (nitrobenzene compound, nitroimidazole compound).

[0005] Among them, the representative drug of nitroxide compound is tirapazamine (shown above). Between 1997-2007, tirapazamine completed multiple I / II / III phase clinical trials for different clinical indications, and nearly 2000 people received experimental treatment with tirapazamine. Unfortunately, all clinical trials did not show statistically significant benefits for patients. Tirapazamine is a very specific cytotoxic compound, which can reversibly form a free radical intermediate under hypoxic conditions through the action of single-electron reductase (such as cytochrome P450 reductase). The oxidized hydroxyl radical and benzotriazine radical will take an electron from DNA to form a free radical of DNA (mostly on C4 of the ribose ring), thereby causing DNA strand breaks and causing cell death (as shown above, Int. J. Mol. Sci. 2019, 20, 4602). According to preclinical experimental studies, the activity of tirapazamine under hypoxia is 15-200 times higher than that under oxygen. Despite this, tirapazamine still has the clinical weaknesses of poor solubility, fast in vivo metabolism, poor penetration, inability to reach a persistent therapeutic concentration in the hypoxic area inside the tumor, and inability to effectively reach the hypoxic area. Therefore, there is an urgent need to develop a class of small molecule compounds with strong targeting ability, stronger killing ability under hypoxic conditions, novel and unique drug structure, good solubility, and strong drug-likeness.

[0006] CN114901646A discloses some work for the modification of tirapazamine. However, for in-depth evaluation of drug metabolic stability and hypoxic selectivity, the field needs a new series of compounds with more drug potential. SUMMARY

[0007] On the basis of the foregoing, based on the principles of FBDD and SBDD, combined with physicochemical property analysis, and taking into full account the biological activity of cells in vitro, the present disclosure develops a class of novel compounds, which can be used to treat or alleviate benign and malignant tumor conditions including liver, intrahepatic duct, pancreas, stomach, esophagus, kidney, colorectum, lung, brain (neuroglioma), malignant glioma, breast, ovary, cervix, head and neck, skin, melanoma, prostate, fibrosarcoma, sarcoma and thyroid, etc. by using the compounds alone or in combination with other drugs.

[0008] The present disclosure provides a benzotriazine dioxide having the following general formula (I) or a pharmaceutically acceptable salt or ester, hydrate, solvate or prodrug thereof,

[0009] The present disclosure also provides a pharmaceutical composition comprising a benzotriazine dioxide according to the present disclosure or a pharmaceutically acceptable salt or ester, hydrate, solvate or prodrug thereof, and a pharmaceutically acceptable carrier.

[0010] The present disclosure also relates to the use of a benzotriazine dioxide according to the present disclosure or a pharmaceutically acceptable salt or ester, hydrate, solvate or prodrug thereof, or a pharmaceutical composition of the present disclosure, in the manufacture of a medicament for treating cancer.

[0011] 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 a benzotriazine dioxide according to the present disclosure or a pharmaceutically acceptable salt or ester, hydrate, solvate or prodrug thereof, or a pharmaceutical composition of the present disclosure. DETAILED DESCRIPTION

[0012] The present disclosure will be further described in the following examples. The features and advantages of the present disclosure will become more apparent from the detailed description in conjunction with the accompanying drawings.

[0013] The term "exemplary" is used herein to mean "serving as an example, instance, or illustration." Any implementation described herein as "exemplary" is not necessarily to be construed as preferred or advantageous over other implementations.

[0014] Moreover, the technical features involved in the different implementations of the present disclosure described below can be combined with each other as long as there is no conflict.

[0015] DEFINITIONS

[0016] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of the claims belongs. All patents, patent applications, published materials, and articles noted herein are hereby incorporated by reference in their entirety. When referring to a trade name herein, it is intended to refer to the corresponding product or its active ingredient.

[0017] It should be understood that the foregoing brief description and the following detailed description are exemplary and explanatory only and do not limit the subject matter of the present invention in any way. In this disclosure, it must be noted that, unless otherwise clearly indicated, the singular forms used in this specification and claims include the plural forms of the referents. It should also be noted that, unless otherwise indicated, the use of "or" and "or" means "and / or". In addition, the use of the term "include" and other forms, such as "comprises", "includes" and "comprising" are not limiting.

[0018] Definitions of standard chemical terms can be found in the literature, including Advanced Organic Chemistry by Carey and Sundberg. th Ed, Vol A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacological methods, are employed. Unless specifically defined, nomenclature and laboratory procedures and techniques in analytical chemistry, organic synthetic chemistry, and medicinal and pharmaceutical chemistry are known to those skilled in the art. Standard techniques can be used for chemical syntheses, chemical analyses, 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, lipid filtration). For example, reactions and purification techniques can be performed using kits with manufacturer's instructions, or according to methods known in the art, or as described in this disclosure. In general, the aforementioned techniques and steps 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 this disclosure.

[0019] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result if the formula were written from right to left. For example, CH2O is equivalent to OCH2.

[0020] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom with a substituent, as long as the valence state of the particular 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 does not occur on aromatic groups.

[0021] When any variable (e.g., R) occurs more than one time in a compound; each definition is independent. Thus, if a group is substituted with 0-2 R, then said group can optionally be substituted with up to two R groups, and at each occurrence R is selected independently. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0022] As used herein, C m～n means having m to n carbon atoms in the moiety. For example, the term "C 1～8 " means having 1 to 8 carbon atoms in the moiety, i.e., the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms,... 8 carbon atoms. Thus, for example, "C 1～8 alkyl" means an alkyl group containing 1 to 8 carbon atoms, i.e., the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl,... octyl, and the like. A numerical range, herein, for example "1 to 8", refers to each integer within the given range, e.g., "1 to 8 carbon atoms" means that the group can 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.

[0023] The term "membered" refers to the number of skeletal atoms that make up a ring. For example, pyridine is a six-membered ring, and pyrrole is a five-membered ring.

[0024] In the present disclosure, each group can have the following definitions:

[0025] Hydrogen can be represented as -H, and can be replaced with isotopes such as deuterium, tritium, and the like.

[0026] Halogen can include fluorine, chlorine, bromine, iodine.

[0027] As used herein, the term "alkyl" means a straight or branched chain aliphatic group having from 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, which optionally has one, two, or three substituents. Preferred alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, and hexyl. A "C0" alkyl group (as in "C0-C3-alkyl") is a covalent bond. C 1～8Alkyl can include methyl, ethyl, n-propyl, isopropyl, 2-methyl-l-propyl, 2-methyl-2-propyl, 2-methyl-l-butyl, 3-methyl-l-butyl, 2-methyl-3-butyl, 2,2-dimethyl-l- propyl, 2-methyl-l-pentyl, 3-methyl-l-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3- methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l-butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l- butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, t-pentyl, hexyl, heptyl, octyl, and the like.

[0028] Deuterated C 1～8 Alkyl, tritiated C 1～8 Alkyl can represent the C 1～8 Alkyl, wherein one or more, or even all, hydrogen atoms have been replaced by deuterium, tritium, or the like isotopes.

[0029] As used herein, the term "alkoxy" means -Oalkyl, wherein alkyl is as defined herein, including, but not limited to, -OCH3, -OCF3, -OEt, -OC(CH3)2CH3, and -OCH2CF3.C 1～8 Alkoxy can be represented as -OC 1～8 Alkyl, wherein C 1～8 Alkyl includes groups as previously defined; for example, C 1～8 Alkoxy can include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, and the like.

[0030] C 1～8 Haloalkyl can be represented as C 1～8 Alkyl, wherein any number of the hydrogen atoms have been replaced by halogen, wherein C 1～8 Alkyl, halogen includes groups as previously defined; for example, C 1～8 Haloalkyl can include -CF3, and the like.

[0031] As used herein, the term "cycloalkyl" means a non-aromatic, saturated or unsaturated, monocyclic or polycyclic C3-C 12 , including, but not limited to, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, cyclohexyl, substituted cyclohexyl.C 3～8 Cycloalkyl can be represented as a non-aromatic, saturated carbocyclic ring, including single carbocyclic rings (having one ring) and double carbocyclic rings (having two rings), for example, C 3～8 Cycloalkyl can include , and the like.

[0032] C 3～8 Cycloalkyl C 1～8Alkyl can be represented as having C 3～8 Cycloalkyl of C 1～8 Alkyl, wherein C 3～8 Cycloalkyl and C 1～8 Alkyl is defined as above, e.g., C 3～8 Cycloalkyl C 1～8 Alkyl can include cyclopropylmethyl, cyclobutylmethyl, cyclohexylethyl, and the like.

[0033] "Aryl" refers to a monocyclic or polycyclic aromatic hydrocarbon, including, for example, phenyl, naphthyl, and phenanthryl. C 6～20 Aryl can include a monocyclic aryl, a bicyclic aryl, or a more highly cyclic aryl, e.g., can include phenyl, biphenyl, naphthyl, phenanthryl, anthryl, azulenyl, and the like. Unless otherwise indicated, "aryl," "C6or C 10 Aryl" or "C6-10 aryl" or "aromatic residue" can be unsubstituted or substituted with 1 to 5 groups, preferably 1 to 3 groups, 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.

[0034] "Heterocyclyl" or "heterocyclic" groups are ring structures having about 3 to 12 atoms, wherein the ring structure has one or more heteroatoms selected from N, O, S, and the like. One or more positions of the carbon of the heterocyclyl are optionally substituted. The nitrogen of the heterocyclyl is likewise 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, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, oxazolidinyl, tetrahydropyrazolyl, pyrrolinyl, dihydrofuranyl, dihydrothienyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyranyl, tetrahydropyranyl, dihydrothiopyranyl, azepinyl, oxepinyl, thiepinyl, oxazepinyl, diazepinyl, 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.

[0035] As used herein, the term "heteroaryl" refers to a group having from 5 to 14 ring atoms, preferably having 5, 6, 9, or 10 ring atoms, which has 6, 10, or 14 shared π-electrons in a cyclic arrangement, and having from 1 to 3 heteroatoms per ring in addition to carbon atoms, the heteroatoms being selected from N, O, and S. The term "heteroaryl" also means to include mono- or bicyclic groups. For example, the heteroaryl group can be pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, and the like. "Heteroaralkyl" or "heteroarylalkyl" includes a heteroaryl group attached to an alkyl group, either of which is independently optionally substituted or unsubstituted. Preferred heteroaralkyl groups include C1-C6alkyl and a heteroaryl group having 5, 6, 9, or 10 ring atoms. Examples of preferred heteroaralkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, and thiazolylethyl.

[0036] For convenience, reference to "n-m membered" heterocyclyl or heteroaryl means a heterocyclyl or heteroaryl group having from "n" to "m" ring atoms, where "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.

[0037] Hydroxy can be represented as -OH.

[0038] Mercapto can be represented as -SH.

[0039] Carboxy can be represented as -COOH.

[0040] Ester can be represented as -COOR', R' can be C 1～8 alkyl, for example C 1～8 Alkyl-substituted ester can be represented as -COOC 1～8 alkyl, for example C 1～8 alkyl, for example C

[0041] Acyl can be represented as -COR', R' can be C 1～8 alkyl, for example C 1～8 Alkyl-substituted acyl can be represented as -COC 1～8 alkyl, for example C 1～8 alkyl, for example C

[0042] Amino can be represented as -NH2, -NHR', or -N(R')2, R' can be C 1～8 alkyl, for example C 1～8Alkyl-substituted amino groups can be represented as -NHC 1～8 Alkyl or -N(C 1～8 alkyl groups include all groups having 1 to 5 carbon atoms as defined previously. 1～8 Alkyl groups include all groups having 1 to 5 carbon atoms as defined previously.

[0043] Amido groups can be represented as -CO amino, where the amino group is as defined previously.

[0044] Sulfonyl groups can be represented as -S(O)2R', where R' can be C 1～8 alkyl, for example C 1～8 Alkyl-substituted sulfonyl groups can be represented as -S(O)2C 1～8 alkyl, where the C 1～8 alkyl groups include all groups having 1 to 5 carbon atoms as defined previously.

[0045] Cyano groups can be represented as -CN.

[0046] Oxo groups can be represented as (=O).

[0047] In the foregoing definitions, when the number of carbon atoms varies, the foregoing definitions vary only according to the number of carbon atoms, and do not affect the definition of the type of group; for example, "C 1～5 alkyl" can include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, and the like, all of which are included in the foregoing definition of "C 1～8 alkyl" having 1 to 5 carbon atoms.

[0048] As used herein, the term "acyloxy" means -OC(O)alkyl, where the alkyl group 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.

[0049] As used herein, the term "N-acylamino" means N(H)C(O)alkyl, where the alkyl group 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.

[0050] As used herein, the term "aryloxy" means -Oaryl, where the aryl group is phenyl, naphthyl, pyridyl, or biphenyl, optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxyalkyl, alkoxy, trifluoromethyl, acyloxy, amino, N-acylamino, hydroxy, nitro, cyano, halogen, protected hydroxy, and amine.

[0051] As used herein, the term "heteroatom" means oxygen, nitrogen, sulfur, silicon, and phosphorus.

[0052] As used herein, the term "halogen" refers to a substituent selected from bromo, iodo, chloro and fluoro.

[0053] As used herein, the term "treatment" and its derivatives refer to both prophylactic and therapeutic methods.

[0054] All publications cited in this specification, including but not limited to patents and patent applications, are hereby incorporated by reference in their entirety.

[0055] As used herein, the term "protected hydroxyl group" or "protected -OH, -NH2" refers to a group in an alcohol, carboxylic acid, amine, or amide that can be protected by a conventional protecting group in the art. Compounds containing protected hydroxyl or amine groups can also be used as pharmaceutically active compounds of the present disclosure.

[0056] Compound

[0057] The present disclosure provides a benzotriazine dioxide having the following general formula (I) or a pharmaceutically acceptable salt or ester, hydrate, solvate or prodrug thereof,

[0058] R2, R4 and R5 are selected from hydrogen, halogen, optionally substituted with R 40 C1-C 10 Alkyl, optionally substituted with R 40 C1-C 10 Alkoxy, optionally substituted with R 40 C3-C 10 Cycloalkyl, optionally substituted with R 40 C 6-20 Aryl, optionally substituted with R 40 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from O, S, and N, optionally substituted with R 40 A 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from O, S, and N; wherein R 40 Each is independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl;

[0059] R3 is selected from halogen, optionally substituted with R 50 C1-C 10 Alkyl, optionally substituted with R 50 C1-C 10 Alkoxy, optionally substituted with R 50 C3-C 10 Cycloalkyl, optionally substituted with R 50 C 6-20 Aryl, optionally substituted with R 505- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from O, S, N, optionally substituted with R 50 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N; wherein R 50 each independently is selected from the group consisting of hydrogen, oxygen, halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl;

[0060] X is selected from NH, S, Se, CHF, C(=S), S(=O) or S(=O)2,

[0061] R X is selected from one of the following groups: optionally substituted with R X1 C1-C6alkyl, optionally substituted with R 1-10 C1-C6alkyl, optionally substituted with R X1 C3-C6cycloalkyl, optionally substituted with R 3-10 C3-C6cycloalkyl, optionally substituted with R

[0062] wherein R X1 each independently is selected from the group consisting of halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl; 10 C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl; 10 C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl; 10 C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl; 10 C3-C6cycloalkyl, optionally substituted with R X11 C3-C6cycloalkyl, optionally substituted with R 6-20 C3-C6cycloalkyl, optionally substituted with R X11 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from O, S, N, optionally substituted with R X11 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N, optionally substituted with R X11 each independently is selected from the group consisting of halogen, halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl;

[0063] R6and R7are each independently selected from the group consisting of hydrogen, C1-C6alkyl, optionally substituted with R X12 C1-C6alkyl, optionally substituted with R 10 C1-C6alkyl, optionally substituted with R X12 C1-C6alkyl, optionally substituted with R 10 C1-C6alkyl, optionally substituted with R X12 C3-C6cycloalkyl, optionally substituted with R 10 C3-C6cycloalkyl, optionally substituted with R X12 C3-C6cycloalkyl, optionally substituted with R 6-20 C3-C6cycloalkyl, optionally substituted with R X12 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from O, S, N, optionally substituted with RX12 A 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from O, S, and N; wherein R X12 are each independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl; or, R6 and R7 together with the N atom to which they are attached form a 5- to 10-membered ring structure;

[0064] In formula A, R8 and R9 are each independently selected from hydrogen or C1-C6 alkyl, or, R8 and R9 together with the C atoms to which they are attached form a C3-C6 ring structure;

[0065] Y is selected from one of the following: O, S, Se, C (= S), NR6,

[0066] * indicates Y and CR 8 R 9 The connection site, Indicates Y and R 10 The site of attachment;

[0067] R 10 is selected from hydrogen, optionally substituted with R 30 C1-C 20 Alkyl, optionally substituted with R 30 C1-C 20 haloalkyl, optionally substituted with R 30 C1-C 10 Alkoxy, optionally substituted with R 30 C3-C 10 Cycloalkyl, optionally substituted with R 30 C2-C 20 Alkenyl, optionally substituted with R 30 C 6-20 Aryl, optionally substituted with R 30 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from O, S, and N, optionally substituted with R 30 A 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from O, S, and N, wherein R 30 Each is independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C 6-20 Aryl, C 6-20 Aryloxy, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from O, S, and N, 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from O, S, and N, optionally substituted with R31 C3-C6cycloalkyl, C3-C6cycloalkenyl; wherein R 31 each independently is selected from the group consisting of hydrogen, halogen, C1-C6alkyl;

[0068] n is an integer from 1 to 11 ;

[0069] in formula B, R 20 is selected from the group consisting of hydrogen or -C(=O)R 21 , wherein R 21 is selected from the group consisting of hydrogen, optionally substituted with R 22 C1-C 20 alkyl, optionally substituted with R 22 C1-C 20 haloalkyl, optionally substituted with R 22 C1-C 10 alkoxy, optionally substituted with R 22 C3-C 10 cycloalkyl, optionally substituted with R 22 C2-C 20 alkenyl, optionally substituted with R 22 C 6-20 aryl, optionally substituted with R 22 5- to 10-membered-heteroaryl comprising 1 to 3 heteroatoms selected from the group consisting of O, S, N, optionally substituted with R 22 5- to 10-membered-heterocyclyl comprising 1 to 3 heteroatoms selected from the group consisting of O, S, N, optionally substituted with R 22 each independently is selected from the group consisting of hydrogen, halogen, cyano, hydroxyl, mercapto, nitro, amino, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C6cycloalkyl, C 6-20 aryl, C 6-20 aryloxy, 5- to 10-membered-heteroaryl comprising 1 to 3 heteroatoms selected from the group consisting of O, S, N, 5- to 10-membered-heterocyclyl comprising 1 to 3 heteroatoms selected from the group consisting of O, S, N, optionally substituted with R 23 C3-C6cycloalkyl, C3-C6cycloalkenyl; wherein R 23 each independently is selected from the group consisting of hydrogen, halogen, C1-C6alkyl;

[0070] m is an integer from 1 to 10;

[0071] in formula C, k is an integer from 1 to 10.

[0072] The present inventors found that by a judicious choice of X and R XThe obtained compounds and their salts and their metabolites have excellent hypoxic activity and good metabolic stability, as well as good water solubility (easy to form salts), and have potential clinical application value in the treatment of solid tumors including liver cancer, bile duct cancer, lung cancer, gastric cancer and other fields.

[0073] In one embodiment, R2, R4 and R5 are all hydrogen. That is, the 7-position of the benzotriazine ring carries a substituent R 3 , 3-bit connection-XR X .

[0074] In one embodiment, R3 is selected from bromo, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, Me, Et, n Pr, i Pr, cyclopropyl, n Bu, i Bu, t In one embodiment, R3 is bromo. In one embodiment, R3 is trifluoromethyl. In one embodiment, R3 is trifluoromethoxy. In one embodiment, R3 is methoxy.

[0075] According to R X In one embodiment, the benzotriazine dioxide has the following general formula II-1, general formula II-2, or general formula II-3

[0076] Wherein, in general formula II-1, general formula II-2, and general formula II-3, R3 is selected from halogen, optionally substituted with R 50 C1-C 10 Alkyl, optionally substituted with R 50 C1-C 10 Alkoxy, optionally substituted with R 50 C3-C 10 Cycloalkyl, optionally substituted with R 50 C 6-20 Aryl, optionally substituted with R 50 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from O, S, and N, optionally substituted with R 50 A 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from O, S, and N; wherein R 50 Each is independently selected from hydrogen, oxygen, halogen, cyano, hydroxyl, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl;

[0077] X is selected from NH or CH2.

[0078] In general formula II-1, R 0 is selected from the group consisting of C X1 alkyl optionally substituted with R 1-10 alkyl or C X1 cycloalkyl optionally substituted with R 3-10 ;

[0079] wherein R X1 each independently is selected from the group consisting of halogen, cyano, hydroxy, mercapto, nitro, amino, C 10 alkyl, C 10 haloalkyl, C 10 alkoxy, C 10 cycloalkyl optionally substituted with R X11 ; 6-20 aryl optionally substituted with R X11 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, N optionally substituted with R X11 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, S, N optionally substituted with R 16 R 17 ; wherein R X11 each independently is selected from the group consisting of halogen, halogen, cyano, hydroxy, mercapto, nitro, amino, C

[0080] R 16 and R 17 each independently are selected from the group consisting of hydrogen, C X12 alkyl optionally substituted with R 10 alkyl, C X12 alkoxy optionally substituted with R 10 cycloalkyl optionally substituted with R X12 ; 10 aryl optionally substituted with R X12 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, S, N optionally substituted with R 6-20 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, S, N optionally substituted with R X12 each independently is selected from the group consisting of hydrogen, halogen, cyano, hydroxy, mercapto, nitro, amino, C 16 alkyl, C 17 or R 8 and R 9 together with the N atom to which they are attached form a 5- to 10-membered ring structure.

[0081] In formula II-2, R8 and R9 are each independently selected from hydrogen or C1-C6 alkyl, or R8 and R9 together with the C atoms to which they are attached form a C3-C6 ring structure;

[0082] n is 1, 2, or 3;

[0083] Y is selected from one of the following:

[0084] O、NR6、

[0085] * indicates Y and CR 8 R 9 The connection site, Indicates Y and R 10 The site of attachment;

[0086] R 10 is selected from hydrogen, optionally substituted with R 30 C1-C 20 Alkyl, optionally substituted with R 30 C1-C 20 Haloalkyl, optionally substituted with R 30 C1-C 10 Alkoxy, optionally substituted with R 30 C3-C 10 Cycloalkyl, optionally substituted with R 30 C2-C 20 Alkenyl, optionally substituted with R 30 C 6-20 Aryl, optionally substituted with R 30 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from O, S, and N, optionally substituted with R 30 A 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from O, S, and N, wherein R 30 Each is independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C 6-20 Aryl, C 6-20 Aryloxy, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from O, S, and N, 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from O, S, and N, optionally substituted with R 31 C3-C6 cycloalkenyl; wherein R 31 Each is independently selected from hydrogen, halogen, C1-C6 alkyl;

[0087] R6 is independently selected from hydrogen, optionally substituted with R X32 C1-C 10Alkyl, optionally substituted with R X32 C1-C 10 Alkoxy, optionally substituted with R X32 C3-C 10 Cycloalkyl, optionally substituted with R X32 C 6-20 Aryl, optionally substituted with R X32 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from O, S, and N, optionally substituted with R X32 A 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from O, S, and N; wherein R X32 Each is independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl.

[0088] In formula II-3, R 20 Selected from hydrogen or -C(=O)R 21 , where R 21 is selected from hydrogen, optionally substituted with R 22 C1-C 20 Alkyl, optionally substituted with R 22 C1-C 20 haloalkyl, optionally substituted with R 22 C1-C 10 Alkoxy, optionally substituted with R 22 C3-C 10 Cycloalkyl, optionally substituted with R 22 C2-C 20 Alkenyl, optionally substituted with R 22 C 6-20 Aryl, optionally substituted with R 22 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from O, S, and N, optionally substituted with R 22 A 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from O, S, and N, wherein R 22 Each is independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C 6-20 Aryl, C 6-20 Aryloxy, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from O, S, and N, 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from O, S, and N, optionally substituted with R 23 C3-C6 cycloalkenyl; wherein R 23 Each is independently selected from hydrogen, halogen, C1-C6 alkyl;

[0089] m is 1, 2 or 3.

[0090] In one embodiment, benzotriazine dioxide may have the general formula II-2

[0091] Among them, R 10 Selected from one of the following aromatic ring or heterocyclic ring structures:

[0092] wherein R1 is selected from H, optionally substituted with R 11 C1-C7 alkyl, optionally substituted with R 11 C1-C7 cycloalkyl, optionally substituted with R 11 C1-C7 alkoxy, optionally substituted with R 11 C1-C7 acyl, wherein R 11 selected from halogen, hydroxy, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 alkoxy, C1-C7 substituted or unsubstituted alkenyl, C1-C 12 Substituted or unsubstituted aryl, C3-C 12 a substituted or unsubstituted heterocyclic group.

[0093] In one embodiment, benzotriazine dioxide may have the general formula II-2

[0094] R 10 Selected from one of the following aromatic ring or heterocyclic ring structures:

[0095] Among them, R 71 Selected from H, optionally substituted with R 12 C1-C7 alkyl, optionally substituted with R 12 C1-C7 cycloalkyl, optionally substituted with R 12 C1-C7 acyl, wherein R 12 selected from halogen, hydroxy, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 alkoxy, C1-C7 substituted or unsubstituted alkenyl, C1-C 12 Substituted or unsubstituted aryl, C3-C 12 a substituted or unsubstituted heterocyclic group.

[0096] In one embodiment, benzotriazine dioxide may have the general formula II-2

[0097] Y is NR6;

[0098] R 10 selected from hydrogen or C 1-10 alkyl, for example, methyl;

[0099] R6is selected from hydrogen or C 1-10 alkyl, for example, methyl.

[0100] In one embodiment, the benzotriazine dioxide can have the general formula II-2

[0101] Y is

[0102] R 10 selected from hydrogen or C 1-10 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, and hexyl.

[0103] For the embodiment of the above general formula II-2, further, X can be NH,

[0104] R8and R9may each independently be selected from hydrogen or C1-C6alkyl, for example, methyl, or, R8and R9together with the C atom to which they are attached form a C3-C6ring structure, for example, a cyclopropyl structure; preferably, R8and R9may be hydrogen;

[0105] n can be 1, 2, or 3; preferably, n can be 2.

[0106] For formula II-3, when m is 1, it has the structural formula of II-31 below

[0107] For formula II-3, when m is 2, it has the structural formula of II-32 below

[0108] For formula II-3, when m is 3, it has the structural formula of II-33 or II-34 below

[0109] In one embodiment, the benzotriazine dioxide can have the general formula II-3

[0110] wherein R 20 is selected from one of the following structures:

[0111] In one embodiment, the benzotriazine dioxide can have the general formula II-3

[0112] wherein R 20 is -C(=O)R 21 wherein R21 Selected from hydrogen, or C1-C 20 Alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0113] In the embodiment of the above general formula II-3, further, X may be NH.

[0114] In one embodiment, the benzotriazine dioxide may have the following general formula III-1,

[0115] Wherein, W1 is O or NR6,

[0116] R W11 、R W12 and R W13 Each independently selected from hydrogen or C 1-3 Alkyl, or R W12 and R W13 Together with the C atoms to which they are attached, they form C 3-6 Cycloalkyl;

[0117] R6 is selected from hydrogen or C 1-3 Alkyl, or, when W1 is NR6, R W11 Together with R6 and the atoms to which they are attached, they form a 4-6 membered heterocyclic group containing one nitrogen atom;

[0118] R 10 is selected from hydrogen, optionally substituted with R 30 C1-C 20 Alkyl, optionally substituted with R 30 C1-C 20 Haloalkyl, optionally substituted with R 30 C1-C 10 Alkoxy, optionally substituted with R 30 C3-C 10 Cycloalkyl, optionally substituted with R 30 C2-C 20 Alkenyl, optionally substituted with R 30 C 6-20 Aryl, optionally substituted with R 30 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from O, S, and N, optionally substituted with R 30 A 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from O, S, and N, wherein R 30 Each is independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C6-20 Aryl, C 6-20 Aryloxy, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from O, S, and N, 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from O, S, and N, optionally substituted with R 31 C3-C6 cycloalkenyl; wherein R 31 Each is independently selected from hydrogen, halogen, and C1-C6 alkyl.

[0119] In the embodiment of the above general formula III-1, further, R 10 can be selected from optionally substituted with R 30 C1-C 20 Alkyl, optionally substituted with R 30 C3-C 10 Cycloalkyl, optionally substituted with R 30 C 6-20 Aryl, optionally substituted with R 30 A 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from O, S, and N,

[0120] R 30 is halogen, hydroxy or -NH2.

[0121] In the embodiment of the above general formula III-1, further, R 10 Can be selected from one of the following:

[0122] Cyclopropyl.

[0123] In the embodiment of the above general formula III-1, further, R 10 Can be C 1-6 Alkyl, such as isopropyl or tert-butyl.

[0124] In the embodiment of the above general formula III-1, further, R W11 、R W12 and R W13 may each independently be selected from hydrogen;

[0125] W1 can be 0.

[0126] In the embodiment of the above general formula III-1, further, R W12 and R W13 may each independently be selected from hydrogen;

[0127] R W11 Can be hydrogen or C 1-3 alkyl;

[0128] W1 can be NR6, wherein R6 is hydrogen or C1-3 Alkyl, or R W11 Together with R6 and the atoms to which they are attached, they form a 5- or 6-membered heterocyclic group containing one nitrogen atom.

[0129] In the embodiment of the above general formula III-1, further, R W12 and R W13 may each independently be selected from hydrogen;

[0130] W1 can be NR6, where R W11 Together with R6 and the atoms to which they are attached, they form a 5-membered heterocyclic group containing one nitrogen atom.

[0131] In one embodiment, the benzotriazine dioxide may have the following general formula III-2,

[0132] Where W2 is O or NR W25 , where R W25 is hydrogen or C 1-3 alkyl,

[0133] R W21 、R W22 and R W23 Each independently selected from hydrogen, hydroxyl or C 1-3 alkyl,

[0134] Or, when W2 is NR W25 When R W21 With R W25 Together with the atoms to which they are attached, they form a 4-membered, 5-membered or 6-membered heterocyclic group containing one N atom;

[0135] R W24 are each independently selected from hydrogen, C 1-3 Alkyl, optionally substituted with R W20 A 5-membered or 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from O, S, and N, optionally substituted with R W20 C 6-20 Aryl, optionally substituted with R W20 C 6-20 Aralkyl,

[0136] Among them, R W20 Halogen, C 1-3 alkyl or hydroxyl groups.

[0137] In the embodiment of the above general formula III-2, further, W2 can be O,

[0138] R W21 、R W22 and R W23may each independently be selected from hydrogen.

[0139] In the above embodiment of general formula III-2, further, R W24 may be selected from hydrogen, C 1-3 alkyl, optionally substituted with R W20 of phenyl, wherein R W20 is halogen, e.g. fluorine, C 1-3 alkyl or hydroxy.

[0140] In the above embodiment of general formula III-2, further, R W24 may be phenyl or monofluoro-substituted phenyl.

[0141] In one embodiment, the benzotriazine dioxide can have the following general formula III-3,

[0142] R W31 and R W32 are each independently selected from hydrogen, halogen, hydroxy or C 1-3 alkyl,

[0143] R W33 are each independently selected from hydrogen, halogen, C 1-3 alkyl, optionally substituted with R W30 of 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from O, S, N, optionally substituted with R W30 of C 6-20 aryl, optionally substituted with R W30 of C 6-20 aralkyl,

[0144] wherein R W30 is halogen, C 1-3 alkyl or hydroxy.

[0145] In the above embodiment of general formula III-3, further, R W31 and R W32 may be hydrogen,

[0146] R W33 are each independently selected from hydrogen, halogen, C 1-3 alkyl, optionally substituted with R W30 of phenyl, wherein R W30 is halogen, e.g. fluorine, C 1-3 alkyl or hydroxy.

[0147] In the above embodiment of general formula III-3, further, R W33 may be phenyl or monofluoro-substituted phenyl.

[0148] In each of the above embodiments, R3may be selected from halogen, C 1-6 alkyl, C 1-3 haloalkyl or C 3-6 cycloalkyl, for example selected from bromine, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, Me, Et, n Pr, i Pr, cyclopropyl, n Bu, i Bu, t Bu, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethyl, trifluoromethyl and trifluoroethyl.

[0149] In each of the above embodiments, R 3 may be bromine, C 1-3 haloalkyl, for example trifluoromethyl, C 1-6 alkoxy, for example methoxy or C 1-3 haloalkoxy, for example trifluoromethoxy.

[0150] In each of the above embodiments, R3may be halogen, for example fluorine, chlorine, bromine or iodine, in particular bromine.

[0151] In each of the above embodiments, R3may be trifluoromethyl.

[0152] In particular, the benzotriazine dioxide can be selected from the following compounds:

[0153] A-1 : 3-((2-(pyridin-3-yloxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide

[0154] A-2: 3-(2-(3-fluorophenoxy)ethyl)amino-7-trifluoromethylbenzo[1,2,4]triazine 1,4-dioxide

[0155] A-3: 3-(2-(benzyloxy)ethyl)amino)-7-trifluoromethylbenzo[1,2,4]triazine 1,4-dioxide

[0156] A-4: 3-((1 -methoxy-2-propyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide

[0157] A-5: 3-((3-aminotetrahydrofuran)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide

[0158] B-1 : 3-(2,2,2-trifluoroethyl)amino-7-trifluoromethylbenzo[1,2,4]triazine 1,4-dioxide

[0159] B-2: 3-((3,3-difluorocyclopentyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide

[0160] B-3: 3-((2-(pyridin-3-yl)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide

[0161] B-4: 3-((3-fluorophenyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide

[0162] B-5: 7-cyclopropyl-3-((2,2,2-trifluoroethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide

[0163] 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

[0164] B-7: 7-(2-chloro-6-methylpyridin-4-yl)-3-((3,3-difluorocyclopentyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide

[0165] 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

[0166] B-9: 7-(2-chloro-6-methylpyridin-4-yl)-3-((2,2,2-trifluoroethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide

[0167] 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

[0168] C-1: 7-bromo-3-((2-ethoxy)amino)benzo[e][1,2,4]triazine 1,4-dioxide

[0169] C-2: 3-((2-hydroxyethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide

[0170] C-3: 3-((2-hydroxy-2-methylpropyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide

[0171] C-4: 3-((1S,4S)-4-hydroxycyclohexyl)amino)-7-trifluoromethylbenzo[e][1,2,4]triazine 1,4-bioxide

[0172] C-5: 3-(2-hydroxypropyl)amino-7-trifluoromethylbenzo[1,2,4]triazine 1,4-bioxide

[0173] 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

[0174] C-7: 7-bromo-3-((2-(4-fluorophenyl)-2-hydroxyethyl)amino)benzo[e][1,2,4]triazine 1,4-bioxide

[0175] C-8: 7-bromo-3-((2-(isobutyryloxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-bioxide

[0176] C-9: 7-bromo-3-((2-(hexadecanoyloxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-bioxide

[0177] C-10: 7-bromo-3-((2-((2-bromohexadecanoyl)oxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide

[0178] C-11: 3-((2-(neopentanoyloxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-bioxide

[0179] C-12: 3-((2-(isobutyryloxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-bioxide

[0180] C-13: 3-((2-((3-hydroxytetradecanoyl)oxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide

[0181] C-14: 3-((2-(nicotinoyloxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-bioxide

[0182] 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

[0183] C-16: 7-(trifluoromethyl)-3-((2-(propyloxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide

[0184] C-17: 3-((2-((thiophene-3-carbonyl)oxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide

[0185] C-18: 3-((2-(isobutyryloxy)ethyl)amino)-7-(trifluoromethoxy)benzo[e][1,2,4]triazine 1,4-dioxide

[0186] C-19: 3-(2-hydroxyethyl)amino)-7-(trifluoromethoxy)benzo[e][1,2,4]triazine 1,4-dioxide

[0187] C-20: 3-((2-((2-bromohexadecanoyl)oxy)ethyl)amino)-7-(trifluoromethoxy)benzo[e][1,2,4]triazine 1,4-dioxide

[0188] C-21: 6-bromo-3-((2-(isobutyryloxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide

[0189] C-22: 8-bromo-3-((2-(isobutyryloxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide

[0190] C-23: 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

[0191] C-24: 7-cyclopropyl-3-((2-(neopentyloxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide

[0192] C-25: 3-((2-((thiophene-3-carbonyl)oxy)propyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide

[0193] C-26: 3-((2-((cyclopropanecarbonyl)oxy)propyl)amino)-7- (trifluoromethyl)benzo [e] [1, 2, 4] triazine 1, 4-dioxide

[0194] C-27: 3-((2-(tert-pentanoyloxy)propyl)amino)-7-(trifluoromethyl)benzo [e] [1, 2, 4] triazine 1, 4-dioxide

[0195] C-28: 3-((2-((3-hydroxytetradecanoyl)oxy)propyl)amino)-7- (trifluoromethyl)benzo [e] [1, 2, 4] triazine 1, 4-dioxide

[0196] C-29: 3-((2-pentanoyloxy)ethyl)amino)-7-(thiazol-5-yl)benzo [e] [1, 2, 4] triazine 1, 4-dioxide

[0197] D-1: 3-((2-aminoethyl)amino)-7-(trifluoromethyl)benzo [e] [1, 2, 4] triazine 1, 4-dioxide

[0198] D-2: 3-(pyrrolidin-3-ylamino)-7-(trifluoromethyl)benzo [e] [1, 2, 4] triazine 1, 4-dioxide

[0199] D-3: 3-(azetidin-3-ylamino)-7-(trifluoromethyl)benzo [e] [1, 2, 4] triazine 1, 4-dioxide

[0200] D-4: 3-((2-(methylamino)ethyl)amino)-7-(trifluoromethyl)benzo [e] [1, 2, 4] triazine 1, 4-dioxide

[0201] D-5: 3-((2-neopentanamidoethyl)amino)-7-(trifluoromethyl)benzo [e] [1, 2, 4] triazine 1, 4-dioxide

[0202] D-6: 3-((1-neopentanoylpyrrolidin-3-yl)amino)-7-(trifluoromethyl)benzo [e] [1, 2, 4] triazine 1, 4-dioxide D-7: 3-((1-neopentanoylazetidin-3-yl)amino)-7-(trifluoromethyl)benzo [e] [1, 2, 4] triazine 1, 4-dioxide

[0203] D-8: 3-((2-(N-methylpivalamido)ethyl)amino)-7-(trifluoromethyl)benzo [e] [1, 2, 4] triazine 1, 4-dioxide

[0204] D-9: 3-((2-(N-methylcyclopropanecarboxamido)ethyl)amino)-7- (trifluoromethyl)benzo [e] [1, 2, 4] triazine 1, 4-dioxide

[0205] 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

[0206] D-11 : 3-(((1 -(neopentanoyloxy)cyclopropyl)methyl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide

[0207] D-12: 3-((1-((R)-3-hydroxytetradecanoyl)pyrrolidin-3-yl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine-1,4-dioxide

[0208] D-13: 3-((1-(2,2,2-trifluoroacetyl)pyrrolidin-3-yl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine-1,4-dioxide

[0209] D-14: 3-((1-(thiophene-3-carbonyl)pyrrolidin-3-yl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine-1,4-dioxide

[0210] D-15: 3-((2-aminoethyl)amino)-7-bromobenzo[e][1,2,4]triazine 1,4-dioxide

[0211] D-16: 3-(((1 -aminocyclopropyl)methyl)amino)-7-bromobenzo[e][1,2,4]triazine 1,4-dioxide

[0212] D-17: (R)-3-((2-aminopropyl)amino)-7-bromobenzo[e][1,2,4]triazine 1,4-dioxide

[0213] D-18: (S)-3-((2-aminopropyl)amino)-7-bromobenzo[e][1,2,4]triazine 1,4-dioxide

[0214] D-19: 3-((2-aminoethyl)amino)-7-fluorobenzo[e][1,2,4]triazine 1,4-dioxide

[0215] D-20: 3-((2-aminoethyl)amino)-7-chlorobenzo[e][1,2,4]triazine 1,4-dioxide

[0216] D-21 : 3-((2-aminoethyl)amino)-7-iodobenzo[e][1,2,4]triazine 1,4-dioxide

[0217] D-22: 3-((2-aminoethyl)amino)-7-methoxybenzo[e][1,2,4]triazine 1,4-dioxide

[0218] D-23: 7-bromo-3-((2-(methylamino)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide.

[0219] The present disclosure likewise encompasses the following salt forms:

[0220] D-1 ': 3-((2-aminoethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide trifluoroacetate

[0221] D-2': 3-(pyrrolidin-3-ylamino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide trifluoroacetate D-4': 3-((2-(methylamino)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide trifluoroacetate

[0222] D-16': 3-((2-aminoethyl)amino)-7-bromobenzo[e][1,2,4]triazine 1,4-dioxide trifluoroacetate

[0223] D-17': 3-(((1 -aminocyclopropyl)methyl)amino)-7-bromobenzo[e][1,2,4]triazine 1,4-dioxide hydrochloride

[0224] D-18': (R)-3-((2-aminopropyl)amino)-7-bromobenzo[e][1,2,4]triazine 1,4-dioxide hydrochloride.

[0225] Pharmaceutically acceptable salt or ester or pharmaceutically acceptable salt or ester

[0226] As used herein, the term "pharmaceutically acceptable salt or ester or pharmaceutically acceptable salt or ester" refers to any pharmaceutically acceptable salt or ester that can be prepared from a benzotriazine dioxide compound of the disclosure, including salts formed from the acidic and basic functional groups, such as nitrogen groups, of one of the benzotriazine dioxide compounds of the 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, gentisinate, fumarate, gluconate, glucoronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term "pharmaceutically acceptable salt or ester" also includes salts prepared from a benzotriazine dioxide compound of the disclosure having an acidic functional group, such as a carboxylic acid functional group, and a pharmaceutically acceptable inorganic or organic base. Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia and organic amines, such as unsubstituted or hydroxy-substituted mono-, di- or trialkyl amines; dicyclohexylamine; tributylamine; pyridine; N,N-methyl-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 tri-(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 compounds (I) and salts thereof produce tautomers, any tautomers are included in the disclosure, and compounds (I) and salts thereof can be in any of a solvate, a hydrate, a non-solvate, and a non-hydrate. In one embodiment, the kind of acid used for salt formation includes inorganic acids and organic acids. Inorganic acids include, but are not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, 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, oxalic acid.

[0227] Compounds of formula (I) are included in the pharmaceutical compositions of the disclosure and used in the methods of the disclosure. If a -COOH or -OH group is present, pharmaceutically acceptable esters can be employed, for example, methyl, ethyl, pivaloyloxymethyl, and the like for -COOH, and acetate, maleate, and the like for -OH, which are known in the art to be useful for improving solubility or hydrolysis properties, as sustained release or prodrug dosage forms.

[0228] Therapeutic / Prophylactic Administration and Compositions of the Disclosure

[0229] Because of their activity, the benzotriazine dioxide compounds of the present disclosure are advantageously useful in veterinary and human medicine. As described above, the benzotriazine dioxide compounds of the present disclosure are useful in the treatment or prevention of a disease in an animal in need thereof.

[0230] When administered to an animal, the benzotriazine dioxide compounds of the present disclosure are administered as components of compositions comprising a pharmaceutically acceptable carrier or excipient. The compositions of the present disclosure comprising the benzotriazine dioxide compounds of the present disclosure can be administered orally. The benzotriazine dioxide compounds of the present disclosure can also be administered by any other convenient route of administration, such as injection, either subcutaneously, intradermally, or intramuscularly, or by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral, rectal, and intestinal mucosa), and can be administered together with other therapeutically active agents. Administration can be systemic or local, such as hepatic arterial, hepatic tumor-feeding vessels by direct injection of the drug into the interior of a hepatic tumor via a catheter; bronchial arterial, pulmonary tumor-feeding vessels by direct injection of the drug into the interior of a pulmonary tumor via a catheter; tumor-feeding vessels of any tumor by direct injection of the drug into the interior of any tumor via a catheter; direct injection into the interior of a tumor from outside the tumor through the surface of the tumor; and the like. Various drug delivery systems are known, such as liposomes, microparticles, microcapsules, capsules, and the like, and can be used to administer the benzotriazine dioxide compounds of the present disclosure.

[0231] 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 to the ear, nose, eye, or skin. Also included are local administration, such as hepatic arterial, hepatic tumor-feeding vessels by direct injection of the drug into the interior of a hepatic tumor via a catheter; bronchial arterial, pulmonary tumor-feeding vessels by direct injection of the drug into the interior of a pulmonary tumor via a catheter; tumor-feeding vessels of any tumor by direct injection of the drug into the interior of any tumor via a catheter; direct injection into the interior of a tumor from outside the tumor through the surface of the tumor; and the like. The mode of administration is left to the discretion of the medical practitioner. In most cases, administration will result in the release of the benzotriazine dioxide compounds of the present disclosure into the bloodstream.

[0232] In particular embodiments, it can be preferred to administer the benzotriazine dioxide compounds of the disclosure topically. This can be accomplished in a non-limiting manner, for example, by local infusion during surgery, topical application, e.g., in conjunction 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, the implant being a porous, non-porous, or gelatinous material including various membranes such as sialastic membranes or fibers.

[0233] In certain embodiments, it can be preferred to introduce the benzotriazine dioxide compounds of the disclosure into the central nervous system or gastrointestinal tract by any suitable route, including intraventricular, intrathecal, and epidural injection, and also intracerobrospinal. Intraventricular injection can be facilitated by intraventricular catheters, for example, attached to a reservoir, e.g., an Ommaya reservoir.

[0234] Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosol or insufflation, or by use of a pump, spray, atomizer, or nebulizer, alone or in combination with an atomizer or nebulizer. In certain embodiments, the benzotriazine dioxide compounds of the disclosure can be formulated as a suppository, with traditional binders and excipients such as triglycerides.

[0235] In another embodiment, the benzotriazine dioxide compounds of the disclosure can be delivered in a vesicle, in particular a liposome (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)).

[0236] In yet another embodiment, the benzotriazine dioxide compounds of the present disclosure can be delivered in a controlled release system or sustained release system (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)). Other controlled release systems can also be used, as discussed in Langer, Sci. 249:1527-1533 (1990). In one embodiment, a pump can 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 can be used (see Medical Applications of Controlled Release (Langer and Wise eds., 1974); Controlled Drug Bioavailability, Drug Product Design and Performance (Smolen and Ballas., 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, the controlled or sustained release system can be placed in proximity to the target of the benzotriazine dioxide compounds of the present disclosure, such as the spinal column, brain, or gastrointestinal tract, in which case systemic administration avoids the need for direct application.

[0237] The compositions of the present disclosure can optionally contain appropriate amounts of pharmaceutically acceptable excipients to obtain a shape suitable for administration to an animal.

[0238] Such pharmaceutical excipients can be liquids such as water or oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. The pharmaceutical excipients can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, etc. Additionally, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used. In one embodiment, the pharmaceutically acceptable excipient is sterile when the benzotriazine dioxide compound of the present disclosure is to be administered intravenously. Water is a particularly useful excipient when the benzotriazine dioxide compound of the present disclosure is to be administered intravenously. In particular, for injectable solutions, saline solutions and aqueous dextrose and glycerol solutions can be employed as liquid excipients. Suitable pharmaceutical excipients further include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dry

[0239] The compositions of the present disclosure are in solution, suspension, emulsion, tablet, pill, granule, capsule, liquid-containing capsule, powder, sustained-release formulation, suppository, aerosol, spray, suspension, or any other suitable form. In one embodiment, the composition takes the form of a capsule (see, e.g., U.S. Patent 5,698,155). Further examples of suitable pharmaceutical excipients are found in Remington's Pharmaceutical Sci. 1447-1676 (Alfonso R. Gennaro ed., 19th ed. 1995), which is incorporated herein by reference.

[0240] In one embodiment, the benzotriazine dioxide compounds of the present disclosure can be formulated into compositions suitable for oral administration to humans in accordance with conventional methods. Compositions for oral delivery can be formulated, for example, as tablets, troches, suspensions, granules, powders, emulsions, capsules, syrups, or elixirs. Compositions for oral administration can contain one or more agents such as, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation. Moreover, where these compositions are in the form of tablets and pills, such compositions can be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over an extended period of time. Selectively permeable membranes surrounding an osmotically active driving compound are also suitable for orally administered compositions. In these later platforms, fluid is imbibed by the active driving compound, swells, and exerts pressure against the semipermeable membrane, which drives the release of the agent or agents or composition through the pores of the membrane. These delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release dosage forms. Delayed- release, time-impregnated materials such as glyceryl monostearate or glyceryl stearate can also be used. Oral compositions can include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. In one embodiment, the excipients are pharmaceutical grade excipients.

[0241] 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 sterile isotonic aqueous buffers. If desired, the compositions can also include a solubilizing agent. Compositions for intravenous administration can optionally include a local anesthetic such as lidocaine to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampule or sachette indicating the quantity of active agent. Where the benzotriazine dioxide compounds of the present disclosure are to be administered by infusion, they can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the benzotriazine dioxide compounds of the present disclosure are administered by injection, an ampule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.

[0242] The benzotriazine dioxide compounds of the present disclosure can be administered by controlled- or sustained-release means, or by delivery devices known to those of ordinary skill in the art. Examples of these include, but are not limited to, those described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,566, each incorporated herein by reference. Controlled- or sustained-release formulations can be employed to provide controlled or sustained release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile. Appropriate controlled- or sustained-release formulations known to those of ordinary skill in the art can be readily selected according to the active ingredient(s) employed in the present disclosure, including those mentioned herein. Thus, the present disclosure encompasses single unit dosage forms suitable for oral administration, such as, but not limited to, tablets, capsules, soft gel capsules, and controlled- or sustained-release caplets.

[0243] Controlled- or sustained-release pharmaceutical compositions can have the common goal of achieving a therapeutic regimen that maintains a desirable blood level of a drug over a certain period of time. In one embodiment, a controlled- or sustained-release composition contains a minimum amount of a benzotriazine dioxide compound of the present disclosure to cure or control the disease state in the shortest time possible. Advantages of controlled- or sustained-release compositions include: prolonged 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 of the blood concentration of a benzotriazine dioxide compound of the present disclosure, and thus can reduce the incidence of adverse side effects.

[0244] A controlled- or sustained-release composition can begin with an initial release of a benzotriazine dioxide compound of the present disclosure that produces the amount needed to have a therapeutic or prophylactic effect, and then release additional amounts of the benzotriazine dioxide compound of the present disclosure in a gradual, continuous, or sustained way to maintain that level of therapeutic or prophylactic effect over an extended period of time. To maintain a constant blood level of a benzotriazine dioxide compound of the present disclosure, the benzotriazine dioxide compound of the present disclosure can be released from the dosage form at a rate that matches its rate of metabolism and excretion from the body. Controlled- or sustained-release of an active ingredient can be stimulated by various conditions, including, but not limited to, changes in pH, changes in temperature, enzyme concentration or availability, concentration or availability of water, or other physiological conditions or compounds.

[0245] In another embodiment, the composition is prepared by mixing a benzotriazine dioxide compound of the present disclosure, or a pharmaceutically acceptable salt or ester thereof, with a pharmaceutically acceptable carrier or excipient. The mixing can be accomplished using known methods for mixing compounds (or salts) with pharmaceutically acceptable carriers or excipients. In another embodiment, the benzotriazine dioxide compound of the present disclosure, or a pharmaceutically acceptable salt or ester thereof, is present in an effective amount.

[0246] The amount of the disclosed benzotriazine bioxide compound effective for treating or preventing a condition can be determined according to standard clinical techniques. Additionally, in vitro or in vivo assays may be optionally employed to help determine the optimal dosage range. The precise dosage to be employed also depends on the route of administration and the severity of the condition, and can be determined based on the judgment of the practitioner and / or the specific details of the individual animal. However, suitable effective doses in humans are from about 0.001 mg / kg to 500 mg / kg body weight, although they are typically about 100 mg / kg or less. In one embodiment, the effective dose is from about 0.01 mg / kg to 100 mg / kg body weight of the disclosed benzotriazine bioxide compound, in another embodiment, from about 0.02 mg / kg to 50 mg / kg body weight, and in another embodiment, from about 0.025 mg / kg to 20 mg / kg body weight. In one embodiment, the effective dose is administered approximately every 24 hours until the condition is alleviated. In another embodiment, the effective dose is administered approximately every 12 hours until the condition is alleviated. The effective dose is administered approximately every 8 hours until the condition is alleviated. In another embodiment, an effective dose is administered approximately every 6 hours until the condition is relieved. In another embodiment, an effective dose is administered approximately every 4 hours until the condition is relieved. The effective dose as 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 is equivalent to the total amount administered.

[0247] The disclosed benzotriazine dioxide can kill cancer cells through a hypoxia-selective mechanism, thereby curing tumors. It can be used in the treatment of liver cancer, bile duct cancer, lung cancer, gastric cancer, esophageal cancer, colorectal cancer, kidney cancer, ovarian cancer, head and neck malignancies, fibrosarcoma, sarcoma, and benign prostatic hyperplasia. Therefore, the present disclosure also relates to the use of the disclosed benzotriazine dioxide or a pharmaceutically acceptable salt, ester, hydrate, solvate, or prodrug thereof in the preparation of a medicament for treating cancer.

[0248] The compound can be used alone or in combination with other drugs to treat or alleviate benign and malignant tumors including cancers of the liver, bile duct, pancreas, stomach, esophagus, kidney, colorectum, lung, brain (glioma), malignant glioma, breast, ovary, cervix, head and neck, skin, melanoma, prostate, fibrosarcoma, sarcoma, and thyroid.

[0249] The present disclosure also relates to a method of treating or reducing cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of a benzotriazine dioxide of the present disclosure, or a pharmaceutically acceptable salt or ester, hydrate, solvate or prodrug thereof.

[0250] The phrase "therapeutically effective amount" when used in connection with a benzotriazine dioxide compound of the present disclosure means an amount that is effective to treat or prevent a disease. When used in connection with another therapeutic agent, the phrase "therapeutically effective amount" means an amount that allows the other therapeutic agent to exert its therapeutic effect. The term "effective amount" and its derivatives as used herein means that amount of a drug or pharmaceutical agent that elicits the biological or medicinal response that a researcher or clinician is seeking, for example, in an animal or patient. In addition, the term "therapeutically effective amount" and its derivatives also means any amount that results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder, as compared to that which would occur in the absence of the amount (of the drug). The scope of the term is also intended to include an amount that is effective to promote normal functioning.

[0251] The phrase "treat", "treatment", and the like, includes alleviating or abrogating a disease or its symptoms.

[0252] In one embodiment, treatment includes inhibiting, e.g., reducing the overall frequency of events of a disease or its symptoms.

[0253] The phrase "prevent", "prevention", and the like, includes avoiding the onset of a disease or its symptoms.

[0254] The term "mammal" includes, but is not limited to, a cow, a monkey, a baboon, a chimpanzee, a horse, a sheep, a pig, a cat, a dog, a mouse, a rat, a rabbit, a guinea pig, and a human.

[0255] In one embodiment, the mammal is a mouse, a dog, a pig, a monkey, and a human.

[0256] The benzotriazine dioxide of the present disclosure can effectively inhibit the proliferation, metastasis, differentiation, etc. of tumor cells based on a hypoxic microenvironment, and is mainly used for treating liver cancer, cholangiocarcinoma, pancreatic cancer, lung cancer, gastric cancer, etc. In one embodiment, the cancer is selected from tumors of the liver, intrahepatic bile 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, fibrosarcoma, sarcoma, and thyroid, and includes solid tumors derived from endodermal, mesodermal, and ectodermal germ layers.

[0257] In one embodiment, the cancer is selected from tumors of the liver, intrahepatic bile duct, pancreas, stomach, esophagus, kidney, colon, lung, brain (glioma), malignant glioma, breast, head and neck, melanoma, ovary, prostate, fibrosarcoma, sarcoma, and thyroid.

[0258] Methods of preparing the compounds of the present disclosure

[0259] Compound (I) or salts thereof and starting compounds therefor can be prepared according to known methods, for example, the methods shown in the following reaction schemes, etc. Hereinafter, "room temperature" generally means 20 to 25°C, and each symbol in the chemical structural formula described in the reaction schemes is defined as above, unless otherwise specifically stated. The compounds in the formula include specific forms of salts, and as such salts, for example, those similar to the salts of Compound (I) can be mentioned.

[0260] The intermediates or final products obtained in each step can be used in the next reaction as a mixture or a crude product. They can also be isolated by conventional methods, such as recrystallization, distillation, column chromatography, preparative plate, liquid phase preparative column, and refined.

[0261] Throughout this application, the following abbreviations have the following meanings: Me methyl n Pr n-propyl i Pr i-propyl n Bu n-butyl i Bu i-butyl tBu t-butyl Cbz benzyloxycarbonyl Boc t-butoxycarbonyl (Boc)20 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 l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride HATU 2-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate PyBOP lH-benzotriazol-l-yloxytripyrrolidinophosphonium hexafluorophosphate HOBT 1-hydroxybenzotriazole LiOH lithium hydroxide NaOH sodium hydroxide NaIO4 sodium periodate NaBH4 sodium borohydride NaBH3CN sodium cyano borohydride STAB sodium triacetoxyborohydride KOH potassium hydroxide K2CO3 potassium carbonate K2OsO4 potassium osmium carbonate KOAc potassium acetate Cs2CO3 cesium carbonate CuI copper iodide Dioxane (1,4-dioxane) 1,4-dioxane THF tetrahydrofuran PE petroleum ether EA ethyl acetate EtOH ethanol MeOH methanol DCM dichloromethane Toluene toluene THF tetrahydrofuran Hexane n-hexane AcOH acetic acid AcCl acetyl chloride TFA trifluoroacetic acid TFAA trifluoroacetic anhydride Tf20 trifluoromethanesulfonic anhydride DMA N,N-dimethylacetamide DMF N,N-dimethylformamide 2,6-Lutidine 2,6-lutidine TMSCN trimethylsilyl cyanide m-CPBA meta-chloroperbenzoic acid BPO benzoyl peroxide SOCl2 thionyl chloride POCl3 phosphorous oxychloride H2O2 hydrogen peroxide (30%) Pd(dppf)Cl2 1,1 -bis (diphenylphosphino) ferrocene dichloropalladium Pd2(dba)3 tri(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 tetra-n-butylammonium fluoride RT room temperature, generally 20-25 °C N2 nitrogen Reflux reflux HPLC high pressure liquid chromatography Pre-HPLC preparative high pressure 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 product tR retention time HNMR / CNMR / FNMR nuclear magnetic resonance hydrogen spectrum, carbon spectrum, fluorine spectrum,

[0262] Preparative liquid conditions: semi-preparative reverse phase HPLC (column: Welch Ultimate XB-C18 250 x 21.2 mm x 5 um; mobile phase: 40-64% acetonitrile + 0.1% TFA / water, 8 min)

[0263] Reagents, solvents, instruments related to the experiment

[0264] All chemicals and solvents were purchased from commercial reagent companies and were used without further purification, unless otherwise noted. All reactions were performed in dry glassware under a nitrogen or argon atmosphere as required. Nuclear magnetic resonance spectra were recorded on a 400M instrument (Bruker AV 400, Bruker Corporation, Billerica, MA, USA). Chemical shifts (δ) were referenced to tetramethylsilane (TMS) and multiplicity was also reported, including s (singlet), d (doublet), dd (doublet of doublets), t (triplet), q (quartet), qui (quintet), spt (septet), m (multiplet).

[0265] The solvent described in the step is: acetone, tetrahydrofuran, acetonitrile, dichloromethane, trichloromethane, toluene, n-hexane, cyclohexane, ethyl formate, ethyl acetate, isopropyl acetate, butyl acetate, trimethyl phosphate, triethyl phosphate, diethyl ether or isopropyl ether.

[0266] The acid scavenger in the step is a heterocyclic amine, triethylamine, diisopropyl ethylamine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, etc.

[0267] The specific implementation case is as follows.

[0268] The first type: terminal aromatic ether or alkyl ether

[0269] Example A-1: Synthesis of 3-((2-(pyridin-3-yloxy)ethyl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide

[0270] The synthesis of IM-1 refers to WO 2023019912 A1, and the total yield of three steps is about 15%.

[0271] At room temperature (25°C), DIEA (233 mg, 1.81 mmol) and 3-(2- aminoethoxy)pyridine (SM-2, 100 mg, 0.72 mmol) were added 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), and the mixture was stirred at room temperature for 1 hour. LCMS monitoring showed that the raw material was completely converted, and the reaction was stopped. Water (10 mL) was added to the reaction solution, and yellow solid was precipitated. The solid was filtered and dried to obtain compound IM-2 (165 mg) in the form of a yellow solid with a yield of 77.8%. Molecular formula: C 15 H 12 F3N5O2; molecular weight: 351.28.

[0272] At room temperature (25°C), TFAA (2 mL) and hydrogen peroxide (2 mL) were added to a solution of compound IM-2 (165 mg, 0.47 mmol) in EA (5 mL), and the reaction solution gradually turned red. The reaction solution was heated to 40°C and stirred for 8 hours. LCMS monitoring showed that the raw material was completely converted, and the reaction was stopped. Water (10 mL) was added to the reaction solution, and DCM (20 mL*3) was used for extraction. After the organic layer was concentrated, silica gel column chromatography (MeOH:DCM=0%~5%) was performed to obtain 3-((2-(pyridin-3-yloxy)ethyl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (A-1) in the form of a red solid with a yield of 37 mg and a yield of 28%. Molecular formula: C 15 H12 F3N5O3; M.W.: 367.28; LCMS: (ESI+): m / z 368.1 [M+1] + .

[0273] Example A-2: Synthesis of 3-(2-(3-fluorophenoxy)ethyl)amino-7- trifluoromethylbenzo[l,2,4]triazine 1,4-dioxide

[0274] To a solution of IM-1 (150 mg, 0.6 mmol) in DMF (5 mL) was added a mixture of DIPEA (90 mg, 0.72 mmol) and SM-3 (100 mg, 0.64 mmol) at room temperature (25 °C) and stirred for 30 min at room temperature. LCMS was used to monitor the complete conversion of the starting material. Water (10 mL) was added to the reaction mixture, and yellow solid was precipitated. The product IM-3 was obtained by filtration and used directly in the next step.

[0275] To a solution of IM-3 in EA (10 mL) was added TFAA (2 mL) and hydrogen peroxide (2 mL) at room temperature (25 °C) and stirred overnight at room temperature. TLC was used to monitor the complete conversion of the starting material. Water (10 mL) was added to the reaction mixture, and EA (20 mL*3) was used to extract the product. The organic layer was concentrated and purified by column chromatography using DCM / MeOH = 25 / 1 as eluent. The target product 3-(2-(3-fluorophenoxy)ethyl)amino-7- trifluoromethylbenzo[l,2,4]triazine 1,4-dioxide (A-2, 23 mg, 0.06 mmol) was obtained as a purple solid with a two-step yield of 10%. Molecular formula: C 16 H 12 F4N4O3; M.W.: 384.29; LCMS: (ESI+): m / z 385.4 [M+1] + .

[0276] Example A-3: Synthesis of 3-(2-(benzyloxy)ethyl)amino)-7- trifluoromethylbenzo[l,2,4]triazine 1,4-dioxide

[0277] To a solution of IM-1 (150 mg, 0.6 mmol) in DMF (5 mL) was added a mixture of DIPEA (90 mg, 0.72 mmol) and SM-4 (100 mg, 0.66 mmol) at room temperature (25 °C) and stirred for 30 min at room temperature. LCMS was used to monitor the complete conversion of the starting material. Water (10 mL) was added to the reaction mixture, and yellow solid was precipitated. The product IM-4 was obtained by filtration and used directly in the next step.

[0278] To a solution of IM-4 (100 mg, 0.26 mmol) in EA (10 mL) was added TFAA (2 mL) and hydrogen peroxide (2 mL) at room temperature (25 °C). The mixture was stirred at room temperature overnight. TLC monitoring showed that a small amount of starting material remained. Water (10 mL) was added to the reaction mixture, and EA (20 mL*3) was used to extract the product. The organic layer was concentrated and then passed through a silica gel column. DCM / MeOH = 25 / 1 was used to elute the product. The target product 3-(2-(benzyloxy)ethyl)amino)-7-trifluoromethylbenzo[l,2,4]triazine 1,4-dioxide (A-3, 43 mg, 0.11 mmol) was obtained as a purple solid. The yield of the two steps was 18%. Molecular formula: C 17 H 15 F3N4O3; Molecular weight: 380.33; LCMS: (ESI+): m / z 380.1 [M+1] + .

[0279] Example A-4: Synthesis of 3-((l-methoxy-2-propyl)amino)-7-(trifluoromethyl)benzo[e][l,2,4]triazine 1,4-dioxide

[0280] To a solution of 3-chloro-7-(trifluoromethyl)benzo[e][l,2,4]triazine 1-oxide (IM-1, 140 mg, 0.56 mmol) in DMF (5 mL) was added DIEA (217 mg, 1.69 mmol) and l-methoxypropan-2-amine (SM-5, 50 mg, 0.56 mmol) at room temperature (25 °C). The mixture was stirred at room temperature for 1 h. LCMS monitoring showed that the starting material was completely converted. The reaction was stopped. Water (10 mL) was added to the reaction mixture. A yellow solid was precipitated. The compound (IM-5, 130 mg) was obtained by filtration and drying. The yield was 76%. Molecular formula: C 12 H 13 F3N4O2; Molecular weight: 302.25.

[0281] To a solution of compound (IM-5, 130 mg, 0.43 mmol) in EA (5 mL) was added TFAA (1 mL) and hydrogen peroxide (1 mL) at room temperature (25 °C). The reaction mixture gradually turned red. The reaction mixture was heated to 40 °C and stirred for 8 h. LCMS monitoring showed that the starting material was completely converted. The reaction was stopped. Water (10 mL) was added to the reaction mixture. DCM (20 mL*3) was used to extract the product. The organic layer was concentrated and then passed through a silica gel column. 3-((l-methoxy-2-propyl)amino)-7-(trifluoromethyl)benzo[e][l,2,4]triazine 1,4-dioxide (A-4, 68 mg) was obtained as a red solid. The yield was 50%. Molecular formula: C 12 H 13F3N4O3; Molecular Weight: 318.25; LCMS: (ESI+): m / z 319.2 [M+1] + .

[0282] Example A-5: Synthesis of 3-((3-aminotetrahydrofuran)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide

[0283] 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) was added DIEA (233 mg, 1.81 mmol) and 3-aminotetrahydrofuran (SM-6, 81.5 mg, 0.66 mmol) at room temperature (25 °C), the mixture was stirred at room temperature for 1 h, LCMS monitored the complete conversion of starting material, the reaction was stopped. Water (10 mL) was added to the reaction mixture, a yellow solid was precipitated, filtered and dried to give compound (IM-6, 175 mg) as a yellow solid in 97% yield. Molecular Formula: C 12 H 11 F3N4O2; Molecular Weight: 300.24.

[0284] To a solution of compound (IM-6, 175 mg, 0.58 mmol) in EA (5 mL) was added TFAA (1 mL) and hydrogen peroxide (1 mL) at room temperature (25 °C), the reaction mixture gradually turned red, the reaction mixture was warmed to 40 °C and stirred for 4 h, LCMS monitored the presence of starting material, the mixture was continued to stir at room temperature overnight, LCMS monitored the complete conversion of starting material, the reaction was stopped. Water (10 mL) was added to the reaction mixture, DCM (20 mL*3) was extracted, the organic layer was concentrated and purified by 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: C 12 H 11 F3N4O3; Molecular Weight: 316.24; LCMS: (ESI+): m / z 317.4 [M+1] + .

[0285] Second type: terminal aryl, alkyl, cycloalkyl or halogenated alkyl

[0286] Example B-1: Synthesis of 3-(2,2,2-trifluoroethyl)amino-7-trifluoromethylbenzo[1,2,4]triazine 1,4-dioxide

[0287] To a solution of 3-chloro-7-(trifluoromethyl)benzo[e][l,2,4]triazine 1-oxide (IM-1, 150 mg, 0.60 mmol) in DMF (5 mL) was added trifluoroethylamine (SM-7, 100 mg, 1.0 mmol) and DIPEA (90 mg, 0.72 mmol) at room temperature (25 °C). The mixture was stirred at room temperature for 30 min. LCMS was used to monitor the reaction. When the starting material was consumed, water (10 mL) was added to the reaction mixture. The yellow solid was collected by filtration. The product IM-7 was used directly in the next step. Molecular Formula: C 10 H6F6N4O; Molecular Weight: 312.18.

[0288] To a solution of IM-7 in EA (10 mL) was added TFAA (2 mL) and hydrogen peroxide (2 mL) at room temperature. The mixture was stirred at room temperature overnight. TLC was used to monitor the reaction. When the starting material was consumed, water (10 mL) was added to the reaction mixture. The product was extracted with EA (20 mL*3). The organic layer was concentrated and purified by column chromatography with DCM / MeOH = 25 / 1. The target product 3-(2,2,2-trifluoroethyl)amino-7- trifluoromethylbenzo[l,2,4]triazine 1,4-dioxide (B-1, 26 mg) was obtained as a red solid. The yield was 10% for two steps. Molecular Formula: C 10 H6F6N4O2; Molecular Weight: 328.17; LCMS: (ESI+): m / z 329.1 [M+1] + .

[0289] Example B-2: Synthesis of 3-((3,3-difluorocyclopentyl)amino)-7- (trifluoromethyl)benzo[e][l,2,4]triazine 1,4-dioxide

[0290] To a solution of 3-chloro-7-(trifluoromethyl)benzo[e][l,2,4]triazine 1-oxide (IM-1, 150 mg, 0.60 mmol) in DMF (5 mL) was added 3,3-difluorocyclopentylamine (SM-8, 104 mg, 0.66 mmol) and DIEA (232 mg, 1.80 mmol) at room temperature (25 °C). The mixture was stirred at room temperature for 1 h. LCMS was used to monitor the reaction. When the starting material was consumed, the reaction was stopped. Water (10 mL) was added to the reaction mixture. The yellow solid was collected by filtration and dried to give compound (IM-8, 180 mg) as a yellow solid. The yield was 89%. Molecular Formula: C 13 H 11 F5N4O; Molecular Weight: 334.24.

[0291] To a solution of compound (IM-8, 180 mg, 0.54 mmol) in EA (10 mL) was added TFAA (2 mL) and hydrogen peroxide (2 mL) at room temperature (25 °C), the mixture was warmed to 40 °C and stirred for 3 h, then stirred at room temperature overnight, LCMS monitored the complete conversion of the starting material, water (20 mL) was added to the reaction solution, extracted with DCM (20 mL*3), the organic layer was concentrated, and purified by 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), red solid, yield 85%. Molecular formula: C 13 H 11 F5N4O2; Molecular weight: 350.24; LCMS: (ESI+): m / z 351.3 [M+1] + .

[0292] Example B-3: Synthesis of 3-((2-(pyridin-3-yl)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide

[0293] 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) was added DIEA (233 mg, 1.81 mmol) and 3-(2-aminoethyl)pyridine (SM-9, 88 mg, 0.72 mmol) at room temperature (25 °C), the mixture was stirred at room temperature for 1 h, LCMS monitored the complete conversion of the starting material, the reaction was stopped. Water (10 mL) was added to the reaction solution, a yellow solid was precipitated, filtered and dried to give compound IM-9 (160 mg), yellow solid, yield 79%. Molecular formula: C 15 H 12 F3N5O; Molecular weight: 335.28.

[0294] To a solution of compound IM-9 (160 mg, 0.48 mmol) in EA (5 mL) was added TFAA (2 mL) and hydrogen peroxide (2 mL) at room temperature (25 °C), the reaction solution gradually turned red, the reaction solution was warmed to 40 °C and stirred for 8 h, LCMS monitored the complete conversion of the starting material, the reaction was stopped. Water (10 mL) was added to the reaction solution, extracted with DCM (20 mL*3), the organic layer was concentrated, and purified by 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), red solid, yield 28%. Molecular formula: C 15 H12 F3N5O2; Molecular Weight: 351.28; LCMS: (ESI+): m / z 352.2 [M+1] + .

[0295] Example B-4: Synthesis of 3-((3-fluorophenyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide

[0296] 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) was added DIEA (310 mg, 2.41 mmol) and 2-(3-fluorophenyl)ethylamine (SM-10, 134 mg, 0.96 mmol) at room temperature (25 °C), the mixture was stirred at room temperature for 1 h, LCMS monitored the complete conversion of starting material, the reaction was stopped. Water (10 mL) was added to the reaction, a yellow solid was precipitated, filtered, and the solid was dried to give compound (IM-10, 250 mg) as a yellow solid in 88.6% yield. Molecular Formula: C 16 H 12 F4N4O; Molecular Weight: 352.29.

[0297] To a solution of compound IM-10 (250 mg, 0.71 mmol) in EA (5 mL) was added TFAA (2 mL) and hydrogen peroxide (2 mL) at room temperature (25 °C), the reaction solution gradually turned red, the reaction solution was warmed to 40 °C and stirred for 8 h, LCMS monitored the complete conversion of starting material, the reaction was stopped. Water (10 mL) was added to the reaction, extracted with DCM (20 mL*3), the organic layer was concentrated, and purified by 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: C 16 H 12 F4N4O2; Molecular Weight: 368.29; LCMS: (ESI+): m / z 369.3 [M+1] + .

[0298] Example B-5: Synthesis of 7-cyclopropyl-3-((2,2,2-trifluoroethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide

[0299] The synthesis of IM-13 is described in WO 2023019912 A1.

[0300] To a solution of 7-bromo-3-chlorobenzo[e][l,2,4]triazine 1-oxide (IM-13, 500 mg, 1.92 mmol) in DMF (10 mL) was added trifluoroethylamine (SM-7, 285 mg, 2.88 mmol) and DIEA (744 mg 5.76 mmol) at room temperature (25 °C), the mixture was stirred at 50 °C for 6 h, LCMS monitored the complete conversion of starting material, the reaction was stopped. Water (20 mL) was added to the reaction mixture, a yellow solid was precipitated, 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.

[0301] To a solution of compound IM-11 (100 mg, 0.31 mmol) in EA (10 mL) was 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) at room temperature (25 °C), the mixture was heated to 80 °C under nitrogen protection and stirred, LCMS monitored the complete conversion of starting material after 2 h. Water (20 mL) was added to the reaction mixture, extracted with DCM (20 mL*3), the organic layer was concentrated and purified by 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: C 12 H 11 F3N4O; Molecular weight: 284.24.

[0302] To a solution of compound IM-12 (50 mg, 0.17 mmol) in EA (5 mL) was added TFAA (1 mL) and hydrogen peroxide (1 mL) at room temperature (25 °C), the mixture was heated to 40 °C and stirred for 8 h, LCMS monitored the complete conversion of starting material, water (20 mL) was added to the reaction mixture, extracted with DCM (20 mL*3), the organic layer was concentrated and purified by silica gel column chromatography (MeOH: DCM = 0% ~ 1%) to give 7-cyclopropyl-3-((2,2,2-trifluoroethyl)amino)benzo[e][l,2,4]triazine 1,4-dioxide (B-5, 5 mg) as a red solid in 9.4% yield. Molecular formula: C 12 H 11 F3N4O2; Molecular weight: 300.24; LCMS: (ESI+): m / z 301.2 [M+1] + .

[0303] 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

[0304] To a solution of compound IM-11 (350 mg, 1.08 mmol) in EA (10 mL) was added TFAA (2 mL) and hydrogen peroxide (2 mL) at room temperature (25 °C), the mixture was stirred at room temperature for 60 hours, LCMS monitoring showed the starting material was completely converted, water (20 mL) was added to the reaction solution, DCM (20 mL*3) was used to extract, the organic layer was concentrated, and purified by silica gel column chromatography (MeOH:DCM = 0% ~ 1%) to give compound (IM-14, 235 mg), red-brown solid, with a yield of 64%. Molecular formula: C9H6BrF3N4O2; Molecular weight: 339.07.

[0305] Synthesis of IM-15 according to WO 2023019912 A1

[0306] To a solution of compound IM-14 (100 mg, 0.29 mmol) in DMF (4 mL) was 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) at room temperature (25 °C), the mixture was heated to 35 °C under nitrogen protection and stirred, LCMS monitoring showed that the starting material was completely converted after 1 hour, water (10 mL) was added to the reaction solution, and brown solid was precipitated, filtered, and the solid was collected, the organic layer was concentrated, and purified by 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), red-brown solid, with a yield of 17%. Molecular formula: C 19 H 18 F3N5O2S; Molecular weight: 437.44; LCMS: (ESI+): m / z 438.3 [M+1] + .

[0307] 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

[0308] Example B-8: Synthesis of 7-(2-chloro-6-methyl-l-oxidopyridin-4-yl)-3-((3,3- difluorocyclopentyl)amino)benzo[e][l,2,4]triazine 1,4-dioxide

[0309] To a solution of 7-bromo-3-chlorobenzo[e][l,2,4]triazine-l-oxide (200 mg, 0.77 mmol) in DMF (5 mL) was added DIEA (298 mg, 2.3 mmol) and 3,3-difluorocyclopentanamine (SM-8, 120 mg, 0.77 mmol) at room temperature (25 °C). The mixture was stirred at room temperature for 1 h. LCMS monitoring showed that the starting material was completely converted. Water (10 mL) was added to the reaction mixture. Yellow solid was precipitated. After filtration, compound IM-15 (200 mg) was obtained as a yellow solid in 75% yield.

[0310] To a solution of compound IM-15 (200 mg, 0.58 mmol) in EA (6 mL) was added SM-13 (220 mg, 0.87 mmol), K2CO3 (60 mg, 1.74 mmol), water (0.5 mL) and Pd(dppf)Cl2 (20 mg) at room temperature (25 °C). The mixture was stirred at 80 °C for 2 h under nitrogen protection. LCMS monitoring showed that the starting material was completely converted. The reaction was stopped. After the reaction mixture was cooled to room temperature, it was filtered through celite. The filtrate was collected and concentrated. Compound IM-16 (200 mg) was obtained as a yellow solid in 88% yield by silica gel column chromatography (PE / EA = 2 / 1).

[0311] To a solution of compound IM-16 (200 mg, 0.51 mmol) in EA (6 mL) was added TFAA (2 mL) and hydrogen peroxide (2 mL) slowly at room temperature (25 °C). The mixture was stirred at 40 °C for 3.5 h. The reaction mixture gradually turned red. LCMS monitoring showed that the starting material was completely converted and the trioxide product was generated. The reaction was stopped. Water (20 mL) was added to the reaction mixture. The mixture was extracted with DCM (20 mL*3). The organic layer was concentrated and purified by silica gel column chromatography (DCM / MeOH = 100 / 1) to give (B-7, 110 mg) as a red solid in 53% yield. Molecular formula: C 18 H 16 ClF2N5O2; Molecular weight: 407.81; LCMS: (ESI+): m / z 408.1 [M+1] + . DCM / MeOH = 30 / 1 to give (B-8, 70 mg) as a red solid in 32% yield. Molecular formula: C 18 H 16 ClF2N5O3; Molecular weight: 423.80; LCMS: (ESI+): m / z 424.1 [M+1] + .

[0312] Example B-9: Synthesis of 7-(2-chloro-6-methylpyridin-4-yl)-3-((2,2,2- trifluoroethyl)amino)benzo[e][l,2,4]triazine 1,4-dioxide

[0313] Example B-10: Synthesis of 7-(2-chloro-6-oxopyridin-4-yl)-3-((2,2,2- trifluoroethyl)amino)benzo[e][l,2,4]triazine 1,4-dioxide

[0314] To a solution of compound IM-11 (200 mg, 0.62 mmol) in EA (6 mL) was 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) at room temperature (25 °C) under nitrogen protection, the mixture was stirred at 80 °C for 2 hours, LCMS monitoring showed that the starting material was completely converted, the reaction was stopped. After the reaction solution was restored to room temperature, it was filtered with diatomite, the filtrate was collected and concentrated, and silica gel chromatography (EA:PE = 0% ~ 30%) was performed to obtain compound IM-17 (180 mg), yellow solid, with a yield of 78.9%. Molecular formula: C 15 H 11 ClF3N5O; Molecular weight: 369.73.

[0315] To a solution of compound IM-17 (180 mg, 0.49 mmol) in EA (6 mL) was slowly added TFAA (2 mL) and hydrogen peroxide (2 mL) at room temperature (25 °C), and the mixture was stirred at 40 °C for 3.5 hours, and the reaction solution gradually turned red. LCMS monitoring showed that the starting material was completely converted, and the trioxide product was generated, the reaction was stopped. Water (20 mL) was added to the reaction solution, and DCM (20 mL*3) was extracted, and the organic layer was concentrated and subjected to silica gel column chromatography (MeOH:DCM = 0% ~ 1%) to obtain 7-(2-chloro-6-methylpyridin-4-yl)-3-((2,2,2-trifluoroethyl)amino)benzo[e][l,2,4]triazine 1,4-dioxide (B-9, 33 mg), red solid, with a yield of 17.6%. Molecular formula: C 15 H 11 ClF3N5O2; Molecular weight: 385.73; LCMS: (ES+): m / z 386.4 [M+1] + .

[0316] 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), red solid, yield 13.3%. Molecular Formula: C 15 H 11 ClF3N5O3; Molecular Weight: 401.73; LCMS: (ES+): m / z 402.3 [M+1] + .

[0317] The third type: the end is OH, OCOR

[0318] Example C-1: Synthesis of 7-bromo-3-((2-ethoxy)amino)benzo[e][1,2,4]triazine 1,4- dioxide

[0319] 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) was added DIEA (8.9 g, 69.23 mmol) and ethanolamine (2.81 g, 46.15 mmol) at room temperature (25 °C), the mixture was stirred at room temperature for 1 h, LCMS monitored the complete conversion of the starting material, water (40 mL) was added to the reaction solution, a yellow solid was precipitated, filtered, dried, and the solid was collected to give compound (IM-18, 6 g), yellow solid, yield 92%. Molecular Formula: C9H9BrN4O2; Molecular Weight: 285.10.

[0320] To a suspension of compound IM-18 (1.5 g, 5.26 mmol) in EA (20 mL) was added TFAA (2 mL) and hydrogen peroxide (2 mL) at room temperature (25 °C), the mixture was stirred at room temperature for 60 h, LCMS monitored that there was some starting material left, the reaction was stopped, the reaction solution was filtered, water (30 mL) was added to the filtrate, DCM (50 mL*3) was extracted, the organic layer was concentrated, combined with the filter cake, and silica gel column chromatography (MeOH:DCM = 0%~3%) gave 7-bromo-3-((2-ethoxy)amino)benzo[e][1,2,4]triazine 1,4-dioxide (C-1, 1.26 g), red solid, yield 79%. Molecular Formula: C9H9BrN4O3; Molecular Weight: 301.10; LCMS: (ESI+): m / z 302.3 [M+1] + .

[0321] Example C-2: Synthesis of 3-((2-hydroxyethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide

[0322] To a solution of compound IM-1 (280 mg, 1.12 mmol) in DMF (4 mL) was added DIEA (435 mg, 3.37 mmol) and ethanolamine (137 mg, 2.25 mmol) at room temperature (25 °C), the mixture was stirred at room temperature for 30 minutes, LCMS monitoring the complete conversion of raw materials, water (10 mL) was added to the reaction solution, a yellow solid was precipitated, filtered and dried to give the product compound IM-19 (250 mg), yellow solid, yield 81%. Molecular formula: C 10 H9F3N4O2; Molecular weight: 274.20.

[0323] To a solution of compound IM-19 (250 mg) in EA (5 mL) was added TFAA (2 mL) and hydrogen peroxide (2 mL) at room temperature (25 °C), the mixture was stirred at room temperature for 16 hours, LCMS monitoring the complete conversion of raw materials, water (10 mL) was added to the reaction solution, extracted with DCM (20 mL*3), the organic layer was concentrated, and purified by 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), red solid, yield 25%. Molecular formula: C 10 H9F3N4O3; Molecular weight: 290.20; LCMS: (ESI+) m / z 291.3 [M+1] + .

[0324] Example C-3: Synthesis of 3-((2-hydroxy-2-methylpropyl)amino)-7- (trifluoromethyl)benzo [e] [1, 2, 4] triazine 1, 4-dioxide

[0325] 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) was added DIEA (932 mg, 7.23 mmol) and 1-amino-2-methylpropanol (429 mg, 4.82 mmol) at room temperature (25 °C), the mixture was stirred at room temperature for 1 hour, LCMS monitoring the complete conversion of raw materials, the reaction was stopped, water (20 mL) was added to the reaction solution, a yellow solid was precipitated, filtered and dried to give compound IM-20 (650 mg), yellow solid, yield 89%. Molecular formula: C 12 H 13 F3N4O2; Molecular weight: 302.25.

[0326] To a solution of compound IM-20 (100 mg, 0.33 mmol) in EA (5 mL) was added TFAA (1 mL) and hydrogen peroxide (1 mL) at room temperature (25 °C), the reaction solution gradually turned red, the reaction solution was warmed to 40 °C and stirred for 4 h, LCMS monitoring showed that the starting material was still present, the mixture was continued to stir overnight at room temperature, LCMS monitoring showed that the starting material was still present, the reaction was stopped. Water (10 mL) was added to the reaction solution, and DCM (20 mL*3) was extracted, and the organic layer was concentrated. Silica gel column chromatography (MeOH:DCM = 0% ~ 2%) gave 3-((2-hydroxy-2-methylpropyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (C-3, 21 mg), red solid, yield 26%. Molecular formula: C 12 H 13 F3N4O3; Molecular weight: 318.25; LCMS: (ESI+): m / z 319.2 [M+1] + .

[0327] Example C-4: Synthesis of 3-((1S,4S)-4-hydroxycyclohexyl)amino)-7- trifluoromethylbenzo[e][1,2,4]triazine 1,4-dioxide

[0328] To a solution of IM-1 (150 mg, 0.6 mmol) in DMF (5 mL) was added a mixture of DIPEA (90 mg, 0.72 mmol) and 4-hydroxycyclohexylamine (115 mg, 1.0 mmol) at room temperature. The reaction solution was stirred at room temperature for 30 min, LCMS monitoring showed that the starting material was completely converted. Water (10 mL) was added to the reaction solution, and a yellow solid was precipitated. The product IM-21 was filtered directly for the next step.

[0329] To a solution of IM-21 in EA (10 mL) was added TFAA (1.5 mL) and hydrogen peroxide (1.5 mL) at room temperature. The mixture was stirred at room temperature overnight, TLC monitoring showed that there was a small amount of starting material left. Water (10 mL) was added to the reaction solution, and EA (20 mL*3) was extracted. The organic layer was concentrated and silica gel was added. The product 3-((1S,4S)-4-hydroxycyclohexyl)amino)-7-trifluoromethylbenzo[e][1,2,4]triazine 1,4-dioxide (C-4, 65 mg) was obtained as a red solid. The two-step yield was 31%. Molecular formula: C 14 H 15 F3N4O3; Molecular weight: 344.29; LCMS: (ESI+): m / z 345.3 [M+1] + .

[0330] Example C-5: Synthesis of 3-(2-hydroxypropyl)amino-7-trifluoromethylbenzo[l,2,4]triazine 1,4-dioxide

[0331] To a solution of IM-1 (150 mg, 0.6 mmol) in DMF (5 mL) was added DIPEA (90 mg, 0.72 mmol) and 2-methyl ethanolamine (100 mg, 1.3 mmol) at room temperature. The mixture was stirred at room temperature for 30 min. LCMS was used to monitor the reaction. When the starting material was consumed, water (10 mL) was added to the reaction mixture. No yellow solid was precipitated. The mixture was extracted with EA. The product IM-22 was obtained directly and used for the next step without further purification.

[0332] To a solution of IM-22 in EA (10 mL) was added TFAA (1.5 mL) and hydrogen peroxide (1.5 mL) at room temperature. The mixture was stirred at room temperature overnight. TLC was used to monitor the reaction. When the starting material was consumed, water (10 mL) was added to the reaction mixture. The mixture was extracted with EA (20 mL*3). The organic layer was concentrated and applied to a silica gel column. The product was eluted with DCM / MeOH = 25 / 1. The target product 3-(2-hydroxypropyl)amino-7-trifluoromethylbenzo[l,2,4]triazine 1,4-dioxide (C-5, 45 mg) was obtained as a purple solid. The yield was 24% for two steps. Molecular formula: C 11 H 11 F3N4O3; Molecular weight: 304.23; LCMS: (ESI+): m / z 305.3 [M+1] + .

[0333] Example C-6: 7-(5-cyclopropyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-3-((2- hydroxyethyl)amino)benzo[e][l,2,4]triazine 1,4-dioxide

[0334] To a suspension of 7-bromo-3-((2-hydroxyethyl)amino)benzo[e][l,2,4]triazine 1,4-dioxide (C-l, 900 mg, 2.99 mmol) in DMF (10 mL) was added 5-cyclopropyl-2-(4,4,5,5-tetramethyl-l,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) at room temperature (25 °C), the mixture was stirred at 35 °C under nitrogen atmosphere for 1 hour, LCMS monitored the complete conversion of starting material, the reaction was stopped. Water (20 mL) was added to the reaction mixture, a dark brown solid was precipitated, which was filtered. The filter cake was slurried with DCM / MeOH = (6 / 1), the solid was collected and dried to give a red solid (C-6, 580 mg) in 48.5% yield. Molecular Formula: C 19 H 21 N5O3S; Molecular Weight: 399.47; LCMS: (ESI+) m / z 400.2 [M+l] + .

[0335] Example C-7: Synthesis of 7-bromo-3-((2-(4-fluorophenyl)-2- hydroxyethyl)amino)benzo[e][l,2,4]triazine 1,4-dioxide

[0336] To a solution of 2-amino-l-(4-fluorophenyl)ethan-l-one hydrochloride (300 mg, 1.58 mmol) in MeOH (5 mL) was added NaBH4(90 mg, 2.37 mmol) at room temperature (25 °C). The mixture was stirred for 2 hours, water (25 mL) was added to the reaction and extracted with DCM / MeOH = (10 / 1). The organic layer was concentrated to give the crude product 2-amino-l-(4-fluorophenyl)ethan-l-ol (145 mg) as a white solid, which was used directly in the next step. Molecular Formula: C8H 10 FNO; Molecular Weight: 155.17.

[0337] 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 h. To the reaction was added water (15 mL) and filtered. The filter cake was dried to give yellow solid IM-23 (180 mg), which was used directly for the next step. To a solution of compound IM-23 (180 mg, 0.47 mmol) in DCM (5 mL) was added TFAA (3 mL) with hydrogen peroxide (3 mL) at room temperature (25 °C), stirred for 20 h, to the reaction was added water (10 mL), extracted with DCM (20 mL*3), the organic layer was concentrated, and 7-bromo-3-((2-(4-fluorophenyl)-2-hydroxyethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide (C-7, 9.5 mg) was obtained by high pressure liquid phase preparation, red solid, yield 5.1%. Molecular formula: C 15 H 12 BrFN4O3; Molecular weight: 395.19; 1 H NMR (400 MHz, DMSO-d6, ppm): δ 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] + .

[0338] Example C-8: Synthesis of 7-bromo-3-((2-(isobutyryloxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide

[0339] Compound IM-18 (300 mg, 1.05 mmol) and isobutyric acid (370 mg, 4.21 mmol) were added to a flask at room temperature (25 °C), SOCl2 (1 mL) was slowly added to the suspension, the reaction was heated to 90 °C and stirred to reflux, the reaction changed from yellow suspension to red suspension, after 3 h, LCMS monitoring showed that the target product was generated and no starting material was left, the reaction was cooled to room temperature, water was added to the reaction, and yellow solid was precipitated, which was filtered to give compound IM-24 (310 mg), yellow solid, yield 83%. Molecular formula: C 13 H 15 BrN4O3; Molecular weight: 355.19.

[0340] Compound IM-24 (310 mg, 0.87 mmol) was added to a flask with isopropyl acetate (5 mL), 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 h, then stirred at room temperature for 64 h. LCMS monitoring showed no starting material remained. Water (10 mL) was added to the reaction mixture, which was extracted with DCM (20 mL*3). The organic layer was concentrated and purified by 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), red solid, yield 11%. Molecular formula: C 13 H 15 BrN4O4; Molecular weight: 371.19; LCMS: (ESI+): m / z 374.2 [M+1] + .

[0341] Example C-9: Synthesis of 7-bromo-3-((2-(hexadecanoyloxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide

[0342] 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) was added n-hexadecanoic acid (256 mg, 0.99 mmol), EDCI (152 mg, 0.79 mmol), and DMAP (122 mg, 0.99 mmol) at room temperature (25 °C). The mixture was stirred at room temperature overnight. TLC spotting showed a small amount of starting material remained and a product spot was generated. The reaction mixture was concentrated and purified by 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), red solid, yield 30.7%. Molecular formula: C 25 H 39 BrN4O4; Molecular weight: 539.51; LCMS: (ESI+): m / z 541.2 [M+1] + .

[0343] Example C-10: 7-bromo-3-((2-((2-bromohexadecanoyl)oxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide

[0344] To a solution of 7-bromo-3-((2-hydroxyethyl)amino)benzo[e][l,2,4]triazine 1,4-dioxide (C-l, 100 mg, 0.33 mmol) in DCM (6 mL) was added 2-bromohexadecanoic acid (166 mg, 0.50 mmol), EDCI (76 mg, 0.40 mmol) and DMAP (36 mg, 0.40 mmol) at room temperature (25 °C). The mixture was stirred at room temperature for 16 h. TLC showed a little starting material remained, so the reaction was stopped. The reaction mixture was concentrated and purified by Prep-TLC (PE / EA = 1 / 1) to give 7-bromo-3-((2-((2-bromohexadecanoyl)oxy)ethyl)amino)benzo[e][l,2,4]triazine 1,4-dioxide (C-10, 20 mg) as a red solid in 9.7% yield. Molecular formula: C 25 H 38 Br2N4O4; Molecular weight: 618.40; LCMS: (ESI+): m / z 620.4 [M+l] + .

[0345] Example C-11: Synthesis of 3-((2-(neopentanoyloxy)ethyl)amino)-7- (trifluoromethyl)benzo[e][l,2,4]triazine 1,4-dioxide

[0346] To a solution of 3-((2-hydroxyethyl)amino)-7-(trifluoromethyl)benzo[e][l,2,4]triazine 1-oxide (IM-19, 300 mg, 1.09 mmol) in DMF (5 mL) was added DIEA (424 mg, 3.28 mmol) and pivaloyl chloride (394 mg, 3.28 mmol) at room temperature (25 °C). The mixture was stirred at 45 °C for 2 h. LCMS showed the starting material was completely converted. The reaction was stopped. Water (20 mL) was added to the reaction mixture. The mixture was extracted with EA (20 mL*3). The organic layer was washed with water and concentrated. The compound (IM-25, 147 mg) was obtained as a yellow solid in 37.5% yield by silica gel column chromatography (EA:PE = 0%~15%). Molecular formula: C 15 H 17 F3N4O3; Molecular weight: 358.32.

[0347] To a solution of compound IM-25 (147 mg, 0.41 mmol) in EA (5 mL) was added TFAA (1 mL) and hydrogen peroxide (1 mL) at room temperature (25 °C), the reaction solution gradually turned red, the reaction solution was warmed to 40 °C and stirred for 8 hours, LCMS monitoring of the complete conversion of raw materials, stop the reaction. Water (20 mL) was added to the reaction solution, extracted with DCM (20 mL*3), the organic layer was concentrated, and purified by silica gel column chromatography (MeOH:DCM = 0% ~ 1%) to give 3-((2-(neopentanoyloxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (C-11, 40 mg), red solid, yield 26%. Molecular formula: C 15 H 17 F3N4O4; Molecular weight: 374.32; LCMS: (ESI+): m / z 375.3 [M+1] + .

[0348] Example C-12: Synthesis of 3-((2-(isobutyryloxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide

[0349] 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) was added DIEA (212 mg, 1.64 mmol) and isobutyryl chloride (174 mg, 1.64 mmol) at room temperature (25 °C), the mixture was warmed to 45 °C and stirred for 2 hours, LCMS monitoring of the complete conversion of raw materials. Stop the reaction, water (20 mL) was added to the reaction solution, extracted with EA (20 mL*3), the organic layer was washed with water and concentrated to give compound IM-26 (100 mg), yellow solid, the crude product was directly used for the next reaction.

[0350] To a solution of compound IM-26 (100 mg, 0.29 mmol) in EA (5 mL) was added TFAA (1 mL) and hydrogen peroxide (1 mL) at room temperature (25 °C), the reaction solution gradually turned red, the reaction solution was warmed to 40 °C and stirred for 8 hours, LCMS monitoring of the complete conversion of raw materials, stop the reaction. Water (20 mL) was added to the reaction solution, extracted with DCM (20 mL*3), the organic layer was concentrated, and purified by 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), red solid, yield 38%. Molecular formula: C 14 H 15F3N4O4; Molecular Weight: 360.29; LCMS: (ESI+): m / z 361.5 [M+1] + .

[0351] Example C-13: Synthesis of 3-((2-((3-hydroxytetradecanoyl)oxy)ethyl)amino)-7- (trifluoromethyl)benzo[e][l,2,4]triazine 1,4-dioxide

[0352] 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), DCM 4 mL, the mixture was stirred at room temperature for 4 h, TLC monitoring, a small amount of raw material remained, the reaction solution was concentrated and columned, the product was eluted with DCM / MeOH = 100 / 1, and the target product 3-((2-((3-hydroxytetradecanoyl)oxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][l,2,4]triazine 1,4-dioxide (C-13, 52 mg, 0.03 mmol) was obtained by concentration, red solid, two-step yield was 16%. Molecular formula: C 24 H 35 F3N4O5; Molecular Weight: 516.56; LCMS: (ESI+): m / z 517.7 [M+1] + .

[0353] Example C-14: Synthesis of 3-((2-(nicotinoyloxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][l,2,4]triazine 1,4-dioxide

[0354] 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), DCM 4 mL, the mixture was stirred at room temperature for 4 h, TLC monitoring, a small amount of raw material remained, the reaction solution was concentrated and columned, the product was eluted with DCM / MeOH = 50 / 1, and the target product 3-((2-(nicotinoyloxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][l,2,4]triazine 1,4-dioxide (C-14, 14.6 mg, 0.04 mmol) was obtained by concentration, red solid, yield was 54%. Molecular formula: C 16 H 12 F3N5O4; Molecular Weight: 395.30; LCMS: (ESI+): m / z 396.5 [M+1] + .

[0355] 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

[0356] 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), DCM 4 mL, the mixture was stirred at room temperature for 12 h, TLC monitoring showed that there was a small amount of raw material left, the reaction solution was concentrated and columned, the product was eluted with DCM / MeOH=100 / 1, and 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) was obtained as a red solid with a yield of 5%. Molecular formula: C 30 H 35 F3N4O4; Molecular weight: 572.63; LCMS: (ESI+): m / z 573.5 [M+1] + .

[0357] Example C-16: Synthesis of 7-(trifluoromethyl)-3-((2-(propyloxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide

[0358] C-2 (150 mg, 0.55 mmol) was added to (130 mg, 0.60 mmol) N-Boc valine, EDCI (110 mg, 0.6 mmol), DMAP (5 mg, 0.025 mmol), DCM 4 mL at room temperature (25°C), the mixture was stirred at room temperature overnight, TLC monitoring showed that there was a small amount of raw material left, the reaction solution was concentrated and columned, the product IM-27 was eluted with DCM / MeOH=100 / 1, and the oil was obtained and directly used in the next step.

[0359] To a solution of IM-27 (50 mg, 0.17 mmol) in EA (10 mL) was added TFAA (2 mL) and hydrogen peroxide (2 mL) at room temperature. The mixture was stirred at room temperature overnight. TLC monitoring showed that there was a little starting material left. Water (10 mL) was added to the reaction mixture. EA (20 mL*3) was used to extract the product. The organic layer was concentrated and silica gel was added to the mixture. The mixture was concentrated and passed through a column. DCM / MeOH = 10 / 1 was used to elute the product. The product, 7-(trifluoromethyl)-3-((2-(propyloxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide (C-16, 38 mg), was obtained as a red solid. It was hygroscopic. The yield of the two steps was 17%. Molecular formula: C 15 H 18 F3N5O4; Molecular weight: 389.34; LCMS: (ESI+): m / z 390.4 [M+1] + .

[0360] Example C-17: Synthesis of 3-((2-((thiophene-3-carbonyl)oxy)ethyl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide

[0361] 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) was added 3-thiophene carboxylic acid (27 mg, 0.20 mmol), EDCI (50 mg, 0.25 mmol) and DMAP (31 mg, 0.25 mmol) at room temperature (25 °C). The mixture was stirred at room temperature for 4.5 hours. LCMS monitoring showed that the starting material was completely converted. The reaction was stopped. Water (10 mL) was added to the reaction mixture. DCM (20 mL*3) was used to extract the product. The organic layer was concentrated and purified by 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. The yield was 39%. Molecular formula: C 15 H 11 F3N4O4S; Molecular weight: 400.33; LCMS: (ESI+): m / z 401.1 [M+1] + .

[0362] Example C-18: Synthesis of 3-((2-(isobutyryloxy)ethyl)amino)-7- (trifluoromethoxy)benzo[e][1,2,4]triazine 1,4-dioxide

[0363] Example C-19: Synthesis of 3-(2-hydroxyethylamino)-7-(trifluoromethoxy)benzo[e][1,2,4]triazine 1,4-dioxide

[0364] IM-28 was synthesized according to WO 2023019912 Al.

[0365] To a solution of compound IM-29 (850 mg, 2.93 mmol) in DCM (8 mL) was added DIEA (1.13 g, 8.79 mmol) and isobutyryl chloride (928 mg, 8.79 mmol) at room temperature (25 °C), the mixture was stirred at room temperature for 4 hours, LCMS monitored the complete conversion of raw materials, the reaction was stopped, water (20 mL) was added to the reaction solution, extracted with DCM (20 mL*3), the organic layer was combined and concentrated to give compound IM-30 (940 mg), the crude product was directly used in the next step. 10 H9F3N4O3; Mw: 290.20.

[0366] To a solution of compound IM-29 (850 mg, 2.93 mmol) in DCM (8 mL) was added DIEA (1.13 g, 8.79 mmol) and isobutyryl chloride (928 mg, 8.79 mmol) at room temperature (25 °C), the mixture was stirred at room temperature for 4 hours, LCMS monitored the complete conversion of raw materials, the reaction was stopped, water (20 mL) was added to the reaction solution, extracted with DCM (20 mL*3), the organic layer was combined and concentrated to give compound IM-30 (940 mg), the crude product was directly used in the next step.

[0367] To a solution of compound IM-30 (940 mg, 2.61 mmol) in EA (10 mL) was added TFAA (3 mL) and hydrogen peroxide (3 mL) at room temperature (25 °C), the mixture was stirred at room temperature for 16 hours, LCMS monitored the complete conversion of raw materials, the reaction was stopped. Water (20 mL) was added to the reaction solution, extracted with DCM (20 mL*3), the organic layer was concentrated, and 3-((2-(isobutyryloxy)ethyl)amino)-7-(trifluoromethoxy)benzo[e][1,2,4]triazine 1,4-dioxide (C-18, 700 mg) was obtained as a red solid with a yield of 71% by silica gel column chromatography (DCM:MeOH=0%~1%). Molecular formula: C 14 H 15 F3N4O5; Mw: 376.29; LCMS: (ESI+): m / z 377.4 [M+1] + .

[0368] 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) at room temperature (25 °C), the mixture was stirred at room temperature for 1 hour, LCMS monitoring, the starting material was completely converted, the reaction was stopped. Water (20 mL) was added to the reaction solution, DCM (20 mL*3) was extracted, 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), red solid, yield 98%. Molecular formula: C 10 H9F3N4O4; MW: 306.20; LCMS: (ESI+): m / z 370.7.2 [M+1] + .

[0369] Example C-20: Synthesis of 3-((2-((2-bromohexadecanoyl)oxy)ethyl)amino)-7- (trifluoromethoxy)benzo[e][1,2,4]triazine 1,4-dioxide

[0370] 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) was added 2-bromohexadecanoic acid (83 mg, 0.24 mmol), EDCI (38 mg, 0.19 mmol) and DMAP (18 mg, 0.19 mmol) at room temperature (25 °C), the mixture was stirred at room temperature for 1 hour, TLC monitoring, the starting material was left, and a new spot was generated, the mixture was continued to stir overnight, TLC, there was still a small amount of starting material left, 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), red solid, yield 19%. Molecular formula: C 26 H 38 BrF3N4O5; MW: 623.50; LCMS: (ESI+): m / z 623.4 [M+1] + .

[0371] Example C-21: 6-bromo-3-((2-(isobutyryloxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide

[0372] The synthesis of IM-31 refers to WO 2023019912 A1, and the starting material is 2-nitro-5-bromoaniline.

[0373] 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) was added DIEA (372 mg, 2.88 mmol) and ethanolamine (88 mg, 1.44 mmol) at room temperature (25°C). The mixture was stirred at room temperature for 1 hour. LCMS confirmed complete conversion of the starting material, and the reaction was terminated. Water (20 mL) was added to the reaction mixture to precipitate a yellow solid, which was filtered and dried to afford compound IM-32 (140 mg) as a yellow solid in a 51% yield. Molecular formula: C9H9BrN4O2; molecular weight: 285.10.

[0374] To a solution of compound IM-32 (140 mg, 0.49 mmol) in dichloromethane (5 mL) at room temperature (25°C) was 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 confirmed the substantial reaction of the starting material, and the reaction was stopped. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL x 3). The organic layer was concentrated to afford compound IM-33 (100 mg) as a yellow solid, which was directly used in the next reaction.

[0375] At room temperature (25°C), TFAA (1 mL) and hydrogen peroxide (1 mL) were added to a solution of compound IM-33 (100 mg, 0.28 mmol) in EA (6 mL). The mixture was heated to 35°C and stirred for 8 hours. LCMS monitoring confirmed complete conversion of the starting material and the reaction was stopped. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL*3). The organic layer was concentrated and purified by silica gel column chromatography (DCM:MeOH = 0% to 1%) to obtain 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 a yield of 19%. Molecular formula: C 13 H 15 BrN4O4; molecular weight: 371.19; LCMS: (ESI+): m / z 372.4[M+1] + .

[0376] Example C-22: Synthesis of 8-bromo-3-((2-(isobutyryloxy)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide

[0377] The synthesis of C-22 was similar to that of C-21.

[0378] Example C-23: Synthesis of 7-(5-cyclopropyl-4,5,6,7-tetrahydrothieno[3,2- c]pyridin-2-yl)-3-((2-(isobutyryloxy)ethyl)amino)benzo[e][l,2,4]triazine 1,4-dioxide

[0379] To a solution of 7-bromo-3-((2-(isobutyryloxy)ethyl)amino)benzo[e][l,2,4]triazine 1,4-dioxide (C-8, 180 mg, 0.48 mmol) in DMF (4 mL) was added 5-cyclopropyl-2-(4,4,5,5-tetramethyl-l,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), nitrogen was purged, then warmed to 35 °C for 1 hour, LCMS monitored the starting material was almost completely converted, the reaction was stopped. To the reaction was added water (10 mL), stirred at room temperature for 30 minutes, a dark red solid was precipitated, filtered, the solid was collected, purified by 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][l,2,4]triazine 1,4-dioxide (C-23, 130 mg), red solid, yield 45%. Molecular Formula: C 23 H 27 N5O4S; Molecular Weight: 469.56; LCMS: (ESI+): m / z 470.4 [M+1] + .

[0380] Example C-24: Synthesis of 7-cyclopropyl-3-((2-(neopentyloxy)ethyl)amino)benzo[e][l,2,4]triazine 1,4-dioxide

[0381] To a solution of 7-bromo-3-((2-hydroxyethyl)amino)benzo[e][l,2,4]triazine 1-oxide (IM-18, 500 mg, 1.75 mmol) in DMF (6 mL) was added DIEA (679 mg, 5.26 mmol), DMAP (321 mg, 2.62 mmol) and pivaloyl chloride (252 mg, 2.1 mmol) at room temperature (25 °C). The mixture was stirred at room temperature for 3 h. LCMS monitoring showed that the starting material was almost completely reacted. Water (20 mL) was added to the reaction mixture. A yellow solid was precipitated. It was filtered and dried to give compound IM-34 (600 mg) as a yellow solid in 92.7% yield. Molecular formula: C 14 H 17 BrN4O3; Molecular weight: 369.21.

[0382] To a solution of compound IM-34 (200 mg, 0.54 mmol) in EA (10 mL) was 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) at room temperature (25 °C). The mixture was stirred at 80 °C for 2 h under nitrogen protection. LCMS monitoring showed that the starting material was completely converted. The reaction was stopped. The reaction mixture was filtered through celite. It was concentrated. Compound IM-35 (160 mg) was obtained as a yellow solid in 89% yield by silica gel column chromatography (EA: PE = 0% ~ 20%). Molecular formula: C 17 H 22 N4O3; Molecular weight: 330.38.

[0383] To a solution of compound IM-35 (160 mg, 0.48 mmol) in EA (6 mL) was added TFAA (2 mL) and hydrogen peroxide (2 mL) at room temperature (25 °C). The mixture was stirred at 40 °C for 3.5 h. LCMS monitoring showed that the starting material was completely reacted. The reaction was stopped. Water (20 mL) was added to the reaction mixture. It was extracted with DCM (20 mL*3). The organic layer was concentrated. 7-cyclopropyl-3-((2-(neopentanoyloxy)ethyl)amino)benzo[e][l,2,4]triazine 1,4-dioxide (C-24, 84 mg) was obtained as a red solid in 50% yield by silica gel column chromatography (MeOH: DCM = 0% ~ 1%). Molecular formula: C 17 H 22 N4O4; Molecular weight: 346.38; LCMS: (ESI+): m / z 347.4 [M+1] + .

[0384] Example C-25: Synthesis of 3-((2-((thiophene-3-carbonyl)oxy)propyl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide

[0385] To a solution of IM-22 (90 mg, 0.3 mmol), 2-thiophene carboxylic acid (76 mg, 0.6 mmol), EDCI (57 mg, 0.3 mmol), DMAP (3 mg, 0.015 mmol) in DCM 4 mL was added at room temperature (25 °C) and stirred at room temperature for 12 h. TLC monitoring showed that there was a small amount of starting material left. The product IM-36 was obtained by rotary evaporation and used directly in the next step.

[0386] To a solution of IM-36 in EA (10 mL) was added TFAA (2 mL) and hydrogen peroxide (2 mL) at room temperature. The mixture was stirred at room temperature overnight. TLC monitoring showed that there was a small amount of starting material left. Water (10 mL) was added to the reaction solution, and EA (20 mL*3) was used to extract the product. The organic layer was concentrated by silica gel column chromatography, and the product was eluted with DCM / MeOH = 100 / 1. 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) was obtained by concentration, which was a red solid. The two-step yield was 65%. Molecular formula: C 16 H 13 F3N4O4S; Molecular weight: 414.36; LCMS: (ESI+): m / z 415.5 [M+1] + .

[0387] Example C-26: Synthesis of 3-((2-((cyclopropanecarbonyl)oxy)propyl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide

[0388] To a solution of IM-22 (90 mg, 0.3 mmol), 2-thiophene carboxylic acid (76 mg, 0.6 mmol), EDCI (57 mg, 0.3 mmol), DMAP (3 mg, 0.015 mmol) in DCM 4 mL was added at room temperature (25 °C) and stirred at room temperature for 12 h. TLC monitoring showed that there was a small amount of starting material left. The product IM-36 was obtained by rotary evaporation and used directly in the next step.

[0389] To a solution of IM-37 (100 mg, 0.27 mmol) in EA (10 mL) was added TFAA (2 mL) and hydrogen peroxide (2 mL) at room temperature. The mixture was stirred at room temperature overnight. TLC monitoring showed that there was a small amount of starting material left. Water (10 mL) was added to the reaction solution, and EA (20 mL*3) was used to extract the product. The organic layer was concentrated and then passed through a silica gel column. DCM / MeOH = 100 / 1 was used to elute the product. The concentrated solution was obtained 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-26, 42 mg), red solid. The yield of two steps was 37%. Molecular formula: C 15 H 15 F3N4O4; Molecular weight: 372.30; LCMS: (ESI+): m / z 373.5 [M+1] + .

[0390] Example C-27: 3-((2-(Tert-butyloxy)propyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide

[0391] To a solution of compound IM-22 (220 mg, 0.76 mmol) in DMF (5 mL) was added tert-butyloxyacetyl chloride (136 mg, 1.14 mmol), DIEA (294 mg, 2.28 mmol) and DMAP (139 mg, 1.14 mmol) at room temperature (25 °C). The mixture was stirred at room temperature for 16 hours. LCMS monitoring showed that the reaction was complete. Water (10 mL) was added to the reaction solution to precipitate a yellow solid. The solid was filtered and dried to give compound IM-50 (280 mg) with a yield of 98%. Molecular formula: C 16 H 19 F3N4O3; Molecular weight: 372.34.

[0392] To a solution of compound IM-50 (280 mg) in EA (6 mL) was slowly added TFAA (2 mL) and hydrogen peroxide (2 mL) at room temperature (25 °C). The mixture was heated to 40 °C and stirred for 3.5 hours, and then stirred at room temperature for 16 hours. LCMS monitoring showed that the starting material was almost completely converted. Water (20 mL) was added to the reaction solution, and DCM (20 mL*3) was used to extract the product. The organic layer was concentrated and then passed through a silica gel column (MeOH: DCM = 0% ~ 1%) to give (C-27, 208 mg), red solid. The yield was 71%. Molecular formula: C 16 H 19 F3N4O4; Molecular weight: 388.34; LCMS: (ES+): m / z 389.4 [M+1] + .

[0393] Example C-28: Synthesis of 3-((2-((3-hydroxytetradecanoyl)oxy)propyl)amino)-7- (trifluoromethyl)benzo[e][l,2,4]triazine 1,4-dioxide

[0394] To a solution of IM-22 (288 mg, 1.0 mmol), 3-hydroxymyristic acid (240 mg, 1.1 mmol), EDCI (200 mg, 1.2 mmol), DMAP (6 mg, 0.05 mmol) in DCM 4 mL was stirred at room temperature for 24 h. TLC monitoring showed that there was a small amount of starting material left. Water (10 mL) was added to the reaction solution, and DCM (20 mL*3) was used to extract. After drying, 3-((2-((3-hydroxytetradecanoyl)oxy)propyl)amino)-7- (trifluoromethyl)benzo[e][l,2,4]triazine-1-oxide was obtained directly for the next step.

[0395] To a solution of 3-((2-((3-hydroxytetradecanoyl)oxy)propyl)amino)-7- (trifluoromethyl)benzo[e][l,2,4]triazine-1-oxide in EA (10 mL) was added TFAA (2 mL) and hydrogen peroxide (2 mL) at room temperature. The mixture was stirred at room temperature overnight. TLC monitoring showed that there was a small amount of starting material left. Water (10 mL) was added to the reaction solution, and EA (20 mL*3) was used to extract. The organic layer was concentrated over a column after silica gel was added. DCM / MeOH = 40 / 1 was used to elute the product. After concentration, the target product 3-((2-((thiophene-3-carbonyl)oxy)propyl)amino)-7- (trifluoromethyl)benzo[e][l,2,4]triazine 1,4-dioxide (C-28, 55 mg) was obtained as a red solid. The two-step yield was 10%. Molecular formula: C 25 H 37 F3N4O5; Molecular weight: 530.59; LCMS: (ESI+): m / z 531.6 [M+1] + .

[0396] Example C-29: Synthesis of 3-((2-pentanoyloxy)ethyl)amino)-7-(thiazol-5-yl)benzo[e][l,2,4]triazine 1,4-dioxide

[0397] To a solution of IM-18 (150 mg, 1 eq) in DMF (10 mL) was added pivaloyl chloride (76 mg, 1.2 eq), DMAP (77 mg, 1.2 eq) and DIEA (203 mg, 3 eq) at room temperature (15 °C). The mixture was stirred at room temperature for 1 h. LCMS monitoring showed that the starting material was completely converted. Water (30 mL) was added to the reaction solution, and a yellow solid was precipitated. After filtration and drying, 156 mg of a yellow solid was obtained for the next step.

[0398] To a solution of IM-56 (100 mg) in EA (20 mL) was added TFAA (2 mL) and hydrogen peroxide (2 mL) at room temperature (15 °C). The mixture was stirred at room temperature for 4.5 h. LCMS monitoring showed that the starting material was almost consumed. The reaction was stopped. Water was added to the reaction mixture. The mixture was purified by column chromatography on silica gel with MeOH / DCM = 25%. 3-((2-pentanoyloxy)ethyl)amino)-7-(thiazol-5-yl)benzo[e][1,2,4]triazine 1,4-dioxide, (C-29, 20 mg) was obtained as a red solid. The yield was 19%. Molecular formula: C

[0399] To a solution of IM-56 (100 mg) in EA (20 mL) was added TFAA (2 mL) and hydrogen peroxide (2 mL) at room temperature (15 °C). The mixture was stirred at room temperature for 4.5 h. LCMS monitoring showed that the starting material was almost consumed. The reaction was stopped. Water was added to the reaction mixture. The mixture was purified by column chromatography on silica gel with MeOH / DCM = 25%. 3-((2-pentanoyloxy)ethyl)amino)-7-(thiazol-5-yl)benzo[e][1,2,4]triazine 1,4-dioxide, (C-29, 20 mg) was obtained as a red solid. The yield was 19%. Molecular formula: C 17 H 19 N5O4S; Molecular weight: 389.43; LCMS: (ESI+): m / z 390.4 [M+1] + .

[0400] The fourth type: the end is amine or substituted amine

[0401] Example D-1: Synthesis of 3-((2-aminoethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide

[0402] To a solution of IM-1 (200 mg, 0.8 mmol) in DMF (5 mL) was added DIPEA (104 mg, 0.8 mmol) and N-tert-butoxycarbonyl ethylenediamine (160 mg, 1 mmol) at room temperature (25 °C). The mixture was stirred at room temperature for 3 h. LCMS monitoring showed that the starting material was almost consumed. Water (10 mL) was added to the reaction mixture. A yellow solid was precipitated. The product IM-38 was obtained by filtration and used directly in the next step.

[0403] To a solution of IM-38 in EA (10 mL) was added TFAA (2 mL) and hydrogen peroxide (2 mL) at room temperature. The mixture was stirred at room temperature overnight. TLC monitoring showed that there was a small amount of starting material. Aqueous sodium carbonate solution was added to the reaction mixture to adjust the pH to weak alkaline. EA (20 mL*3) was used to extract the mixture. IM-39 was obtained by rotary evaporation and used directly in the next step.

[0404] To the concentrate IM-39, add DCM about 10 mL to dissolve, TFA 2 ml, stir at room temperature overnight, TLC monitor no starting material left, spin dry the reaction solution and column, DCM / MeOH=5 / 1 to elute the product, add 0.1% triethylamine to elute, concentrate to get the target product 3-((2-aminoethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (D-1, 132 mg), red solid, three-step yield 57%. Molecular formula: C 10 H 10 F3N5O2; Molecular weight: 289.22; LCMS: (ES+): m / z 290.2 [M+1] + .

[0405] Example D-2: Synthesis of 3-(pyrrolidin-3-ylamino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide

[0406] To the solution of IM-1 (200 mg, 0.8 mmol) in DMF (5 mL), add DIPEA (104 mg, 0.8 mmol) and tert-butyl 3-aminopyrrolidine-1-carboxylate (186 mg, 1.05 mmol) at room temperature (25 °C), stir the mixture at room temperature for 3 h, LCMS monitor the starting material is completely converted, add water (10 mL) to the reaction solution, no precipitation, EA extraction spin dry to get the product IM-40 directly used in the next step.

[0407] To the solution of IM-40 in EA (10 mL) at room temperature, add TFAA (2 mL) and hydrogen peroxide (2 mL), stir the mixture at room temperature overnight, TLC monitor a small amount of starting material is left, EA (20 mL*3) extraction, spin dry to get IM-41, used in the next step.

[0408] To the spin dry solution IM-41, add DCM 10 mL to dissolve, TFA 2 mL, stir at room temperature overnight, TLC monitor no starting material left, spin dry the reaction solution and column, DCM / MeOH=10 / 1 to elute the product, add 0.1% triethylamine to elute, concentrate to get the target product 3-(pyrrolidin-3-ylamino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (D-2, 93 mg), red solid, three-step yield 36%. Molecular formula: C 12 H 12 F3N5O2; Molecular weight: 315.26; LCMS: (ES+): m / z 316.3 [M+1] + .

[0409] Example D-3: Synthesis of 3-(azetidin-3-ylamino)-7-(trifluoromethyl)benzo[e][1, 2, 4]triazine 1, 4-dioxide

[0410] To a solution of IM-1 (200 mg, 0.8 mmol) in DMF (5 mL) was added DIPEA (104 mg, 0.8 mmol) and 3-aminocyclobutane-1-carboxylic acid tert-butyl ester (186 mg, 1.08 mmol) at room temperature (25 °C). The mixture was stirred at room temperature for 3 h. LCMS monitoring showed that the starting material was completely converted. Water (10 mL) was added to the reaction mixture. The precipitate was collected by filtration and dried to give the product IM-42, which was used directly in the next step.

[0411] To a solution of IM-42 in EA (10 mL) was added TFAA (2 mL) and hydrogen peroxide (2 mL) at room temperature. The mixture was stirred at room temperature overnight. TLC monitoring showed that there was a small amount of starting material left. EA (20 mL*3) was used to extract the reaction mixture. The solvent was removed by rotary evaporation to give IM-43, which was used directly in the next step.

[0412] The residue IM-43 was dissolved in DCM (10 mL) and TFA (2 mL). The mixture was stirred at room temperature overnight. TLC monitoring showed that there was no starting material left. The reaction mixture was concentrated and purified by column chromatography. DCM / MeOH = 10 / 1 was used to elute the product. 0.1% triethylamine was used to remove the solvent. The target product 3-(azetidin-3-ylamino)-7-(trifluoromethyl)benzo[e][1, 2, 4]triazine 1, 4-dioxide (D-3, 20 mg) was obtained as a red solid. The yield was 8% for three steps. Molecular formula: C 11 H 10 F3N5O2; Molecular weight: 301.23; LCMS: (ES+): m / z 302.2 [M+1] + .

[0413] Example D-4: Synthesis of 3-((2-(methylamino)ethyl)amino)-7-(trifluoromethyl)benzo[e][1, 2, 4]triazine 1, 4-dioxide

[0414] To a solution of 3-chloro-7-(trifluoromethyl)benzo[e][l,2,4]triazine 1-oxide (IM-1, 200 mg, 0.80 mmol) in DMF (5 mL) was added N-methyl-N-tert-butoxycarbonyl- 1,2-ethanediamine (169 mg, 0.96 mmol) and DIEA (310 mg, 2.4 mmol) at room temperature (25 °C). The mixture was stirred at room temperature for 1 h. LCMS was used to monitor the reaction. When the starting material was consumed, the reaction was stopped. Water (10 mL) was added to the reaction mixture. A yellow solid was precipitated. It was filtered and dried to give compound IM-44 (250 mg) as a yellow solid in 80% yield. Formula: C 16 H 20 F3N5O3; M.W.: 387.36.

[0415] To a solution of compound IM-44 (250 mg, 0.64 mmol) in EA (10 mL) was added TFAA (2 mL) and hydrogen peroxide (2 mL) at room temperature (25 °C). The mixture was stirred at 40 °C for 8 h. LCMS was used to monitor the reaction. When the starting material was consumed, water (20 mL) was added to the reaction mixture. The mixture was extracted with DCM (20 mL*3). The organic layer was concentrated to give compound IM-45. Compound IM-45 was dissolved in DCM (10 mL). TFA (3 mL) was added to the solution. The mixture was stirred at room temperature for 3 h. LCMS was used to monitor the reaction. When the starting material was consumed, the reaction was concentrated. The residue was purified by silica gel column chromatography (MeOH:DCM = 0%~20%) to give 3-((2-(methylamino)ethyl)amino)-7-(trifluoromethyl)benzo[e][l,2,4]triazine 1,4-dioxide (D-4, 70 mg) as a red solid in 35% yield. Formula: C 11 H 12 F3N5O2; M.W.: 303.24; LCMS: (ESI+): m / z 304.2 [M+1] + .

[0416] Example D-5: Synthesis of 3-((2-neopentylamidoethyl)amino)-7- (trifluoromethyl)benzo[e][l,2,4]triazine 1,4-dioxide

[0417] Take D-1 (95 mg, 0.32 mmol), add EDCI (64 mg, 0.32 mmol) pivalic acid (30 mg, 0.34 mmol), DMAP (6 mg, 0.016 mmol), DCM 10 mL, stir at room temperature overnight, LCMS raw material is consumed, spin dry column, DCM / MeOH = 20 / 1 to elute the product, spin dry to obtain the target product 3-((2-pivalamidoethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (D-5, 27.5 mg), red solid, yield 22%. Molecular formula: C 15 H 18 F3N5O3; Molecular weight: 373.34; LCMS: (ES+): m / z 374.3 [M+1] + .

[0418] Example D-6: Synthesis of 3-((1-pivaloylpyrrolidin-3-yl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide

[0419] Take D-2 (51 mg, 0.16 mmol), add EDCI (32 mg, 0.16 mmol) pivalic acid (13 mg, 0.16 mmol), DMAP (3 mg, 0.008 mmol), DCM 10 mL, stir at room temperature overnight, LCMS raw material is consumed, spin dry column, DCM / MeOH = 20 / 1 to elute the product, spin dry to obtain 3-((1-pivaloylpyrrolidin-3-yl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (D-6, 24 mg, 0.06 mmol), red solid, yield 37%. Molecular formula: C 17 H 20 F3N5O3; Molecular weight: 399.37; LCMS: (ES+): m / z 400.4 [M+1] + .

[0420] Example D-7: Synthesis of 3-((1-pivaloylazetidin-3-yl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide

[0421] To D-3 (78 mg, 0.25 mmol), add EDCI (50 mg, 0.25 mmol), pivalic acid (20 mg, 0.25 mmol), DMAP (5 mg, 0.0125 mmol), DCM 10 mL, stir at room temperature overnight, LCMS monitor the starting material is consumed, spin dry column DCM / MeOH = 20 / 1 to elute the product, spin dry to obtain the target product 3-((1-oxoazetidin-3-yl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (D-7, 10 mg), red solid, yield 10%. Molecular formula: C 16 H 18 F3N5O3; Molecular weight: 385.35; LCMS: (ES+): m / z 386.4 [M+1] + .

[0422] Example D-8: Synthesis of 3-((2-(N-methylpivalamido)ethyl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide

[0423] To a solution of D-4 (50 mg, 0.17 mmol) in DCM (5 mL) at room temperature (25 °C), add pivalic acid (25 mg, 0.25 mmol), EDCI (47 mg, 0.25 mmol) and DMAP (30 mg, 0.25 mmol), stir the mixture at room temperature for 8 hours, LCMS monitor the starting material is completely converted, add water (20 mL) to the reaction solution, extract with DCM (20 mL*3), concentrate the organic layer and then pass through a silica gel column (MeOH:DCM = 0% ~ 2%) to obtain 3-((2-(N-methylpivalamido)ethyl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (D-8, 22 mg), red solid, yield 34%. Molecular formula: C 16 H 20 F3N5O3; Molecular weight: 387.36; LCMS: (ESI+): m / z 388.5 [M+1] + .

[0424] Example D-9: Synthesis of 3-((2-(N-methylcyclopropionamido)ethyl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide

[0425] To a solution of 3-((2-((tert-butoxycarbonyl)(methyl)amino)ethyl)amino)-7- (trifluoromethyl)benzo[e][l,2,4]triazine 1-oxide (IM-44, 640 mg, 1.65 mmol) in DCM (5 mL) was added hydrogen chloride in dioxane (4 M, 3 mL) slowly at room temperature (25 °C), the mixture was stirred at room temperature for 1 h, a yellow solid was precipitated, LCMS monitoring showed the starting material was completely converted, the reaction was concentrated to give compound IM-46 crude, yellow solid, which was directly used in the next step.

[0426] To a suspension of compound IM-46 (200 mg, 0.70 mmol) in DCM (6 mL) was added cyclopropylcarboxylic acid (120 mg, 0.14 mmol), EDCI (199 mg, 1.04 mmol) and DMAP (127 mg, 1.04 mmol) at room temperature (25 °C), the mixture was stirred at room temperature for 16 h, LCMS monitoring showed the starting material was completely converted, water (20 mL) was added to the reaction, DCM (20 mL*3) was used to extract, the organic layer was concentrated to give compound IM-47 crude (210 mg), yellow oil, which was directly used in the next step.

[0427] To a solution of compound IM-47 (210 mg, 0.59 mmol) in EA (6 mL) was added TFAA (2 mL) and hydrogen peroxide (2 mL) slowly at room temperature (25 °C), the mixture was stirred at 40 °C for 3.5 h, the reaction solution gradually turned red. LCMS monitoring showed that the starting material was basically completely converted, water (20 mL) was added to the reaction, DCM (20 mL*3) was used to extract, the organic layer was concentrated and then purified by silica gel column chromatography (MeOH:DCM = 0% ~ 2%) to give 3-((2-(N- methylcyclopropylcarboxamido)ethyl)amino)-7-(trifluoromethyl)benzo[e][l,2,4]triazine 1,4-dioxide (D-9, 116 mg), red solid, yield 53%. Molecular formula: C 15 H 16 F3N5O3; Molecular weight: 371.31; LCMS: (ESI+): m / z 372.6 [M+1] + .

[0428] Example D-10: Synthesis of 3-((l-((2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6- trimethylcyclohex-l-en-l-yl)nona-2,4,6,8-tetraenyl)pyrrolidin-3-yl)amino)-7- (trifluoromethyl)benzo[e][l,2,4]triazine 1,4-dioxide

[0429] To a solution of D-2 (51 mg, 0.25 mmol) in DCM (10 mL) was added EDCI (50 mg, 0.25 mmol), retinoic acid (65 mg, 0.3 mmol), DMAP (3 mg, 0.0125 mmol) at room temperature. The mixture was stirred at room temperature overnight. LCMS showed the starting material was consumed. The mixture was concentrated and purified by column chromatography (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), red solid, yield 45%. Molecular formula: C 32 H 38 F3N5O3; Molecular weight: 597.68; LCMS: (ES+): m / z 598.7 [M+1] + .

[0430] Example D-11: Synthesis of 3-(((1-(neopentanoyloxy)cyclopropyl)methyl)amino)-7- (trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide

[0431] 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) was added DIEA (310 mg, 2.41 mmol) and 1- (aminomethyl)cyclopropanol (70 mg, 0.80 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. LCMS showed the starting material was consumed. Water (10 mL) was added to the reaction mixture. The yellow solid was collected by filtration to give compound IM-48 (220 mg), yellow solid, yield 91%. Molecular formula: C 12 H 11 F3N4O2; Molecular weight: 300.24.

[0432] To a solution of compound IM-48 (200 mg, 0.67 mmol) in DMF (5 mL) was added pivaloyl chloride (120 mg, 1.00 mmol), DIEA (258 mg, 2.00 mmol) and DMAP (122 mg, 1.00 mmol) at room temperature. The mixture was stirred at room temperature for 16 h. LCMS showed some starting material remained. The reaction was stopped. Water (10 mL) was added to the reaction mixture. The mixture was extracted with EA (20 mL*3). The organic layer was concentrated to give crude IM-49, which was used directly for the next step.

[0433] To a solution of compound IM-49 (200 mg) in EA (6 mL) was added TFAA (2 mL) and hydrogen peroxide (2 mL) slowly at room temperature (25 °C), the mixture was warmed to 40 °C and stirred for 3.5 h, then stirred at room temperature for 16 h. LCMS monitoring showed that the starting material was almost completely converted. Water (20 mL) was added to the reaction solution, and DCM (20 mL*3) was used to extract the mixture. The organic layer was concentrated and purified by silica gel column chromatography (PE / EA = 1 / 1) to give 3-(((1-(neopentanoyloxy)cyclopropyl)methyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide (D-11, 26 mg), red solid, in a yield of 12.5%. Molecular formula: C 17 H 19 F3N4O4; Molecular weight: 400.35; LCMS: (ES+): m / z 401.1 [M+1] + .

[0434] 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

[0435] To a solution of IM-50 (299 mg, 1.0 mmol), R-3-hydroxymyristic acid (240 mg, 1.1 mmol), EDCI (200 mg, 1.2 mmol), HOBT (150 mg, 1.1 mmol) in DCM 4 mL was added at room temperature (25 °C) and stirred for 24 h. TLC monitoring showed that there was a small amount of starting material left. Water (10 mL) was added to the reaction solution, and DCM (20 mL*3) was used to extract the mixture. The organic layer was concentrated to give IM-51, which was directly used in the next step.

[0436] To a solution of IM-51 in DCM (10 mL) was added TFAA (2 mL) and hydrogen peroxide (2 mL) at room temperature. The mixture was stirred at room temperature overnight. TLC monitoring showed that there was a small amount of starting material left. Water (10 mL) was added to the reaction solution, and DCM (20 mL*3) was used to extract the mixture. The organic layer was concentrated and purified by silica gel column chromatography (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), red solid, in a yield of 42% for two steps. Molecular formula: C 26 H 38 F3N5O4; Molecular weight: 541.6; LCMS: (ESI+): m / z 542.6 [M+1] + .

[0437] 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

[0438] To a solution of IM-50 (299 mg, 1.0 mmol) in DCM (15 mL) was added TFAA (2 mL) and hydrogen peroxide (2 mL) at room temperature (25 °C). The mixture was stirred at room temperature overnight. TLC monitoring showed that a small amount of starting material remained. Water (10 mL) was added to the reaction mixture, and DCM (20 mL*3) was added to extract the organic layer. The organic layer was concentrated and purified by column chromatography using DCM / MeOH = 100 / 1 to elute the product. 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) was obtained as a red solid in 76% yield. Molecular formula: C 14 H 11 F6N5O3; Molecular weight: 411.2; LCMS: (ESI+): m / z 412.5 [M+1] + .

[0439] 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

[0440] To a solution of 3-thiophene carboxylic acid (45 mg, 0.35 mmol), D2 (110 mg, 0.35 mmol), EDCI (80 mg, 0.42 mmol), HOBT (57 mg, 0.42 mmol), TEA (43 mg, 0.42 mmol) in DCM (4 mL) was added at room temperature (25 °C). The mixture was stirred at room temperature overnight. LCMS monitoring showed that the starting material was consumed. Water (10 mL) was added to the reaction mixture, and DCM (20 mL*3) was added to extract the organic layer. The organic layer was concentrated and purified by column chromatography using DCM / MeOH = 50 / 1 to elute the product. 3-((1-(thiophene-3-carbonyl)pyrrolidin-3-yl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine-1,4-dioxide (D-14, 20 mg) was obtained as a red solid in 13% yield. Molecular formula: C 17 H 14 F3N5O3S; Molecular weight: 425.38; LCMS: (ESI+): m / z 426.3 [M+1] + .

[0441] Example D-15: Synthesis of 3-((2-aminoethyl)amino)-7-bromobenzo[e][1,2,4]triazine 1,4-dioxide

[0442] Reference Example D-1 gave 3-((2-aminoethyl)amino)-7-bromobenzo[e][1,2,4]triazine 1,4-dioxide (D-15), red solid. Molecular Formula: C9H 10 BrN5O2; Molecular Weight: 300.16; LCMS: (ES+): m / z 301.2 [M+1] + .

[0443] Example D-16: Synthesis of 3-(((1-aminocyclopropyl)methyl)amino)-7- bromobenzo[e][1,2,4]triazine 1,4-dioxide

[0444] Into a reaction flask containing IM-13 (104 mg, 0.4 mmol), 1-aminomethyl-1- (BOC-amino)cyclopropane (83 mg, 0.45 mmol), DIPEA (78 mg, 0.6 mmol) was added DMF 5 mL and stirred at room temperature for 2 h. TLC monitoring showed that the starting material was almost consumed. Water (10 mL) was added to the reaction mixture, which was then filtered and dried to give 148 mg of IM-71, which was used directly in the next step.

[0445] Into a reaction flask containing 140 mg of IM-71 was added EA (10 mL) and the solution was ultrasonically dissolved. A small amount of undissolved substance was observed. TFAA 1.5 mL and H2O2 1.5 mL were added dropwise, and the mixture was stirred at 30 °C overnight. TLC monitoring showed that IM-71 was almost consumed. The reaction was stopped, the reaction solution was rotary evaporated, EA (10 mL) was added, and the mixture was extracted and dried over anhydrous sodium sulfate. The organic phase was rotary evaporated to give 110 mg of IM-72, which was used directly in the next step.

[0446] Into a reaction flask containing 110 mg of IM-72 was added DCM (10 mL). HCl / Dioxane (4 M) 1.2 mL was added dropwise, and the mixture was stirred at room temperature for 4 h. TLC monitoring showed that IM-2 was almost consumed. At this time, a solid was precipitated. The reaction was stopped, the mixture 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), brick red solid, with a three-step yield of 50%. Molecular Formula: C 11 H 12 BrN5O2; Molecular Weight: 326.1; LCMS: (ESI+): m / z 326.1, 328.1 [M+1] +.

[0447] Example D-17: Synthesis of (R)-3-((2-aminopropyl)amino)-7-bromobenzo[e][1,2,4]triazine 1,4-dioxide

[0448] To a reaction flask containing 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) was added DMF 5 mL and stirred at room temperature for 2 h. TLC monitoring showed that the starting material was almost consumed. Water (10 mL) was added to the reaction mixture and precipitate was obtained. The precipitate was filtered and dried to give 160 mg of IM-73, which was used directly in the next step.

[0449] To a reaction flask containing 150 mg of IM-73 was added EA (10 mL) and the solution was ultrasonically dissolved. A small amount of undissolved substance was observed. TFAA 2 mL and H2O2 2 mL were added dropwise. The mixture was stirred at 30 °C overnight. TLC monitoring showed that IM-73 was still present in large amounts. TFAA 1 mL and H2O2 1 mL were added. The reaction was stirred for 3 h. TLC monitoring showed that IM-73 was still present. The reaction was stopped. The reaction mixture was rotary evaporated. EA (10 mL) was added. The mixture was extracted. Anhydrous sodium sulfate was added to dry the organic phase. The organic phase was rotary evaporated. The product was purified by column chromatography using DCM / MeOH = 50 / 1 to give 60 mg of IM-74, which was used in the next step.

[0450] 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 monitoring showed that IM-74 was almost consumed. At this time, a solid precipitated. The reaction was stopped. The precipitate 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. The yield of the three steps was 17%. Molecular formula: C 10 H 12 BrN5O2; Molecular weight: 314.1; LCMS: (ESI+): m / z 314.1, 316.1 [M+1] + .

[0451] Example D-18: Synthesis of (S)-3-((2-aminopropyl)amino)-7-bromobenzo[e][1,2,4]triazine 1,4-dioxide

[0452] To a reaction flask containing IM-13 (130 mg, 0.5 mmol) was added (S)-(1- aminopropan-2-yl)carbamic acid tert-butyl ester (96 mg, 0.55 mmol), DIPEA (78 mg, 0.6 mmol) in DMF 5 mL and stirred at room temperature for 2 h. TLC monitoring showed that the starting material was almost consumed. Water (10 mL) was added to the reaction mixture and precipitate was collected by filtration and dried to give 240 mg of IM-75, which was used directly in the next step.

[0453] To a reaction flask containing IM-75 (230 mg) was added DCM (10 mL) and the solution was dissolved by ultrasonic. TFAA (3 mL) and H2O2 (3 mL) were added dropwise and the mixture was stirred at 30 °C overnight. TLC monitoring showed that IM-75 was almost consumed. The reaction was stopped and the reaction mixture was dried by rotary evaporation. The product was purified by column chromatography (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. Yield: 33% over two steps. Molecular Formula: C 10 H 12 BrN5O2; Molecular Weight: 314.1; LCMS: (ESI+): m / z 314.1, 316.1 [M+1] + .

[0454] Example D-19: Synthesis of 3-((2-aminoethyl)amino)-7-fluorobenzo[e][1,2,4]triazine 1,4-dioxide

[0455] The synthesis of IM-76 was referenced from WO 2023019912 A1.

[0456] To a solution of IM-76 (200 mg, 1 eq) in DMF (10 mL) was added mono-Boc ethylenediamine (241 mg, 1.5 eq) and DIEA (389 mg, 3 eq) at room temperature (15 °C). The mixture was stirred at room temperature for 1 h. LCMS monitoring showed that the starting material was completely converted. Water (30 mL) was added to the reaction mixture and yellow solid was precipitated. The solid was collected by filtration and dried to give 280 mg of product IM-77 as a yellow solid, which was used directly in the next step.

[0457] To IM-77 280 mg in DCM 10 mL, add TFAA and hydrogen peroxide 2 mL each, the mixture is warmed to 40 °C and stirred for 5 hours, LCMS monitor the remaining raw material is less, stop the reaction, the reaction liquid is concentrated, add silica gel column, MeOH / DCM=17%, collect the product, concentrated to get 3-((2-aminoethyl)amino)-7-fluorobenzo[e][1,2,4]triazine 1,4-dioxide, (D-19, 78 mg) red solid, yield 25%. Molecular formula: C9H 10 FN5O2, Molecular weight: 239.2; LCMS: (ESI+): m / z 240.1 [M+1] + .

[0458] Example D-20: Synthesis of 3-((2-aminoethyl)amino)-7-chlorobenzo[e][1,2,4]triazine 1,4-dioxide

[0459] The synthesis of IM-78 refers to WO 2023019912 A1.

[0460] To IM-78 (200 mg, 1 eq) in DMF (10 mL) at room temperature (15 °C), add mono-Boc ethylenediamine (241 mg, 1.5 eq) and DIEA (389 mg, 3 eq), the mixture is stirred at room temperature for 1 hour, LCMS monitor the complete conversion of raw materials, add water (30 mL) to the reaction solution, precipitate yellow solid, filter and dry to get 250 mg of product IM-79, yellow solid, for the next step.

[0461] To IM-77 250 mg in DCM 10 mL, add TFAA and hydrogen peroxide 2 mL each, the mixture is warmed to 40 °C and stirred for 6 hours, LCMS monitor the remaining raw material is less, stop the reaction, the reaction liquid is concentrated, add silica gel column, MeOH / DCM=17%, collect the product, concentrated to get 3-((2-aminoethyl)amino)-7-chlorobenzo[e][1,2,4]triazine 1,4-dioxide, (D-20, 129 mg) red solid, yield 47%. Molecular formula: C9H 10 ClN5O2, Molecular weight: 255.7; LCMS: (ESI+): m / z 256.1, 258.1 [M+1] + .

[0462] Example D-21: Synthesis of 3-((2-aminoethyl)amino)-7-iodobenzo[e][1,2,4]triazine 1,4-dioxide

[0463] The synthesis of IM-80 is referenced to WO 2023019912 Al.

[0464] To a solution of IM-80 (200 mg, 1 eq) in DMF (10 mL) was added mono-Boc ethylenediamine (156 mg, 1.5 eq) and DIEA (252 mg, 3 eq) at room temperature (15 °C), the mixture was stirred at room temperature for 1 hour, LCMS monitoring showed that the raw material was completely converted, water (30 mL) was added to the reaction solution, yellow solid was precipitated, filtered and dried to give the product 260 mg of IM-81, yellow solid, used in the next step.

[0465] To IM-81 250 mg in DCM 10 mL, TFAA and hydrogen peroxide were added each 2 mL, the mixture was warmed to 40 °C and stirred for 6 hours, LCMS monitoring showed that the raw material was less remaining, the reaction was stopped, the reaction solution was concentrated, silica gel column was added, MeOH / DCM = 17%, the product was collected and concentrated to give 3-((2-aminoethyl)amino)-7-iodobenzo[e][l,2,4]triazine 1,4-dioxide, (D-21, 159 mg) red solid, yield 57%. Molecular formula: C9H 10 IN5O2, molecular weight: 347.1; LCMS: (ESI+): m / z 348.0 [M+1] + .

[0466] Example D-22: Synthesis of 3-((2-aminoethyl)amino)-7-methoxybenzo[e][l,2,4]triazine 1,4-dioxide

[0467] The synthesis of IM-82 is referenced to WO 2023019912 Al.

[0468] To a solution of IM-82 (200 mg, 1 eq) in DMF (10 mL) was added mono-Boc ethylenediamine (227 mg, 1.5 eq) and DIEA (366 mg, 3 eq) at room temperature (15 °C), the mixture was stirred at room temperature for 1 hour, LCMS monitoring showed that the raw material was completely converted, water (30 mL) was added to the reaction solution, yellow solid was precipitated, filtered and dried to give the product 280 mg of IM-83, yellow solid, used in the next step.

[0469] To IM-83 280 mg in DCM 10 mL, add TFAA and hydrogen peroxide 2 mL each, the mixture is warmed to 40 °C and stirred for 10 hours, LCMS monitoring shows that the raw material is less remaining, stop the reaction, the reaction solution is concentrated, silica gel column is added, MeOH / DCM=17%, the product is collected and concentrated to obtain 3-((2-aminoethyl)amino)-7-methoxybenzo[e][1,2,4]triazine 1,4-dioxide, (D-22, 80 mg), red solid, yield 26%. Molecular formula: C 10 H 13 N5O3, molecular weight: 251.3; LCMS: (ESI+): m / z 252.1 [M+1] + .

[0470] Example D-23: Synthesis of 7-bromo-3-((2-(methylamino)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide trifluoroacetate salt

[0471] At room temperature (25 °C), IM-13 (130 mg, 0.50 mmol), N-Boc-N-methyl ethylenediamine (71 mg, 0.55 mmol), DIPEA (104 mg, 0.80 mmol) are added to a reaction bottle, the mixture is stirred at room temperature for 2 h, TLC monitoring shows that the raw material is basically not remaining, water (10 mL) is added to the reaction solution, precipitated, filtered, dried to obtain 139 mg of IM-84, which is directly used in the next step.

[0472] At room temperature, DCM (10 mL) is added to a reaction bottle containing 130 mg of IM-84, the solution is ultrasonically dissolved, and a little is not dissolved, TFAA 3 ml and H2O2 3 ml are added dropwise, the mixture is stirred at 30 °C overnight, TLC monitoring shows that IM-84 is less remaining, stop the reaction, the reaction solution is rotary evaporated, column chromatography is carried out, DCM / MeOH=5 / 1 to obtain 7-bromo-3-((2-(methylamino)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide (D-23, 40 mg), red solid, yield 19%. Molecular weight: C 10 H 12 BrN5O2; molecular formula: 314.1; LCMS: (ESI+): m / z 314.1, 316.1 [M+1] + .

[0473] I. In vitro biological activity and anti-tumor activity test

[0474] Background: Hypoxia is a prominent feature of the tumor microenvironment, and modulation of cellular activity under hypoxic conditions is a major pathway for inhibiting tumor growth, proliferation, and differentiation. Therefore, screening for drug molecules with hypoxic activity, releasing free radicals through bioreductase to act on DNA, and then killing tumor cells, has great clinical application significance.

[0475] In vitro cell test method: The influence of different compounds on the activity of HT29 cells (human colon cancer cells) under anaerobic conditions was detected by CTG method.

[0476] Brief introduction of CTG test principle: CTG (full name is CellTiter-Glo) Luminescent Cell Viability Assay is a high-sensitivity luminescence detection method for rapid cell viability based on ATP detection.

[0477] The detection principle is as follows:

[0478] ATP exists in living cells, and luciferase reaction depends on ATP in living cells. 3D detection reagent contains Ultra-Glo recombinant luciferase and luciferin, which can be directly added to cultured cells for detection. The detection reagent can automatically lyse cells to release ATP in living cells, and can protect ATP from degradation. ATP in living cells participates in luciferase reaction, and the light produced is proportional to the number of living cells in the microorganism. Luminescence cell viability assay is a homogeneous detection method for detecting the number of living cells in culture by quantitatively detecting ATP (a key indicator of cell metabolism), and the amount of ATP is directly proportional to the number of cells in the culture. The detection kit produces a "glowing" luminescence signal with a half-life of more than 5 hours, which varies with cell type and culture medium. Because of the long signal half-life, there is no need to use a reagent autosampler, and continuous detection can be flexibly carried out.

[0479] Specific experimental scheme: A series of concentrations of compounds were prepared and incubated with 2000 HT29 cells under anaerobic and aerobic conditions for 3 days, respectively. CTG reagent was added, and the fluorescence value was read using a microplate reader, and the compound activity curve was drawn using GraphPad Prism 5.0 drawing software. The EC50 value was obtained from the viability curve.

[0480] Detailed information:

[0481] 1. Cell information

[0482] 2. Reagents and consumables

[0483] Fetal Bovine Serum FBS (Hyclone, Cat# SH30406.05)

[0484] DME / F12 1:1 (1X) medium (Hyclone, Cat# SH30023.01)

[0485] Cell Titer-Glo (CTG) Luminescent Cell Viability Assay (Promega, Cat# G7571)

[0486] 96-well cell culture plates (Corning, Cat# 3603)

[0487] PBS (Hyclone, Cat# SH30256.01)

[0488] Trypsin 0.25% (Hyclone, Cat# SH30042.01)

[0489] Pen / Strep, 10,000 units / ml (Hyclone, Cat# SV30010)

[0490] DMSO (SIGMA, D4540-100ML)

[0491] Anaerobic Incubator: purchased from Gene Science. Set mode: 0% O2; 5% CO2; 95% N2; 94-97% humidity

[0492] 3. Experimental procedure

[0493] 3.1 Cell culture and plating

[0494] HT29 cells were cultured using DME / F12 + 10% FBS + 1% Pen / Strep complete medium, maintaining T75 flask density at 2 x 105- 1 x 106viable cells / mL.

[0495] Cells were collected, old medium was discarded, cells were washed once with sterile PBS, trypsin was added to digest cells, complete medium was added to pipette cells to single cells. After trypan blue staining, the cell viability was greater than 95% when the subsequent experiment was performed.

[0496] The cell density was adjusted to 2.0 x 104viable cells / mL using complete medium.

[0497] 100 μL of cell suspension was added to the 96-well cell culture plate wells, and the cell density was 2 x 103viable cells / well.

[0498] Incubate in incubator for 24h.

[0499] 3.2 Compound dilution

[0500] a) 4-fold compound starting concentration preparation and 3-fold gradient dilution: 10 gradient concentration points for 3-fold gradient dilution of the test compound with complete medium containing 2% (4-fold final concentration) DMSO.

[0501] b) Add 50 μL complete medium to the cell plate containing 100 μL cells, and then add 50 μL of 4-fold concentration compound (3-fold gradient dilution) solution to the designed cell plate containing a total of 150 μL, two duplicate wells for each concentration, and finally 200 μL of culture solution per well. The final DMSO concentration in the complete medium is 0.5%. Use the DMSO well as the 100% growth control, and the complete medium without cells as the 0% control.

[0502] c) After drug addition, the cell culture plate is placed in an anaerobic incubator for incubation for 3 days (72 hours).

[0503] 3.3 CTG detection

[0504] a) Melt the CTG Buffer at room temperature and add it to the CTG substrate bottle to completely dissolve it, and then prepare the CTG reagent.

[0505] b) Add an equal amount of CTG reagent to the cell suspension.

[0506] c) Place the cell plate in the dark on a shaker for 10 min to induce cell lysis.

[0507] d) Place the lysed cells in the dark at room temperature for 30 min to stabilize the fluorescence signal, and finally read the luminescence value.

[0508] e) Read the fluorescence value with an enzyme marker (i3X, Molecular Device).

[0509] 7. Data processing: Use GraphPad Prism 5.0 software to analyze the raw data, use nonlinear S-curve regression to fit the data to obtain the dose-effect curve, and calculate the EC50 value.

[0510] The effects of the example compounds on the activity of HT29 cells in anaerobic / aerobic conditions are shown in Table 1 below.

[0511] Among them, the anaerobic state is represented by “*” or “> 6 μM / L” for the EC50 value range, which is as follows:

[0512] “*” represents 4-6 μM / L;

[0513] "**" means 2-4 μM / L;

[0514] "***" means 1-2 μM / L;

[0515] "****" means <1 μM / L;

[0516] Aerobic condition is represented by "+" for EC50 value range, i.e.:

[0517] "++" means 40-60 μM / L;

[0518] "++" means 40-60 μM / L;

[0519] "+++" means 60-80 μM / L;

[0520] "++++" means >80 μM / L;

[0521] " / " means not tested.

[0522] The selectivity refers to the ratio of EC50 value under aerobic condition and EC50 value under anaerobic condition, the larger the better.

[0523] The data in Table 1 above show that the activity of the compounds of the present disclosure is mostly better than that of tirapazamine, with EC50 value under anaerobic condition lower than 4 μM, and the selectivity is still good. In particular, the following compounds with EC50 value under anaerobic activity lower than 1 μM: A-4 / A-5 / B-1 / B-4 / B-7 / B-8 / B-9 / B-10 / C-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.

[0524] II. Metabolic stability and pharmacokinetic analysis

[0525] Cpd A is a terminal carboxylate ester or acylate; Cpd B is a terminal alcohol ester, amine acylate or alkyl / aryl.

[0526] Drug metabolism impact: Cpd A has an ester group, which is metabolized quickly, and after metabolism, COOH is obtained, without hypoxic or aerobic activity. Taking compound A-7 in CN114901646A as an example, the half-life is about 40 min, and after metabolism, carboxylic acid is obtained, with EC50 value >100 uM / L, no activity; the half-life of Cpd B analogs is significantly prolonged, and the metabolite alcohol or amine also has strong activity.

[0527] The analysis scheme for metabolic stability of selected compounds is as follows:

[0528] 1. Detailed description

[0529] 2. Research methods

[0530] 2.1 In vivo experiment

[0531] a) SD rats were fasted overnight, and free water was provided.

[0532] b) After drug administration, the animal state was observed and abnormal performance was recorded.

[0533] c) The plasma sample was centrifuged at 3500 rpm for 10 min at 4°C, and after separation, the sample was transferred to an EP tube and immediately stored at -80°C for analysis.

[0534] 2.2 Acceptable standards for biological analysis of samples

[0535] 2.2.1 Calibration curve

[0536] At least six non-zero concentration points should be used, excluding blank samples (matrix samples containing no 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%.

[0537] 2.2.2 Lower limit acceptable standard

[0538] The lower limit of quantification (LLOQ) is defined as the lowest concentration of the standard curve, and the relative error is not more than ± 20%.

[0539] 2.2.3. Upper limit acceptable standard

[0540] The upper limit of quantification (ULOQ) is defined as the highest concentration of the measurable standard curve, and the relative error of accuracy is not more than ± 15%.

[0541] 2.2.4 Acceptable standards for reagent blank, single blank, and double blank

[0542] In sample analysis, at least one reagent blank and double blank (without internal standard) are included in each batch to prove the absence of substances that interfere with the detection of analytes or internal standards. Double blank and blank samples should be analyzed after reagent blank to eliminate possible residual interference. At least one blank biological matrix spiked with internal standard is included and analyzed according to the method to prove that the internal standard does not interfere with the detection of the analyte. The animal matrix must have no interfering peaks (at LLOQ, should be ≤ 20% of the analyte response).

[0543] 2.2.5 Acceptable standards for quality control (QC) samples

[0544] The accuracy value of the QC samples should be within ± 15% of the nominal value. Four of the at least 6 (67%) QC samples and at least 50% of each concentration level should meet this criterion. If this criterion is not met, the analytical operation should be stopped and the analytical investigation of the samples should be repeated. The minimum number of QC samples should be at least 5% of the number of unknown samples.

[0545] 2.2.6 Acceptable criteria for internal standard

[0546] The coefficient of variation (CV value) of the internal standard is calculated for each data set. If the incubation and analytical operation is functioning properly, the CV value should not exceed 15%.

[0547] 3. Data analysis, pharmacokinetic parameter calculation and reporting

[0548] The standard curve is established using the internal standard method. The theoretical standard curve concentration is the abscissa and the peak area ratio is the ordinate (peak area of test compound / peak area of internal standard). The linear regression method (weighting factor 1 / X2) is used, R 2 > 0.9900. The unknown samples are calculated by the standard curve. The pharmacokinetic parameters are calculated by the non-compartmental analysis model of WinNonlin 8.2 software and presented in the report, including T 1 / 2 , T max , C max , AUC, etc.

[0549] Instrument: API-4000 Qtrap - Shimadzu Controller - CBM20A

[0550] Liquid phase condition: mobile phase A: 0.1% formic acid in water, mobile phase B: 0.1% formic acid in acetonitrile

[0551] Chromatographic column: Waters Xbridge C18 3.5um 2.1*50mm

[0552] Elution procedure:

[0553] Sample preparation:

[0554] a) Transfer 50ul plasma sample to 96-well plate;

[0555] b) Add 500ul acetonitrile to precipitate protein;

[0556] c) Centrifuge for 20min (4℃ 4000rpm);

[0557] d) Transfer 300ul supernatant to a new 96-well plate and mix with 300ul 0.1% formic acid in water;

[0558] e) LC-MS / MS injection volume was 5 uL.

[0559] Results of the tested compounds are as follows:

[0560] Pharmacokinetics are shown in Table 2 below.

[0561] Table 2: Pharmacokinetic data

[0562] *Synthesized according to Example A-7 of CN11490164A.

[0563] The results show that, compared with the known compound A-7, some compounds IV of the present disclosure have significantly higher half-life and higher AUC when administered 0-∞ , indicating better pharmacokinetic performance.

[0564] III. Solubility-related drugability analysis

[0565] Some compounds of the present disclosure, such as D-1 to D-4 and D-16 to D-24, are prone to salt formation and can form salts with some acids such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, formic acid, acetic acid, etc. Hydrochloric acid or trifluoroacetic acid is used to prepare the salts of these compounds, and the solubility (mg / mL) of these salts in pure water at room temperature is tested. The results are shown in Table 3.

[0566] For comparison, hydrochloric acid and trifluoroacetic acid are also used to prepare the salts of the known compound A-7 and tiazolinium. However, it is found in the experiment that, like tiazolinium, the known compound A-7 does not form a salt with an acid radical. Therefore, the solubility (mg / mL) of the known compound A-7 and tiazolinium in pure water at room temperature is directly determined. The results are shown in Table 3.

[0567] Table 3: Solubility data of compound salts

[0568] The results show that the water solubility of the corresponding salts of the compounds of the present disclosure is much higher than that of tiazolinium (tiazolinium is not prone to salt formation, and the water solubility is less than 2 mg / mL) and the known compound A-7 (the known compound A-7 is also not prone to salt formation, and the water solubility is less than 0.5 mg / mL), which is beneficial to the development of various prescription processes.

[0569] 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, etc.

[0570] The use of the drug: oral, IV or intratumoral administration.

[0571] The present disclosure has been described above with the aid of preferred embodiments of the application; these embodiments are illustrative only, and do not limit the scope of the present disclosure. Numerous alternatives, modifications and variations of the present disclosure are possible in the scope of the following claims.

Claims

1. A benzotriazine dioxides having the following general formula (I), or a pharmaceutically acceptable salt or ester, hydrate, solvate or prodrug thereof, ###0001### (I) R2, R4and R5are selected from the group consisting of hydrogen, halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkoxy, optionally substituted C3-C6cycloalkyl, optionally substituted C6-C10aryl, optionally substituted 5- to 10-membered-heteroaryl having 1 to 3 heteroatoms selected from the group consisting of O, S, N, and optionally substituted 5- to 10-membered-heterocyclyl having 1 to 3 heteroatoms selected from the group consisting of O, S, N; wherein, 40 10 40 10 40 10 40 6-20 40 40 R 40 each independently is selected from the group consisting of hydrogen, halogen, cyano, hydroxyl, mercapto, nitro, amino, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl; ​​​​​​​​​​ R3is selected from the group consisting of halogen, optionally substituted with R 50 C1-C 10 alkyl, optionally substituted with R 50 C1-C 10 alkoxy, optionally substituted with R 50 C3-C 10 cycloalkyl, optionally substituted with R 50 C 6-20 aryl, optionally substituted with R 50 5- to 10-membered-heteroaryl comprising 1 to 3 heteroatoms selected from the group consisting of O, S, N, optionally substituted with R 50 5- to 10-membered-heterocyclyl comprising 1 to 3 heteroatoms selected from the group consisting of O, S, N; wherein R 50 each independently is selected from the group consisting of hydrogen, O, halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl; X is selected from NH, S, Se, CHF, C(=S), S(=O) or S(=O)2, R X selected from one of the following groups: C X1 alkyl, optionally substituted with R 1-10 C X1 cycloalkyl, 3-10 alkenyl, optionally substituted with R Among them, R X1 Each independently selected from halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Alkoxy, C3-C 10 Cycloalkyl, optionally substituted with R X11 C 6-20 Aryl, optionally substituted with R X11 A 5- to 10-membered heteroaryl group containing a heteroatom selected from O, S, and N, optionally substituted with R X11 A 5- to 10-membered heterocyclic group containing a heteroatom selected from O, S, and N, or -NR6R7; wherein R X11 Each is independently selected from halogen, halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl; R6 and R7 are each independently selected from hydrogen, optionally substituted with R X12 C1-C 10 Alkyl, optionally substituted with R X12 C1-C 10 Alkoxy, optionally substituted with R X12 C3-C 10 Cycloalkyl, optionally substituted with R X12 C 6-20 Aryl, optionally substituted with R X12 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from O, S, and N, optionally substituted with R X12 A 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from O, S, and N; wherein R X12 are each independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl; or, R6 and R7 together with the N atom to which they are attached form a 5- to 10-membered ring structure; In formula A, R8and R9are each independently selected from hydrogen or C1-C6alkyl, or, R8and R9together with the C atom to which they are attached form a C3-C6ring structure; Y is selected from one of: O, S, Se, C(=S), NR6, * indicates Y is attached to CR 8 R 9 the site of attachment, represents Y and R 10 the site of attachment; R 10 is selected from hydrogen, optionally substituted with R 30 C1-C 20 Alkyl, optionally substituted with R 30 C1-C 20 Haloalkyl, optionally substituted with R 30 C1-C 10 Alkoxy, optionally substituted with R 30 C3-C 10 Cycloalkyl, optionally substituted with R 30 C2-C 20 Alkenyl, optionally substituted with R 30 C 6-20 Aryl, optionally substituted with R 30 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from O, S, and N, optionally substituted with R 30 A 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from O, S, and N, wherein R 30 Each is independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C 6-20 Aryl, C 6-20 Aryloxy, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from O, S, and N, 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from O, S, and N, optionally substituted with R 31 C3-C6 cycloalkenyl; wherein R 31 Each is independently selected from hydrogen, halogen, C1-C6 alkyl; n is an integer from 1 to 11; In formula B, R 20 Selected from hydrogen or -C(=O)R 21 , where R 21 is selected from hydrogen, optionally substituted with R 22 C1-C 20 Alkyl, optionally substituted with R 22 C1-C 20 Haloalkyl, optionally substituted with R 22 C1-C 10 Alkoxy, optionally substituted with R 22 C3-C 10 Cycloalkyl, optionally substituted with R 22 C2-C 20 Alkenyl, optionally substituted with R 22 C 6-20 Aryl, optionally substituted with R 22 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from O, S, and N, optionally substituted with R 22 A 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from O, S, and N, wherein R 22 Each is independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C 6-20 Aryl, C 6-20 Aryloxy, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from O, S, and N, 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from O, S, and N, optionally substituted with R 23 C3-C6 cycloalkenyl; wherein R 23 Each is independently selected from hydrogen, halogen, 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 dioxides or pharmaceutically acceptable salts or esters, hydrates, solvates or prodrugs thereof according to claim 1, wherein, R2, R4and R5are each hydrogen.

3. The benzotriazine dioxides according to claim 1 or a pharmaceutically acceptable salt or ester, hydrate, solvate or prodrug thereof, wherein, The benzotriazine dioxides have the following general formula II-1, general formula II-2, or general formula II-3 wherein, in the general formula II-1, the general formula II-2, and the general formula II-3, R3is selected from the group consisting of halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, optionally substituted C1-C6alkoxy, optionally substituted C3-C6cycloalkyl, optionally substituted C6-C10aryl, optionally substituted 5- to 10-membered-heteroaryl having 1 to 3 heteroatoms selected from the group consisting of O, S, N, optionally substituted 5- to 10-membered-heterocyclyl having 1 to 3 heteroatoms selected from the group consisting of O, S, N; wherein R 50 is each independently selected from the group consisting of hydrogen, O, halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl; 10 50 10 50 10 50 6-20 50 50 50 is each independently selected from the group consisting of hydrogen, O, halogen, cyano, hydroxy, mercapto, nitro, amino, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl;​​​​​​​​​ X is selected from NH or CH2, In general formula II-1, R 0 is selected from H, C X1 alkyl optionally substituted with R 1-10 , or C X1 cycloalkyl optionally substituted with R 3-10 ; wherein R X1 each independently is selected from the group consisting of halogen, cyano, hydroxy, mercapto, nitro, amino, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, C3-C6-cycloalkyl; 10 Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, C3-C6-cycloalkyl; 10 Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, C3-C6-cycloalkyl; 10 Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, C3-C6-cycloalkyl; 10 C3-C6-cycloalkyl, optionally substituted with R X11 C 6-20 aryl, optionally substituted with R X11 5- to 10-membered-heteroaryl, containing 1, 2, 3, or 4 heteroatoms selected from O, S, N, optionally substituted with R X11 5- to 10-membered-heterocyclyl, containing 1, 2, 3, or 4 heteroatoms selected from O, S, N, or -NR 16 R 17 ; wherein R X11 each independently is selected from the group consisting of halogen, halogen, cyano, hydroxy, mercapto, nitro, amino, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, C3-C6-cycloalkyl; R 16 and R 17 are each independently selected from hydrogen, optionally substituted with R X12 C1-C 10 Alkyl, optionally substituted with R X12 C1-C 10 Alkoxy, optionally substituted with R X12 C3-C 10 Cycloalkyl, optionally substituted with R X12 C 6-20 Aryl, optionally substituted with R X12 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from O, S, and N, optionally substituted with R X12 A 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from O, S, and N; wherein R X12 are each independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl; or, R 16 and R 17 Together with the N atom to which they are attached, they form a 5- to 10-membered ring structure; In formula II-2, R8and R9are each independently selected from hydrogen or C1-C6alkyl, or, R8and R9together with the C atom to which they are attached form a C3-C6ring structure; n is 1, 2, or 3; Y is selected from one of the following: O, NR6, * indicates Y is attached to CR 8 R 9 the site of attachment, Indicates Y and R 10 The site of attachment; R 10 is selected from hydrogen, optionally substituted with R 30 C1-C 20 Alkyl, optionally substituted with R 30 C1-C 20 Haloalkyl, optionally substituted with R 30 C1-C 10 Alkoxy, optionally substituted with R 30 C3-C 10 Cycloalkyl, optionally substituted with R 30 C2-C 20 Alkenyl, optionally substituted with R 30 C 6-20 Aryl, optionally substituted with R 30 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from O, S, and N, optionally substituted with R 30 A 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from O, S, and N, wherein R 30 Each is independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C 6-20 Aryl, C 6-20 Aryloxy, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from O, S, and N, 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from O, S, and N, optionally substituted with R 31 C3-C6 cycloalkenyl; wherein R 31 Each is independently selected from hydrogen, halogen, C1-C6 alkyl; R6 is independently selected from hydrogen, optionally substituted with R X32 C1-C 10 Alkyl, optionally substituted with R X32 C1-C 10 Alkoxy, optionally substituted with R X32 C3-C 10 Cycloalkyl, optionally substituted with R X32 C 6-20 Aryl, optionally substituted with R X32 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from O, S, and N, optionally substituted with R X32 A 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from O, S, and N; wherein R X32 Each is independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl; R is selected from hydrogen, -C(=O)R 20 R is selected from hydrogen, -C(=O)R 21 R is selected from hydrogen, -C(=O)R 21 R is selected from hydrogen, -C(=O)R 22 R is selected from hydrogen, -C(=O)R 20 R is selected from hydrogen, -C(=O)R 22 R is selected from hydrogen, -C(=O)R 20 R is selected from hydrogen, -C(=O)R 22 R is selected from hydrogen, -C(=O)R 10 R is selected from hydrogen, -C(=O)R 22 R is selected from hydrogen, -C(=O)R 10 R is selected from hydrogen, -C(=O)R 22 R is selected from hydrogen, -C(=O)R 20 R is selected from hydrogen, -C(=O)R 22 R is selected from hydrogen, -C(=O)R 6-20 R is selected from hydrogen, -C(=O)R 22 R is selected from hydrogen, -C(=O)R 22 R is selected from hydrogen, -C(=O)R 22 R is selected from hydrogen, -C(=O)R 6-20 R is selected from hydrogen, -C(=O)R 6-20 R is selected from hydrogen, -C(=O)R 23 R is selected from hydrogen, -C(=O)R 23 R is selected from hydrogen, -C(=O)R m is 1, 2, or 3.

4. The benzotriazine dioxides or pharmaceutically acceptable salts or esters, hydrates, solvates or prodrugs thereof according to claim 3, wherein, Benzotriazine dioxide has general formula II-2 wherein R 10 selected from one of the following aromatic or heterocyclic ring structures: wherein R1is selected from H, optionally substituted with R 11 C1-C7alkyl, optionally substituted with R 11 C1-C7cycloalkyl, optionally substituted with R 11 C1-C7alkoxy, optionally substituted with R 11 C1-C7acyl, wherein R 11 is selected from halogen, hydroxy, C1-C7alkyl, C1-C7haloalkyl, C1-C7alkoxy, C1-C 12 substituted or unsubstituted aryl, C3-C 12 substituted or unsubstituted heterocyclyl.

5. The benzotriazine dioxides of claim 1, or a pharmaceutically acceptable salt or ester, hydrate, solvate or prodrug thereof, wherein, Benzotriazine dioxide has general formula II-2 R 10 selected from one of the following aromatic or heterocyclic ring structures: Among them, R 71 Selected from H, optionally substituted with R 12 C1-C7 alkyl, optionally substituted with R 12 C1-C7 cycloalkyl, optionally substituted with R 12 C1-C7 acyl, wherein R 12 selected from halogen, hydroxy, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 alkoxy, C1-C7 substituted or unsubstituted alkenyl, C1-C 12 Substituted or unsubstituted aryl, C3-C 12 a substituted or unsubstituted heterocyclic group.

6. The benzotriazine dioxides of claim 3, or a pharmaceutically acceptable salt or ester, hydrate, solvate or prodrug thereof, wherein, Benzotriazine dioxide has general formula II-2 Y is NR6; R 10 selected from hydrogen or C 1-10 alkyl, for example methyl; R6is selected from hydrogen or C 1-10 alkyl, for example methyl.

7. The benzotriazine dioxides of claim 3, or a pharmaceutically acceptable salt or ester, hydrate, solvate or prodrug thereof, wherein, Benzotriazine dioxide has general formula II-2 Y is R 10 selected from hydrogen or C 1-10 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, and hexyl.

8. The benzotriazine dioxide or pharmaceutically acceptable salt, ester, hydrate, solvate or prodrug thereof of any one of claims 3-7, wherein, X is NH, R8and R9are each independently selected from hydrogen or C1-C6alkyl, for example methyl, or, R8and R9together with the C atom to which they are attached form a C3-C6ring structure, for example a cyclopropyl structure; preferably, R8and R9are hydrogen; n is 1, 2, or 3; preferably, n is 2.

9. The benzotriazine dioxides of claim 1, or a pharmaceutically acceptable salt or ester, hydrate, solvate or prodrug thereof, wherein, The benzotriazine dioxides have the general formula II-3 wherein R 20 is selected from one of the following structures:

10. The benzotriazine dioxides of claim 1, or a pharmaceutically acceptable salt or ester, hydrate, solvate or prodrug thereof, wherein, The benzotriazine dioxides have the general formula II-3 wherein R 20 is -C(=O)R 21 wherein R 21 is selected from hydrogen, or C1-C 20 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, and hexyl.

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

12. The benzotriazine dioxides of claim 1, or a pharmaceutically acceptable salt or ester, hydrate, solvate or prodrug thereof, wherein, The benzotriazine dioxides have the following general formula III-1, wherein W1is O or NR6, R W11 R W12 R W13 each independently is selected from hydrogen or C 1-3 alkyl, or, R W12 and R W13 together with the C atom to which they are attached form a C 3-6 cycloalkyl; R6is selected from hydrogen or C 1-3 alkyl, or, when W1is NR6, R W11 and R6, together with the atoms to which they are attached, form a 4-6 membered heterocyclyl containing one N atom; R 10 is selected from hydrogen, optionally substituted with R 30 C1-C 20 Alkyl, optionally substituted with R 30 C1-C 20 Haloalkyl, optionally substituted with R 30 C1-C 10 Alkoxy, optionally substituted with R 30 C3-C 10 Cycloalkyl, optionally substituted with R 30 C2-C 20 Alkenyl, optionally substituted with R 30 C 6-20 Aryl, optionally substituted with R 30 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from O, S, and N, optionally substituted with R 30 A 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from O, S, and N, wherein R 30 Each is independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C 6-20 Aryl, C 6-20 Aryloxy, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from O, S, and N, 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from O, S, and N, optionally substituted with R 31 C3-C6 cycloalkenyl; wherein R 31 Each is independently selected from hydrogen, halogen, and C1-C6 alkyl.

13. The benzotriazine dioxide or pharmaceutically acceptable salt, ester, hydrate, solvate or prodrug thereof of claim 12, wherein, R 10 Selected from optionally substituted with R 30 C1-C 20 Alkyl, optionally substituted with R 30 C3-C 10 Cycloalkyl, optionally substituted with R 30 C 6-20 Aryl, optionally substituted with R 30 A 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from O, S, and N, R 30 is halogen, hydroxy or -NH2.

14. The benzotriazine dioxides of claim 13, or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof, wherein, R 10 selected from one of the following: cyclopropyl.

15. The benzotriazine dioxides of claim 13, or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof, wherein, R 10 is C 1-6 alkyl, for example isopropyl or tert-butyl.

16. The benzotriazine dioxide or pharmaceutically acceptable salt, ester, hydrate, solvate or prodrug thereof of any one of claims 12-15, wherein, R W11 , R W12 , and R W13 are each independently selected from hydrogen; W1is O.

17. The benzotriazine dioxide or pharmaceutically acceptable salt, ester, hydrate, solvate or prodrug thereof of any one of claims 12-15, wherein, R W12 and R W13 are each independently selected from hydrogen; R W11 is hydrogen or C 1-3 alkyl; W1is NR6, wherein R6is hydrogen or C 1-3 alkyl, or R W11 and R6and the atom to which they are attached form a 5- or 6-membered heterocyclyl ring containing one N atom.

18. The benzotriazine dioxide or pharmaceutically acceptable salt, ester, hydrate, solvate or prodrug thereof of any one of claims 12-15, wherein, R W12 and R W13 are each independently selected from hydrogen; W1is NR6, wherein R6is H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, or C6-10aryl; W11 R6and the atom to which it is attached form a 5-membered heterocyclyl containing one N atom.

19. The benzotriazine dioxides of claim 1, or a pharmaceutically acceptable salt or ester, hydrate, solvate or prodrug thereof, wherein, The benzotriazine dioxides have the following general formula III-2, wherein W2 is O or NR W25 wherein R W25 is hydrogen or C 1-3 alkyl, R W21 , R W22 and R W23 are each independently selected from hydrogen, hydroxyl or C 1-3 alkyl, or, when W2is NR W25 R W21 and R W25 and the atom to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring containing one N atom; R W24 each independently selected from the group consisting of hydrogen, C 1-3 alkyl, optionally substituted with R W20 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from O, S, N, optionally substituted with R W20 C 6-20 aryl, optionally substituted with R W20 C 6-20 aralkyl, wherein R W20 is halogen, C 1-3 alkyl or hydroxy.

20. The benzotriazine dioxide or pharmaceutically acceptable salt, ester, hydrate, solvate or prodrug thereof of claim 19, wherein, W2is O, R W21 , R W22 , and R W23 are each independently selected from hydrogen.

21. The benzotriazine dioxide or pharmaceutically acceptable salt, ester, hydrate, solvate or prodrug thereof of claim 19 or 20, wherein, R W24 selected from hydrogen, C 1-3 alkyl, optionally substituted with R W20 phenyl, wherein R W20 is halogen, e.g. fluorine, C 1-3 alkyl or hydroxyl.

22. The benzotriazine dioxide or pharmaceutically acceptable salt, ester, hydrate, solvate or prodrug thereof of claim 21, wherein, R W24 is phenyl or mono-fluoro substituted phenyl.

23. The benzotriazine dioxides of claim 1, or a pharmaceutically acceptable salt or ester, hydrate, solvate or prodrug thereof, wherein, The benzotriazine dioxides have the following general formula III-3, R W31 and R W32 each independently is selected from hydrogen, halogen, hydroxyl or C 1-3 alkyl, R W33 each independently selected from the group consisting of hydrogen, halogen, C 1-3 alkyl, optionally substituted with R W30 C W30 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, S, N, optionally substituted with R 6-20 aryl, optionally substituted with R W30 C 6-20 aralkyl, wherein R W30 is halogen, C 1-3 alkyl or hydroxy.

24. The benzotriazine dioxide or pharmaceutically acceptable salt, ester, hydrate, solvate or prodrug thereof of claim 23, wherein, R W31 and R W32 is hydrogen, R W33 each independently selected from hydrogen, halogen, C 1-3 alkyl, optionally substituted with R W30 of phenyl, wherein R W30 is halogen, e.g. fluorine, C 1-3 alkyl or hydroxyl.

25. The benzotriazine dioxide or pharmaceutically acceptable salt, ester, hydrate, solvate or prodrug thereof of claim 24, wherein, R W33 is phenyl or mono-fluoro substituted phenyl.

26. The benzotriazine dioxides of any one of claims 1-25, or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof, wherein, R3is selected from halogen, C 1-6 alkoxy, C 1-3 haloalkyl or C 3-6 cycloalkyl, for example selected from the group consisting of bromo, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, Me, Et, n Pr, i Pr, cyclopropyl, n Bu, i Bu, t Bu, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethyl, trifluoromethyl and trifluoroethyl.

27. The benzotriazine dioxides or a pharmaceutically acceptable salt or ester, hydrate, solvate or prodrug thereof according to claim 26, wherein, R 3 haloalkyl, for example trifluoromethyl, C 1-3 haloalkyl, for example trifluoromethyl, C 1-6 alkoxy, for example methoxy or C 1-3 haloalkoxy, for example trifluoromethoxy.

28. The benzotriazine dioxides or a pharmaceutically acceptable salt or ester, hydrate, solvate or prodrug thereof according to claim 26, wherein, R3is bromo.

29. The benzotriazine dioxides according to claim 26, or a pharmaceutically acceptable salt or ester, hydrate, solvate or prodrug thereof, wherein, R3is trifluoromethyl.

30. The benzotriazine dioxides of claim 1, or a pharmaceutically acceptable salt or ester, hydrate, solvate, or prodrug thereof, wherein, The benzotriazine dioxide is selected from the following compounds: A-1: 3-((2-(pyridin-3-yloxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][l,2,4]triazine 1,4-dioxide A-2: 3-(2-(3-fluorophenoxy)ethyl)amino-7-trifluoromethylbenzo[l,2,4]triazine 1,4-bioxide A-3: 3-(2-(benzyloxy)ethyl)amino)-7-trifluoromethylbenzo[l,2,4]triazine 1,4-bioxide A-4: 3-((l-methoxy-2-propyl)amino)-7-(trifluoromethyl)benzo[e][l,2,4]triazine 1,4-bioxide A-5: 3-((3-aminotetrahydrofuran)-7-(trifluoromethyl)benzo[e][l,2,4]triazine 1,4-bioxide B-1: 3-(2,2,2-trifluoroethyl)amino-7-trifluoromethylbenzo[l,2,4]triazine 1,4-bioxide B-2: 3-((3,3-difluorocyclopentyl)amino)-7-(trifluoromethyl)benzo[e][l,2,4]triazine 1,4-bioxide B-3: 3-((2-(pyridin-3-yl)ethyl)amino)-7-(trifluoromethyl)benzo[e][l,2,4]triazine 1,4-bioxide B-4: 3-((3-fluorophenyl)amino)-7-(trifluoromethyl)benzo[e][l,2,4]triazine 1,4-bioxide B-5: 7-cyclopropyl-3-((2,2,2-trifluoroethyl)amino)benzo[e][l,2,4]triazine 1,4-bioxide B-6: 7-(5-cyclopropyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-3-((2,2,2-trifluoroethyl)amino)benzo[e][l,2,4]triazine 1,4-bioxide B-7: 7-(2-chloro-6-methylpyridin-4-yl)-3-((3,3-difluorocyclopentyl)amino)benzo[e][l,2,4]triazine 1,4-bioxide B-8: 7-(2-chloro-6-methyl-l-oxidopyridin-4-yl)-3-((3,3-difluorocyclopentyl)amino)benzo[e][l,2,4]triazine 1,4-bioxide B-9: 7-(2-chloro-6-methylpyridin-4-yl)-3-((2,2,2-trifluoroethyl)amino)benzo[e][l,2,4]triazine 1,4-bioxide B-10: 7-(2-chloro-6-l-oxidopyridin-4-yl)-3-((2,2,2-trifluoroethyl)amino)benzo[e][l,2,4]triazine 1,4-bioxide C-1: 7-bromo-3-((2-ethoxy)amino)benzo[e][l,2,4]triazine 1,4-bioxide C-2: 3-((2-hydroxyethyl)amino)-7-(trifluoromethyl)benzo[e][l,2,4]triazine 1,4-bioxide C-3: 3-((2-hydroxy-2-methylpropyl)amino)-7-(trifluoromethyl)benzo[e][l,2,4]triazine 1,4-bioxide C-4: 3-((lS,4S)-4-hydroxycyclohexyl)amino)-7-trifluoromethylbenzo[e][l,2,4]triazine 1,4-bioxide C-5: 3-(2-hydroxypropyl)amino-7-trifluoromethylbenzo[l,2,4]triazine 1,4-bioxide C-6: 7-(5-cyclopropyl-4,5,6,7-tetrahydrothiophene[3,2-c]pyridin-2-yl)-3-((2- hydroxyethyl)amino)benzo[e][l,2,4]triazine 1,4-dioxide C-7: 7-bromo-3-((2-(4-fluorophenyl)-2-hydroxyethyl)amino)benzo[e][l,2,4]triazine 1,4-bioxide C-8: 7-bromo-3-((2-(isobutyryloxy)ethyl)amino)benzo[e][l,2,4]triazine 1,4-bioxide C-9: 7-bromo-3-((2-(hexadecanoyloxy)ethyl)amino)benzo[e][l,2,4]triazine 1,4-bioxide C-10: 7-bromo-3-((2-((2-bromohexadecanoyl)oxy)ethyl)amino)benzo[e][l,2,4]triazine 1,4-dioxide C-11: 3-((2-(neopentanoyloxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][l,2,4]triazine 1,4-bioxide C-12: 3-((2-(isobutyryloxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][l,2,4]triazine 1,4-bioxide C-13: 3-((2-((3-hydroxytetradecanoyl)oxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][l,2,4]triazine 1,4-dioxide C-14: 3-((2-(nicotinoyloxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][l,2,4]triazine 1,4-bioxide C-15: 3-((((2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-l-en-l-yl)nona-2,4,6,8-tetraenyl)oxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][l,2,4]triazine 1,4-bioxide C-16: 7-(trifluoromethyl)-3-((2-(propyloxy)ethyl)amino)benzo[e][l,2,4]triazine 1,4-bioxide C-17: 3-((2-((thiophene-3-carbonyl)oxy)ethyl)amino)-7-(trifluoromethyl)benzo[e][l,2,4]triazine 1,4-bioxide C-18: 3-((2-(isobutyryloxy)ethyl)amino)-7-(trifluoromethoxy)benzo[e][l,2,4]triazine 1,4-bioxide C-19: 3-(2-hydroxyethyl)amino)-7-(trifluoromethoxy)benzo[e][l,2,4]triazine 1,4-bioxide C-20: 3-((2-((2-bromohexadecanoyl)oxy)ethyl)amino)-7-(trifluoromethoxy)benzo[e][l,2,4]triazine 1,4-bioxide C-21: 6-bromo-3-((2-(isobutyryloxy)ethyl)amino)benzo[e][l,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)ethyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide C-24: 7-cyclopropyl-3-((2-(neopentanoyloxy)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]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-dioxide 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-dioxide D-5: 3-((2-neopentanamidoethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide D-6: 3-((1-neopentanoylpyrrolidin-3-yl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide D-7: 3-((1-neopentanoylazetidin-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]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-(neopentyloxy)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)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-dioxide 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 trifluoroacetate D-2': 3-(pyrrolidin-3-ylamino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide trifluoroacetate D-4': 3-((2-(methylamino)ethyl)amino)-7-(trifluoromethyl)benzo[e][1,2,4]triazine 1,4-dioxide trifluoroacetate D-16': 3-((2-aminoethyl)amino)-7-bromobenzo[e][l,2,4]triazine 1,4-dioxide trifluoroacetate salt D-17': 3-(((l-aminocyclopropyl)methyl)amino)-7-bromobenzo[e][l,2,4]triazine 1,4-dioxide hydrochloride salt D-18': (R)-3-((2-aminopropyl)amino)-7-bromobenzo[e][l,2,4]triazine 1,4-dioxide hydrochloride salt.

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

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

33. A method of treating or reducing cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of a benzotriazine dioxide according to any one of claims 1-30, or a pharmaceutically acceptable salt or ester, hydrate, solvate or prodrug thereof, or a pharmaceutical composition of 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 the group consisting of tumors of the liver, biliary tract, pancreas, stomach, esophagus, kidney, colon, lung, brain (gliomas), malignant gliomas, breast, cervix, head and neck, melanoma, skin, muscle, blood vessels, nerves, ovary, prostate, sarcomas, and thyroid, including solid tumors of endodermal, mesodermal, and ectodermal origin.

36. The method according to claim 35, wherein the cancer is selected from the group consisting of tumors of the liver, biliary tract, pancreas, stomach, esophagus, kidney, colon, lung, brain (gliomas), malignant gliomas, breast, head and neck, melanoma, ovary, prostate, sarcomas, and thyroid.

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