Nitrogen-containing compound, pharmaceutical composition and use thereof

Abstract

Provided in the present invention are a nitrogen-containing compound and the use thereof. The nitrogen-containing compound of the present invention is a compound as represented by formula (I), or a solvate, tautomer, enantiomer, diastereomer, isotopically labeled compound (preferably a deuterated compound) or pharmaceutically acceptable salt of the compound as represented by formula (I). The compound can be used in the preparation of a drug for preventing or treating inflammation-related diseases and / or diseases associated with necroptosis and autophagy.

Description

Nitrogen-containing compounds, pharmaceutical compositions and uses thereof TECHNICAL FIELD

[0001] The present application relates to the field of biological medicine, in particular to a class of nitrogen-containing compounds, pharmaceutical compositions and uses thereof, especially in the preparation of drugs for inflammatory diseases and / or cell necrotic apoptosis, autophagy-related diseases. BACKGROUND

[0002] Inflammation is a dynamic immune process initiated by the innate and adaptive immune system, aiming to protect the organism from harmful factors such as viruses, bacteria, fungi or dead cells. However, if not controlled, unresolved inflammation can lead to the development of autoimmune diseases or some chronic diseases, and is involved in multiple systems and organs such as the nervous system, endocrine system, cardiovascular system, and inflammation-related diseases. In such inflammatory diseases, the inflammatory stimulus is often difficult to accurately identify, even if it is identified, it needs to be eradicated. Therefore, it is of great significance to inhibit excessive inflammation and accelerate disease remission by treating inflammation.

[0003] Apoptosis, especially necrotic apoptosis, is a programmed cell death mode discovered in recent years and has attracted widespread attention. Its morphological characteristics are plasma membrane disintegration, organelle swelling, and cell content overflow. Necrotic apoptosis is a complementary cell death mode after the failure of apoptosis, activated by a unique caspase-independent signaling pathway, and is a characteristic cell death mode closely related to homeostasis, inflammation, cancer, neurodegenerative diseases, infectious diseases, cardiovascular diseases, and various skin diseases. Therefore, participating in the regulation of necrotic apoptosis has important diagnostic and therapeutic value for the treatment of diseases.

[0004] Autophagy is a self-degradation process that plays an important role in normal cell metabolism and response to nutritional stress. At the same time, autophagy also plays an important role in removing misfolded or aggregated proteins, eliminating damaged organelles (such as mitochondria, endoplasmic reticulum and peroxisomes), and eliminating intracellular pathogens. Autophagy has become a new and effective disease progression regulator with scientific and clinical significance in combating and treating various diseases, including infections, neurodegenerative diseases, aging-related diseases and heart disease.

[0005] Therefore, developing more new compounds that can simultaneously regulate and treat diseases from multiple perspectives such as anti-inflammatory and anti-apoptotic and autophagy activation is helpful for the treatment and prevention of inflammation-related or / and cell necrotic apoptosis-related diseases. SUMMARY

[0006] The present application aims to find small molecule drugs that are more effective in treating inflammation-related or / and cell necrotic apoptosis-related diseases of the central or peripheral system.

[0007] On one hand, the present invention provides a nitrogen-containing compound, said nitrogen-containing compound being a compound of Formula I, or a solvate, tautomer, enantiomer, diastereomer, isotope-labeled compound (preferably deuterated), or pharmaceutically acceptable salt of a compound of Formula I:

[0008] R1 and R2 are each independently selected from hydrogen, deuterium, C1-C10 alkyl, and C6-C20 aryl, or R1 and R2 are connected together with the nitrogen atom attached to them to form an unsaturated heterocycle, wherein the C1-C10 alkyl, C6-C20 aryl and the unsaturated heterocycle may optionally be substituted by one or more substituents selected from deuterium, hydroxyl, halogen, nitro, cyano, -NH2, NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, C1-C6 alkyl, C3-C10 cycloalkyl, C1-C6 alkoxy, -C(=O)OR, -C(=O)R, and C6-C20 aryl, wherein R is selected from hydrogen, deuterium, C1-C6 alkyl, and C1-C6 haloalkyl;

[0009] Z1 is selected from O, S, and NR3; R3 is selected from hydrogen, deuterium, C1-C10 alkyl, C3-C10 cycloalkyl, and C6-C20 aryl, wherein the C1-C10 alkyl, C3-C10 cycloalkyl, and C6-C20 aryl may optionally be substituted by one or more substituents selected from deuterium, hydroxyl, halogen, nitro, cyano, -NH2, NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, C1-C6 alkyl, C3-C10 cycloalkyl, C1-C6 alkoxy, -C(=O)OR, -C(=O)R, and C6-C20 aryl, wherein R is selected from hydrogen, deuterium, C1-C6 alkyl, and C1-C6 haloalkyl;

[0010] Z2 is selected from S, O, S(=O), S(=O)2, NR a and C1-C10 alkylene, R a The group is selected from hydrogen, deuterium, C1-C10 alkyl, C3-C10 cycloalkyl and C6-C20 aryl, wherein the C1-C10 alkyl, C3-C10 cycloalkyl and C6-C20 aryl may optionally be substituted by one or more substituents selected from deuterium, hydroxyl, halogen, nitro, cyano, -NH2, NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, C1-C6 alkyl, C3-C10 cycloalkyl, C1-C6 alkoxy, -C(=O)OR, -C(=O)R, C6-C20 aryl, wherein R is selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl;

[0011] R4 and R5 are each independently selected from hydrogen, deuterium, C1-C10 alkyl, C3-C10 cycloalkyl, and C6-C20 aryl, or R4 and R5 are connected together with the carbon atoms they are attached to to form a saturated or unsaturated carbocyclic or heterocyclic ring, or R4 is selected from hydrogen, deuterium, C1-C10 alkyl, C3-C10 cycloalkyl, and C6-C20 aryl, and R5 is connected to a ring atom on ring A to form a saturated or unsaturated carbocyclic or heterocyclic ring fused with ring A, wherein the C1-C10 alkyl, C3-C10 cycloalkyl, and C6-C20 aryl are... The alkyl, C6-C20 aryl, and said saturated or unsaturated carbocyclic or heterocyclic groups may optionally be substituted by one or more substituents selected from deuterium, hydroxyl, halogen, nitro, cyano, -NH2, NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, C1-C6 alkyl, C3-C10 cycloalkyl, C1-C6 alkoxy, -C(=O)OR, -C(=O)R, C6-C20 aryl, wherein R is selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl;

[0012] Ring A is selected from 4-7 membered monocyclic heteroaromatic rings, C7-C20 fused-ring heteroaromatic rings, C6-C20 aromatic rings and C1-C12 saturated or unsaturated heterocycles;

[0013] n represents the number of substituents R6 on ring A, and n is 0, 1, 2, 3, 4, 5 or 6;

[0014] R6 is independently selected from deuterium, hydroxyl, halogen, nitro, cyano, -NH2, NH-C1-C10 alkyl, -N(C1-C10 alkyl)2, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C3-C10 cycloalkyl, C6-C20 aryl, C3-C20 heteroaryl, -C(=O)OR, -C(=O)R, wherein the C1-C10 alkyl, C1-C10 alkoxy, C3-C... The 10-cycloalkyl, C6-C20 aryl, and C3-C20 heteroaryl groups may optionally be substituted with one or more substituents selected from deuterium, halogen, nitro, cyano, -NH2, NH-C1-C5 alkyl, -N(C1-C5 alkyl)2, C1-C5 alkyl, C1-C5 alkoxy, C1-C10 haloalkyl, -C(=O)OR, and -C(=O)R, wherein R is selected from hydrogen, deuterium, C1-C6 alkyl, and C1-C6 haloalkyl.

[0015] Preferably, R6 is independently selected from deuterium, halogen, nitro, cyano, amino, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C3-C10 cycloalkyl, C3-C10 cycloalkyl substituted with one or more C1-C10 haloalkyl, C6-C20 aryl, C6-C20 aryl substituted with one or more C1-C10 haloalkyl, C3-C20 heteroaryl, and C3-C20 heteroaryl substituted with one or more C1-C10 haloalkyl.

[0016] Preferably, when ring A is a C6-C20 aromatic ring, R6 is independently selected from C3-C10 cycloalkyl, C3-C10 cycloalkyl substituted with one or more C1-C10 haloalkyl, C6-C20 aryl, C6-C20 aryl substituted with one or more C1-C10 haloalkyl, C3-C20 heteroaryl, and C3-C20 heteroaryl substituted with one or more C1-C10 haloalkyl.

[0017] On the other hand, the present invention provides a pharmaceutical composition comprising the nitrogen-containing compound described above and one or more pharmaceutically acceptable excipients. The nitrogen-containing compound is a compound as shown in Formula I above, or a solvate, tautomer, enantiomer, diastereomer, isotope-labeled compound (preferably deuterated), or a pharmaceutically acceptable salt of a compound shown in Formula I above. The excipients include, but are not limited to, one or more of: diluents, fillers, binders, humectants, absorption enhancers, surfactants, lubricants, and stabilizers. In the present invention, the pharmaceutical composition may be a pharmaceutical formulation.

[0018] In another aspect, the present invention provides the use of the above-mentioned nitrogen-containing compounds or the above-mentioned pharmaceutical compositions in the preparation of medicaments for the prevention or treatment of inflammation-related diseases and / or cell necrosis and apoptosis, autophagy-related diseases, particularly in the preparation of medicaments for the prevention or treatment of inflammatory central nervous system conditions or diseases, inflammatory peripheral system conditions or diseases.

[0019] According to some embodiments of the present invention, the central nervous system conditions or diseases with inflammation-related diseases and / or cell necrosis and apoptosis, autophagy-related diseases as the main pathogenic mechanism, such as stroke, Parkinson's disease, Alzheimer's disease, etc., or peripheral system conditions or diseases, such as dry eye syndrome, osteoarthritis, inflammatory bowel diseases such as ulcerative colitis, Crohn's disease, etc.

[0020] In another aspect, the present invention provides a method for preventing or treating acute or chronic central or peripheral system diseases related to inflammation and / or necroptosis, autophagy, the method comprising administering the above-described nitrogen-containing compound or pharmaceutical composition of the present invention to a subject in need.

[0021] In another aspect, the present invention provides a method for regulating inflammation, apoptosis, and autophagy in cells or a subject, the method comprising contacting cells with the nitrogen-containing compound or pharmaceutical composition described above; or administering the nitrogen-containing compound or pharmaceutical composition described above to a subject. In some embodiments, the cells are mammalian cells. In some embodiments, the subject is a mammal, preferably a human.

[0022] This application proposes a new class of compounds that can prevent or treat acute or chronic central or peripheral system diseases related to inflammation and / or necrosis-apoptosis through pharmacological mechanisms of anti-inflammation, anti-apoptosis, and activation of autophagy. Furthermore, this application demonstrates that these compounds possess excellent anti-inflammatory and anti-apoptotic effects, and can treat acute or chronic central or peripheral system diseases related to inflammation and / or necrosis-apoptosis. Attached Figure Description

[0023] Figures 1A, 1B, and 1C show the experimental results of the anti-Jurkat cell apoptosis of the compound synthesized in Example 1 of this application.

[0024] Figures 2A, 2B, and 2C show the anti-inflammatory experimental results of the compound synthesized in Example 1 of this application on LPS-stimulated BV2.

[0025] Figure 3 shows the effect of the compound synthesized in Example 1 of this application on the activation of autophagy.

[0026] Figure 4 shows the treatment results of the compound synthesized in Example 1 of this application on dry eye syndrome.

[0027] Figure 5 shows the therapeutic effect of the compound synthesized in Example 1 of this application on osteoarthritis.

[0028] Figure 6 is a graph showing the therapeutic effect of the compound synthesized in Example 1 of this application on ischemic stroke.

[0029] Figure 7 is a graph showing the treatment results of the compound synthesized in Example 1 of this application on Parkinson's disease.

[0030] Figure 8 is a graph showing the therapeutic effect of the compound synthesized in Example 1 of this application on enteritis.

[0031] Figure 9 shows the treatment results of the compound synthesized in Example 1 of this application on Alzheimer's disease. Detailed Implementation

[0032] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments and accompanying drawings. The specific embodiments described herein are for illustrative purposes only and are not intended to limit the scope of the invention in any way.

[0033] The term "alkyl" itself, or as part of another substituent, refers to a straight-chain or branched hydrocarbon group having a specified number of carbon atoms. C1-C10 refers to a straight-chain or branched hydrocarbon group containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and similar alkyl groups.

[0034] The term "cycloalkyl" itself, or as part of another substituent, refers to the cyclic form of an alkyl group, which is a non-aromatic cyclic hydrocarbon. Cycloalkyl groups can include monocyclic alkyl groups or polycyclic alkyl groups (e.g., having 2, 3, or 4 fused rings, bridged rings, or spirocyclic alkyl groups). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norcamphenyl, norpineyl, norcareyl, adamantyl, etc. The term "monocyclic alkyl" refers to a cycloalkyl group having one ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. The term "polycyclic alkyl" refers to a cycloalkyl group having two or more rings, such as bridged cycloalkyl groups (e.g., bicyclic alkyl, tricyclic alkyl, tetracyclic alkyl, fused cycloalkyl, etc.) and spirocyclic alkyl groups. "C3-C6 cycloalkyl" indicates a cycloalkyl group having 3-6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups.

[0035] The term "C1-C10 alkyl group substituted with C3-C10 cycloalkyl groups" refers to an alkyl group having 1-10 carbon atoms in which one or more hydrogen atoms attached to a carbon atom are substituted with a cycloalkyl group having 3-10 carbon atoms, such as methyl groups substituted with cyclopropane (cyclopropylmethyl). ).

[0036] The term "halogen" includes, but is not limited to, fluorine, chlorine, bromine, iodine, etc.

[0037] The term “halogenated alkyl”, either on its own or as part of another substituent, refers to a group consisting of any of the aforementioned halogens and an alkyl group (RX), i.e., a group in which one or more hydrogen atoms in the alkyl group are replaced by a halogen, examples of which include methyl chloride, trifluoromethyl, isopropyl bromide, tert-butyl chloride, etc.

[0038] The term "alkoxy" itself, or as part of another substituent, refers to a group consisting of any of the aforementioned alkyl groups and oxygen (alkyl-O- groups), and examples of such groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, etc.

[0039] The term "aryl" itself, or as part of another substituent, refers to an aromatic monocyclic or polycyclic system consisting of carbon atoms as ring atoms. Aryl can be a monocyclic aryl, a fused-ring aryl, two or more monocyclic aryl groups conjugated by carbon-carbon bonds, a monocyclic aryl and a fused-ring aryl group conjugated by carbon-carbon bonds, or two or more fused-ring aryl groups conjugated by carbon-carbon bonds. "Biaryl" refers to two or more aromatic groups conjugated by carbon-carbon bonds; unless otherwise stated, "biaryl" may also be considered as the aryl in this application. Fused-ring aryl can include, for example, bicyclic fused aryl (e.g., naphthyl), tricyclic fused aryl (e.g., phenanthrene, fluorenyl, anthracene), etc. Examples of aryl include, but are not limited to, phenyl, naphthyl, fluorenyl, anthracene, phenanthrene, biphenyl, terphenyl, benzo[9,10]phenanthrene, pyrene, benzofluoranthracene, etc. Base, etc.

[0040] The term “fused cycloalkylaryl”, either on its own or as part of another substituent, refers to a group having one or more aromatic rings fused to a cycloalkyl ring (i.e., sharing a bond with the cycloalkyl ring), such as benzo[i]indanyl derivatives of cyclopentane, benzo[i]indanyl derivatives of cyclopentene, benzo[i]indanyl derivatives of cyclohexane, 5,6,7,8-tetrahydro-2-naphthyl, etc.

[0041] The term "heteroaryl" itself, or as part of another substituent, refers to an aromatic monocyclic or polycyclic system (including fused rings) consisting of at least one carbon atom and one or more heteroatoms as ring atoms. The heteroatoms include, but are not limited to, B, N, O, S, P, Si, Se, etc. Examples of heteroaryl groups include, but are not limited to, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isooxazolyl, 4-isooxazolyl, 5-isooxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrroleyl, 2-pyrroleyl, pyrazinyl, 3-pyrroleyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl pyridyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, benzimidazolyl, benzofuranyl, benzothiopheneyl, indoleyl (e.g., 2-indoleyl), purineyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g., 1-isoquinolinyl, 3-... Isoquinolinyl or 4-isoquinolinyl), imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridyl, etc.

[0042] The term "monocyclic heteroaryl ring" itself or as part of another substituent refers to a heteroaryl group having one ring, such as a 5-6 membered monocyclic heteroaryl ring, including but not limited to: pyridine, pyrimidine, furan, thiophene, pyrrole, thiazole, imidazole, pyrazole, oxazole, pyran, pyridazine, etc.

[0043] The term "fused heteroaromatic ring" itself, or as part of another substituent, refers to a group having one or more heteroaromatic rings fused with (i.e. sharing bonds with) aromatic rings, heteroaromatic rings, cycloalkyl rings, heterocycloalkyl rings, etc., such as quinoline rings, isoquinoline rings, indole rings, benzimidazole rings, benzothiazole rings, benzoxazole rings, 5-aza-6-indanyl, pyrido derivatives of cyclopentane, pyrido derivatives of cyclohexane, etc.

[0044] The term "pharmaceutically acceptable," as used in the compositions of the present invention, means the molecular whole and other components of such compositions that are physiologically tolerable and generally do not produce adverse reactions when administered to mammals (e.g., humans).

[0045] The term "isomer" refers to compounds that have the same molecular formula but differ in structure ("structural isomer") or the geometrical orientation of functional groups and / or atoms ("stereoisomer"). "Enantiomers" are a pair of mirror-image, non-overlapping stereoisomers. "Diabeta-isomers" are mirror-image, non-overlapping stereoisomers. A "tautomer" is one of two or more structural isomers that exist in equilibrium and readily convert from one isomer to another. This conversion results in the migration of hydrogen atoms and is accompanied by the conversion of adjacent conjugated double bonds. Chemical equilibrium of tautomers can be achieved in solutions where tautomerization is possible. The exact proportions of tautomers depend on several factors, including temperature, solvent, and pH. The concept that tautomers can interconvert through tautomerization is called tautomerism. Common tautomer pairs are: keto-enol, amide-nitrile, lactam-lactamimide, amide-imine tautomerism in heterocycles (e.g., in nucleic acid bases such as guanine, thymine, and cytosine), imine-enamine, and enamine-enamine. An example of a keto-enol equilibrium is between pyridin-2(1H)-one and the corresponding pyridin-2-ol. It should be understood that the compounds of the present invention can be described as different tautomers. It should also be understood that when a compound has tautomer forms, all tautomer forms are intended to be included within the scope of the invention, and the naming of the compound does not exclude any tautomer form. It should be understood that some tautomers may have higher levels of activity than others.

[0046] Examples of isotopes suitable for incorporation into the compounds of the present invention include: isotopes of hydrogen (e.g., 2 H and 3 H), carbon isotopes (e.g., 11 C 13 C and 14 C) Isotopes of chlorine (e.g., 36 Cl), isotopes of fluorine (e.g., 18 F), isotopes of iodine (e.g., 123 I and 125 I) Isotopes of nitrogen (e.g., 13 N and 15 N), isotopes of oxygen (e.g., 15 O、 17 O and 18 O), isotopes of phosphorus (e.g., 32 P) and isotopes of sulfur (e.g.,35 S), etc.

[0047] The compounds of this invention may be in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" means that these have the bioavailability and properties of the parent compound and are not biologically or otherwise undesirable salts. The nature of the salt is not strictly required, but it is essential that it is non-toxic and does not substantially interfere with the desired pharmacological activity. Suitable anions for forming pharmaceutically acceptable salts include chloride, bromide, iodide, sulfate, bisulfate, aminosulfonate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronide, glutarate, malate, maleate, succinate, fumarate, tartrate, toluenesulfonate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

[0048] The term "solvent" refers to a solvation form containing stoichiometric or non-stoichiometric amounts of solvent. Some compounds tend to trap a fixed molar ratio of solvent molecules in their crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate; if the solvent is an alcohol, the solvate formed is an alcohol. A hydrate is formed when one or more water molecules combine with one molecule of a substance, where the water retains its molecular state (H₂O). Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0049] The term “treatment” encompasses both preventative and remedial treatment, including reversing, alleviating, mitigating, or slowing the progression of a disease (or symptom or condition) or any tissue damage associated with one or more symptoms of the disease (or symptom or condition).

[0050] Nitrogen-containing compounds of the present invention

[0051] This invention provides a nitrogen-containing compound, which is a compound of Formula I, or a solvate, tautomer, enantiomer, diastereomer, isotope-labeled compound (preferably deuterated), or pharmaceutically acceptable salt of a compound of Formula I.

[0052] R1 and R2 are each independently selected from hydrogen, deuterium, C1-C10 alkyl, and C6-C20 aryl, or R1 and R2 are connected together with the nitrogen atom attached to them to form an unsaturated heterocycle, wherein the C1-C10 alkyl, C6-C20 aryl and the unsaturated heterocycle may optionally be substituted by one or more substituents selected from deuterium, hydroxyl, halogen, nitro, cyano, -NH2, NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, C1-C6 alkyl, C3-C10 cycloalkyl, C1-C6 alkoxy, -C(=O)OR, -C(=O)R, and C6-C20 aryl, wherein R is selected from hydrogen, deuterium, C1-C6 alkyl, and C1-C6 haloalkyl;

[0053] Z1 is selected from O, S, and NR3; R3 is selected from hydrogen, deuterium, C1-C10 alkyl, C3-C10 cycloalkyl, and C6-C20 aryl, wherein the C1-C10 alkyl, C3-C10 cycloalkyl, and C6-C20 aryl may optionally be substituted by one or more substituents selected from deuterium, hydroxyl, halogen, nitro, cyano, -NH2, NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, C1-C6 alkyl, C3-C10 cycloalkyl, C1-C6 alkoxy, -C(=O)OR, -C(=O)R, and C6-C20 aryl, wherein R is selected from hydrogen, deuterium, C1-C6 alkyl, and C1-C6 haloalkyl;

[0054] Z2 is selected from S, O, S(=O), S(=O)2, NR a and C1-C10 alkylene, R a The group is selected from hydrogen, deuterium, C1-C10 alkyl, C3-C10 cycloalkyl and C6-C20 aryl, wherein the C1-C10 alkyl, C3-C10 cycloalkyl and C6-C20 aryl may optionally be substituted by one or more substituents selected from deuterium, hydroxyl, halogen, nitro, cyano, -NH2, NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, C1-C6 alkyl, C3-C10 cycloalkyl, C1-C6 alkoxy, -C(=O)OR, -C(=O)R, C6-C20 aryl, wherein R is selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl;

[0055] R4 and R5 are each independently selected from hydrogen, deuterium, C1-C10 alkyl, C3-C10 cycloalkyl, and C6-C20 aryl, or R4 and R5 are connected together with the carbon atoms they are attached to to form a saturated or unsaturated carbocyclic or heterocyclic ring, or R4 is selected from hydrogen, deuterium, C1-C10 alkyl, C3-C10 cycloalkyl, and C6-C20 aryl, and R5 is connected to a ring atom on ring A to form a saturated or unsaturated carbocyclic or heterocyclic ring fused with ring A, wherein the C1-C10 alkyl, C3-C10 cycloalkyl, and C6-C20 aryl are... The alkyl, C6-C20 aryl, and said saturated or unsaturated carbocyclic or heterocyclic groups may optionally be substituted by one or more substituents selected from deuterium, hydroxyl, halogen, nitro, cyano, -NH2, NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, C1-C6 alkyl, C3-C10 cycloalkyl, C1-C6 alkoxy, -C(=O)OR, -C(=O)R, C6-C20 aryl, wherein R is selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl;

[0056] Ring A is selected from 4-7 membered monocyclic heteroaromatic rings, C7-C20 fused-ring heteroaromatic rings, C6-C20 aromatic rings and C1-C12 saturated or unsaturated heterocycles;

[0057] n represents the number of substituents R6 on ring A, and n is 0, 1, 2, 3, 4, 5 or 6;

[0058] R6 is independently selected from deuterium, hydroxyl, halogen, nitro, cyano, -NH2, NH-C1-C10 alkyl, -N(C1-C10 alkyl)2, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C3-C10 cycloalkyl, C6-C20 aryl, C3-C20 heteroaryl, -C(=O)OR, -C(=O)R, wherein the C1-C10 alkyl, C1-C10 alkoxy, C3-C... The 10-cycloalkyl, C6-C20 aryl, and C3-C20 heteroaryl groups may optionally be substituted with one or more substituents selected from deuterium, halogen, nitro, cyano, -NH2, NH-C1-C5 alkyl, -N(C1-C5 alkyl)2, C1-C5 alkyl, C1-C5 alkoxy, C1-C10 haloalkyl, -C(=O)OR, and -C(=O)R, wherein R is selected from hydrogen, deuterium, C1-C6 alkyl, and C1-C6 haloalkyl.

[0059] Preferably, R6 is independently selected from deuterium, halogen, nitro, cyano, amino, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C3-C10 cycloalkyl, C3-C10 cycloalkyl substituted with one or more C1-C10 haloalkyl, C6-C20 aryl, C6-C20 aryl substituted with one or more C1-C10 haloalkyl, C3-C20 heteroaryl, and C3-C20 heteroaryl substituted with one or more C1-C10 haloalkyl.

[0060] Preferably, when ring A is a C6-C20 aromatic ring, R6 is independently selected from C3-C10 cycloalkyl, C3-C10 cycloalkyl substituted with one or more C1-C10 haloalkyl, C6-C20 aryl, C6-C20 aryl substituted with one or more C1-C10 haloalkyl, C3-C20 heteroaryl, and C3-C20 heteroaryl substituted with one or more C1-C10 haloalkyl.

[0061] Alternatively, in another aspect of this application, the present invention provides a nitrogen-containing compound, which is a compound of Formula I, or a solvate, tautomer, enantiomer, diastereomer, isotope-labeled compound (preferably deuterated), or pharmaceutically acceptable salt of a compound of Formula I:

[0062] R1 and R2 are each independently selected from hydrogen, deuterium, C1-C10 alkyl, and C6-C20 aryl, or R1 and R2 are connected together with the nitrogen atom attached to them to form an unsaturated heterocycle. The C1-C10 alkyl, C6-C20 aryl and the unsaturated heterocycle may optionally be substituted by one or more substituents selected from deuterium, hydroxyl, halogen, nitro, cyano, -NH2, NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, C1-C6 alkyl, C3-C10 cycloalkyl, C1-C6 alkoxy, -C(=O)OR, -C(=O)R, and C6-C20 aryl, wherein R is selected from hydrogen, deuterium, C1-C6 alkyl, and C1-C6 haloalkyl.

[0063] Z1 is selected from O, S, and NR3; R3 is selected from hydrogen, deuterium, C1-C10 alkyl, C3-C10 cycloalkyl, and C6-C20 aryl, wherein the C1-C10 alkyl, C3-C10 cycloalkyl, and C6-C20 aryl may optionally be substituted by one or more substituents selected from deuterium, hydroxyl, halogen, nitro, cyano, -NH2, NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, C1-C6 alkyl, C3-C10 cycloalkyl, C1-C6 alkoxy, -C(=O)OR, -C(=O)R, and C6-C20 aryl, wherein R is selected from hydrogen, deuterium, C1-C6 alkyl, and C1-C6 haloalkyl; or, when Z1 is NR3, R1 and R3 together with the N atom to which they are attached form a 4-8 membered heterocycle;

[0064] Z2 is selected from S, O, S(=O), S(=O)2, NR a and C1-C10 alkylene, R aThe group is selected from hydrogen, deuterium, C1-C10 alkyl, C3-C10 cycloalkyl and C6-C20 aryl, wherein the C1-C10 alkyl, C3-C10 cycloalkyl and C6-C20 aryl may optionally be substituted by one or more substituents selected from deuterium, hydroxyl, halogen, nitro, cyano, -NH2, NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, C1-C6 alkyl, C3-C10 cycloalkyl, C1-C6 alkoxy, -C(=O)OR, -C(=O)R, C6-C20 aryl, wherein R is selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl;

[0065] R4 and R5 are each independently selected from hydrogen, deuterium, C1-C10 alkyl, C3-C10 cycloalkyl, and C6-C20 aryl, or R4 and R5 are connected together with the carbon atoms they are attached to to form a saturated or unsaturated carbocyclic or heterocyclic ring, or R4 is selected from hydrogen, deuterium, C1-C10 alkyl, C3-C10 cycloalkyl, and C6-C20 aryl, and R5 is connected to a ring atom on ring A to form a saturated or unsaturated carbocyclic or heterocyclic ring fused with ring A, wherein the C1-C10 alkyl, C3-C10 cycloalkyl, and C6-C20 aryl are... The alkyl, C6-C20 aryl, and said saturated or unsaturated carbocyclic or heterocyclic groups may optionally be substituted by one or more substituents selected from deuterium, hydroxyl, halogen, nitro, cyano, -NH2, NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, C1-C6 alkyl, C3-C10 cycloalkyl, C1-C6 alkoxy, -C(=O)OR, -C(=O)R, C6-C20 aryl, wherein R is selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl;

[0066] Ring A is selected from 4-7 membered monocyclic heteroaromatic rings, C7-C20 fused-ring heteroaromatic rings, C6-C20 aromatic rings and C1-C12 saturated or unsaturated heterocycles;

[0067] n represents the number of substituents R6 on ring A, and n is 0, 1, 2, 3, 4, 5 or 6;

[0068] R6 is independently selected from deuterium, hydroxyl, halogen, nitro, cyano, -NH2, NH-C1-C10 alkyl, -N(C1-C10 alkyl)2, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C3-C10 cycloalkyl, C6-C20 aryl, C3-C20 heteroaryl, -C(=O)OR, -C(=O)R, wherein the C1-C10 alkyl, C1-C10 alkoxy, C3-C... The 10-cycloalkyl, C6-C20 aryl, and C3-C20 heteroaryl groups may optionally be substituted with one or more substituents selected from deuterium, halogen, nitro, cyano, -NH2, NH-C1-C5 alkyl, -N(C1-C5 alkyl)2, C1-C5 alkyl, C1-C5 alkoxy, C1-C10 haloalkyl, -C(=O)OR, and -C(=O)R, wherein R is selected from hydrogen, deuterium, C1-C6 alkyl, and C1-C6 haloalkyl.

[0069] Preferably, R6 is independently selected from deuterium, halogen, nitro, cyano, amino, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C3-C10 cycloalkyl, C3-C10 cycloalkyl substituted with one or more C1-C10 haloalkyl, C6-C20 aryl, C6-C20 aryl substituted with one or more C1-C10 haloalkyl, C3-C20 heteroaryl, and C3-C20 heteroaryl substituted with one or more C1-C10 haloalkyl.

[0070] Preferably, when ring A is a C6-C20 aromatic ring, R6 is independently selected from C3-C10 cycloalkyl, C3-C10 cycloalkyl substituted with one or more C1-C10 haloalkyl, C6-C20 aryl, C6-C20 aryl substituted with one or more C1-C10 haloalkyl, C3-C20 heteroaryl, and C3-C20 heteroaryl substituted with one or more C1-C10 haloalkyl.

[0071] In some embodiments, R1 is selected from hydrogen, deuterium, C1-C10 alkyl, and C6-C20 aryl;

[0072] R2 is selected from hydrogen, deuterium, C1-C10 alkyl and C6-C20 aryl;

[0073] Z1 is selected from O, S, and NR3; R3 is selected from hydrogen, deuterium, C1-C10 alkyl, C3-C10 cycloalkyl, and C6-C20 aryl;

[0074] Z2 is selected from S, O, O=S=O, NR a and C1-C10 alkylene groups; R a Selected from hydrogen, deuterium, C1-C10 alkyl, C3-C10 cycloalkyl, and C6-C20 aryl;

[0075] R4 is selected from hydrogen, deuterium, C1-C10 alkyl, C3-C10 cycloalkyl, C6-C20 aryl, C1-C10 alkyl substituted with C3-C10 cycloalkyl, and C1-C10 alkyl substituted with C6-C20 aryl.

[0076] R5 is selected from hydrogen, deuterium, C1-C10 alkyl, C3-C10 cycloalkyl, C6-C20 aryl, C1-C10 alkyl substituted with C3-C10 cycloalkyl, and C1-C10 alkyl substituted with C6-C20 aryl.

[0077] Ring A is selected from 4-7 membered monocyclic heteroaromatic rings, C7-C20 fused-ring heteroaromatic rings, C6-C20 aromatic rings and C1-C12 saturated or unsaturated heterocycles;

[0078] n represents the number of substituents R6 on ring A, and n is 0, 1, 2, 3, 4, 5 or 6;

[0079] R6 is independently selected from hydrogen, deuterium, halogen, nitro, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C3-C10 cycloalkyl, C3-C10 cycloalkyl substituted with one or more C1-C10 haloalkyl groups, C6-C20 aryl, C6-C20 aryl substituted with one or more C1-C10 haloalkyl groups, C3-C20 heteroaryl, and substituted with one or more C1-C10 haloalkyl groups. The C3-C20 heteroaryl group; preferably, when ring A is a C6-C20 aromatic ring, R6 is independently selected from C3-C10 cycloalkyl, C3-C10 cycloalkyl substituted with one or more C1-C10 haloalkyl, C6-C20 aryl, C6-C20 aryl substituted with one or more C1-C10 haloalkyl, C3-C20 heteroaryl, and C3-C20 heteroaryl substituted with one or more C1-C10 haloalkyl.

[0080] Alternatively, R1 and R2, together with the nitrogen atom they are attached to, can form an unsaturated heterocycle;

[0081] Alternatively, R4 and R5 can be linked together with the carbon atoms they are attached to to form saturated or unsaturated carbon rings or heterocycles.

[0082] According to some embodiments of the present invention, R1 is selected from hydrogen, deuterium, C1-C6 alkyl, and C6-C12 aryl, such as phenyl. In some embodiments, R1 is selected from hydrogen and C1-C6 alkyl. In some embodiments, R1 is selected from hydrogen and C1-C4 alkyl. In some specific embodiments, R1 is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. In some embodiments, R1 is selected from hydrogen, deuterium, methyl, and ethyl. In some embodiments, R1 is selected from methyl and ethyl.

[0083] According to some embodiments of the present invention, R2 is selected from hydrogen, deuterium, C1-C6 alkyl, and C6-C12 aryl, such as phenyl. In some embodiments, R2 is selected from hydrogen and C1-C6 alkyl. In some embodiments, R2 is selected from hydrogen and C1-C4 alkyl. In some specific embodiments, R2 is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. In some embodiments, R2 is selected from hydrogen, deuterium, methyl, and ethyl. In some embodiments, R1 is selected from methyl and ethyl.

[0084] According to some embodiments of the present invention, R1 and R2, together with the nitrogen atom they are attached to, are connected to form a 5-membered, 6-membered, or 7-membered ring, for example...

[0085] According to some embodiments of the present invention, Z1 is selected from O and S.

[0086] According to some embodiments of the present invention, Z1 is selected from NR3; R3 is selected from hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, and C6-C12 aryl. In some embodiments, R3 is selected from hydrogen, deuterium, C1-C6 alkyl, and C3-C8 cycloalkyl. In some embodiments, R3 is selected from hydrogen, deuterium, C1-C4 alkyl, and C3-C6 cycloalkyl. In some embodiments, R3 is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, R3 is selected from hydrogen, deuterium, methyl, and cyclopropyl.

[0087] According to some embodiments of the present invention, Z2 is selected from S, O, O=S=O, NR a and C1-C6 alkylene; R a Z2 is selected from hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, and C6-C12 aryl. In some embodiments, Z2 is selected from S, O, O=S=O, and NR. a and C1-C4 alkylene; R a It is selected from hydrogen, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl, and phenyl. In some embodiments, Z2 is O or S. In some embodiments, Z2 is S.

[0088] According to some embodiments of the present invention, the compound shown in Formula I has the structure shown in Formula II:

[0089] The definitions of R1, R2, R3, R4, R5, R6, Z2, ring A, and n are the same as those defined in the foregoing of this invention.

[0090] According to some embodiments of the present invention, the compound shown in Formula I has the structure shown in Formula II:

[0091] The definitions of R1, R2, R3, R4, R5, R6, Z2, ring A, and n are the same as those defined in the foregoing definition of this invention; or, R1 and R3 together with the N atoms they are attached to form a 4-8 membered ring, such as a azirmonobutane ring, an azirmonopentane ring, or an azirmonohexane ring.

[0092] According to some embodiments of the present invention, the compound shown in Formula I has the structure shown in Formula III:

[0093] Where m is 1, 2 or 3; the definitions of Z2, R3, R4, R5, R6, ring A and n are the same as those defined above in this invention.

[0094] According to some embodiments of the present invention, the compound shown in Formula I has the structure shown in Formula I-1, Formula I-2 or Formula I-3:

[0095] Where m is 1, 2 or 3; the definitions of Z2, R4, R5, R6, ring A and n are the same as those defined above in this invention.

[0096] According to some embodiments of the present invention, the compound shown in Formula I has the structure shown in Formula I-4 or Formula I-5:

[0097] Where m is 1, 2 or 3; the definitions of R3, R4, R5, R6, ring A and n are the same as those defined above in this invention.

[0098] According to some embodiments of the present invention, the compound shown in Formula I has the structure shown in Formula IV:

[0099] The definitions of R3, R4, R5, R6, ring A, and n are the same as those defined in the foregoing of this invention.

[0100] According to some embodiments of the present invention, R4 is selected from hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl substituted with C3-C8 cycloalkyl, C1-C6 alkyl substituted with C6-C12 aryl, and C6-C12 aryl. In some embodiments, R4 is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, phenyl, and benzyl.

[0101] According to some embodiments of the present invention, R4 is selected from hydrogen, deuterium, C1-C6 alkyl, and C1-C6 alkyl substituted with C6-C12 aryl (e.g., phenyl). According to some embodiments of the present invention, R4 is selected from hydrogen, deuterium, C1-C4 alkyl, and C1-C4 alkyl substituted with phenyl. According to some embodiments of the present invention, R4 is selected from hydrogen, deuterium, C1-C3 alkyl, and C1-C3 alkyl substituted with phenyl. In some embodiments, R4 is selected from hydrogen, deuterium, methyl, ethyl, and benzyl.

[0102] According to some embodiments of the present invention, R5 is selected from hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl substituted with C3-C8 cycloalkyl, C1-C6 alkyl substituted with C6-C12 aryl, and C6-C12 aryl. In some embodiments, R5 is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, phenyl, and benzyl.

[0103] According to some embodiments of the present invention, R5 is selected from hydrogen, deuterium, C1-C6 alkyl, and C1-C6 alkyl substituted with C6-C12 aryl (e.g., phenyl). According to some embodiments of the present invention, R5 is selected from hydrogen, deuterium, C1-C4 alkyl, and C1-C4 alkyl substituted with phenyl. According to some embodiments of the present invention, R5 is selected from hydrogen, deuterium, C1-C3 alkyl, and C1-C3 alkyl substituted with phenyl. In some embodiments, R5 is selected from hydrogen, deuterium, methyl, ethyl, and benzyl. In some embodiments, R5 is hydrogen, deuterium, methyl, or ethyl. In some embodiments, R5 is hydrogen. In some embodiments, R5 is methyl.

[0104] According to some embodiments of the present invention, R4 and R5, together with their attached carbon atoms, are connected to form 3, 4, 5, 6, or 7-membered saturated or unsaturated carbon rings or heterocycles. In some embodiments, R4 and R5, together with their attached carbon atoms, are connected to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups.

[0105] According to some embodiments of the present invention, R4 is selected from hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl substituted with C3-C8 cycloalkyl, C1-C6 alkyl substituted with C6-C12 aryl, and C6-C12 aryl. R5 is connected to a ring atom on ring A to form a 5-7 member saturated or unsaturated carbon ring or heterocycle fused with ring A. In some embodiments, R5 is connected to a ring atom on ring A to form a 5- or 6-membered nitrogen-containing heterocycle fused with ring A. In some embodiments, R5 is connected to an adjacent ring atom on ring A to form a 5- or 6-membered nitrogen-containing heterocycle fused with ring A. In some embodiments, R5 is connected to a ring atom on ring A to form a pyrrole ring, dihydropyrrole ring, tetrahydropyrrole ring, imidazole ring, imidazoline ring, imidazoline ring, pyridine ring, pyrimidine ring, piperidine ring, or piperazine ring fused with ring A. In some embodiments, R5 connects to an adjacent ring atom on ring A to form a pyrrole ring, dihydropyrrole ring, tetrahydropyrrole ring, imidazole ring, imidazoleline ring, imidazolealkyl ring, pyridine ring, pyrimidine ring, piperidine ring, or piperazine ring fused to ring A. In some embodiments, R5 connects to an adjacent ring atom on ring A to form In some embodiments, R5 is attached to an adjacent ring atom on ring A to form a group selected from:

[0106] According to some embodiments of the present invention, ring A is selected from 5-6 membered monocyclic heteroaromatic rings, C7-C12 fused heteroaromatic rings, C6-C12 aromatic rings, and C6-C12 saturated or unsaturated heterocycles. According to some embodiments of the present invention, ring A is selected from 5-6 membered monocyclic heteroaromatic rings, C7-C12 fused heteroaromatic rings, C6-C12 aromatic rings, and C6-C12 unsaturated heterocycles. According to some embodiments of the present invention, ring A is selected from 5-6 membered monocyclic heteroaromatic rings, C7-C12 fused heteroaromatic rings, and C6-C12 saturated or unsaturated heterocycles. The inventors of this application have also unexpectedly discovered that, compared to compounds where ring A is a benzene ring, when ring A is a group containing heteroatoms (e.g., 5-6 membered monocyclic heteroaromatic rings, C7-C12 fused heteroaromatic rings, and C6-C12 saturated or unsaturated heterocycles), and When at least one heteroatom is present in the adjacent position of the position connected to ring A, the resulting compound has significantly higher efficacy. This embodiment is the preferred embodiment of this application.

[0107] According to some embodiments of the present invention, ring A is selected from the group consisting of the following structures:

[0108] Among them, X1, X2, X3, X4, X5, and X6 are each independently selected from N and CH, and Y is independently selected from NH, O, S, and CH2; t1 and t2 are each independently 0, 1, 2, 3, 4, 5, or 6; *- indicates ring A and The connection position. In some implementations, when X1 is CH, X2 is not CH, and Y is not CH2. In some implementations, any one or two of X3, X4, X5, and X6 are N, or X3, X4, X5, and X6 are all CH.

[0109] According to some embodiments of the present invention, the following structures may be selected for ring A. At least one of X1 and Y is a heteroatom, for example, X1 can be N and Y can be CH2; or X1 can be CH and Y can be NH, O or S. Even more specifically, both X1 and Y can be heteroatoms, for example, X1 can be N and Y can be NH, O or S. Embodiments containing such a ring A are a preferred embodiment of this application.

[0110] According to some embodiments of the present invention, the following structures may be selected for ring A.

[0111] At least one of X1 and X2 is a heteroatom, such as N. For example, X1 can be N and X2 can be CH; or X1 can be CH and X2 can be N. Even more specifically, both X1 and X2 can be heteroatoms, such as N. An embodiment containing such a ring A is another preferred embodiment of this application.

[0112] According to some embodiments of the present invention, ring A is not a benzene ring.

[0113] According to some embodiments of the present invention, ring A is selected from the group consisting of the following structures:

[0114] Where X1 is independently selected from N and CH, and Y is independently selected from NH, O, and S; *- indicates ring A and The location of the connection. An embodiment including such a ring A is another preferred embodiment of this application.

[0115] According to some embodiments of the present invention, ring A is selected from the group consisting of the following structures:

[0116] Where X1 is independently selected from N and CH, and Y is independently selected from NH, O, and S; *- indicates ring A and The location of the connection. An embodiment including such a ring A is another preferred embodiment of this application.

[0117] According to some embodiments of the present invention, ring A is selected from the group consisting of the following structures:

[0118] *- indicates the position where ring A is connected to -CR4R5.

[0119] According to some embodiments of the present invention, ring A is selected from the group consisting of the following structures:

[0120] * indicates the position where ring A is connected to -CR4R5. In these embodiments, ring A is a group containing heteroatoms (e.g., a 5-6 membered monocyclic heteroaromatic ring, a C7-C12 fused heteroaromatic ring, and a C6-C12 saturated or unsaturated heterocycle), and An embodiment containing a ring A is another preferred embodiment of this application, wherein at least one heteroatom is present in the adjacent position of the position connected to the ring A.

[0121] According to some embodiments of the present invention, R6 is independently selected from hydrogen, deuterium, halogen, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one or more C3-C6 cycloalkyl groups, C3-C6 cycloalkyl substituted with one or more C1-C6 haloalkyl groups, C6-C12 aryl, C6-C12 aryl substituted with one or more C1-C6 haloalkyl groups, C3-C12 heteroaryl, and C3-C12 heteroaryl substituted with one or more C1-C6 haloalkyl groups.

[0122] According to some embodiments of the present invention, R6 is independently selected from hydrogen, deuterium, fluorine, chlorine, nitro, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C3-C6 cycloalkyl, C1-C4 alkyl substituted with one or more C3-C6 cycloalkyl, phenyl, phenyl substituted with one or more C1-C4 haloalkyl, 5-6 heteroaryl, and 5-6 heteroaryl substituted with one or more C1-C4 haloalkyl.

[0123] According to some embodiments of the present invention, R6 is independently selected from hydrogen, deuterium, fluorine, chlorine, nitro, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, phenyl, trifluoromethyl-substituted phenyl, pyridyl, and trifluoromethyl-substituted pyridyl.

[0124] According to some embodiments of the present invention, R6 is independently selected from hydrogen, deuterium, fluorine, chlorine, nitro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, cyclopropyl, cyclopropylmethyl, phenyl, o-trifluoromethylphenyl, p-trifluoromethylphenyl, and m-trifluoromethylphenyl.

[0125] According to some embodiments of the present invention, when ring A is an aromatic ring, R6 is independently selected from C3-C6 cycloalkyl, C1-C6 alkyl substituted with one or more C3-C6 cycloalkyl groups, C3-C6 cycloalkyl substituted with one or more C1-C6 haloalkyl groups, C6-C12 aryl, C6-C12 aryl substituted with one or more C1-C6 haloalkyl groups, C3-C12 heteroaryl, and C3-C12 heteroaryl substituted with one or more C1-C6 haloalkyl groups. Preferably, when ring A is an aromatic ring, R6 is independently selected from C3-C6 cycloalkyl, C1-C4 alkyl substituted with one or more C3-C6 cycloalkyl groups, phenyl, phenyl substituted with one or more C1-C4 haloalkyl groups, 5-6-membered heteroaryl, and 5-6-membered heteroaryl substituted with one or more C1-C4 haloalkyl groups. Preferably, when ring A is an aromatic ring, R6 is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, phenyl, trifluoromethyl-substituted phenyl, pyridyl, and trifluoromethyl-substituted pyridyl.

[0126] According to some embodiments of the present invention, in Formula I, n is 0, 1, 2, or 3. According to some embodiments of the present invention, in Formula I, n is 1, 2, or 3. According to some embodiments of the present invention, in Formula I, n is 1 or 2.

[0127] According to some embodiments of the present invention, in formulas I, II, III, IV, I-1, I-2, I-3, I-4, and I-5, Selected from the group consisting of the following groups:

[0128] * indicates that ring A and The location of the connection.

[0129] According to some embodiments of the present invention, in formulas I, II, III, IV, I-1, I-2, I-3, I-4, and I-5, Selected from the group consisting of the following structures:

[0130] * indicates the position where ring A is connected to -CR4R5. In these embodiments, ring A is a group containing heteroatoms (e.g., a 5-6 membered monocyclic heteroaromatic ring, a C7-C12 fused heteroaromatic ring, and a C6-C12 saturated or unsaturated heterocycle), and An embodiment containing a ring A is another preferred embodiment of this application, wherein at least one heteroatom is present in the adjacent position of the position connected to the ring A.

[0131] According to some embodiments of the present invention, the nitrogen-containing compound is selected from the following compounds, or solvates, tautomers, enantiomers, diastereomers, isotope-labeled compounds (preferably deuterated compounds), or pharmaceutically acceptable salts of the following compounds:

[0132] The pharmaceutical composition of the present invention

[0133] The pharmaceutical composition comprises the above-described nitrogen-containing compound and one or more pharmaceutically acceptable excipients, wherein the nitrogen-containing compound is a compound as shown in Formula I, II, III, IV, I-1, I-2, I-3, I-4, or I-5 above, or a solvate, tautomer, enantiomer, diastereomer, isotope-labeled compound (preferably deuterated), or pharmaceutically acceptable salt of the compound shown in Formula I, II, III, IV, I-1, I-2, I-3, I-4, or I-5.

[0134] The excipients described in this invention include, but are not limited to, conventional pharmaceutical excipients, diluents, fillers, binders, humectants, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, absorption enhancers, surfactants, lubricants, buffers, and stabilizers.

[0135] The drug composition of the present invention can be administered via parenteral, injection, or oral routes. It can be administered intravascularly, subcutaneously, intraperitoneally, intramuscularly, by inhalation, intranasally, through airway instillation, or via intrapleural instillation. The drug composition can also be administered nasally; or intrathecally, intramedullaryly, or intraventricularly; or transdermally, percutaneously, locally, intraenterically, intravaginally, sublingually, or rectally. The drug composition can be formulated into various dosage forms as needed, and the physician can determine the beneficial dosage for the patient based on factors such as patient type, age, weight, general disease condition, and method of administration.

[0136] Application of the nitrogen-containing compounds and pharmaceutical compositions of the present invention

[0137] The present invention also provides the use of the nitrogen-containing compounds and pharmaceutical compositions described above in the preparation of medicaments for the prevention or treatment of inflammation-related diseases and / or cell necrosis, apoptosis, and autophagy-related diseases.

[0138] According to some embodiments of the present invention, the inflammation-related disease is an inflammatory central nervous system condition or disease or an inflammatory peripheral nervous system condition or disease.

[0139] According to some embodiments of the present invention, the central nervous system conditions such as stroke, Parkinson's disease, and Alzheimer's disease, or peripheral system conditions or diseases such as dry eye syndrome, osteoarthritis, inflammatory bowel diseases such as ulcerative colitis, and Crohn's disease, are the main pathogenic mechanisms of inflammation-related diseases and / or cell necrosis and apoptosis, and autophagy-related diseases.

[0140] Prevention or treatment methods

[0141] The present invention also provides a method for preventing or treating acute or chronic central or peripheral system diseases related to inflammation and / or cell necrosis and apoptosis, comprising administering to a subject in need a therapeutically effective amount of a compound such as those shown in Formula I, II, III, IV, I-1, I-2, I-3, I-4, or I-5 above, or a solvate, tautomer, enantiomer, diastereomer, isotope-labeled compound (preferably deuterated), or pharmaceutically acceptable salt of the compounds shown in Formula I, II, III, IV, I-1, I-2, I-3, I-4, or I-5, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof.

[0142] According to some embodiments of the present invention, the inflammation-related disease is an inflammatory central nervous system condition or disease or an inflammatory peripheral nervous system condition or disease.

[0143] According to some embodiments of the present invention, the central nervous system conditions such as stroke, Parkinson's disease, and Alzheimer's disease, or peripheral system conditions or diseases such as dry eye syndrome, osteoarthritis, inflammatory bowel diseases such as ulcerative colitis, and Crohn's disease, are the main pathogenic mechanisms of inflammation-related diseases and / or cell necrosis and apoptosis, and autophagy-related diseases.

[0144] In this invention, the subject can be a mammal, but the preferred subject is a human.

[0145] Methods to regulate inflammation, apoptosis, and autophagy

[0146] The present invention also provides a method for regulating inflammation, apoptosis, and autophagy in cells or a subject, the method comprising: contacting cells with the nitrogen-containing compound or the pharmaceutical composition described above; or administering the nitrogen-containing compound or the pharmaceutical composition described above to a subject. The nitrogen-containing compound is a compound as shown in Formula I, II, III, IV, I-1, I-2, I-3, I-4, or I-5 above, or a solvate, tautomer, enantiomer, diastereomer, isotope-labeled compound (preferably deuterated), or pharmaceutically acceptable salt of a compound shown in Formula I, II, III, IV, I-1, I-2, I-3, I-4, or I-5 above.

[0147] In some embodiments, the cells are mammalian cells. In some embodiments, the subject is a mammal, preferably a human.

[0148] Example 1: Synthesis of the compound

[0149] Synthesis of REJT-1

[0150] 2-(chloromethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazolium (80 mg, 0.34 mmol) was dissolved in ethanol (5 mL), and imidazolium-2-thionone (41.8 mg, 0.41 mmol) was added. The mixture was stirred at 70 °C for 16 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a brown solid. The solid was purified by high performance liquid chromatography and lyophilized to obtain a yellow oily 2-(((4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-6-(trifluoromethyl)-1H-benzo[d]imidazolium carbamate (22 mg, yield 18.6%).

[0151] MS(ESI)m / z = 301.0[M+H] + .

[0152] 1 H NMR (DMSO-d6, 400MHz): δ8.21 (s, 1H), 7.92 (s, 1H), 7.73 (d, J=8.4Hz, 1H), 7.4 9 (dd, J1=8.4Hz, J2=1.2Hz, 1H), 7.30-6.10 (m, 1H), 4.56 (s, 2H), 3.61 (s, 4H).

[0153] The compounds in Table 1 below were prepared using the same methods as in the examples described above.

[0154] Table 1

[0155] Synthesis of REJT-2

[0156] Step 1 Synthesis

[0157] 1-Iodo-3-(trifluoromethyl)benzene (2.00 g, 7.3 mmol), 2-methyl-1,3-thiazole (0.87 g, 8.76 mmol), palladium acetate (0.08 g, 0.36 mmol), and potassium acetate (2.87 g, 0.029 mmol) were dissolved in N,N-dimethylformamide (40 mL) and reacted overnight at 120 °C under nitrogen protection. The reaction mixture was then diluted with 400 mL of water and extracted with ethyl acetate (100 mL × 3). The organic phase was concentrated under vacuum and purified by silica gel column chromatography to obtain a yellow oily 2-methyl-5-(3-(trifluoromethyl)phenyl)thiazole (1.21 g, yield 64.4%).

[0158] MS(ESI)m / z = 245.2[M+H] + .

[0159] Second step of synthesis

[0160] 2-Methyl-5-(3-(trifluoromethyl)phenyl)thiazole (200 mg, 0.82 mmol), azobisisobutyronitrile (4 mg, 0.025 mmol), and N-bromosuccinimide (153 mg, 0.86 mmol) were dissolved in 1,2-dichloroethane (10 mL) and reacted overnight at 80 °C with stirring. The reaction solution was concentrated under vacuum and purified by silica gel column chromatography to obtain a yellow oily 2-(bromomethyl)-5-(3-(trifluoromethyl)phenyl)thiazole (140 mg, yield 50.3%).

[0161] MS(ESI)m / z = 324.0 [M+H] + .

[0162] Third step of synthesis

[0163] 2-(bromomethyl)-5-(3-(trifluoromethyl)phenyl)thiazole (140 mg, 0.43 mmol) was dissolved in ethanol (10 mL), and imidazole-2-thionone (46 mg, 0.45 mmol) was added. The mixture was stirred at 70 °C for 16 h. After cooling, the reaction solution was concentrated under reduced pressure. The solid was purified by high performance liquid chromatography and lyophilized to give a colorless oily 2-(((4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-5-(3-(trifluoromethyl)phenyl)thiazole carbamate (44 mg, yield 26.1%).

[0164] MS(ESI)m / z = 344.0 [M+H] +

[0165] 1H NMR (DMSO-d6, 400MHz): δ8.27(s,1H),8.19(s,1H),7.98(s,1H),7.92(d,J=7.6Hz,1H),7.72-7.65(m,2H),4.64(s,2H),3.57(s,4H).

[0166] Synthesis of REJT-3

[0167] Step 1 Synthesis

[0168] 2-Bromo-1-(3-(trifluoromethyl)phenyl)ethane-1-one (2 g, 7.45 mmol) and sodium dimethamide (1.07 g, 11.25 mmol) were dissolved in acetonitrile (100 mL) and stirred at 70 °C for 16 hours. The reaction solution was concentrated under vacuum, and then the mixture was dissolved in methanol (100 mL) and concentrated hydrochloric acid (80 mL) and stirred at 80 °C for 2 hours. The reaction solution was concentrated under vacuum, and isopropanol (20 mL) was added and slurryed to purify the mixture, yielding a yellow solid 2-amino-1-(3-(trifluoromethyl)phenyl)ethane-1-one (1.50 g, 98.7%).

[0169] MS(ESI)m / z = 204.1[M+H] + .

[0170] Second step of synthesis

[0171] 2-Amino-1-(3-(trifluoromethyl)phenyl)ethane-1-one (600 mg, 2.95 mmol) and triethylamine (1.20 g, 11.81 mmol) were dissolved in dichloromethane (30 mL). Chloroacetyl chloride (400 mg, 3.54 mmol) was added under ice bath conditions, and the mixture was stirred at room temperature for 16 hours. 30 mL of water was added to the reaction mixture, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phase was concentrated under vacuum and purified by silica gel column chromatography to obtain a yellow solid, 2-chloro-N-(2-oxo-2-(3-(trifluoromethyl)phenyl)ethyl)acetamide (380 mg, 46.0%).

[0172] MS(ESI)m / z = 280.1[M+H] + .

[0173] Third step of synthesis

[0174] 2-Chloro-N-(2-oxo-2-(3-(trifluoromethyl)phenyl)ethyl)acetamide (440 mg, 1.57 mmol) was dissolved in phosphorus oxychloride (7 mL) and stirred at 120 °C for 2 hours. The reaction mixture was added dropwise to 30 mL of ice water and extracted with ethyl acetate (20 mL × 3). The organic phase was concentrated under vacuum and purified by silica gel column chromatography to obtain a yellow solid 2-(chloromethyl)-5-(3-(trifluoromethyl)phenyl)oxazole (220 mg, 53.6%).

[0175] MS(ESI)m / z = 262.1[M+H] + .

[0176] Fourth step synthesis

[0177] 2-(chloromethyl)-5-(3-(trifluoromethyl)phenyl)oxazole (150 mg, 0.57 mmol) was dissolved in ethanol (7 mL), and imidazole-2-thionone (117 mg, 1.15 mmol) was added. The mixture was stirred at 70 °C for 16 hours. After cooling, the reaction solution was concentrated under reduced pressure. The solid was purified by high performance liquid chromatography and lyophilized to give a yellow solid 2-(((4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-5-(3-(trifluoromethyl)phenyl)oxazole carboxylate (68.77 mg, yield 32.1%).

[0178] MS(ESI)m / z = 328.0 [M+H] + .

[0179] 1 H NMR (DMSO-d6, 400MHz): δ8.16(s,1H), 8.01-7.96(m,2H), 7.84(s,1H), 7.75-7.71(m,2H), 4.54(s,2H), 3.54(s,4H).

[0180] The compounds in Table 2 below were prepared using the same methods as in the examples described above.

[0181] Table 2

[0182] Synthesis of REJT-4

[0183] Step 1 Synthesis

[0184] 2-Amino-1-(3-(trifluoromethyl)phenyl)ethane-1-one (2 g, 9.80 mmol), ethyl thiocarbamate (1.31 g, 9.80 mmol), and sodium acetate (2.41 g, 29.39 mmol) were dissolved in acetic acid (20 mL), and the mixture was stirred at 125 °C for 3 hours. The reaction solution was concentrated under vacuum, and the pH was adjusted to >7 by adding saturated sodium bicarbonate aqueous solution. The solution was extracted with ethyl acetate (50 mL × 3). After vacuum concentration of the organic phase, the solution was purified by silica gel column chromatography to obtain a yellow solid, ethyl 5-(3-(trifluoromethyl)phenyl)-1H-imidazolium-2-carboxylate (1.44 g, 51.8%).

[0185] MS(ESI)m / z = 285.0 [M+H] + .

[0186] Second step of synthesis

[0187] Ethyl 5-(3-(trifluoromethyl)phenyl)-1H-imidazolium-2-carboxylate (1.58 g, 5.56 mmol) and potassium carbonate (1.55 g, 11.20 mmol) were dissolved in acetonitrile (50 mL), and 2-(trimethylsilyl)ethoxymethyl chloride (1.12 g, 6.72 mmol) was added. The mixture was stirred at 20 °C for 16 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was concentrated under vacuum and purified by silica gel column chromatography to obtain a white solid ethyl 5-(3-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium-2-carboxylate (1.60 g, 69.3%).

[0188] MS(ESI)m / z = 415.9[M+H] + .

[0189] Third step of synthesis

[0190] Ethyl 5-(3-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-carboxylate (420 mg, 1.01 mmol) was dissolved in tetrahydrofuran (20 mL), and 2 mol / L lithium borohydride (0.8 mL, 1.52 mmol) was added. The mixture was stirred at 20 °C for 16 hours. The reaction solution was added to a saturated sodium bicarbonate aqueous solution (30 mL), extracted with ethyl acetate (30 mL × 3), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a white solid (5-(3-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol (370 mg, 98.0%).

[0191] MS(ESI)m / z = 373.3[M+H]+ .

[0192] Fourth step synthesis

[0193] (5-(3-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol (370 mg, 0.99 mmol) and triethylamine (201 mg, 1.98 mmol) were dissolved in dichloromethane (15 mL), and methanesulfonyl chloride (170 mg, 1.49 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was added to saturated sodium bicarbonate aqueous solution (30 mL), extracted with ethyl acetate (20 mL × 3), and the organic phase was concentrated under vacuum and purified by silica gel column chromatography to obtain a yellow oily 2-(chloromethyl)-5-(3-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium (350 mg, 90.2%).

[0194] MS(ESI)m / z = 391.3[M+H] + .

[0195] Fifth step synthesis

[0196] 2-(chloromethyl)-5-(3-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium (350 mg, 0.89 mmol) was dissolved in ethanol (20 mL), and imidazolium-2-thionone (137 mg, 1.34 mmol) was added. The mixture was stirred at 70 °C for 16 hours. The reaction solution was then diluted with water (30 mL), extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a yellow solid 2-(((4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-5-(3-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium (300 mg, 73.4%).

[0197] MS(ESI)m / z = 457.4 [M+H] + .

[0198] Step 6 Synthesis

[0199] 2-(((4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-5-(3-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium (270 mg, 0.59 mmol) was dissolved in dichloromethane (9 mL) and trifluoroacetic acid (6 mL), and the mixture was stirred at room temperature for 16 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a yellow oil. The solid was purified by high performance liquid chromatography (mobile phase: acetonitrile / water (0.5% formic acid)) to obtain a brown oil, which gave a white solid 2-(((4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-5-(3-(trifluoromethyl)phenyl)-1H-imidazolium carbamate (15.79 mg, 7.2%).

[0200] MS(ESI)m / z = 327.0 [M+H] + .

[0201] 1 H NMR (D2O, 400MHz): δ8.36 (s, 1H), 7.79 (s, 1H), 7.71 (d, J = 9.6Hz, 1H), 7.51-7.40 (m, 2H), 7.36 (s, 1H), 4.41 (s, 2H), 3.86 (s, 4H).

[0202] The compounds in Table 3 below were prepared using the same methods as in the examples described above.

[0203] Table 3

[0204] Synthesis of REJT-5

[0205] Step 1 Synthesis

[0206] 2-Bromo-1-(4-(trifluoromethyl)phenyl)ethane-1-one (3.00 g, 1.12 mmol) was dissolved in ethanol (20 mL), and ethyl 2-amino-2-thioethyl (1.49 g, 1.12 mmol) was added. The reaction was stirred at 80 °C for 3 hours under nitrogen protection. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography to give ethyl 4-(4-(trifluoromethyl)phenyl)thiazolium-2-carboxylate (2.50 g, yield 73.41%) as a yellow solid.

[0207] MS(ESI)m / z = 301.9[M+H] + .

[0208] Second step of synthesis

[0209] Ethyl 4-(4-(trifluoromethyl)phenyl)thiazol-2-carboxylate (2.50 g, 0.83 mmol) was dissolved in dichloromethane (20 mL), and lithium borohydride (0.36 g, 1.66 mmol) was added at 0 °C. The reaction was stirred at room temperature for 16 hours under nitrogen protection. After the reaction was quenched, the organic phase was concentrated under reduced pressure and purified by silica gel column chromatography to give a white solid (4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)methanol (1.90 g, yield 88.35%).

[0210] MS(ESI)m / z = 260.5[M+H] + .

[0211] Third step of synthesis

[0212] (4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)methanol (1.90 g, 0.73 mmol) was dissolved in dichloromethane (20 mL), and thionyl chloride (1.74 g, 1.46 mmol) was added. The mixture was stirred at room temperature for 16 hours. After the reaction was quenched, the solution was concentrated under reduced pressure and purified by silica gel column chromatography to give a yellow oily substance, 2-(chloromethyl)-4-(4-(trifluoromethyl)phenyl)thiazol (1.80 g, yield 87.96%).

[0213] MS(ESI)m / z = 278.2 / 280.2[M+H] + .

[0214] Fourth step synthesis

[0215] 2-(chloromethyl)-4-(4-(trifluoromethyl)phenyl)thiazole (500 mg, 1.79 mmol) was dissolved in ethanol (10 mL), and imidazolidine-2-thione (183 mg, 1.79 mmol) was added. The mixture was stirred at 70 °C for 16 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a yellow oil. The solid was purified by high performance liquid chromatography to obtain a yellow oil, 2-(((4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-4-(4-(trifluoromethyl)phenyl)thiazole carboxylate (125 mg, yield 16.96%).

[0216] MS(ESI)m / z = 344.0 [M+H] + .

[0217] 1 H NMR (DMSO-d6, 400MHz): δ8.25(s,1H),8.18(s,1H),8.15(d,J=8.0Hz,2H),7.80(d,J=8.0Hz,2H),4.67(s,2H),3.56(s,4H).

[0218] The compounds in Table 4 below were prepared using the same methods as in the examples described above.

[0219] Table 4

[0220] Synthesis of REJT-6

[0221] Step 1 Synthesis

[0222] 2-Iodo-4-(trifluoromethyl)phenol (1 g, 3.47 mmol) was dissolved in pyridine (20 mL), followed by the addition of propan-2-yn-1-ol (0.39 g, 6.96 mmol) and cuprous oxide (0.32 g, 2.24 mmol). The reaction was stirred at 115 °C for 16 hours under nitrogen protection. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure, diluted with water (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a yellow oil (5-(trifluoromethyl)benzofuran-2-yl)methanol (660 mg, yield 85.71%).

[0223] MS(ESI)m / z = 199.1 [M+H] + .

[0224] Second step of synthesis

[0225] 5-(trifluoromethyl)benzofuran-2-yl)methanol (660 mg, 3.05 mmol) was dissolved in tetrahydrofuran (15 mL) and N,N-dimethylformamide (2 mL). Thionyl chloride (726 mg, 6.11 mmol) was added, and the mixture was stirred at 60 °C for 1 hour under nitrogen protection. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure, diluted with saturated sodium bicarbonate aqueous solution (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain a colorless oily substance, 2-(chloromethyl)-5-(trifluoromethyl)benzofuran (600 mg, yield 83.8%).

[0226] MS(ESI)m / z = 199.1 [M+H] + .

[0227] Third step of synthesis

[0228] 2-(chloromethyl)-5-(trifluoromethyl)benzofuran (600 mg, 2.56 mmol) was dissolved in ethanol (10 mL), and imidazolidine-2-thione (314 mg, 3.07 mmol) was added. The mixture was stirred at 70 °C for 16 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a brown oily substance. The solid was purified by high performance liquid chromatography, lyophilized, and then slurried in acetonitrile to obtain a white solid 2-(((5-(trifluoromethyl)benzofuran-2-yl)methyl)thio)-4,5-dihydro-1H-imidazolium hydrochloride (571 mg, yield 74.2%).

[0229] MS(ESI)m / z = 301.0[M+H] + .

[0230] 1 H NMR (DMSO-d6, 400MHz): δ10.53(br s,2H),8.10(s,1H),7.82(d,J=8.4Hz,1H),7.67(d,J=8.8Hz,1H),7.16(s,1H),4.92(s,2H),3.86(s,4H).

[0231] The compounds in Table 5 below were prepared using the same methods as in the examples described above.

[0232] Table 5

[0233] Synthesis of REJT-7

[0234] Step 1 Synthesis

[0235] 2-Amino-4-(trifluoromethyl)phenol (200 mg, 1.13 mmol) was dissolved in acetic acid (10 mL), and then 2-chloro-1,1,1-triethoxyethane (266 mg, 1.36 mmol) was added. The reaction was stirred at 120 °C for 3 hours under nitrogen protection. After the reaction was completed, the mixture was cooled, concentrated under reduced pressure, diluted with saturated sodium bicarbonate aqueous solution (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to give a yellow oily substance 2-(chloromethyl)-5-(trifluoromethyl)benzoxazole (170 mg, yield 63.91%).

[0236] MS(ESI)m / z = 236.1[M+H] + .

[0237] Second step of synthesis

[0238] 2-(chloromethyl)-5-(trifluoromethyl)benzoxazole (270 mg, 1.15 mmol) was dissolved in ethanol (10 mL), and imidazolidine-2-thione (234 mg, 2.29 mmol) was added. The mixture was stirred at 70 °C for 16 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a brown oil. The solid was purified by high performance liquid chromatography (mobile phase: acetonitrile / water (0.5% trifluoroacetic acid)). After lyophilization, a colorless oily 2-((4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-5-(trifluoromethyl)benzoxazole trifluoroacetate (60 mg, yield 17.4%) was obtained.

[0239] MS(ESI)m / z = 301.9[M+H] + .

[0240] 1 H NMR (CD3OD, 400MHz): δ8.09 (s, 1H), 7.87 (d, J = 8.8Hz, 1H), 7.81 (d, J = 8.8Hz, 1H), 4.90 (s, 2H), 4.21 (s, 4H).

[0241] Synthesis of REJT-8

[0242] Step 1 Synthesis

[0243] 3-Phenylacetaldehyde (4.00 g, 0.031 mol) was dissolved in acetonitrile (60 mL), followed by the addition of 1-aza-ethylenediamine hydrochloride (3.48 g, 0.037 mmol) and sodium carbonate (7.81 g, 0.074 mol). The reaction was carried out at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was cooled, concentrated under reduced pressure, diluted with water (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a brown solid 2-methyl-4-phenylpyrimidine (0.98 g, yield 18.82%).

[0244] MS(ESI)m / z = 171.0 [M+H] + .

[0245] Second step of synthesis

[0246] 2-Methyl-4-phenylpyrimidine (300 mg, 1.76 mmol) was dissolved in pyridine (10 mL), and selenium dioxide (978 mg, 8.81 mmol) was added. The mixture was stirred at 110 °C for 16 hours under nitrogen protection. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure, and the pH was adjusted to <7 with 1 M dilute hydrochloric acid. The solid after concentration under reduced pressure was purified by high performance liquid chromatography and lyophilized to obtain a white solid 4-phenylpyrimidine-2-carboxylic acid (235 mg, yield 66.6%).

[0247] MS(ESI)m / z=201.0[M+H]+.

[0248] Third step of synthesis

[0249] 4-Phenyrimidine-2-carboxylic acid (400 mg, 1.99 mmol) was dissolved in tetrahydrofuran (10 mL), and N-methylmorpholine (243 mg, 2.39 mmol) and isobutyl chloroformate (327 mg, 2.39 mmol) were added. The mixture was stirred at 0 °C for 1 hour under nitrogen protection. The reaction solution was filtered, and the filtrate was cooled to 0 °C. 2 mL of an aqueous solution of sodium borohydride (151 mg, 3.99 mmol) was added, and the mixture was stirred at 0 °C for 0.5 hours. The solution was diluted with saturated sodium bicarbonate aqueous solution (20 mL) and ethyl acetate (20 mL). The mixture was extracted with ethyl acetate (20 mL × 2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain yellow oil 2-(hydroxymethyl)-4-phenylpyrimidine (230 mg, yield 61.81%).

[0250] Fourth step synthesis

[0251] 2-(hydroxymethyl)-4-phenylpyrimidine (230 mg, 1.24 mmol) was dissolved in tetrahydrofuran (15 mL) and N,N-dimethylformamide (2 mL). After adding sulfoxide (726 mg, 6.11 mmol), the mixture was stirred at 60 °C for 1 hour under nitrogen protection. After the reaction was complete, the reaction solution was concentrated under reduced pressure, diluted with saturated sodium bicarbonate aqueous solution (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain a colorless oily substance, 2-(chloromethyl)-4-phenylpyrimidine (210 mg, yield 83.1%).

[0252] MS(ESI)m / z = 205.1[M+H] + .

[0253] Fifth step synthesis

[0254] 2-(chloromethyl)-4-phenylpyrimidine (210 mg, 1.03 mmol) was dissolved in ethanol (10 mL), and imidazolidine-2-thione (126 mg, 1.23 mmol) was added. The mixture was stirred at 70 °C for 16 hours. The reaction solution was cooled and concentrated under reduced pressure, and dried to give a brown oily substance. The solid was purified by high performance liquid chromatography and lyophilized to give a white solid 2-((4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-4-phenylpyrimidine carboxylate (185 mg, yield 66.8%).

[0255] MS(ESI)m / z = 271.0[M+H] + .

[0256] 1 H NMR (DMSO-d6, 400MHz): δ8.84(d,J=5.2Hz,1H),8.23-8.21(m,3H),7.99(d,J=5.2Hz,1H),7.58-7.56(m,3H),4.62(s,2H),3.55(s,4H).

[0257] The compounds in Table 6 below were prepared using the same methods as in the examples described above, with the corresponding compounds.

[0258] Table 6

[0259] Synthesis of REJT-9

[0260] Step 1 Synthesis

[0261] Triethylamine (260.1 mg, 2.86 mmol) was added to a 10 mL solution of 4-fluoro-5-(trifluoromethyl)benzene-1,2-diamine (500.0 mg, 2.58 mmol) in 1,2-dichloroethane. Chloroacetyl chloride (290.9 mg, 2.58 mmol) was then slowly added dropwise under ice bath conditions, and the reaction was allowed to proceed overnight at room temperature. The reaction mixture was extracted three times with dichloromethane (3 × 50 mL), washed three times with water (3 × 50 mL), and the resulting pale yellow oil was concentrated under vacuum and dissolved in 10 mL of glacial acetic acid. The mixture was then stirred at 80 °C for 2 hours under nitrogen protection. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure. The resulting oil was extracted three times with dichloromethane (3×50mL), washed three times with water (3×50mL), dried with magnesium sulfate, and the solvent was removed by rotary evaporation. The resulting light brown oil, 5-fluoro-2-(chloromethyl)-6-(trifluoromethyl)-1H-benzimidazole, was directly used in the next step of the reaction (700.0 mg, yield 75.32%).

[0262] MS(ESI)m / z = 252.9[M+H]+ .

[0263] Second step of synthesis

[0264] 5-Fluoro-2-(chloromethyl)-6-(trifluoromethyl)-1H-benzimidazole (1.40 g, 5.50 mmol) was dissolved in ethanol (40 mL), and imidazolidine-2-thione (0.56 g, 5.50 mmol) was added. The mixture was stirred at 70 °C for 4 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to give a yellow oil. The solid was separated by silica gel column chromatography to give 900 mg of white solid. This solid was recrystallized from ethanol / water in a 10 / 1 ratio to give a white solid 2-(((4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-5-fluoro-6-(trifluoromethyl)-1H-benzimidazole hydrochloride (620 mg, yield 34.55%).

[0265] MS(ESI)m / z = 319.0 [M+H] + .

[0266] 1 H NMR (DMSO-d6, 400MHz): δ11.03-10.90(brs,1H),7.99(d,J=6.4Hz,1H),7.72(d,J=11.2Hz,1H),4.56(s,2H),3.89(s,4H).

[0267] The compounds in Table 7 below were prepared using the same methods as in the examples described above.

[0268] Table 7

[0269] Synthesis of REJT-10

[0270] Step 1 Synthesis

[0271] (4-Methoxy-3-nitrophenyl)methanol (300 mg, 1.64 mmol) was dissolved in dichloromethane (10 mL), and then thionyl chloride (390 mg, 3.28 mmol) was added. The reaction mixture was stirred at 15 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was diluted with saturated sodium bicarbonate aqueous solution (20 mL) and dichloromethane (20 mL), extracted with dichloromethane (20 mL × 2), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a yellow oily substance 4-(chloromethyl)-1-methoxy-2-nitrobenzene (280 mg, 84.8% yield).

[0272] MS(ESI)m / z = 141.0[M+H] + .

[0273] Second step of synthesis

[0274] 4-(chloromethyl)-1-methoxy-2-nitrobenzene (280 mg, 1.39 mmol) was dissolved in ethanol (20 mL), and imidazolidin-2-thione (284 mg, 2.78 mmol) was added. The mixture was stirred at 70 °C for 16 hours. After cooling, the reaction solution was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography and lyophilized to give a white solid 2-((4-methoxy-3-nitrobenzyl)thio)-4,5-dihydro-1H-imidazolium carbamate (90.26 mg, yield 24.3%).

[0275] MS(ESI)m / z = 268.0[M+H] + .

[0276] 1 H NMR (DMSO-d6, 400MHz): δ8.18(s,1H),7.97(d,J=1.2Hz,1H),7.73(d,J=8.4Hz,1H),7.33(d,J=8.8Hz,1H),4.40(s,2H),3.91(s,3H),3.62(s,4H).

[0277] The synthesis of REJT-11

[0278] Step 1 Synthesis

[0279] 2-Iodo-5-(trifluoromethyl)aniline (1.50 g, 5.21 mmol) and ethynyltrimethylsilane (1.02 g, 10.42 mmol) were dissolved in triethylamine (30 mL), followed by the addition of cuprous iodide (198 mg, 1.04 mmol) and palladium dichloride bis(triphenylphosphine) (366 mg, 0.52 mmol). The reaction mixture was stirred at room temperature for 16 hours under nitrogen protection. After the reaction was complete, the pH of the reaction mixture was adjusted to <7 with 2 M hydrochloric acid solution, extracted with ethyl acetate (100 mL × 3), and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a yellow solid 5-(trifluoromethyl)-2-((trimethylsilyl)ethynyl)aniline (1.3 g, yield 96.2%).

[0280] MS(ESI)m / z = 258.0 [M+H] + .

[0281] Second step of synthesis

[0282] 5-(trifluoromethyl)-2-((trimethylsilyl)ethynyl)aniline (1.25 g, 4.86 mmol) was dissolved in methanol (20 mL), and potassium fluoride (0.84 g, 14.40 mmol) was added. The reaction mixture was stirred at 10 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was diluted with water (100 mL) and ethyl acetate (100 mL), extracted with ethyl acetate (100 mL × 2), and the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a yellow oily substance, 2-ethynyl-5-(trifluoromethyl)aniline (800 mg, yield 89.6%).

[0283] MS(ESI)m / z = 186.1 [M+H] + .

[0284] Third step of synthesis

[0285] 2-Ethynyl-5-(trifluoromethyl)aniline (300 mg, 1.64 mmol), ethyl 2-oxoacetate (960 mg, 5.64 mmol), sodium sulfate (2.14 g, 15.04 mmol), piperidine (320 mg, 3.76 mmol), and copper bromide (84 mg, 0.38 mmol) were dissolved in dichloroethane (20 mL), followed by the addition of trifluoroacetic acid (43 mg, 0.38 mmol). The reaction mixture was stirred at 90 °C for 1 hour under nitrogen protection. After the reaction was complete, the reaction solution was diluted with water (40 mL) and dichloromethane (20 mL), extracted with dichloromethane (40 mL × 2), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a yellow oily substance, ethyl 7-(trifluoromethyl)quinoline-2-carboxylate (450 mg, yield 46.9%).

[0286] MS(ESI)m / z = 270.3[M+H] + .

[0287] Fourth step synthesis

[0288] Ethyl 7-(trifluoromethyl)quinoline-2-carboxylate (450 mg, 1.67 mmol) was dissolved in tetrahydrofuran (15 mL), followed by the addition of 2N lithium borohydride tetrahydrofuran solution (1.3 mL, 2.51 mmol). The reaction mixture was stirred at 0 °C for 2 hours under nitrogen protection. After the reaction was complete, the reaction solution was diluted with saturated sodium bicarbonate aqueous solution (20 mL) and ethyl acetate (20 mL). The solution was extracted with ethyl acetate (20 mL × 2), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a yellow oil (7-(trifluoromethyl)quinoline-2-yl)methanol (320 mg, 84.3% yield).

[0289] MS(ESI)m / z = 228.2[M+H] + .

[0290] Fifth step synthesis

[0291] (7-(trifluoromethyl)quinoline-2-yl)methanol (320 mg, 1.41 mmol) was dissolved in dichloromethane (10 mL), and then thionyl chloride (251 mg, 2.11 mmol) was added. The reaction was carried out under nitrogen protection at 15 °C with stirring for 16 hours. After the reaction was completed, the reaction solution was diluted with saturated sodium bicarbonate aqueous solution (10 mL) and dichloromethane (10 mL), extracted with dichloromethane (20 mL × 2), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and the crude product was purified by high performance liquid chromatography (mobile phase: acetonitrile / water (0.5% ammonium bicarbonate)). The crude product was concentrated under reduced pressure to give a yellow solid 2-(chloromethyl)-7-(trifluoromethyl)quinoline (140 mg, 40.5% yield).

[0292] MS(ESI)m / z = 246.2[M+H] + .

[0293] Step 6 Synthesis

[0294] 2-(chloromethyl)-7-(trifluoromethyl)quinoline (120 mg, 0.49 mmol) was dissolved in ethanol (7 mL), and imidazolidine-2-thione (100 mg, 0.98 mmol) was added. The mixture was stirred at 70 °C for 16 hours. After cooling, the reaction solution was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (mobile phase: acetonitrile / water (0.5% formic acid)) to give a white solid 2-(((4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-7-(trifluoromethyl)quinoline carbamate (90.32 mg, 59.4% yield).

[0295] MS(ESI)m / z = 312.0[M+H] + .

[0296] 1 H NMR(DMSO-d6,400MHz): δ8.54(d,J=8.4Hz,1H),8.33(s,1H),8.25(d,J=8.4Hz,1H), 8.18(s,1H),7.89(d,J=8.8Hz,1H),7.83(d,J=8.4Hz,1H),4.78(s,2H),3.69(s,4H).

[0297] Synthesis of REJT-13

[0298] Step 1 Synthesis

[0299] (4-bromopyridin-2-yl)methanol (700 mg, 3.72 mmol) was dissolved in dioxane (20 mL) and water (4 mL), followed by the addition of cyclohexyl-1-en-1-ylboronic acid (563 mg, 4.47 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (272 mg, 0.37 mmol), and sodium carbonate (592 mg, 5.58 mmol). The reaction was stirred at 90 °C for 16 hours under nitrogen protection. After the reaction was completed and cooled, the reaction solution was diluted with water (20 mL) and ethyl acetate (20 mL). The solution was extracted with ethyl acetate (20 mL × 2), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a brown oily substance (4-(cyclohexyl-1-en-1-yl)pyridin-2-yl)methanol (650 mg, yield 92.3%).

[0300] MS(ESI)m / z = 190.2[M+H] + .

[0301] Second step of synthesis

[0302] (200 mg, 1.06 mmol) of (4-(cyclohexyl-1-en-1-yl)pyridin-2-yl)methanol was dissolved in 10 mL of methanol, and then platinum dioxide (20 mg) was added. The reaction was carried out under hydrogen protection at 25 °C with stirring for 16 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under vacuum and purified by silica gel column chromatography to obtain a yellow oily substance, 2-(hydroxymethyl)-4-cyclohexylpyridine (115 mg, yield 56.9%).

[0303] MS(ESI)m / z = 192.2[M+H] + .

[0304] Third step of synthesis

[0305] 2-(hydroxymethyl)-4-cyclohexylpyridine (115 mg, 0.60 mmol) was dissolved in dichloromethane (10 mL), and thionyl chloride (143 mg, 1.20 mmol) was added. The mixture was stirred at 25 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure, diluted with saturated sodium bicarbonate aqueous solution (20 mL) and dichloromethane (20 mL), extracted with dichloromethane (20 mL × 2), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a yellow oily substance, 2-(chloromethyl)-4-cyclohexylpyridine (100 mg, yield 79.3%).

[0306] MS(ESI)m / z = 210.2[M+H] + .

[0307] Fourth step synthesis

[0308] 2-(chloromethyl)-4-cyclohexylpyridine (170 mg, 0.81 mmol) was dissolved in ethanol (10 mL), and imidazolidin-2-thione (99 mg, 0.97 mmol) was added. The mixture was stirred at 70 °C for 16 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a brown oily substance. The solid was purified by high performance liquid chromatography to obtain a white solid 4-cyclohexyl-2-(((4,5-dihydro-1H-imidazolidin-2-yl)thio)methyl)pyridinecarboxylate (170 mg, 76.1% yield).

[0309] MS(ESI)m / z = 276.1 [M+H] + .

[0310] 1 H NMR(DMSO-d,400MHz): δ8.38(d,J=5.4Hz,1H),8.22(s,1H),7.34(s,1H),7.16(d,J=5.2Hz ,1H),4.37(s,2H),3.57(s,4H),2.52-2.48(m,1H),1.79-1.68(m,5H),1.39-1.34(m,5H).

[0311] The compounds in Table 8 below were prepared using the same methods as in the examples described above.

[0312] Table 8

[0313] The synthesis of REJT-15

[0314] Step 1 Synthesis

[0315] Ethyl 4-bromooxazole-2-carboxylate (500 mg, 2.27 mmol) was dissolved in 1,4-dioxane (15 mL), and (3-(trifluoromethyl)phenyl)boronic acid (475 mg, 2.50 mmol), palladium acetate (26 mg, 0.11 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (66 mg, 0.11 mmol), and potassium phosphate (1447 mg, 6.82 mmol) were added. The reaction was stirred at 80 °C for 16 hours under nitrogen protection. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure, diluted with water (30 mL), extracted with ethyl acetate (20 mL × 3), and purified by silica gel column chromatography to obtain a colorless oily substance, ethyl 4-(3-(trifluoromethyl)phenyl)oxazole-2-carboxylate (550 mg, yield 76.37%).

[0316] MS(ESI)m / z = 286.3[M+H] + .

[0317] Second step of synthesis

[0318] Ethyl 4-(3-(trifluoromethyl)phenyl)oxazol-2-carboxylate (550 mg, 1.93 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium borohydride (63 mg, 2.89 mmol) was added at 0 °C. The mixture was stirred at room temperature under nitrogen protection for 16 hours. After the reaction was quenched, the organic phase was concentrated under reduced pressure and purified by silica gel column chromatography to give a white solid (4-(3-(trifluoromethyl)phenyl)oxazol-2-yl)methanol (270 mg, 54.70% yield).

[0319] MS(ESI)m / z = 244.2[M+H] + .

[0320] Third step of synthesis

[0321] (270 mg, 1.11 mmol) of (4-(3-(trifluoromethyl)phenyl)oxazol-2-yl)methanol was dissolved in dichloromethane (10 mL), and thionyl chloride (5 mL) was added. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the solution was concentrated under reduced pressure and purified by silica gel column chromatography to give a yellow oily substance, 2-(chloromethyl)-4-(3-(trifluoromethyl)phenyl)oxazol (250 mg, yield 77.46%).

[0322] MS(ESI)m / z = 262.2[M+H] + .

[0323] Fourth step synthesis

[0324] 2-(chloromethyl)-4-(3-(trifluoromethyl)phenyl)oxazole (100 mg, 0.3822 mmol) was dissolved in ethanol (10 mL), and imidazolidine-2-thione (59 mg, 0.5733 mmol) was added. The mixture was stirred at 70 °C for 16 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a yellow oil. The solid was purified by high performance liquid chromatography to obtain a yellow oil 2-(((4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-4-(3-(trifluoromethyl)phenyl)oxazole carbamate (45 mg, yield 29.88%).

[0325] MS(ESI)m / z = 328.0 [M+H] + .

[0326] 1H NMR (DMSO-d6, 400MHz): δ8.25(d,J=8.0Hz,1H),8.19-8.17(m,3H),7.92(d,J=7.6Hz,1H),7.80(t,J=8Hz,1H),4.29(s,2H),3.57(s,4H).

[0327] The synthesis of REJT-16

[0328] Step 1 Synthesis

[0329] 2-Amino-4-(trifluoromethyl)benzylthiol (800 mg, 4.14 mmol) was dissolved in ethanol (20 mL), and then 2-chloro-1,1,1-trimethoxyethane (1.28 g, 8.28 mmol) was added. The reaction was carried out under nitrogen protection at 60 °C with stirring for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, diluted with water (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL × 2), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a colorless oily substance 2-(chloromethyl)-5-(trifluoromethyl)benzothiazole (610 mg, yield 58.5%).

[0330] MS(ESI)m / z = 252.2[M+H] + .

[0331] Second step of synthesis

[0332] 2-(chloromethyl)-5-(trifluoromethyl)benzothiazole (250 mg, 0.99 mmol) was dissolved in ethanol (10 mL), and imidazolidine-2-thione (152 mg, 1.49 mmol) was added. The mixture was stirred at 70 °C for 16 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a brown oily substance. The solid was purified by high performance liquid chromatography to obtain a white solid 2-((4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-5-(trifluoromethyl)benzothiazole carboxylate (240 mg, yield 76.1%).

[0333] MS(ESI)m / z = 317.9 [M+H] + .

[0334] 1 H NMR (DMSO-d6, 400MHz): δ8.37-8.34(m,2H),8.14(s,1H),7.79(d,J=8.4Hz,1H),4.94(s,2H),3.69(s,4H).

[0335] The synthesis of REJT-17

[0336] Step 1 Synthesis

[0337] 2-Fluoro-5-(trifluoromethyl)benzaldehyde (300 mg, 1.55 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of methyl 2-mercaptoacetate (181 mg, 1.71 mmol) and potassium carbonate (859 mg, 6.21 mmol). The reaction mixture was stirred at 60 °C for 3 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure, diluted with water (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a white solid methyl 5-(trifluoromethyl)benzothiophene-2-carboxylic acid (280 mg, yield 69.3%).

[0338] Second step of synthesis

[0339] Methyl 5-(trifluoromethyl)benzothiophene-2-carboxylate (280 mg, 1.08 mmol) was dissolved in tetrahydrofuran (15 mL), and lithium borohydride (1.1 mL, 2.15 mmol) was added. The mixture was stirred at 60 °C for 61 hours under nitrogen protection. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure, diluted with saturated sodium bicarbonate aqueous solution (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a white solid (5-(trifluoromethyl)benzothiophene-2-yl)methanol (240 mg, yield 96.1%).

[0340] Third step of synthesis

[0341] (5-(trifluoromethyl)benzothiophene-2-yl)methanol (240 mg, 1.03 mmol) was dissolved in dichloromethane (15 mL), and thionyl chloride (246 mg, 2.07 mmol) was added. The mixture was stirred at 25 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure, diluted with saturated sodium bicarbonate aqueous solution (20 mL) and dichloromethane (20 mL), extracted with dichloromethane (20 mL × 2), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a colorless oily substance 2-(chloromethyl)-5-(trifluoromethyl)benzothiophene (221 mg, yield 85.3%).

[0342] MS(ESI)m / z = 251.2[M+H] + .

[0343] Fourth step synthesis

[0344] 2-(chloromethyl)-5-(trifluoromethyl)benzothiophene (220 mg, 0.88 mmol) was dissolved in ethanol (10 mL), and imidazolidin-2-thione (134 mg, 1.32 mmol) was added. The mixture was stirred at 70 °C for 16 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a brown oily substance. The solid was purified by high performance liquid chromatography, and acetonitrile was removed under reduced pressure. After lyophilization, a white solid 2-(((5-(trifluoromethyl)benzothiophene-2-yl)methyl)thio)-4,5-dihydro-1H-imidazolium carbamate (190 mg, yield 68.4%) was obtained.

[0345] MS(ESI)m / z = 316.9[M+H] + .

[0346] 1 H NMR (DMSO-d6, 400MHz): δ8.24 (s, 1H), 8.18 (d, J = 8.4Hz, 1H), 8.14 (s, 1H), 7.63 (dd, J 1=8.4Hz, J2=1.6Hz,1H),7.59(s,1H),4.82(s,2H),3.69(s,4H).

[0347] Synthesis of REJT-18

[0348] Step 1 Synthesis

[0349] 2-Nitro-4-(trifluoromethyl)benzaldehyde (1.00 g, 4.54 mmol) was dissolved in ethanol / water / acetic acid (24 mL / 12 mL / 24 mL), and then iron powder (1.76 g, 31.50 mmol) was added. The reaction mixture was stirred at 25 °C for 0.5 hours. After the reaction was completed, the pH of the reaction solution was adjusted to >7 with saturated sodium bicarbonate solution, extracted with ethyl acetate (100 mL × 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a yellow oily substance, 2-amino-4-(trifluoromethyl)benzaldehyde (800 mg, yield 93.3%).

[0350] MS(ESI)m / z = 190.0[M+H] + .

[0351] Second step of synthesis

[0352] 2-Amino-4-(trifluoromethyl)benzaldehyde (900 mg, 4.73 mmol) and triethylamine (958 mg, 9.47 mmol) were dissolved in dichloromethane (30 mL), and chloroacetyl chloride (802 mg, 7.10 mmol) was added under ice bath conditions. The reaction mixture was stirred at 15 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was diluted with water (30 mL) and dichloromethane (30 mL), extracted with dichloromethane (30 mL × 2), and the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a yellow oily substance, 2-chloro-N-(2-formyl-5-(trifluoromethyl)phenyl)acetamide (460 mg, 36.5% yield).

[0353] MS(ESI)m / z = 266.2[M+H] + .

[0354] Third step of synthesis

[0355] 2-Chloro-N-(2-formyl-5-(trifluoromethyl)phenyl)acetamide (280 mg, 1.05 mmol) was dissolved in acetic acid (4 mL), and then ammonium acetate (809 mg, 10.50 mmol) was added. The reaction was stirred at 110 °C for 1 hour under nitrogen protection. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure, diluted with saturated sodium bicarbonate aqueous solution (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a yellow solid 2-(chloromethyl)-7-(trifluoromethyl)quinazoline (180 mg, 69.5% yield).

[0356] MS(ESI)m / z = 247.2[M+H] + .

[0357] Fourth step synthesis

[0358] 2-(chloromethyl)-7-(trifluoromethyl)quinazoline (180 mg, 0.73 mmol) was dissolved in ethanol (15 mL), and imidazoline-2-thione (149 mg, 1.46 mmol) was added. The mixture was stirred at 70 °C for 16 hours. After cooling, the reaction solution was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography to obtain a yellow solid 2-(((4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-7-(trifluoromethyl)quinazoline formate (33.4 mg, yield 14.7%).

[0359] MS(ESI)m / z = 313.0[M+H] + .

[0360] 1H NMR (DMSO-d6, 400MHz): δ9.79 (s, 1H), 8.42 (d, J = 8.4Hz, 1H), 8.36 (s, 1H), 8.22 (s, 1H), 8.04 (d, J = 8.4Hz, 1H), 4.77 (s, 2H), 3.55 (s, 4H).

[0361] Synthesis of REJT-19

[0362] Step 1 Synthesis

[0363] Triethylamine (201.8 mg, 2.00 mmol) was added to a 15 mL solution of 4,5-difluorophenyl-1,2-diamine (288.0 mg, 2.00 mmol) in 1,2-dichloroethane. Chloroacetyl chloride (225.7 mg, 2.00 mmol) was then slowly added dropwise under ice bath conditions, and the reaction was allowed to proceed overnight at room temperature. The reaction mixture was extracted three times with dichloromethane (3 × 50 mL), washed three times with water (3 × 50 mL), and the resulting pale yellow oil was concentrated under vacuum and dissolved in 10 mL of glacial acetic acid. The mixture was then stirred at 80 °C for 2 hours under nitrogen protection. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure. The resulting oily substance was extracted three times with dichloromethane (3×50mL), washed three times with water (3×50mL), dried with magnesium sulfate, and the solvent was removed by rotary evaporation. The resulting light brown oily substance 2-(chloromethyl)-5,6-difluoro-1H-benzimidazole was directly used in the next step of the reaction (420.0 mg, yield 41.50%).

[0364] MS(ESI)m / z = 203.0[M+H] + .

[0365] Second step of synthesis

[0366] 2-(chloromethyl)-5,6-difluoro-1H-benzimidazole (200.0 mg, 0.99 mmol) was dissolved in ethanol (20 mL), and imidazolidine-2-thione (201.7 mg, 1.97 mmol) was added. The mixture was stirred at 70 °C for 4 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a yellow oily substance. The solid was purified by high performance liquid chromatography and lyophilized to obtain a white solid 2-(((4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-5,6-difluoro-1H-benzimidazole carbamate (60 mg, yield 22.43%).

[0367] MS(ESI)m / z = 269.0 [M+H] + .

[0368] 1H NMR (DMSO-d6, 400MHz): δ10.61 (brs, 1H), 8.16 (s, 1H), 7.58 (t, J = 8.4Hz, 2H), 4.44 (s, 2H), 3.57 (s, 4H).

[0369] The synthesis of REJT-20

[0370] Step 1 Synthesis

[0371] Triethylamine (303.0 mg, 3.00 mmol) was added to a 1,2-dichloroethane solution of 4-chlorophenyl-1,2-diamine (426.0 mg, 2.99 mmol) (20 mL), followed by slow dropwise addition of chloroacetyl chloride (336.0 mg, 2.99 mmol) under ice bath conditions. The reaction mixture was allowed to react overnight at room temperature. The solution was extracted three times with dichloromethane (3 × 50 mL), washed three times with water (3 × 50 mL), and the resulting pale yellow oil was concentrated under vacuum and dissolved in 10 mL of glacial acetic acid. The mixture was then stirred at 70 °C for 2 hours under nitrogen protection. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure. The resulting oily substance was extracted three times with dichloromethane (3×50mL), washed three times with water (3×50mL), dried with magnesium sulfate, and the solvent was removed by rotary evaporation. The resulting light brown oily substance 2-(chloromethyl)-6-chloro-1H-benzimidazole was directly used in the next step of the reaction (510.0 mg, yield 55.19%).

[0372] MS(ESI)m / z = 201.0[M+H] + .

[0373] Second step of synthesis

[0374] 2-(chloromethyl)-6-chloro-1H-benzimidazole (400.0 mg, 1.99 mmol) was dissolved in ethanol (20 mL), and imidazolidine-2-thione (406.5 mg, 3.98 mmol) was added. The mixture was stirred at 70 °C for 4 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a yellow oily substance. The solid was purified by high performance liquid chromatography to obtain a white solid 2-(((4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-6-chloro-1H-benzimidazole carbamate (87 mg, yield 14.01%).

[0375] MS(ESI)m / z = 267.0 [M+H] + .

[0376] 1H NMR (DMSO-d6, 400MHz): δ10.62(brs,1H),8.17(s,1H),7.59(s,1H),7.53(d,J=8.4Hz,1H),7.18(d,J=8.4Hz,1H),4.47(s,2H),3.58(s,4H).

[0377] The synthesis of REJT-21

[0378] Step 1 Synthesis

[0379] 4-(trifluoromethyl)phenyl-1,2-diamine (3.00 g, 0.017 mol) was dissolved in 4M hydrochloric acid (40 mL), and then 2-chloropropionic acid (2.20 g, 0.020 mol) was added. The reaction was stirred at 120 °C for 4 hours. After the reaction was completed and cooled, the pH of the reaction solution was adjusted to >7 with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate (100 mL × 3), the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a yellow solid 2-(1-chloroethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (1.2 g, yield 28.4%).

[0380] MS(ESI)m / z = 249.3 [M+H] + .

[0381] Second step of synthesis

[0382] 2-(1-chloroethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazolium (150 mg, 0.60 mmol) was dissolved in ethanol (10 mL), and imidazolidine-2-thione (123 mg, 1.21 mmol) was added. The mixture was stirred at 70 °C for 16 hours. After cooling, the reaction solution was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography to obtain a white solid 2-(1-((4,5-dihydro-1H-imidazol-2-yl)thio)ethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazolium carbamate (32.69 mg, yield 17.24%).

[0383] MS(ESI)m / z = 315.0 [M+H] + .

[0384] 1H NMR (DMSO-d6, 400MHz): δ8.19(s,1H),7.92(s,1H),7.72(d,J=8.4Hz,1H),7.49(dd,J1=1 .2Hz,J2=8.4Hz,1H),5.15(q,J=7.2Hz,1H),3.58(t,J=3.2Hz,4H),1.79(d,J=7.2Hz,3H).

[0385] The compounds in Table 9 below were prepared using the same methods as in the examples described above, with the corresponding compounds.

[0386] Table 9

[0387] The synthesis of REJT-22

[0388] 2-(chloromethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazolium (150 mg, 0.64 mmol) was dissolved in ethanol (15 mL), and 1-methylimidazolidine-2-thione (111 mg, 0.96 mmol) was added. The mixture was stirred at 70 °C for 16 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a brown oil. The solid was purified by high performance liquid chromatography, and acetonitrile was removed under reduced pressure. After lyophilization, a colorless oil, 2-(((1-methyl-4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-6-(trifluoromethyl)-1H-benzo[d]imidazolium carbamate (80 mg, yield 32.98%), was obtained.

[0389] MS(ESI)m / z = 315.0 [M+H] + .

[0390] 1 H NMR (DMSO-d6, 400MHz): δ8.15(s,1H),7.91(s,1H),7.72(t,J=8.4Hz,1H),7.49(dd,J=1 .2,8.4Hz,1H),4.58(s,4H),3.70(t,J=9.6Hz,2H),3.41(t,J=9.2Hz,1H),2.76(s,3H).

[0391] The synthesis of REJT-23

[0392] Step 1 Synthesis

[0393] 2-Fluoro-1-nitro-4-(trifluoromethyl)benzene (420 mg, 2.01 mmol) was dissolved in dichloromethane (20 mL), followed by the addition of cyclopropylamine (229.4 mg, 4.02 mmol) and potassium carbonate (555.2 mg, 4.02 mmol). The reaction was stirred at 25 °C for 16 hours under nitrogen protection. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a yellow solid N-cyclopropyl-2-nitro-5-(trifluoromethyl)aniline (490 mg, yield 89.2%).

[0394] MS(ESI)m / z = 247.1 [M+H] + .

[0395] Second step of synthesis

[0396] N-cyclopropyl-2-nitro-5-(trifluoromethyl)aniline (487 mg, 1.98 mmol) was dissolved in ethanol (10 mL) and water (2 mL), and zinc powder (1.29 g, 19.81 mmol) and ammonium chloride (1.06 g, 19.81 mmol) were added. The mixture was then stirred at 30 °C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was diluted with saturated sodium bicarbonate aqueous solution (20 mL) and ethyl acetate (20 mL). The mixture was extracted with ethyl acetate (20 mL × 2), and the organic phase was washed with saturated brine (20 mL). After drying with anhydrous sodium sulfate, the mixture was filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a yellow oily substance, N-cyclopropyl-5-(trifluoromethyl)benzene-1,2-diamine (321 mg, yield 75.1%).

[0397] 1 H NMR (CDCl3, 400MHz): δ7.28 (d, J = 2.0Hz, 1H), 7.03-7.00 (m, 1H), 6.76 (d, J = 10.8Hz, 1H), 4.0 8-3.95(m,1H),3.62-3.45(m,2H),2.56-2.50(m,1H),0.88-0.82(m,2H),0.62-0.57(m,2H).

[0398] Third step of synthesis

[0399] Triethylamine (124.2 mg, 1.23 mmol) was added to a 1,2-dichloroethane solution (15 mL) of N-cyclopropyl-5-(trifluoromethyl)benzene-1,2-diamine (321.0 mg, 1.23 mmol), followed by slow dropwise addition of chloroacetyl chloride (137.8 mg, 1.23 mmol) under ice bath conditions. The reaction mixture was allowed to react overnight at room temperature. The reaction solution was extracted three times with dichloromethane (3 × 50 mL), washed three times with water (3 × 50 mL), and the resulting pale yellow oily substance was concentrated under vacuum and dissolved in 10 mL of glacial acetic acid. The mixture was stirred at 80 °C for 2 hours under nitrogen protection. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure. The resulting oily substance was extracted three times with dichloromethane (3×50mL), washed three times with water (3×50mL), dried with magnesium sulfate, and the solvent was removed by rotary evaporation. The resulting light brown oily substance, 2-(chloromethyl)-1-cyclopropyl-6-(trifluoromethyl)-1H-benzimidazole, was directly used in the next step of the reaction (220.0 mg, yield 48.2%).

[0400] MS(ESI)m / z = 275.2[M+H] + .

[0401] Fourth step synthesis

[0402] 2-(chloromethyl)-1-cyclopropyl-6-(trifluoromethyl)-1H-benzimidazole (250 mg, 0.91 mmol) was dissolved in ethanol (20 mL), and imidazolidine-2-thione (186 mg, 1.82 mmol) was added. The mixture was stirred at 70 °C for 4 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a yellow oily substance. The solid was purified by high performance liquid chromatography to obtain a white solid 2-(((4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-1-cyclopropyl-6-(trifluoromethyl)-1H-benzimidazole carbamate (110 mg, yield 34.79%).

[0403] MS(ESI)m / z = 341.0[M+H] + .

[0404] 1 H NMR (DMSO-d6, 400MHz): δ8.17(s,1H),7.90(s,1H),7.83(d,J=8.4Hz,1H),7.56(dd,J1=8.7Hz,J2 =1.2Hz,1H),4.79(s,2H),3.62(s,4H),3.49-3.44(m,1H),1.30-1.27(m,2H),1.17-1.16(m,2H).

[0405] REJT-25 synthesis

[0406] Step 1 Synthesis

[0407] Triethylamine (523.2 mg, 5.18 mmol) was added to a 1,2-dichloroethane solution (20 mL) of naphthalene-2,3-diamine (410.0 mg, 2.59 mmol), followed by slow dropwise addition of chloroacetyl chloride (290.1 ​​mg, 2.59 mmol) under ice bath conditions. The reaction mixture was allowed to react overnight at room temperature. The reaction solution was extracted three times with dichloromethane (3 × 50 mL), washed three times with water (3 × 50 mL), and the resulting pale yellow oil was concentrated under vacuum and dissolved in 10 mL of glacial acetic acid. The mixture was then stirred at 70 °C for 2 hours under nitrogen protection. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure. The resulting oily substance was extracted three times with dichloromethane (3×50mL), washed three times with water (3×50mL), dried with magnesium sulfate, and the solvent was removed by rotary evaporation. The resulting light brown oily substance 2-(chloromethyl)-1H-naphthalene[2,3-naphthene]imidazole was directly used in the next step of the reaction (420mg, yield 37.54%).

[0408] MS(ESI)m / z = 217.0[M+H] + .

[0409] Second step of synthesis

[0410] 2-(chloromethyl)-1H-naphthyl[2,3-naphthyl]imidazolium (400.0 mg, 1.85 mmol) was dissolved in ethanol (40 mL), and imidazolidine-2-thione (377.2 mg, 3.69 mmol) was added. The mixture was stirred at 70 °C for 4 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a yellow oily substance. The solid was purified by high performance liquid chromatography to obtain a white solid 2-(((4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-1H-naphthyl[2,3-naphthyl]imidazolium carbamate (10 mg, yield 1.86%).

[0411] MS(ESI)m / z = 283.0[M+H] + .

[0412] 1 H NMR (DMSO-d6, 400MHz): δ11.05-10.08(brs,1H),8.16(s,1H),8.03(s,2H),7.98-7.95(m,2H),7.37-7.34(m,2H),4.54(s,2H),3.59(s,4H).

[0413] The synthesis of REJT-26

[0414] Step 1 Synthesis

[0415] 2-Bromo-5-fluoro-4-(trifluoromethyl)pyridine (500 mg, 2.05 mmol) was dissolved in methanol (15 mL), and sodium methoxide (133 mg, 2.46 mmol) was added. The reaction was carried out under nitrogen atmosphere and stirred at 70 °C for 16 hours. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain a white solid 2-bromo-5-methoxy-4-(trifluoromethyl)pyridine (220 mg, 56.5% yield).

[0416] MS(ESI)m / z = 258.1 [M+H] + .

[0417] Steps 2 and 3: Synthesis of REJT-26A2 and REJT-26A3

[0418] 2-Bromo-5-methoxy-4-(trifluoromethyl)pyridine (150 mg, 0.59 mmol) was dissolved in anhydrous toluene (10 mL). Butyllithium tetrahydrofuran solution (1.5 equivalences) was added at -78 °C, and the mixture was stirred at low temperature for 40 minutes. Then, N,N-dimethylformamide (1.5 equivalences) was slowly added dropwise, and stirring continued at low temperature for two hours. Sodium borohydride (44 mg, 1.17 mmol) was then added, and the mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was concentrated under reduced pressure, diluted with water (10 mL) and dichloromethane (10 mL), and extracted with dichloromethane (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a colorless oil (5-methoxy-4-(trifluoromethyl)pyridin-2-yl)methanol (103 mg, 76.38% yield).

[0419] MS(ESI)m / z = 208.1[M+H] + .

[0420] Fourth step synthesis

[0421] (5-Methoxy-4-(trifluoromethyl)pyridin-2-yl)methanol (70 mg, 0.34 mmol) was dissolved in dichloromethane (10 mL), and thionyl chloride (2.0 equivalents) was added. The reaction was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove residual thionyl chloride, yielding a yellow oily substance, 2-(chloromethyl)-5-methoxy-4-(trifluoromethyl)pyridine (67 mg, 79.11% yield).

[0422] MS(ESI)m / z = 226.1 / 228.1[M+H] + .

[0423] Fifth step synthesis

[0424] 2-(chloromethyl)-5-methoxy-4-(trifluoromethyl)pyridine (67 mg, 0.297 mmol) was dissolved in ethanol (10 mL), and imidazolidine-2-thione (30 mg, 0.297 mmol) was added. The mixture was stirred at 70 °C for 16 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a pale yellow oil. The solid was purified by high performance liquid chromatography, and acetonitrile was removed under reduced pressure. After lyophilization, a brown oily substance, 2-(((4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-5-methoxy-4-(trifluoromethyl)pyridinecarboxylate (40 mg, yield 39.53%), was obtained.

[0425] MS(ESI)m / z = 292.0 [M+H] + .

[0426] 1 H NMR (DMSO-d6, 400MHz): δ8.60(s,1H),8.20(s,1H),7.76(s,1H),4.40(s,2H),4.02(s,3H),3.52(s,4H).

[0427] The synthesis of REJT-27

[0428] Step 1 Synthesis

[0429] Triethylamine (53.1 mg, 0.53 mmol) was added to N 1 A solution of methyl-4-(trifluoromethyl)benzene-1,2-diamine (100.0 mg, 0.53 mmol) in 1,2-dichloroethane (20 mL) was added, followed by slow dropwise addition of chloroacetyl chloride (59.4 mg, 0.53 mmol) under ice bath conditions. The reaction mixture was reacted overnight at room temperature. The solution was extracted three times with dichloromethane (3 × 50 mL), washed three times with water (3 × 50 mL), and the resulting pale yellow oil was concentrated under vacuum and dissolved in 10 mL of glacial acetic acid. The mixture was stirred at 70 °C for 2 hours under nitrogen protection. After cooling, the reaction mixture was concentrated under reduced pressure. The resulting oil was extracted three times with dichloromethane (3 × 50 mL), washed three times with water (3 × 50 mL), dried over magnesium sulfate, and the solvent was removed by rotary evaporation. The resulting pale brown oil, 2-(chloromethyl)-1-methyl-5-(trifluoromethyl)-1H-benzimidazole, was directly used in the next step of the reaction (90.0 mg, yield 61.95%).

[0430] MS(ESI)m / z = 248.9[M+H] + .

[0431] Second step of synthesis

[0432] 2-(chloromethyl)-1-methyl-5-(trifluoromethyl)-1H-benzimidazole (210.0 mg, 0.84 mmol) was dissolved in ethanol (10 mL), and imidazolidine-2-thione (172.6 mg, 1.69 mmol) was added. The mixture was stirred at 70 °C for 4 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a yellow oily substance. The solid was purified by high performance liquid chromatography to obtain a white solid 2-(((4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-1-methyl-5-(trifluoromethyl)-1H-benzimidazole carboxylate (160 mg, yield 59.06%).

[0433] MS(ESI)m / z = 315.0 [M+H] + .

[0434] 1 H NMR (DMSO-d6, 400MHz): 8.18 (s, 1H), 7.94 (s, 1H), 7.76 (d, J = 8.4Hz, 1H), 7.58 (d, J = 8.4Hz, 1H), 4.64 (s, 2H), 3.88 (s, 3H), 3.52 (s, 4H).

[0435] REJT-30 synthesis

[0436] Step 1 Synthesis

[0437] 2-Bromo-4-(trifluoromethyl)benzaldehyde (2.5 g, 9.88 mmol), propynyl alcohol (1.11 g, 19.76 mmol), and triethylamine (2 g, 19.76 mmol) were dissolved in dimethylformamide (30 mL), followed by the addition of cuprous iodide (380 mg, 1.98 mmol) and palladium dichloride bis(triphenylphosphine) (690 mg, 0.99 mmol). The reaction mixture was stirred at 50 °C for 16 hours under nitrogen protection. After the reaction was complete, the reaction solution was diluted with water (200 mL) and ethyl acetate (100 mL), extracted with ethyl acetate (100 mL × 2), and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a yellow oily substance, 2-(3-hydroxyprop-1-yn-1-yl)-4-(trifluoromethyl)benzaldehyde (320 mg, yield 14.1%).

[0438] MS(ESI)m / z = 229.9[M+H] + .

[0439] Second step of synthesis

[0440] 2-(3-hydroxyprop-1-yn-1-yl)-4-(trifluoromethyl)benzaldehyde (320 mg, 1.42 mmol) and water (101 mg, 5.61 mmol) were dissolved in acetonitrile (7 mL), and then palladium dichloride diacetonitrile (36 mg, 0.14 mmol) was added. The reaction mixture was stirred at 15 °C for 2 hours under nitrogen protection. TLC monitoring showed no remaining starting material. Ammonium acetate (216 mg, 2.81 mmol) was added to the reaction mixture, and the mixture was stirred at 15 °C for 2 hours under nitrogen protection. After the reaction was complete, the reaction mixture was diluted with water (20 mL) and ethyl acetate (30 mL). The mixture was extracted with ethyl acetate (30 mL × 2), and the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a yellow oil (6-(trifluoromethyl)isoquinoline-3-yl)methanol (100 mg, yield 31.4%).

[0441] MS(ESI)m / z = 228.2[M+H] + .

[0442] Third step of synthesis

[0443] (6-(trifluoromethyl)isoquinoline-3-yl)methanol (100 mg, 0.44 mmol) was dissolved in dichloromethane (4 mL), and then thionyl chloride (105 mg, 0.88 mmol) was added. The reaction was carried out under nitrogen protection at 15 °C with stirring for 16 hours. After the reaction was completed, the reaction solution was diluted with saturated sodium bicarbonate aqueous solution (20 mL) and dichloromethane (20 mL), extracted with dichloromethane (20 mL × 2), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain a yellow oily substance 2-3-(chloromethyl)-6-(trifluoromethyl)isoquinoline (100 mg, yield 92.5%).

[0444] MS(ESI)m / z = 246.2[M+H] + .

[0445] Fourth step synthesis

[0446] 2-3-(chloromethyl)-6-(trifluoromethyl)isoquinoline (100 mg, 0.41 mmol) was dissolved in ethanol (10 mL), and imidazolidine-2-thione (83 mg, 6 mmol) was added. The mixture was stirred at 70 °C for 4 hours. After cooling, the reaction solution was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography to obtain a yellow oily substance 3-(((4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-6-(trifluoromethyl)isoquinoline carboxylate (20.57 mg, yield 16.2%).

[0447] MS(ESI)m / z = 312.0[M+H] + .

[0448] 1 H NMR (DMSO-d6, 400MHz): δ9.46 (s, 1H), 8.49 (s, 1H), 8.37 (d, J = 8.8Hz, 1H), 8.18 (s ,1H),8.09(s,1H),7.92(dd,J1=1.2Hz,J2=8.4Hz,1H),4.60(s,2H),3.56(s,4H).

[0449] The synthesis of REJT-32

[0450] Step 1 Synthesis

[0451] 6-(trifluoromethyl)benzothiazole-2-amine (1.00 g, 4.58 mmol) was dissolved in tetrahydrofuran (20 mL), and then isoamyl nitrite (1.18 g, 10.08 mmol) was added. The reaction was stirred at 80 °C for 2 hours under nitrogen protection. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure, diluted with water (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a yellow oily substance, 6-(trifluoromethyl)benzothiazole (440 mg, yield 47.3%).

[0452] MS(ESI)m / z = 203.9[M+H] + .

[0453] Second step of synthesis

[0454] 6-(trifluoromethyl)benzothiazole (930 mg, 4.58 mmol) and hydrazine hydrate (1796 mg, 54.92 mmol) were dissolved in ethanol (40 mL). The reaction mixture was stirred at 85 °C for 0.5 h under nitrogen protection. After the reaction was completed and cooled, water (20 mL) was added to the reaction solution, and the pH was adjusted to 6 with 50% acetic acid aqueous solution. The mixture was extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, and filtered to obtain a colorless oily substance, 2-amino-5-(trifluoromethyl)benzylthiol (840 mg, yield 95.0%).

[0455] MS(ESI)m / z = 194.0 [M+H] + .

[0456] Third step of synthesis

[0457] 2-Amino-5-(trifluoromethyl)benzylthiol (840 mg, 4.35 mmol) was dissolved in ethanol (20 mL), and then 2-chloro-1,1,1-trimethoxyethane (1.34 g, 8.69 mmol) was added. The reaction mixture was stirred at 60 °C for 1 hour under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure, diluted with water (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a colorless oily substance, 2-(chloromethyl)-6-(trifluoromethyl)benzothiazole (710 mg, yield 64.9%).

[0458] MS(ESI)m / z = 252.1[M+H] + .

[0459] Fourth step synthesis

[0460] 2-(chloromethyl)-6-(trifluoromethyl)benzothiazole (350 mg, 1.39 mmol) was dissolved in ethanol (10 mL), and imidazolidine-2-thione (170 mg, 1.67 mmol) was added. The mixture was stirred at 70 °C for 16 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a brown oily substance. The solid was purified by high performance liquid chromatography to obtain a white solid 2-((4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-6-(trifluoromethyl)benzothiazole carboxylate (326 mg, yield 73.1%).

[0461] MS(ESI)m / z = 318.0[M+H] + .

[0462] 1 H NMR (DMSO-d6, 400MHz): δ10.45 (br s, 1H), 8.67 (s, 1H), 8.19 (d, J = 8.8Hz, 1H), 7.85 (d, J = 8.4Hz, 1H), 5.15 (s, 2H), 3.81 (s, 4H).

[0463] The synthesis of REJT-33

[0464] Step 1 Synthesis

[0465] 4-(trifluoromethyl)phenyl-1,2-diamine (1.00 g, 5.70 mmol) was dissolved in 4M hydrochloric acid solution (20 mL), and then 2-hydroxy-2-phenylacetic acid (950 mg, 6.27 mmol) was added. The reaction was stirred at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was cooled, and the pH was adjusted to >7 with saturated sodium bicarbonate aqueous solution. The mixture was extracted with ethyl acetate (20 mL × 2), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a yellow solid phenyl(6-(trifluoromethyl)-1H-benzimidazol-2-yl)methanol (760 mg, yield 36.3%).

[0466] MS(ESI)m / z = 293.2[M+H] + .

[0467] Second step of synthesis

[0468] Phenyl(6-(trifluoromethyl)-1H-benzimidazol-2-yl)methanol (460 mg, 1.57 mmol) was dissolved in dichloromethane (15 mL), and thionyl chloride (374 mg, 3.15 mmol) was added. The mixture was stirred at 25 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure, diluted with saturated sodium bicarbonate aqueous solution (20 mL) and dichloromethane (20 mL), extracted with dichloromethane (20 mL × 2), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. No purification was required to obtain a colorless oily substance, 2-(chloro(phenyl)methyl)-6-(trifluoromethyl)-1H-benzimidazol (460 mg, yield 94.1%).

[0469] MS(ESI)m / z = 311.0[M+H] + .

[0470] Third step of synthesis

[0471] 2-(chloro(phenyl)methyl)-6-(trifluoromethyl)-1H-benzimidazole (460 mg, 1.48 mmol) was dissolved in acetonitrile (10 mL), and imidazolidine-2-thione (227 mg, 2.22 mmol) was added. The mixture was stirred at 70 °C for 16 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a brown oily substance. The solid was purified by high performance liquid chromatography to obtain a white solid 2-((4,5-dihydro-1H-imidazol-2-yl)thio(phenyl)methyl)-6-(trifluoromethyl)-1H-benzimidazole trifluoroacetate (171 mg, yield 30.4%).

[0472] MS(ESI)m / z = 377.0 [M+H] + .

[0473] 1 H NMR (DMSO-d6, 400MHz): δ10.51(br s,1H),7.99(s,1H),7.76(d,J=8.4Hz,1H),7.56(d,J=8.8Hz,1H),7.49-7.39(m,5H),6.61(s,1H),3.83(s,4H).

[0474] The compounds of the examples listed in Table 10 below were prepared using the same methods as in the examples described above, with the corresponding compounds.

[0475] Table 10

[0476] REJT-36 Synthesis

[0477] Step 1 Synthesis

[0478] 2-Fluoro-1-nitro-4-(trifluoromethyl)benzene (500 mg, 2.39 mmol) was dissolved in dichloromethane (20 mL), followed by the addition of methylamine hydrochloride (646 mg, 9.56 mmol) and potassium carbonate (1.32 g, 9.56 mmol). The reaction was carried out under nitrogen protection at 25 °C with stirring for 16 hours. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a yellow solid N-methyl-2-nitro-5-(trifluoromethyl)aniline (436 mg, yield 82.8%).

[0479] MS(ESI)m / z = 221.1[M+H] + .

[0480] Second step of synthesis

[0481] N-methyl-2-nitro-5-(trifluoromethyl)aniline (436 mg, 1.98 mmol) was dissolved in ethanol (10 mL) and water (2 mL), and zinc powder (1.29 g, 19.81 mmol) and ammonium chloride (1.06 g, 19.81 mmol) were added. The mixture was then stirred at 30 °C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was diluted with saturated sodium bicarbonate aqueous solution (20 mL) and ethyl acetate (20 mL). The mixture was extracted with ethyl acetate (20 mL × 2), and the organic phase was washed with saturated brine (20 mL). After drying with anhydrous sodium sulfate, the mixture was filtered, concentrated under vacuum, and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain a yellow oily substance 2-(methylamino)-4-(trifluoromethyl)aniline (318 mg, yield 84.4%).

[0482] MS(ESI)m / z = 191.1[M+H]+ .

[0483] Third step of synthesis

[0484] 2-(methylamino)-4-(trifluoromethyl)aniline (318 mg, 1.67 mmol) was dissolved in dichloromethane (15 mL), and triethylamine (338 mg, 3.34 mmol) and chloroacetyl chloride (246 mg, 2.17 mmol) were added. The mixture was stirred at 25 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure, diluted with saturated sodium bicarbonate aqueous solution (20 mL) and dichloromethane (20 mL), extracted with dichloromethane (20 mL × 2), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. No purification was required to obtain a colorless oily substance, 2-chloro-N-(2-(methylamino)-4-(trifluoromethyl)phenyl)acetamide (320 mg, yield 71.8%).

[0485] MS(ESI)m / z = 267.2[M+H] + .

[0486] Fourth step synthesis

[0487] 2-Chloro-N-(2-(methylamino)-4-(trifluoromethyl)phenyl)acetamide (320 mg, 1.20 mmol) was dissolved in acetic acid (10 mL) and reacted at 70 °C for 2 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure, diluted with saturated sodium bicarbonate aqueous solution and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a yellow solid 2-(chloromethyl)-1-methyl-6-(trifluoromethyl)-1H-benzimidazole (116 mg, yield 38.9%).

[0488] MS(ESI)m / z = 249.1 [M+H] + .

[0489] Fifth step synthesis

[0490] 2-(chloromethyl)-1-methyl-6-(trifluoromethyl)-1H-benzimidazole (116 mg, 0.47 mmol) was dissolved in acetonitrile (10 mL), and imidazolidine-2-thione (52 mg, 0.51 mmol) was added. The mixture was stirred at 70 °C for 16 hours. After cooling, the reaction solution was filtered, washed with acetonitrile, and dried to give a white solid 2-(((4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-1-methyl-6-(trifluoromethyl)-1H-benzimidazole hydrochloride (130 mg, yield 90.2%).

[0491] MS(ESI)m / z = 315.0 [M+H] + .

[0492] 1 H NMR (DMSO-d6, 400MHz): δ10.47-10.45(brs,2H),8.09(s,1H),7.83(d,J=8.4Hz,1H),7.56(d,J=8.4Hz,1H),4.96(s,2H),3.92(s,3H),3.89(s,4H).

[0493] The compounds in Table 11 below were prepared using the same methods as in the examples described above, with the corresponding compounds.

[0494] Table 11

[0495] The synthesis of REJT-37

[0496] Step 1 Synthesis

[0497] (4-Bromopyridin-2-yl)methanol (200 mg, 1.06 mmol) was dissolved in dioxane (20 mL) and water (4 mL), followed by (4-(trifluoromethyl)phenyl)boronic acid (212 mg, 1.12 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (78 mg, 0.11 mmol), and sodium carbonate (225 mg, 2.13 mmol). The reaction was stirred at 85 °C for 16 hours under nitrogen protection. After the reaction was completed and cooled, the reaction solution was diluted with water (20 mL) and ethyl acetate (20 mL). The solution was extracted with ethyl acetate (20 mL × 2), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a brown solid (4-(4-(trifluoromethyl)phenyl)pyridin-2-yl)methanol (220 mg, yield 90.1%).

[0498] MS(ESI)m / z = 254.2[M+H] + .

[0499] Second step of synthesis

[0500] (4-(4-(trifluoromethyl)phenyl)pyridin-2-yl)methanol (320 mg, 1.26 mmol) was dissolved in dichloromethane (10 mL), and thionyl chloride (301 mg, 2.53 mmol) was added. The mixture was stirred at 25 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure, diluted with saturated sodium bicarbonate aqueous solution (20 mL) and dichloromethane (20 mL), extracted with dichloromethane (20 mL × 2), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a yellow solid 2-(chloromethyl)-4-(4-(trifluoromethyl)phenyl)pyridine (259 mg, yield 75.4%).

[0501] MS(ESI)m / z = 272.2[M+H] + .

[0502] Third step of synthesis

[0503] 2-(chloromethyl)-4-(4-(trifluoromethyl)phenyl)pyridine (259 mg, 0.95 mmol) was dissolved in acetonitrile (10 mL), and imidazolidin-2-thione (107 mg, 1.05 mmol) was added. The mixture was stirred at 70 °C for 16 hours. After cooling, a solid precipitated. The solid was filtered, washed with acetonitrile, and dried to give a white solid 2-((4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-4-(4-(trifluoromethyl)phenyl)pyridine hydrochloride (203 mg, yield 62.8%).

[0504] MS(ESI)m / z = 338.0 [M+H] + .

[0505] 1 H NMR(DMSO-d6,400MHz): δ10.47-10.44(brs,2H),8.70(d,J=5.6Hz,1H),8.03(d,J= 8.0Hz,2H),7.94(t,J=9.2Hz,3H),7.79(d,J=5.2Hz,1H),4.76(s,2H),3.89(s,4H).

[0506] The synthesis of REJT-38

[0507] Step 1 Synthesis

[0508] 4-(trifluoromethyl)phenyl-1,2-diamine (400 mg, 2.27 mmol) was dissolved in 4M hydrochloric acid solution (20 mL), and then 2-hydroxy-3-phenylpropionic acid (377 mg, 2.27 mmol) was added. The reaction was stirred at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was cooled, and the pH was adjusted to >7 with saturated sodium bicarbonate aqueous solution. The mixture was extracted with ethyl acetate (20 mL × 2), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a gray solid 2-phenyl-1-(6-(trifluoromethyl)-1H-benzimidazol-2-yl)ethane-1-ol (350 mg, yield 71.9%).

[0509] MS(ESI)m / z = 307.3[M+H] + .

[0510] Second step of synthesis

[0511] Phenyl(6-(trifluoromethyl)-1H-benzimidazol-2-yl)methanol (350 mg, 1.14 mmol) was dissolved in tetrahydrofuran (10 mL), and N,N-dimethylformamide (1 mL) was added to thionyl chloride (272 mg, 2.28 mmol). The mixture was stirred at 60 °C for 1 hour under nitrogen protection. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure, diluted with saturated sodium bicarbonate aqueous solution (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a gray solid 2-(1-chloro-2-phenylethyl)-6-(trifluoromethyl)-1H-benzimidazol (250 mg, yield 67.4%).

[0512] MS(ESI)m / z = 325.2[M+H] + .

[0513] Third step of synthesis

[0514] 2-(1-chloro-2-phenylethyl)-6-(trifluoromethyl)-1H-benzimidazole (253 mg, 0.78 mmol) was dissolved in acetonitrile (10 mL), and imidazolidine-2-thione (88 mg, 0.86 mmol) was added. The mixture was stirred at 70 °C for 72 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a brown oily substance. The solid was purified by high performance liquid chromatography to obtain a white solid 2-(1-((4,5-dihydro-1H-imidazol-2-yl)thio)-2-phenylethyl)-6-(trifluoromethyl)-1H-benzimidazole carboxylate (55 mg, yield 18.1%).

[0515] MS(ESI)m / z = 391.0 [M+H]+ .

[0516] 1 H NMR (DMSO-d6, 400MHz): δ8.52(s,1H),7.90(s,1H),7.71(d,J=8.4Hz,1H),7.56(d,J=8.8Hz,1H),7 .25-7.21(m,5H),5.26(t,J=8.0Hz,1H),3.83(s,4H),3.64(q,J=7.6Hz,1H),3.55(q,J=7.2Hz,1H).

[0517] The synthesis of REJT-41

[0518] Step 1 Synthesis

[0519] 4-Bromophenyl-1,2-diamine (400.0 mg, 2.14 mmol), 3-(trifluoromethyl)phenylboronic acid (406.2 mg, 2.14 mmol), Pd(PPh3)4 (123.6 mg, 0.107 mmol) and potassium carbonate (2.37 g, 17.11 mmol) were suspended in N,N-dimethylformamide:water (16 mL: 4 mL) and reacted overnight at 90 °C under nitrogen protection. The reaction mixture was extracted three times with ethyl acetate (3 × 50 mL), washed three times with water (3 × 50 mL), dried with magnesium sulfate, and the solvent was removed by rotary evaporation. The resulting light brown oily substance was separated by silica gel column chromatography to obtain a light brown solid 4-(3-trifluoromethylphenyl)phenyl-1,2-diamine (260 mg, yield 40.82%).

[0520] MS(ESI)m / z = 253.0 [M+H] + .

[0521] Second step of synthesis

[0522] Triethylamine (96.1 mg, 0.95 mmol) was added to a 1,2-dichloroethane solution (20 mL) of 4-(3-trifluoromethylphenyl)benzene-1,2-diamine (240.0 mg, 0.95 mmol), followed by slow dropwise addition of chloroacetyl chloride (107.5 mg, 0.95 mmol) under ice bath conditions. The reaction mixture was allowed to react overnight at room temperature. The reaction solution was extracted three times with dichloromethane (3 × 50 mL), washed three times with water (3 × 50 mL), and the resulting pale yellow oil was concentrated under vacuum and dissolved in 10 mL of glacial acetic acid. The mixture was then stirred at 80 °C for 2 hours under nitrogen protection. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure. The resulting oily substance was extracted three times with dichloromethane (3×50mL), washed three times with water (3×50mL), dried with magnesium sulfate, and the solvent was removed by rotary evaporation. The resulting light brown oily substance 2-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1H-1,3-benzimidazole was directly used in the next step of the reaction (115mg, yield 33.20%).

[0523] MS(ESI)m / z = 310.9[M+H] + .

[0524] Third step of synthesis

[0525] 2-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1H-1,3-benzimidazole (100.0 mg, 0.32 mmol) was dissolved in ethanol (5 mL), and imidazolidine-2-thione (65.8 mg, 0.64 mmol) was added. The mixture was stirred at 70 °C for 16 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a yellow oil. The solid was purified by high performance liquid chromatography and lyophilized to obtain a white solid 2-[(4,5-dihydro-1H-imidazol-2-ylthio)methyl]-5-[3-(trifluoromethyl)phenyl]-1H-1,3-benzimidazole carboxylate (9.8 mg, yield 8.12%).

[0526] MS(ESI)m / z = 377.0 [M+H] + .

[0527] 1 H NMR(DMSO-d6,400MHz): δ8.26(s,1H),8.01-7.97(m,2H),7.88(s,1H),7.6 9(s,2H),7.65-7.62(m,1H),7.56-7.54(m,1H),4.49(s,2H),3.60(s,4H).

[0528] The compounds in Table 12 below were prepared using the same methods as in the examples described above.

[0529] Table 12

[0530] The synthesis of REJT-44

[0531] Step 1 Synthesis

[0532] 4-Bromo-2-methylpyrimidine (1.9 g, 0.011 mol), (4-(trifluoromethyl)phenyl)boronic acid (2.19 g, 0.012 mol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.8 g, 0.0011 mol), and sodium carbonate (1.75 g, 0.017 mol) were dissolved in dioxane (50 mL) and water (10 mL). The mixture was stirred at 85 °C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was cooled, water was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a colorless oily substance, 2-methyl-4-(4-(trifluoromethyl)phenyl)pyrimidine (2.1 g, yield 80.97%).

[0533] MS(ESI)m / z=239.2[M+H]+.

[0534] Second step of synthesis

[0535] 2-Methyl-4-(4-(trifluoromethyl)phenyl)pyrimidine (2.22 g, 0.0093 mmol), N-bromosuccinimide (1.66 g, 0.0093 mmol), and azobisisobutyronitrile (0.15 g, 0.00093 mmol) were dissolved in carbon tetrachloride (100 mL) and reacted under nitrogen protection at 80 °C for 48 hours. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure, diluted with saturated sodium bicarbonate aqueous solution (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a yellow solid 2-(bromomethyl)-4-(4-(trifluoromethyl)phenyl)pyrimidine (404 mg, yield 11.10%).

[0536] MS(ESI)m / z = 319.1 [M+3] + .

[0537] Third step of synthesis

[0538] 2-(bromomethyl)-4-(4-(trifluoromethyl)phenyl)pyrimidine (200 mg, 0.63 mmol) was dissolved in acetonitrile (10 mL), and imidazolidin-2-thione (96 mg, 0.94 mmol) was added. The mixture was stirred at 70 °C for 16 hours. After cooling, the reaction solution was filtered, and the filter cake was washed with acetonitrile. The filter cake was dried to give a white solid 2-(((4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-4-(4-(trifluoromethyl)phenyl)pyrimidine hydrobromide (150 mg, yield 70.42%).

[0539] MS(ESI)m / z = 339.0 [M+H] + .

[0540] 1 H NMR(DMSO-d6,400MHz): δ10.26(s,2H),8.99(d,J=5.2Hz,1H),8.42(d,J=8.0H z,2H),8.20(d,J=5.2Hz,1H),7.99(d,J=8.0Hz,2H),4.91(s,2H),3.92(s,4H).

[0541] The compounds in Table 13 below were prepared using the same methods as in the examples described above.

[0542] Table 13

[0543] REJT-53 Synthesis

[0544] Step 1 Synthesis

[0545] 2-Bromo-1-(2-(trifluoromethyl)phenyl)ethane-1-one (2 g, 7.49 mmol) and sodium dimethamide (1.07 g, 11.23 mmol) were dissolved in acetonitrile (60 mL) and stirred at 70 °C for 16 hours. The reaction solution was concentrated under vacuum, and then the mixture was dissolved in methanol (100 mL) and concentrated hydrochloric acid (80 mL) and stirred at 80 °C for 2 hours. The reaction solution was concentrated under vacuum, and purified by slurrying with petroleum ether / ethyl acetate to obtain a yellow solid 2-amino-1-(2-(trifluoromethyl)phenyl)ethane-1-one (1.50 g, 98.58%).

[0546] Second step of synthesis

[0547] 2-Amino-1-(2-(trifluoromethyl)phenyl)ethane-1-one (1.22 g, 6.01 mmol), ethyl thiocarbamate (0.80 g, 6.01 mmol), and sodium acetate (1.48 g, 18.02 mmol) were dissolved in acetic acid (15 mL), and the mixture was stirred at 125 °C for 3 hours. The reaction solution was concentrated under vacuum, and the pH was adjusted to >7 by adding saturated sodium bicarbonate aqueous solution. The solution was extracted with ethyl acetate (50 mL * 3), and the organic phase was concentrated under vacuum and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give a light brown solid ethyl 5-(2-(trifluoromethyl)phenyl)-oxazol-2-carboxylate (650 mg, yield 37.8%).

[0548] MS(ESI)m / z = 286.3[M+H] + .

[0549] Third step of synthesis

[0550] Ethyl 5-(2-(trifluoromethyl)phenyl)oxazol-2-carboxylate (300 mg, 1.05 mmol) was dissolved in tetrahydrofuran (10 mL), and 2 mol / L lithium borohydride tetrahydrofuran solution (0.8 mL, 1.58 mmol) was added. The mixture was stirred at 25 °C for 16 hours. The reaction solution was added to a saturated sodium bicarbonate aqueous solution (20 mL), extracted with ethyl acetate (20 mL × 3), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a yellow oily substance (5-(2-(trifluoromethyl)phenyl)oxazol-2-yl)methanol (245 mg, 95.8%).

[0551] MS(ESI)m / z = 244.2[M+H] + .

[0552] Fourth step synthesis

[0553] (5-(2-(trifluoromethyl)phenyl)oxazol-2-yl)methanol (245 mg, 1.01 mmol) was dissolved in dichloromethane (10 mL), and thionyl chloride (240 mg, 2.02 mmol) was added. The mixture was stirred at 25 °C for 16 hours. The reaction solution was added to a saturated sodium bicarbonate aqueous solution (20 mL), extracted with dichloromethane (20 mL × 3), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain a yellow oily substance 2-(chloromethyl)-5-(2-(trifluoromethyl)phenyl)oxazol (100 mg, 37.9%).

[0554] MS(ESI)m / z = 262.2[M+H] + .

[0555] Fifth step synthesis

[0556] 2-(chloromethyl)-5-(2-(trifluoromethyl)phenyl)oxazole (100 mg, 0.38 mmol) was dissolved in acetonitrile (6 mL), and imidazole-2-thionone (41 mg, 0.40 mmol) was added. The mixture was stirred at 70 °C for 16 hours. The reaction solution was cooled and filtered to give a white solid 2-(((4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-5-(2-(trifluoromethyl)phenyl)oxazole hydrochloride (67.46 mg, yield 53.9%).

[0557] MS(ESI)m / z = 328.0 [M+H] + .

[0558] 1 H NMR (DMSO-d6, 400MHz): δ10.55 (s, 2H), 7.92 (d, J = 8Hz, 1H), 7.84-7.81 (m, 2H), 7.73-7.70 (m, 1H), 7.54 (s, 1H), 4.89 (s, 2H), 3.89 (s, 4H).

[0559] The synthesis of REJT-54

[0560] 1-Cyclopropylimidazolidine-2-thione (20 mg, 0.1462 mmol) was dissolved in acetonitrile (20 mL), and 2-(chloromethyl)-4-(4-(trifluoromethyl)phenyl)thiazole (39 mg, 0.14 mmol) was added. The mixture was stirred at 70 °C for 16 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to give a brown oily substance. The solid was purified by high performance liquid chromatography (mobile phase: acetonitrile / water (0.5% formic acid)). Acetonitrile was removed under reduced pressure, and the solid was lyophilized to give a white solid 2-(((1-cyclopropyl-4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-4-(4-(trifluoromethyl)phenyl)thiazole (7.0 mg, yield 13.05%).

[0561] MS(ESI)m / z = 384.1 [M+H] + .

[0562] 1 H NMR (DMSO-d6, 400MHz): δ8.23 (s, 1H), 8.15 (d, J = 8.4Hz, 2H), 7.80 (d, J = 8.4Hz, 2H), 4. 65(s,2H),3.61-3.59(m,2H),3.41-3.36(m,2H),2.24-2.19(m,1H),0.66-0.58(m,4H).

[0563] The synthesis of REJT-57

[0564] Step 1 Synthesis

[0565] 2-Fluoro-1-nitro-4-(trifluoromethyl)benzene (500 mg, 2.39 mmol) was dissolved in dichloromethane (20 mL), followed by the addition of methylamine hydrochloride (646 mg, 9.56 mmol) and potassium carbonate (1.32 g, 9.56 mmol). The reaction was carried out under nitrogen protection at 25 °C with stirring for 16 hours. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a yellow solid N-methyl-2-nitro-5-(trifluoromethyl)aniline (436 mg, yield 82.8%).

[0566] MS(ESI)m / z = 221.1[M+H] + .

[0567] Second step of synthesis

[0568] N-methyl-2-nitro-5-(trifluoromethyl)aniline (436 mg, 1.98 mmol) was dissolved in ethanol (10 mL) and water (2 mL), and zinc powder (1.29 g, 19.81 mmol) and ammonium chloride (1.06 g, 19.81 mmol) were added. The mixture was stirred at 30 °C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was diluted with saturated sodium bicarbonate aqueous solution (20 mL) and ethyl acetate (20 mL). The mixture was extracted with ethyl acetate (20 mL × 2), and the organic phase was washed with saturated brine (20 mL). After drying with anhydrous sodium sulfate, the mixture was filtered, concentrated under vacuum, and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain a yellow oily substance 2-(methylamino)-4-(trifluoromethyl)aniline (318 mg, yield 84.4%).

[0569] MS(ESI)m / z = 191.1[M+H] + .

[0570] Third step of synthesis

[0571] 2-(methylamino)-4-(trifluoromethyl)aniline (318 mg, 1.67 mmol) was dissolved in dichloromethane (15 mL), and triethylamine (338 mg, 3.34 mmol) and chloroacetyl chloride (246 mg, 2.17 mmol) were added. The mixture was stirred at 25 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure, diluted with saturated sodium bicarbonate aqueous solution (20 mL) and dichloromethane (20 mL), extracted with dichloromethane (20 mL × 2), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. No purification was required to obtain a colorless oily substance, 2-chloro-N-(2-(methylamino)-4-(trifluoromethyl)phenyl)acetamide (320 mg, yield 71.8%).

[0572] MS(ESI)m / z = 267.2[M+H] + .

[0573] Fourth step synthesis

[0574] 2-Chloro-N-(2-(methylamino)-4-(trifluoromethyl)phenyl)acetamide (320 mg, 1.20 mmol) was dissolved in acetic acid (10 mL) and reacted at 70 °C for 2 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure, diluted with saturated sodium bicarbonate aqueous solution and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a yellow solid 2-(chloromethyl)-1-methyl-6-(trifluoromethyl)-1H-benzimidazole (116 mg, yield 38.9%).

[0575] MS(ESI)m / z = 249.1 [M+H] + .

[0576] Fifth step synthesis

[0577] 2-(chloromethyl)-1-methyl-6-(trifluoromethyl)-1H-benzimidazole (120 mg, 0.48 mmol) was dissolved in acetonitrile (5 mL), and 1-cyclopropylimidazolidine-2-thione (68.6 mg, 0.48 mmol) was added. The mixture was stirred at 70 °C for 16 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a yellow oil. The solid was purified by high performance liquid chromatography, and acetonitrile was removed under reduced pressure. After lyophilization, a white solid 2-(((4,5-dihydro-1H-imidazol-2-yl)thio)cyclopropyl)-1-methyl-6-(trifluoromethyl)-1H-benzimidazole carbamate (33 mg, yield 18.90%) was obtained.

[0578] MS(ESI)m / z = 355.0 [M+H] + .

[0579] 1 H NMR (DMSO-d6, 400MHz): δ8.22(s,1H),8.02(s,1H),7.77(d,J=8.4Hz,1H),7.51(d,J=8.4Hz,1H),4.62( s,2H),3.91(s,3H),3.59(t,J=9.2Hz,2H),3.37(t,J=8.4Hz,2H),2.26-2.24(m,1H),0.66-0.58(m,4H).

[0580] REJT-59 Synthesis

[0581] Step 1 Synthesis

[0582] 1-(4-(trifluoromethyl)phenyl)prop-1-one (1.50 g, 7.42 mmol) was dissolved in a 30% hydrobromic acid-acetic acid solution (20 mL). Bromine (1.13 g, 7.05 mmol) dissolved in acetic acid (5 mL) was added to the reaction solution under ice bath conditions. The mixture was stirred at 20 °C for 16 hours. The reaction solution was concentrated under vacuum, and the pH was adjusted to >7 with saturated sodium bicarbonate solution. Extraction was performed with ethyl acetate (50 mL × 3). The organic phase was concentrated under vacuum and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to give a yellow solid 2-bromo-1-(4-(trifluoromethyl)phenyl)prop-1-one (1.90 g, yield 91.1%).

[0583] MS(ESI)m / z = 281.4[M+H] + .

[0584] Second step of synthesis

[0585] 2-Bromo-1-(4-(trifluoromethyl)phenyl)prop-1-one (1.90 g, 6.76 mmol) and sodium dimethamide (0.96 g, 10.14 mmol) were dissolved in acetonitrile (50 mL) and stirred at 70 °C for 16 hours. The reaction solution was concentrated under vacuum, and then the mixture was dissolved in methanol (75 mL) and concentrated hydrochloric acid (60 mL) and stirred at 80 °C for 2 hours. The reaction solution was concentrated under vacuum, and purified by slurry mixing with petroleum ether / ethyl acetate (50 / 5 mL) to obtain a yellow solid 2-amino-1-(4-(trifluoromethyl)phenyl)prop-1-one (1.40 g, yield 95.4%).

[0586] MS(ESI)m / z = 218.1[M+H] + .

[0587] Third step of synthesis

[0588] 2-Amino-1-(4-(trifluoromethyl)phenyl)prop-1-one (1.47 g, 6.76 mmol), ethyl 2-amino-2-thionyl acetate (0.90 g, 6.76 mmol), and sodium acetate (1.66 g, 20.27 mmol) were dissolved in acetic acid (15 mL), and the mixture was stirred at 125 °C for 3 hours. The reaction solution was concentrated under vacuum, and the pH was adjusted to >7 with saturated sodium bicarbonate aqueous solution. The solution was extracted with ethyl acetate (50 mL × 3), and the organic phase was concentrated under vacuum and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give a yellow solid ethyl 4-methyl-5-(4-(trifluoromethyl)phenyl)-1H-imidazolium-2-carboxylate (660 mg, yield 32.7%).

[0589] MS(ESI)m / z = 299.3[M+H] + .

[0590] Fourth step synthesis

[0591] Ethyl 4-methyl-5-(4-(trifluoromethyl)phenyl)-1H-imidazolium-2-carboxylate (400 mg, 1.34 mmol) and potassium carbonate (371 mg, 2.68 mmol) were dissolved in acetonitrile (12 mL), and 2-(trimethylsilyl)ethoxymethyl chloride (268 mg, 1.61 mmol) was added. The mixture was stirred at 25 °C for 16 hours. The reaction solution was then diluted with water (30 mL), extracted with ethyl acetate (30 mL × 3), and the organic phase was concentrated under vacuum and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to give a yellow solid ethyl 4-methyl-5-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium-2-carboxylate (320 mg, yield 55.7%).

[0592] MS(ESI)m / z = 429.5[M+H] + .

[0593] Fifth step synthesis

[0594] Ethyl 4-methyl-5-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-carboxylate (320 mg, 0.75 mmol) was dissolved in tetrahydrofuran (10 mL), and 2 mol / L lithium borohydride tetrahydrofuran solution (0.6 mL, 1.12 mmol) was added. The mixture was stirred at 25 °C for 16 hours. The reaction solution was added to saturated sodium bicarbonate aqueous solution (20 mL), extracted with ethyl acetate (20 mL × 3), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a yellow oil (4-methyl-5-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol (280 mg, yield 97.0%).

[0595] MS(ESI)m / z = 387.4 [M+H] + .

[0596] Step 6 Synthesis

[0597] (4-Methyl-5-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanol (280 mg, 0.72 mmol) was dissolved in dichloromethane (10 mL), and thionyl chloride (172 mg, 1.45 mmol) was added. The mixture was stirred at 25 °C for 16 hours. The reaction solution was added to a saturated sodium bicarbonate aqueous solution (20 mL), extracted with dichloromethane (20 mL × 3), and the organic phase was concentrated under vacuum and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1). The concentrate yielded a yellow oily substance 2-(chloromethyl)-4-methyl-5-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium (140 mg, yield 47.7%).

[0598] MS(ESI)m / z = 405.4 [M+H] + .

[0599] Seventh step synthesis

[0600] 2-(chloromethyl)-4-methyl-5-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium (140 mg, 0.35 mmol) was dissolved in acetonitrile (8 mL), and imidazolium-2-thionone (42 mg, 0.41 mmol) was added. The mixture was stirred at 70 °C for 16 hours. The reaction solution was concentrated under vacuum and purified by silica gel column chromatography to obtain a yellow solid 2-(((4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-4-methyl-5-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium (150 mg, yield 92.2%).

[0601] MS(ESI)m / z = 471.5[M+H] + .

[0602] Step 8 Synthesis

[0603] 2-(((4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-4-methyl-5-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium (150 mg, 0.32 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (5 mL), and the mixture was stirred at 25 °C for 16 hours. The reaction solution was cooled and concentrated under reduced pressure, then dried to obtain a yellow oil. The solid was purified by high-performance liquid chromatography (mobile phase: acetonitrile / water (0.5% trifluoroacetic acid)), and lyophilized to obtain a brown oil, yielding a white solid 2-(((4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-4-methyl-5-(4-(trifluoromethyl)phenyl)-1H-imidazolium trifluoroacetate (41.45 mg, yield 38.2%).

[0604] MS(ESI)m / z = 341.0[M+H] + .

[0605] 1 H NMR (DMSO-d6, 400MHz): δ11.90-10.40(m,1H),7.84-7.77(m,4H),4.61(s,2H),3.93(s,4H),2.44(s,3H).

[0606] REJT-60 synthesis

[0607] Step 1 Synthesis

[0608] 2-Methyl-7-(trifluoromethyl)quinoline (300 mg, 1.42 mmol) was dissolved in dichloromethane (10 mL), and m-chloroperoxybenzoic acid (433 mg, 2.13 mmol) was added under ice bath conditions. The mixture was stirred at room temperature for 16 hours. The reaction solution was extracted with 30 mL of saturated sodium sulfite solution using dichloromethane (30 mL × 3). The combined organic phases were washed with saturated sodium carbonate (30 mL), followed by washing with saturated brine (20 mL). After drying with anhydrous sodium sulfate, the mixture was filtered and concentrated under vacuum to give a white solid, 2-methyl-7-(trifluoromethyl)quinoline 1-oxide (300 mg, yield 93.0%).

[0609] MS(ESI)m / z = 228.2[M+H] + .

[0610] Second step of synthesis

[0611] 2-Methyl-7-(trifluoromethyl)quinoline 1-oxide (280 mg, 1.23 mmol) and triethylamine (624 mg, 6.16 mmol) were dissolved in dichloromethane (12 mL). Triphosgene (183 mg, 0.62 mmol) was added under ice bath conditions, and the mixture was stirred at 25 °C for 1 hour. The reaction solution was then added to 30 mL of water and extracted with dichloromethane (30 mL x 3). The organic phase was concentrated under vacuum and purified by silica gel column chromatography to obtain a white solid 2-(chloromethyl)-7-(trifluoromethyl)quinoline (120 mg, yield 39.6%).

[0612] MS(ESI)m / z = 246.2[M+H] + .

[0613] Third step of synthesis

[0614] 2-(chloromethyl)-7-(trifluoromethyl)quinoline (120 mg, 0.49 mmol) was dissolved in acetonitrile (8 mL), and 1-cyclopropylimidazolidine-2-thione (73 mg, 0.51 mmol) was added. The mixture was stirred at 70 °C for 16 hours. After cooling, the reaction solution was concentrated under reduced pressure. The solid was purified by high performance liquid chromatography (mobile phase: acetonitrile / water (0.5% formic acid)). After lyophilization, a yellow oily substance, 2-(((1-cyclopropyl-4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-7-(trifluoromethyl)quinoline (2.55 mg, yield 1.5%), was obtained.

[0615] MS(ESI)m / z = 352.0 [M+H] + .

[0616] 1H NMR(DMSO-d6,400MHz): δ8.42(d,J=8.8Hz,1H),8.33(s,1H),8.14(d,J=8.8Hz,1H),7.82-7.79(m ,2H),4.62(s,2H),3.73(t,J=2Hz,1H),3.57-3.52(m,2H),2.41-2.37(m,1H),0.79-0.73(m,4H).

[0617] The synthesis of REJT-61

[0618] Step 1 Synthesis

[0619] 2-(methylamino)-5-(trifluoromethyl)aniline (755.3 mg, 3.97 mmol) and 2-hydroxy-3-phenylpropionic acid (600.0 mg, 3.61 mmol) were suspended in 4M hydrochloric acid solution (8 mL), and then reacted at 90 °C for 6 hours. After cooling to room temperature, the reaction solution was adjusted to pH 8 with saturated sodium carbonate solution, extracted three times with ethyl acetate (3 × 50 mL), washed three times with water (3 × 50 mL), dried over magnesium sulfate, and the solvent was removed by rotary evaporation to obtain a brown solid 1-(1-methyl-5-(trifluoromethyl)-1H-benzimidazol-2-yl)-2-phenylethyl-1-ol (430 mg, yield 33.46%), which was used directly in the next step without further purification.

[0620] MS(ESI)m / z = 321.0[M+H] + .

[0621] Second step of synthesis

[0622] 1-(1-methyl-5-(trifluoromethyl)-1H-benzimidazol-2-yl)-2-phenylethyl-1-ol (100.0 mg, 0.31 mmol) was dissolved in tetrahydrofuran (5 mL), and 0.5 mL of N,N-dimethylformamide was added. Then, thionyl chloride (111.4 mg, 0.94 mmol) was slowly added dropwise at 0°C. The reaction phase was stirred at 60°C for 4 hours and concentrated to dryness under reduced pressure to give a brown oily substance, 2-(1-chloro-2-phenylethyl)-1-methyl-5-(trifluoromethyl)-1,3-benzimidazole (95 mg, yield 76.36%), which was used directly in the next step.

[0623] MS(ESI)m / z = 339.3 [M+H] + .

[0624] Second step of synthesis

[0625] 2-(1-chloro-2-phenylethyl)-1-methyl-5-(trifluoromethyl)-1,3-benzimidazole (100.0 mg, 0.30 mmol) was dissolved in acetonitrile (5 mL), and 1-methylimidazolidine-2-thione (68.6 mg, 0.59 mmol) was added. The mixture was stirred at 70 °C for 3 days. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a yellow oily substance. The oil was purified by high performance liquid chromatography, and acetonitrile was removed under reduced pressure. After lyophilization, a gray solid 1-methyl-2-{1-[(1-methyl-4,5-dihydroimidazol-2-yl)thiol]-2-phenylethyl}-5-(trifluoromethyl)-1,3-benzimidazole carbamate (19 mg, yield 15.07%) was obtained.

[0626] MS(ESI)m / z = 419.0 [M+H] + .

[0627] 1 H NMR (DMSO-d6, 400MHz): δ8.19(s,1H),8.01(s,1H),7.69(d,J=8.8Hz,1H),7.56(dd,J1=8.4Hz,J2=1.2Hz,1H),7.20- 7.14(m,5H),5.43-5.39(m,1H),3.66-3.60(m,2H),3.55(s,3H),3.51-3.44(m,2H),3.32-3.24(m,2H),2.65(s,3H).

[0628] The compounds in Table 14 below were prepared using the same methods as in the examples described above, with the corresponding compounds.

[0629] Table 14

[0630] The synthesis of REJT-64

[0631] Step 1 Synthesis

[0632] 2-Methyl-7-(trifluoromethyl)quinoline (650 mg, 3.08 mmol) was dissolved in dioxane (15 mL), and selenium dioxide (410 mg, 3.69 mmol) was added. The mixture was stirred at 80 °C for 2 hours. The reaction solution was filtered, and the organic phase was concentrated under vacuum and purified by silica gel column chromatography to obtain a yellow solid 7-(trifluoromethyl)quinoline-2-carboxaldehyde (620 mg, yield 89.5%).

[0633] MS(ESI)m / z = 226.2[M+H] + .

[0634] Second step of synthesis

[0635] 7-(trifluoromethyl)quinoline-2-carboxaldehyde (570 mg, 2.53 mmol) was dissolved in tetrahydrofuran (15 mL), and 1 mol / L benzyl magnesium bromide tetrahydrofuran solution (3.8 mL, 3.80 mmol) was added under ice bath conditions. The mixture was stirred at 20 °C for 3 hours. The reaction solution was added to a saturated ammonium chloride aqueous solution (30 mL), extracted with ethyl acetate (30 mL × 3), and the organic phase was concentrated under vacuum and purified by silica gel column chromatography to obtain a yellow oily substance, 2-phenyl-1-(7-(trifluoromethyl)quinoline-2-yl)1-ethanol (650 mg, yield 80.9%).

[0636] MS(ESI)m / z = 318.4[M+H] + .

[0637] Third step of synthesis

[0638] 2-Phenyl-1-(7-(trifluoromethyl)quinoline-2-yl)1-ethanol (650 mg, 2.05 mmol) was dissolved in tetrahydrofuran (20 mL) and N,N-dimethylformamide (3 mL), and thionyl chloride (487 mg, 4.10 mmol) was added. The mixture was stirred at 60 °C for 2 hours. The reaction solution was concentrated under vacuum to obtain a yellow oily substance, 2-(1-chloro-2-phenylethyl)-7-(trifluoromethyl)quinoline (650 mg, 94.5%).

[0639] MS(ESI)m / z = 336.3[M+H] + .

[0640] Fourth step synthesis

[0641] 2-(1-chloro-2-phenylethyl)-7-(trifluoromethyl)quinoline (150 mg, 0.45 mmol) was dissolved in acetonitrile (10 mL), and 1-methylimidazolidine-2-thione (55 mg, 0.47 mmol) was added. The mixture was stirred at 70 °C for 72 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a yellow oil. The solid was purified by high performance liquid chromatography (mobile phase: acetonitrile / water (0.5% trifluoroacetic acid)). After lyophilization, a yellow oil 2-(1-((1-methyl-4,5-dihydro-1H-imidazol-2-yl)thio)-2-phenylethyl)-7-(trifluoromethyl)quinoline trifluoroacetate (19.35 mg, yield 10.4%) was obtained.

[0642] MS(ESI)m / z = 416.1[M+H] + .

[0643] 1H NMR (DMSO-d6, 400MHz): δ10.27(s,1H),8.59(d,J=8.8Hz,1H),8.39(s,1H),8.28(d,J=8.4Hz,1H),7.94(dd,J1=8.4Hz J2=1.2Hz,1H),7.79(d,J=8.4Hz,1H),7.30-7.21(m,5H),5.65(t,J=8.4Hz,1H),3.82-3.61(m,5H),3.45-3.40(m,1H),3.00(s,3H).

[0644] The compounds in Table 15 below were prepared using the same methods as in the examples described above, with the corresponding compounds.

[0645] Table 15

[0646] REJT-65 synthesis

[0647] Step 1 Synthesis

[0648] 2-Bromo-1-(4-(trifluoromethyl)phenyl)ethane-1-one (3.0 g, 0.0112 mol) was dissolved in ethanol (20 mL), and then ethyl 2-amino-2-thioethyl (1.49 g, 0.0112 mmol) was added. The mixture was stirred at 50 °C for 3 hours. After the reaction was completed and cooled, the mixture was concentrated under vacuum and purified by silica gel column chromatography to give ethyl 4-(4-(trifluoromethyl)phenyl)thiazolium-2-carboxylate (2.5 g, yield 66.07%) as a yellow solid.

[0649] MS(ESI)m / z = 302.2[M+H] + .

[0650] Second step of synthesis

[0651] Ethyl 4-(4-(trifluoromethyl)phenyl)thiazol-2-carboxylate (200 mg, 0.66 mmol) was dissolved in tetrahydrofuran (5 mL) and 1.5 M diisobutylaluminum hydride toluene solution (151 mg, 1.06 mmol). The mixture was stirred at -78 °C for 1 hour under nitrogen protection. After the reaction was completed, the mixture was cooled and quenched with hydrochloric acid. The reaction solution was concentrated under reduced pressure, diluted with saturated sodium chloride aqueous solution (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a white solid 4-(4-(trifluoromethyl)phenyl)thiazol-2-carboxaldehyde (180 mg, yield 94.88%).

[0652] Third step of synthesis

[0653] (4-(4-(trifluoromethyl)phenyl)thiazol-2-carboxaldehyde (100 mg, 0.39 mmol) was dissolved in dichloromethane (10 mL) and 1.0 M benzyl magnesium bromide tetrahydrofuran solution (92 mg, 0.47 mmol). The mixture was stirred at 0 °C for 3 hours under nitrogen protection. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure, diluted with saturated sodium bicarbonate aqueous solution (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to give a white solid 2-phenyl-1-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)ethane-1-ol (60 mg, yield 39.76%).

[0654] MS(ESI)m / z = 350.0[M+H] + .

[0655] Fourth step synthesis

[0656] 2-Phenyl-1-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)ethane-1-ol (66 mg, 0.19 mmol) was dissolved in dichloromethane (5 mL), and sulfoxide (2 mL) was added. The mixture was stirred at room temperature for 16 hours. After the reaction was completed and cooled, the solution was concentrated under vacuum to give a yellow oily substance, 2-(1-chloro-2-phenylethyl)-4-(4-(trifluoromethyl)phenyl)thiazol (60 mg, yield 77.71%).

[0657] MS(ESI)m / z = 368.3[M+H] + .

[0658] Fifth step synthesis

[0659] 2-(1-chloro-2-phenylethyl)-4-(4-(trifluoromethyl)phenyl)thiazole (60 mg, 0.16 mmol) was dissolved in acetonitrile (2 mL), and 1-methylimidazolidine-2-thione (26 mg, 0.22 mmol) was added. The mixture was stirred at 80 °C for 72 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a brown oily substance. The solid was purified by high performance liquid chromatography to obtain a white solid 2-(1-((1-methyl-4,5-dihydro-1H-imidazol-2-yl)thio)-2-phenylethyl)-4-(4-(trifluoromethyl)phenyl)thiazole hydrochloride (25 mg, yield 34.91%).

[0660] MS(ESI)m / z = 448.0 [M+H] + .

[0661] 1H NMR (DMSO-d6, 400MHz): δ10.29 (s, 1H), 8.39 (s, 1H), 8.18 (d, J = 6.4Hz, 2H), 7.85 (d, J = 8.0Hz, 2H),7.34-7.26(m,5H),5.79-5.77(m,1H),3.86-3.78(m,4H),3.76-3.64(m,2H),3.00(s,3H).

[0662] The synthesis of REJT-68

[0663] Step 1 Synthesis

[0664] 1-Methyl-5-(trifluoromethyl)phenyl-1,2-diamine (600.0 mg, 3.16 mmol) and 2-hydroxy-3-phenylpropionic acid (576.7 mg, 3.47 mmol) were suspended in 4M hydrochloric acid solution (10 mL) and reacted at 90 °C for 16 hours. After cooling to room temperature, the reaction solution was adjusted to pH 8 with saturated sodium carbonate solution, extracted three times with ethyl acetate (3 × 50 mL), washed three times with water (3 × 50 mL), dried over magnesium sulfate, and the solvent was removed by rotary evaporation. The crude product was purified by silica gel column chromatography to obtain a brown solid 1-(1-methyl-6-(trifluoromethyl)-1H-benzimidazol-2-yl)-2-phenylethyl-1-ol (720 mg, yield 60.54%), which was used directly in the next step without further purification.

[0665] MS(ESI)m / z = 321.0[M+H] + .

[0666] Second step of synthesis

[0667] 1-(1-methyl-6-(trifluoromethyl)-1H-benzimidazol-2-yl)-2-phenylethyl-1-ol (70.0 mg, 0.22 mmol) was dissolved in tetrahydrofuran (5 mL), and 0.1 mL of N,N-dimethylformamide was added. Then, sulfoxide (78.0 mg, 0.66 mmol) was slowly added dropwise at 0°C. The reaction phase was stirred at 60°C for 4 hours and concentrated to dryness under reduced pressure to give a brown oily substance, 2-(1-chloro-2-phenylethyl)-1-methyl-6-(trifluoromethyl)-1,3-benzimidazole (68 mg, yield 82.70%), which was used directly in the next step.

[0668] MS(ESI)m / z = 339.3 [M+H] + .

[0669] Third step of synthesis

[0670] 2-(1-chloro-2-phenylethyl)-1-methyl-6-(trifluoromethyl)-1,3-benzimidazole (100.0 mg, 0.30 mmol) was dissolved in acetonitrile (5 mL), and 1-cyclopropylimidazolidine-2-thione (63.0 mg, 0.44 mmol) was added. The mixture was stirred at 80 °C for 3 days. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a yellow oily substance. The oil was purified by high performance liquid chromatography, and acetonitrile was removed under reduced pressure. After lyophilization, a white solid 2-(1-((1-cyclopropyl-4,5-dihydro-1H-imidazol-2-yl)thioether)-2-phenylethyl)-6-(trifluoromethyl)-1H-benzimidazole formate (18.1 mg, yield 13.79%) was obtained.

[0671] MS(ESI)m / z = 445.0 [M+H] + .

[0672] 1 H NMR (DMSO-d6, 400MHz): δ8.35(s,1H),7.94(s,1H),7.82(d,J=8.4Hz,1H),7.51(d,J=7.6Hz,1H),7.21-7.12(m,5H),5.41(t,J=8.0Hz ,1H),3.65-3.60(m,2H),3.56(s,3H),3.50-3.48(m,2H),3.38-3.36(m,1H),3.33-3.31(m,1H),2.21-2.17(m,1H),0.63-0.53(m,4H).

[0673] REJT-70 synthesis

[0674] Step 1 Synthesis

[0675] 2-Bromo-1-(4-(trifluoromethyl)phenyl)ethane-1-one (3.0 g, 0.0112 mol) was dissolved in ethanol (20 mL), and then ethyl 2-amino-2-thioethyl (1.49 g, 0.0112 mmol) was added. The mixture was stirred at 50 °C for 3 hours. After the reaction was completed and cooled, the mixture was concentrated under vacuum and purified by silica gel column chromatography to give ethyl 4-(4-(trifluoromethyl)phenyl)thiazolium-2-carboxylate (2.5 g, yield 66.07%) as a yellow solid.

[0676] MS(ESI)m / z=302.2[M+H]+.

[0677] Second step of synthesis

[0678] Ethyl 4-(4-(trifluoromethyl)phenyl)thiazol-2-carboxylate (200 mg, 0.66 mmol) was dissolved in tetrahydrofuran (5 mL) and diisobutylaluminum hydride (151 mg, 1.06 mmol), and the mixture was stirred at -78 °C for 1 hour under nitrogen protection. After the reaction was completed, the mixture was cooled and quenched with hydrochloric acid. The reaction solution was concentrated under reduced pressure, diluted with saturated sodium chloride aqueous solution (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a white solid 4-(4-(trifluoromethyl)phenyl)thiazol-2-carboxaldehyde (180 mg, yield 94.88%).

[0679] Third step of synthesis

[0680] (4-(4-(trifluoromethyl)phenyl)thiazol-2-carboxaldehyde (100 mg, 0.39 mmol) was dissolved in dichloromethane (10 mL) and methyl magnesium bromide tetrahydrofuran solution (69 mg, 0.58 mmol), and the mixture was stirred at 0 °C for 3 hours under nitrogen protection. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure, diluted with saturated sodium bicarbonate aqueous solution (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a white solid 1-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)ethane-1-ol (35 mg, yield 29.66%).

[0681] MS(ESI)m / z = 274.3[M+H] + .

[0682] Fourth step synthesis

[0683] 1-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)ethane-1-ol (35 mg, 0.13 mmol) was dissolved in dichloromethane (5 mL), and sulfoxide (2 mL) was added. The mixture was stirred at room temperature for 16 hours. After the reaction was completed and cooled, the solution was concentrated under vacuum to give a yellow oily substance, 2-(1-chloroethyl)-4-(4-(trifluoromethyl)phenyl)thiazol (35 mg, yield 88.99%).

[0684] MS(ESI)m / z = 292.2[M+H] + .

[0685] Fifth step synthesis

[0686] 2-(1-chloroethyl)-4-(4-(trifluoromethyl)phenyl)thiazole (35 mg, 0.12 mmol) was dissolved in acetonitrile (2 mL), and 1-methylimidazolidine-2-thione (15 mg, 0.13 mmol) was added. The mixture was stirred at 80 °C for 72 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a brown oily substance. The solid was purified by high performance liquid chromatography to obtain a white solid 2-(1-((1-methyl-4,5-dihydro-1H-imidazol-2-yl)thio)ethyl)-4-(4-(trifluoromethyl)phenyl)thiazole (10 mg, yield 22.43%).

[0687] MS(ESI)m / z = 372.0 [M+H] + .

[0688] 1 H NMR (DMSO-d6, 400MHz): δ8.25 (s, 1H), 8.16 (d, J = 8.0Hz, 2H), 7.81 (d, J = 8.4Hz, 2H), 5.29 -5.24(m,1H),3.67-3.61(m,2H),3.31-3.27(m,2H),2.68(s,3H),1.82(d,J=7.2Hz,3H).

[0689] REJT-71 synthesis

[0690] Step 1 Synthesis

[0691] 2-Iodo-4-(trifluoromethyl)phenol (1.5 g, 5.21 mmol) was dissolved in pyridine (20 mL), followed by the addition of but-3-yn-2-ol (0.73 g, 10.43 mmol) and cuprous oxide (0.47 g, 3.28 mmol). The reaction was stirred at 115 °C for 16 hours under nitrogen protection. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure, diluted with water (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a colorless oily substance, 1-(5-(trifluoromethyl)benzofuran-2-yl)ethanol-1-ol (1.1 g, yield 90.38%).

[0692] MS(ESI)m / z = 213.1 [M-17] + .

[0693] Second step of synthesis

[0694] 1-(5-(trifluoromethyl)benzofuran-2-yl)ethanol-1-ol (600 mg, 2.61 mmol) was dissolved in tetrahydrofuran (10 mL) and N,N-dimethylformamide (1 mL). Thionyl chloride (620 mg, 5.21 mmol) was added, and the mixture was stirred at 60 °C for 1 hour under nitrogen protection. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure, diluted with saturated sodium bicarbonate aqueous solution (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain a yellow oily substance, 2-(1-chloroethyl)-5-(trifluoromethyl)benzofuran (500 mg, yield 77.15%).

[0695] MS(ESI)m / z=225.4[M-23] + .

[0696] Third step of synthesis

[0697] 2-(1-chloroethyl)-5-(trifluoromethyl)benzofuran (300 mg, 1.21 mmol) was dissolved in acetonitrile (4 mL), and 1-methylimidazolidine-2-thione (168 mg, 1.45 mmol) was added. The mixture was stirred at 80 °C for 72 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to give a brown oily substance. Purification yielded a colorless oily 1-methyl-2-((1-(5-(trifluoromethyl)benzofuran-2-yl)ethyl)thio)-4,5-dihydro-1H-imidazolium trifluoroacetate (155 mg, yield 39.4%).

[0698] MS(ESI)m / z = 329.0 [M+H] + .

[0699] 1 H NMR(DMSO-d6,400MHz): δ10.31(br s,1H),8.11(s,1H),7.84(d,J=8.8Hz,1H),7.70(d,J=8.8Hz,1H),7.19(s,1H) ,5.39(q,J=7.2Hz,1H),3.94-3.85(m,4H),3.00(s,3H),1.85(d,J=7.2Hz,3H).

[0700] The compounds in Table 16 below were prepared using the same methods as in the examples described above, with the corresponding compounds.

[0701] Table 16

[0702] REJT-75 synthesis

[0703] Step 1 Synthesis

[0704] 7-(trifluoromethyl)quinoline-2-carboxaldehyde (1.85 g, 8.22 mmol) was dissolved in tetrahydrofuran (30 mL), and 1 mol / L methylmagnesium bromide tetrahydrofuran (12.3 mL, 12.32 mmol) was added under ice bath conditions. The mixture was stirred at 25 °C for 3 hours. The reaction solution was added to a saturated ammonium chloride aqueous solution (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phase was concentrated under vacuum and purified by silica gel column chromatography to obtain a yellow solid 1-[7-(trifluoromethyl)quinoline-2-yl]ethane-1-ol (1.80 g, yield 90.8%).

[0705] MS(ESI)m / z = 242.2[M+H] + .

[0706] Second step of synthesis

[0707] 1-[7-(trifluoromethyl)quinoline-2-yl]ethyl-1-ol (1.00 g, 4.15 mmol) was dissolved in tetrahydrofuran (30 mL) and N,N-dimethylformamide (5 mL), and thionyl chloride (986 mg, 8.29 mmol) was added. The mixture was stirred at 60 °C for 2 hours. The reaction solution was concentrated under vacuum to give a yellow oily substance 2-(1-chloroethyl)-7-(trifluoromethyl)quinoline (1.00 g, yield 92.9%).

[0708] MS(ESI)m / z = 260.2[M+H] + .

[0709] Fourth step synthesis

[0710] 2-(1-chloroethyl)-7-(trifluoromethyl)quinoline (150 mg, 0.58 mmol) was dissolved in acetonitrile (8 mL), and 2-imidazolidinethione (89 mg, 0.87 mmol) was added. The mixture was stirred at 80 °C for 48 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a yellow oil. The solid was purified by high performance liquid chromatography and lyophilized to obtain a yellow oil, 2-(1-((4,5-dihydro-1H-imidazol-2-yl)thio)ethyl)-7-(trifluoromethyl)quinoline carbamate (19.35 mg, yield 10.4%).

[0711] MS(ESI)m / z = 326.0 [M+H] + .

[0712] 1H NMR (DMSO-d6, 400MHz): δ8.50(d,J=8.4Hz,1H),8.32(s,1H),8.23(d,J=8.4Hz,1H),8.15(s,1H),7.87(dd,J1=8.4Hz J2=1.6Hz,1H),7.83(d,J=8.4Hz,1H),5.23(q,J=6.8Hz,1H),3.52(s,4H),1.77(d,J=6.8Hz,3H).

[0713] The compounds in Table 17 below were prepared using the same methods as in the examples described above, with the corresponding compounds.

[0714] Table 17

[0715] The synthesis of REJT-78

[0716] Step 1 Synthesis

[0717] 2-Phenylacetaldehyde (1.0 g, 8.33 mmol) was dissolved in tetrahydrofuran (20 mL), and 0.5 M acetylenyl magnesium bromide tetrahydrofuran solution (19.9 mL, 9.96 mmol) was added under nitrogen protection at 0 °C. The reaction was stirred at 0 °C for 2 hours under nitrogen protection. After the reaction was completed and cooled, it was diluted with water (20 mL) and ethyl acetate (20 mL). The mixture was extracted with ethyl acetate (20 mL × 2), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a yellow oily substance, 1-phenylbut-3-yn-2-ol (373 mg, yield 38.21%).

[0718] MS(ESI)m / z = 147.0 [M+H] + .

[0719] Second step of synthesis

[0720] 2-Iodo-4-(trifluoromethyl)phenol (610 mg, 2.12 mmol) was dissolved in pyridine (10 mL), followed by the addition of 1-phenylbut-3-yn-2-ol (372 mg, 2.54 mmol) and cuprous oxide (212 mg, 1.48 mmol). The reaction was stirred at 115 °C for 16 hours under nitrogen protection. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure, diluted with water (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a yellow solid 2-phenyl-1-[5-(trifluoromethyl)-1-benzofuran-2-yl]ethane-1-ol (500 mg, yield 77.16%).

[0721] Third step of synthesis

[0722] 2-Phenyl-1-[5-(trifluoromethyl)-1-benzofuran-2-yl]ethyl-1-ol (250 mg, 0.82 mmol) was dissolved in tetrahydrofuran (10 mL) and N,N-dimethylformamide (1 mL). After adding thionyl chloride (194 mg, 1.63 mmol), the mixture was stirred at 60 °C for 1 hour under nitrogen protection. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure, diluted with saturated sodium bicarbonate aqueous solution (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain a yellow oily substance, 2-(1-chloro-2-phenylethyl)-5-(trifluoromethyl)benzofuran (241 mg, yield 90.9%).

[0723] Fourth step synthesis

[0724] 2-(1-chloro-2-phenylethyl)-5-(trifluoromethyl)benzofuran (241 mg, 0.74 mmol) was dissolved in acetonitrile (4 mL), and 1-methylimidazolidine-2-thione (168 mg, 1.45 mmol) was added. The mixture was stirred at 80 °C for 48 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a brown oil. The solid was purified by high performance liquid chromatography, and acetonitrile was removed under reduced pressure. After lyophilization, a colorless oily 1-methyl-2-((2-phenyl-1-(5-(trifluoromethyl)benzofuran-2-yl)ethyl)thio)-4,5-dihydro-1H-imidazolium carboxylate (120 mg, yield 39.57%) was obtained.

[0725] MS(ESI)m / z = 405.0 [M+H] + .

[0726] 1 H NMR (DMSO-d6, 400MHz): δ8.15(s,1H),7.98(s,1H),7.78(d,J=8.4Hz,1H),7.62(d,J=8.8Hz,1H),7.22-7.15(m,5H) ,6.91(s,1H),5.32(t,J=7.2Hz,1H),3.68(t,J=9.6Hz,2H),3.47-3.41(m,2H),3.29(t,J=9.2Hz,2H),2.66(s,3H).

[0727] REJT-79 synthesis

[0728] Step 1 Synthesis

[0729] 1-[2-hydroxy-5-(trifluoromethyl)phenyl]ethyl ketone (500 mg, 2.45 mmol), 1,3-diethyl-2-bromomalonide diester (2.63 g, 11.02 mmol), and potassium carbonate (1.52 g, 11.02 mmol) were suspended in a solution of 2-butanone (100 mL). The reaction was carried out under nitrogen protection and stirred at 80 °C for 16 hours. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure, diluted with water (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a gray solid ethyl 3-methyl-5-(trifluoromethyl)-1-benzofuran-2-carboxylate (463 mg, yield 62.50%).

[0730] MS(ESI)m / z = 273.0 [M+H] + .

[0731] Second step of synthesis

[0732] Ethyl 3-methyl-5-(trifluoromethyl)-1-benzofuran-2-carboxylate (50 mg, 0.18 mmol) was dissolved in tetrahydrofuran (5 mL), followed by the addition of lithium borohydride (0.14 mL, 2 M in THF) solution. The reaction phase was stirred at 70 °C for 16 hours. After the reaction was completed, the reaction was quenched by adding saturated ammonium chloride solution. The mixture was diluted with water (50 mL) and ethyl acetate (50 mL), extracted with ethyl acetate (30 mL × 2), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a white solid 3-methyl-5-(trifluoromethyl)-1-benzofuran-2-methanol (35 mg, yield 74.47%).

[0733] 1 H NMR (CDCl3, 400MHz): δ7.78 (s, 1H), 7.54-7.50 (m, 2H), 4.79 (d, J = 5.2Hz, 2H), 2.30 (s, 3H).

[0734] Third step of synthesis

[0735] 3-Methyl-5-(trifluoromethyl)-1-benzofuran-2-methanol (75.0 mg, 0.33 mmol) was dissolved in tetrahydrofuran (5 mL) and N,N-dimethylformamide (0.1 mL). After adding thionyl chloride (116.3 mg, 0.98 mmol), the mixture was stirred at 60 °C for 1 hour under nitrogen protection. After cooling, the reaction solution was concentrated under reduced pressure, diluted with saturated sodium bicarbonate aqueous solution (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain a colorless oily substance, 2-(chloromethyl)-3-methyl-5-(trifluoromethyl)benzofuran (82 mg, p = 80%, yield 80.97%).

[0736] MS(ESI)m / z = 249.0 [M+H] + .

[0737] Fourth step synthesis

[0738] 2-(chloromethyl)-3-methyl-5-(trifluoromethyl)benzofuran (70 mg, 0.28 mmol) was dissolved in acetonitrile (5 mL), and 1-methylimidazolidine-2-thione (65.4 mg, 0.56 mmol) was added. The mixture was stirred at 70 °C for 16 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a brown oily substance. The solid was purified by high performance liquid chromatography, and acetonitrile was removed under reduced pressure. After lyophilization, a white solid 1-methyl-2-(((3-methyl-5-(trifluoromethyl)benzofuran-2-yl)methyl)thiol)-4,5-dihydro-1H-imidazolium trifluoroacetate (32.2 mg, yield 34.78%) was obtained.

[0739] MS(ESI)m / z = 329.0 [M+H] + .

[0740] 1 H NMR (DMSO-d6, 400MHz): δ10.34 (s, 1H), 8.05 (s, 1H), 7.79 (d, J = 8.4Hz, 1H), 7. 70(d,J=8.8Hz,1H),4.90(s,2H),3.94-3.91(s,4H),3.01(s,3H),2.31(s,3H).

[0741] REJT-80 synthesis

[0742] Step 1 Synthesis

[0743] 2-Amino-4-(trifluoromethyl)benzylthiol (800 mg, 4.14 mmol) was dissolved in 4M HCl (20 mL), and then 2-hydroxypropionic acid (746 g, 8.28 mmol) was added. The reaction was stirred at 95 °C for 72 hours under nitrogen protection. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure, diluted with water (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a white solid 1-(5-(trifluoromethyl)benzo[d]thiazolyl)ethanol-1-ol (270 mg, yield 26.4%).

[0744] MS(ESI)m / z = 248.2[M+H] + .

[0745] Second step of synthesis

[0746] 1-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)ethanol-1-ol (270 mg, 1.09 mmol) was dissolved in tetrahydrofuran (10 mL) and N,N-dimethylformamide (1 mL). After adding sulfoxide (260 mg, 2.18 mmol), the mixture was stirred at 60 °C for 1 hour under nitrogen protection. After cooling, the reaction solution was concentrated under reduced pressure, diluted with saturated sodium bicarbonate aqueous solution (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain a brown oily substance, 2-(1-chloroethyl)-5-(trifluoromethyl)benzothiazolium (250 mg, yield 86.2%).

[0747] MS(ESI)m / z = 266.2[M+H] + .

[0748] Third step of synthesis

[0749] 2-(1-chloroethyl)-5-(trifluoromethyl)benzothiazole (250 mg, 0.94 mmol) was dissolved in acetonitrile (4 mL), and 1-methylimidazolidine-2-thione (175 mg, 1.51 mmol) was added. The mixture was stirred at 80 °C for 72 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a brown oily substance. The solid was purified by high performance liquid chromatography to obtain a colorless oily 2-(1-((1-methyl-4,5-dihydro-1H-imidazol-2-yl)thio)ethyl)-5-(trifluoromethyl)benzothiazole trifluoroacetate (110 mg, yield 33.95%).

[0750] MS(ESI)m / z = 345.9 [M+H] + .

[0751] 1 H NMR(DMSO-d6,400MHz): δ10.37(br s, 1H), 8.44 (t, J = 4.0Hz, 2H), 7.85 (d, J = 8.8Hz, 1H), 5.67 (q, J = 4.0Hz, 1H), 3.97-3.81 (m, 4H), 3.06 (s, 3H), 1.93 (d, J = 7.2Hz, 3H).

[0752] The compounds of the examples listed in Table 18 below were prepared using the same methods as in the examples described above, with the corresponding compounds.

[0753] Table 18

[0754] The synthesis of REJT-81

[0755] Step 1 Synthesis

[0756] 2-Amino-4-(trifluoromethyl)benzylthiol (800 mg, 4.14 mmol) was dissolved in 4M hydrochloric acid solution (20 mL), and then 2-hydroxypropionic acid (746 g, 8.28 mmol) was added. The reaction was stirred at 95 °C for 72 hours under nitrogen protection. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure, diluted with water (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL × 2), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a white solid 1-(5-(trifluoromethyl)benzo[d]thiazolyl)ethanol-1-ol (270 mg, yield 26.4%).

[0757] MS(ESI)m / z = 248.2[M+H] + .

[0758] Second step of synthesis

[0759] 1-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)ethanol-1-ol (270 mg, 1.09 mmol) was dissolved in tetrahydrofuran (10 mL) and N,N-dimethylformamide (1 mL). After adding sulfoxide (260 mg, 2.18 mmol), the mixture was stirred at 60 °C for 1 hour under nitrogen protection. After cooling, the reaction solution was concentrated under reduced pressure, diluted with saturated sodium bicarbonate aqueous solution (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain a brown oily substance, 2-(1-chloroethyl)-5-(trifluoromethyl)benzothiazolium (250 mg, yield 86.2%).

[0760] MS(ESI)m / z = 266.2[M+H] + .

[0761] Third step of synthesis

[0762] 2-(1-chloroethyl)-5-(trifluoromethyl)benzothiazole (200 mg, 0.75 mmol) was dissolved in acetonitrile (4 mL), and 1-cyclopropylimidazolidine-2-thione (171 mg, 1.20 mmol) was added. The mixture was stirred at 80 °C for 48 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a brown oil. Purification yielded a colorless oily 2-(1-((1-cyclopropyl-4,5-dihydro-1H-imidazol-2-yl)thio)ethyl)-5-(trifluoromethyl)benzothiazole trifluoroacetate (150 mg, yield 53.76%).

[0763] MS(ESI)m / z = 372.0 [M+H] + .

[0764] 1 H NMR(DMSO-d6,400MHz): δ10.45(br s,1H),8.44(d,J=8.0Hz,2H),7.85(d,J=8.8Hz,1H),5.65(q,J=7.2Hz,1H),3. 95-3.79(m,4H),2.84-2.78(m,1H),1.94(d,J=6.8Hz,3H),0.91-0.82(m,4H).

[0765] The synthesis of REJT-82

[0766] Step 1 Synthesis

[0767] 2-Iodo-4-(trifluoromethyl)aniline (5.00 g, 0.0174 mol) was dissolved in DMF (50 mL), followed by the addition of 2-oxopropionic acid (4.6 g, 0.0522 mmol), 1,4-diazabicyclo[2.2.2]octane (5.86 g, 0.0522 mol), and palladium acetate (1.17 g, 0.0522 mol). The reaction was stirred at 80 °C for 16 hours under nitrogen protection. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure, diluted with water (40 mL) and ethyl acetate (40 mL), extracted with ethyl acetate (40 mL × 2), and the organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a white solid 5-(trifluoromethyl)-1H-indole-2-carboxylic acid (1.84 g, yield 41.38%).

[0768] MS(ESI)m / z = 228.2 [MH] + .

[0769] Second step of synthesis

[0770] 5-(trifluoromethyl)-1H-indole-2-carboxylic acid (500 mg, 2.17 mmol) was dissolved in dichloromethane (15 mL) and thionyl chloride (10 mL), and the mixture was stirred at 80 °C for 4 hours under nitrogen protection. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure, diluted with dichloromethane (2 mL), and then methanol (10 mL) was added. The reaction solution was concentrated under reduced pressure, diluted with water (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL × 2), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a yellow solid methyl 5-(trifluoromethyl)-1H-indole-2-carboxylic acid (250 mg, yield 42.42%).

[0771] Third step of synthesis

[0772] Methyl 5-(trifluoromethyl)-1H-indole-2-carboxylic acid (250 mg, 1.02 mmol) was dissolved in DMF (10 mL), followed by the addition of methyl iodoform (218 mg, 1.53 mmol) and potassium hydroxide (1150 mg, 2.10 mmol). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure, diluted with water (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a pale yellow solid, 1-methyl-5-(trifluoromethyl)-1H-indole-2-carboxylic acid (200 mg, yield 68.09%).

[0773] Fourth step synthesis

[0774] 1-Methyl-5-(trifluoromethyl)-1H-indole-2-carboxylic acid (150 mg, 0.58 mmol) was dissolved in tetrahydrofuran (10 mL), and then boranetetrahydrofuran (1 N, 0.5 mL) was added. The reaction mixture was stirred at 80 °C for 16 hours. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure, diluted with water (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a white solid (1-methyl-5-(trifluoromethyl)-1H-indole-2-yl)methanol (100 mg, yield 67.31%).

[0775] Fifth step synthesis

[0776] (1-Methyl-5-(trifluoromethyl)-1H-indol-2-yl)methanol (100 mg, 0.43 mmol) was dissolved in dichloromethane (5 mL), and then thionyl chloride (103 mg, 0.87 mmol) was added. The reaction was stirred at room temperature for 16 hours. After the reaction was completed and cooled, the solution was concentrated under vacuum to give a yellow oily substance, 3-chloro-2-(chloromethyl)-1-methyl-5-(trifluoromethyl)-1H-indol (97 mg, yield 70.99%).

[0777] Step 6 Synthesis

[0778] 3-Chloro-2-(chloromethyl)-1-methyl-5-(trifluoromethyl)-1H-indole (100 mg, 0.35 mmol) was dissolved in acetonitrile (4 mL), and 1-methylimidazolidine-2-thione (41 mg, 0.35 mmol) was added. The mixture was stirred at 70 °C for 16 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a brown oily substance. The oily substance was purified by high performance liquid chromatography to obtain a colorless oily 3-chloro-1-methyl-2-(((1-methyl-4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-5-(trifluoromethyl)-1H-indole carboxylate (18 mg, yield 13.34%).

[0779] MS(ESI)m / z = 362.0 [M+H] + .

[0780] 1 H NMR(DMSO-d6,400MHz): δ8.32(br s,1H),7.79-7.76(m,2H),7.57-7.54(m,1H),4.65(s,2H),3.87(s,3H),3.69-3.58(m,2H),3.36-3.30(m,2H),2.67(s,3H).

[0781] REJT-84 Synthesis

[0782] Step 1 Synthesis

[0783] 4-(trifluoromethyl)phenyl-1,2-diamine (1.00 g, 5.68 mmol) and 2-chlorobutyric acid (1.04 g, 8.52 mmol) were dissolved in 20 mL of 4 M hydrochloric acid solution and stirred at 90 °C for 16 hours. The pH of the reaction solution was adjusted to >7 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was concentrated under vacuum and purified by silica gel column chromatography to give a yellow solid 2-(1-chloropropyl)-5-(trifluoromethyl)-1H-benzo[d]imidazole (300 mg, yield 20.1%).

[0784] MS(ESI)m / z = 263.3[M+H] + .

[0785] Second step of synthesis

[0786] 2-(1-chloropropyl)-5-(trifluoromethyl)-1H-benzo[d]imidazolium (150 mg, 0.57 mmol) was dissolved in acetonitrile (10 mL), and 2-imidazolidinethione (88 mg, 0.86 mmol) was added. The mixture was stirred at 80 °C for 48 hours. After cooling, the reaction solution was concentrated under reduced pressure. The solid was purified by high performance liquid chromatography and lyophilized to give a white solid 2-(1-((4,5-dihydro-1H-imidazol-2-yl)thio)propyl)-5-(trifluoromethyl)-1H-benzo[d]imidazolium carbamate (68.4 mg, yield 36.5%).

[0787] MS(ESI)m / z = 329.0 [M+H] + .

[0788] 1 H NMR (DMSO-d6, 400MHz): δ8.16 (s, 1H), 7.92 (s, 1H), 7.73 (d, J = 8.4Hz, 1H), 7.50 (dd, J1 = 1.2H z,J2=8.4Hz,1H),5.04-5.00(m,1H),3.59(s,4H),2.26-2.11(m,2H),0.93(t,J=7.2Hz,3H).

[0789] The compounds in Table 19 below were prepared using the same methods as in the examples described above, with the corresponding compounds.

[0790] Table 19

[0791] REJT-90 synthesis

[0792] Step 1 Synthesis

[0793] 4-Bromo-2-methylpyrimidine (1.9 g, 0.011 mol), (4-(trifluoromethyl)phenyl)boronic acid (2.19 g, 0.012 mol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.8 g, 0.0011 mol), and sodium carbonate (1.75 g, 0.017 mol) were dissolved in dioxane (50 mL) and water (10 mL). The mixture was stirred at 85 °C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was cooled, water was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a colorless oily substance, 2-methyl-4-(4-(trifluoromethyl)phenyl)pyrimidine (2.1 g, yield 80.97%).

[0794] MS(ESI)m / z = 239.2[M+H] + .

[0795] Second step of synthesis

[0796] 2-Methyl-4-(4-(trifluoromethyl)phenyl)pyrimidine (1.86 g, 7.82 mmol) was dissolved in pyridine (10 mL), and selenium dioxide (4.33 g, 0.039 mol) was added. The mixture was stirred at 110 °C for 16 hours under nitrogen protection. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure, and the pH was adjusted to <7 with 1 M dilute hydrochloric acid. The solution was extracted with ethyl acetate (20 mL × 2), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow solid 4-(4-(trifluoromethyl)phenyl)pyrimidine-2-carboxylic acid (1.75 g, yield 83.3%).

[0797] MS(ESI)m / z=269.2[M+H]+.

[0798] Third step of synthesis

[0799] 4-(4-(trifluoromethyl)phenyl)pyrimidin-2-carboxylic acid (1.75 g, 6.53 mmol) was dissolved in tetrahydrofuran (50 mL), and N-methylmorpholine (0.85 g, 8.45 mmol) and isobutyl chloroformate (1.15 g, 8.49 mmol) were added. The mixture was stirred at 0 °C for 1 hour under nitrogen protection. The reaction solution was filtered, and the filtrate was cooled to 0 °C. 2 mL of an aqueous solution of sodium borohydride (0.37 g, 9.75 mmol) was added, and the mixture was stirred at 0 °C for 0.5 hours. The solution was diluted with saturated sodium bicarbonate aqueous solution (20 mL) and ethyl acetate (20 mL). The mixture was extracted with ethyl acetate (20 mL × 2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a yellow solid (4-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)methanol (0.74 g, yield 44.62%).

[0800] MS(ESI)m / z = 255.2[M+H] + .

[0801] Fourth step synthesis

[0802] (4-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)methanol (0.69 g, 3.71 mmol) was dissolved in dichloromethane (20 mL), and Dys-Martin oxidant (1.73 g, 4.08 mmol) was added at 0 °C under nitrogen protection. The reaction was stirred at room temperature for 16 hours under nitrogen protection. After the reaction was completed, the mixture was filtered, and the filtrate was diluted with water (20 mL) and dichloromethane (20 mL). The mixture was extracted with dichloromethane (20 mL × 2), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a yellow solid 4-(4-(trifluoromethyl)phenyl)pyrimidin-2-carboxaldehyde (700 mg, yield 92.3%).

[0803] MS(ESI)m / z = 253.2[M+H] + .

[0804] Fifth step synthesis

[0805] 4-(4-(trifluoromethyl)phenyl)pyrimidin-2-carboxaldehyde (500 mg, 1.97 mmol) was dissolved in dichloromethane (10 mL), and then methyl magnesium bromide tetrahydrofuran solution (2 mL) was added. The reaction was stirred at room temperature for 3 hours under nitrogen protection. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure, diluted with water (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL × 2), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a yellow solid 1-(4-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethane-1-ol (150 mg, yield 25.39%).

[0806] MS(ESI)m / z = 269.3 [M+H] + .

[0807] Step 6 Synthesis

[0808] 1-(4-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethane-1-ol (120 mg, 0.45 mmol) was dissolved in dichloromethane (5 mL), and thionyl chloride (5 mL) was added. The mixture was stirred at room temperature under nitrogen protection for 16 hours. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure, diluted with saturated sodium bicarbonate aqueous solution (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a yellow oily substance 2-(1-chloroethyl)-4-(4-(trifluoromethyl)phenyl)pyrimidin (100 mg, yield 70.18%).

[0809] MS(ESI)m / z = 287.2[M+H] + .

[0810] Seventh step synthesis

[0811] 2-(1-chloroethyl)-4-(4-(trifluoromethyl)phenyl)pyrimidine (50 mg, 0.17 mmol) was dissolved in acetonitrile (2 mL), and 1-methylimidazolidine-2-thione (22 mg, 0.19 mmol) was added. The mixture was stirred at 80 °C for 72 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a brown oil. The solid was purified by high performance liquid chromatography (mobile phase: acetonitrile / water (0.5% trifluoroacetic acid)). Acetonitrile was removed under reduced pressure, and the solid was lyophilized to obtain a colorless oily 2-(1-((1-methyl-4,5-dihydro-1H-imidazol-2-yl)thio)ethyl)-4-(4-(trifluoromethyl)phenyl)pyrimidine trifluoroacetate (21 mg, yield 26.73%).

[0812] MS(ESI)m / z = 367.0 [M+H] + .

[0813] 1 H NMR (DMSO-d6, 400MHz): δ10.12(s,1H),9.02(d,J=5.6Hz,1H),8.44(d,J=8.0Hz,2H),8.21(d,J=5.6Hz ,1H),7.99(d,J=8.4Hz,2H),5.35-5.33(m,1H),3.94-3.87(m,4H),3.08(s,3H),1.86(d,J=6.8Hz,3H).

[0814] The compounds in Table 20 below were prepared using the same methods as in the examples described above, with the corresponding compounds.

[0815] Table 20

[0816] The synthesis of REJT-94

[0817] Step 1 Synthesis

[0818] 230 mg (0.91 mmol) of 4-(4-(trifluoromethyl)phenyl)pyrimidin-2-carboxaldehyde was dissolved in 10 mL of dichloromethane, and then 0.8 mL of 1.0 M benzyl magnesium bromide tetrahydrofuran solution was added. The reaction was stirred at room temperature for 3 hours under nitrogen protection. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure, diluted with 20 mL of water and 20 mL of ethyl acetate, extracted with 20 mL of ethyl acetate (20 mL × 2), washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a yellow solid 2-phenyl-1-(4-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethane-1-ol (100 mg, yield 28.69%).

[0819] MS(ESI)m / z = 345.2[M+H] + .

[0820] Second step of synthesis

[0821] 2-Phenylacetyl-1-(4-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethane-1-ol (100 mg, 0.29 mmol) was dissolved in dichloromethane (5 mL), and thionyl chloride (5 mL) was added. The mixture was stirred at room temperature under nitrogen protection for 16 hours. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure, diluted with saturated sodium bicarbonate aqueous solution (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a yellow oily substance 2-(1-chloro-2-phenylethyl)-4-(4-(trifluoromethyl)phenyl)pyrimidin (100 mg, yield 46.5%).

[0822] MS(ESI)m / z = 363.1 [M+H] + .

[0823] Third step of synthesis

[0824] 2-(1-chloro-2-phenylethyl)-4-(4-(trifluoromethyl)phenyl)pyrimidine (100 mg, 0.27 mmol) was dissolved in acetonitrile (2 mL), and 1-methylimidazolidine-2-thione (48 mg, 0.41 mmol) was added. The mixture was stirred at 80 °C for 72 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to give a brown oily substance. Purification yielded a colorless oily 2-(1-((1-methyl-4,5-dihydro-1H-imidazol-2-yl)thio)-2-phenylethyl)-4-(4-(trifluoromethyl)phenyl)pyrimidine trifluoroacetate (22.52 mg, 14.89% yield).

[0825] MS(ESI)m / z = 443.0 [M+H] + .

[0826] 1 H NMR (DMSO-d6, 400MHz): δ10.17(s,1H),9.00(d,J=4.8Hz,1H),8.40(d,J=8.4Hz,2H),8.18(d,J=5.2Hz,1H),7. 98(d,J=8.4Hz,2H),7.30-7.22(m,2H),7.21-7.20(m,3H),5.60-5.56(m,1H),3.84-3.42(m,6H),3.03(s,3H).

[0827] The compounds in Table 21 below were prepared using the same methods as in the examples described above, with the corresponding compounds.

[0828] Table 21

[0829] The synthesis of REJT-98

[0830] Step 1 Synthesis

[0831] 5-(trifluoromethyl)pyridin-2,3-diamine (100.0 mg, 0.56 mmol), 2-chloropropionic acid (67.4 mg, 0.62 mmol), HATU (257.6 mg, 0.68 mmol), and diisopropylethylamine (218.9 mg, 1.69 mmol) were dissolved in N,N-dimethylformamide (5 mL), and the reaction was stirred at 25 °C for 3 hours. The resulting pale yellow oil, obtained by vacuum concentration, was purified by silica gel column chromatography to give a pale brown solid, N-(3-amino-5-(trifluoromethyl)pyridin-2-yl)-2-chloropropionamide (75 mg, p = 90%, yield 44.67%).

[0832] MS(ESI)m / z = 267.9[M+H] + .

[0833] Second step of synthesis

[0834] N-(3-amino-5-(trifluoromethyl)pyridin-2-yl)-2-chloropropionamide (350.0 mg, 1.31 mmol) was dissolved in 10 mL of glacial acetic acid and reacted under nitrogen protection at 80 °C for 16 hours with stirring. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure. The resulting oily substance was extracted three times with dichloromethane (3 × 50 mL), washed three times with water (3 × 50 mL), dried with magnesium sulfate, and the solvent was removed by rotary evaporation. The resulting light brown solid 2-(1-chloroethyl)-6-(trifluoromethyl)-3H-imidazolium[4,5-nor]pyridine was directly used in the next step of the reaction (310 mg, yield 80.72%).

[0835] MS(ESI)m / z = 250.0[M+H] + .

[0836] Third step of synthesis

[0837] 2-(1-chloroethyl)-6-(trifluoromethyl)-3H-imidazol[4,5-nor]pyridine (100.0 mg, 0.40 mmol) was dissolved in acetonitrile (5 mL), and imidazolidine-2-thione (61.4 mg, 0.60 mmol) was added. The mixture was stirred at 80 °C for 16 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a yellow oil. The oil was purified by high performance liquid chromatography (mobile phase: acetonitrile / water (0.05% trifluoroacetic acid)). Acetonitrile was removed under reduced pressure, and the solution was lyophilized to obtain a colorless oil, 2-(1-((4,5-dihydro-1H-imidazol-2-yl)thio)ethyl)-6-(trifluoromethyl)-3H-imidazol[4,5-nor]pyridine trifluoroacetate (62.3 mg, yield 48.80%).

[0838] MS(ESI)m / z = 316.0 [M+H] + .

[0839] 1 H NMR (DMSO-d6, 400MHz): δ10.55-10.43(brs,1H),8.76(s,1H),8.48(s,1H),5.39-5.34(m,1H),3.91(s,4H),1.89(d,J=6.8Hz,3H),.

[0840] The compounds in Table 22 below were prepared using the same methods as in the examples described above, with the corresponding compounds.

[0841] Table 22

[0842] The synthesis of REJT-100

[0843] Step 1 Synthesis

[0844] 5-(trifluoromethyl)pyridine-2,3-diamine (560.0 mg, 3.16 mmol) and diisopropylethylamine (817.2 mg, 6.32 mmol) were dissolved in dichloromethane (5 mL), followed by slow dropwise addition of 2-chloroacetyl chloride (357.1 mg, 3.16 mmol) under ice bath conditions. The reaction mixture was stirred at 25 °C for 4 hours. The resulting pale yellow oil, obtained by vacuum concentration, was purified by silica gel column chromatography to give a pale brown solid, N-(3-amino-5-(trifluoromethyl)pyridine-2-yl)-2-chloroacetamide (350 mg, yield 39.29%).

[0845] MS(ESI)m / z = 253.9[M+H] + .

[0846] Second step of synthesis

[0847] N-(3-amino-5-(trifluoromethyl)pyridin-2-yl)-2-chloroacetamide (350.0 mg, 1.38 mmol) was dissolved in 10 mL of glacial acetic acid and reacted at 95 °C for 16 hours under nitrogen protection. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure. The resulting oily substance was extracted three times with dichloromethane (50 mL × 3), washed three times with water (50 mL × 3), dried with magnesium sulfate, and the solvent was removed by rotary evaporation. The resulting light brown solid 2-chloromethyl-6-(trifluoromethyl)-3H-imidazolium[4,5-nor]pyridine was directly used in the next step of the reaction (220 mg, yield 57.51%).

[0848] MS(ESI)m / z = 235.9[M+H] + .

[0849] Third step of synthesis

[0850] 2-Chloromethyl-6-(trifluoromethyl)-3H-imidazol[4,5-nor]pyridine (100.0 mg, 0.42 mmol) was dissolved in acetonitrile (5 mL), and imidazolidine-2-thione (65.1 mg, 0.64 mmol) was added. The mixture was stirred at 80 °C for 16 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a yellow oily substance. The oil was purified by high performance liquid chromatography, and the acetonitrile was removed under reduced pressure. After lyophilization, a white solid ((4,5-dihydro-1H-imidazol-2-yl)thio)methyl-6-(trifluoromethyl)-1H-imidazol[5,6-nor]pyridine trifluoroacetate (96.2 mg, yield 75.01%) was obtained.

[0851] MS(ESI)m / z = 302.0[M+H] + .

[0852] 1 H NMR (DMSO-d6, 400MHz): δ10.87-10.14(brs,1H),8.74(s,1H),8.46(s,1H),4.85(s,2H),3.90(s,4H).

[0853] Synthesis of REJT-102

[0854] 2-Chloromethyl-6-(trifluoromethyl)-3H-imidazol[4,5-nor]pyridine (120.0 mg, 0.51 mmol) was dissolved in acetonitrile (5 mL), and 1-methylimidazolidine-2-thione (88.8 mg, 0.76 mmol) was added. The mixture was stirred at 80 °C for 16 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a yellow oil. The oil was purified by high performance liquid chromatography, and acetonitrile was removed under reduced pressure. After lyophilization, a colorless oil ((1-methyl-4,5-dihydro-1H-imidazol-2-yl)thio)methyl-6-(trifluoromethyl)-1H-imidazol[5,6-nor]pyridine trifluoroacetate (121.1 mg, yield 81.86%) was obtained.

[0855] MS(ESI)m / z = 316.0 [M+H] + .

[0856] 1 H NMR (DMSO-d6, 400MHz): δ10.38-9.97(brs,1H),8.74(s,1H),8.47(s,1H),4.90(s,2H),3.95-3.88(m,2H),3.85-3.82(m,2H),3.09(s,3H).

[0857] Synthesis of REJT-133

[0858] 2-(chloromethyl)-5-(trifluoromethyl)-3H-1,3-benzimidazole (200.0 mg, 0.85 mmol) and thiourea (97.3 mg, 1.28 mmol) were dissolved in acetonitrile (5 mL). The reaction mixture was stirred at 80 °C for 16 hours. The solvent was removed under reduced pressure. The resulting solid was purified by high performance liquid chromatography and lyophilized to give a white solid (6-(trifluoromethyl)-1H-benzi[d]imidazole-2-yl)methylthiourea (131.18 mg, yield 56.06%).

[0859] MS(ESI)m / z = 275.0 [M+H] + .

[0860] 1 H NMR (DMSO-d6, 400MHz): δ9.52-9.45(brs,2H),9.32-9.25(brs,2H),7.97(s,1H),7.78(d,J=8.8Hz,1H),7.56(d,J=8.4Hz,1H),4.77(s,2H).

[0861] Synthesis of REJT-134

[0862] 2-(chloromethyl)-5-(trifluoromethyl)-3H-1,3-benzimidazole (100.0 mg, 0.43 mmol) and methylthiourea (57.6 mg, 0.64 mmol) were dissolved in acetonitrile (3 mL). The reaction mixture was stirred at 80 °C for 16 hours. The solvent was removed under reduced pressure. The resulting solid was purified by high performance liquid chromatography and lyophilized to give a white solid (6-(trifluoromethyl)-1H-benzi[d]imidazole-2-yl)methyl-methylthiourea (110.54 mg, yield 90.00%).

[0863] MS(ESI)m / z = 289.0 [M+H] + .

[0864] 1 H NMR(DMSO-d6,400MHz): δ10.23-9.91(brs,1H),9.85-9.58(brs,1H),9.24-9.18(brs,1 H),7.97(s,1H),7.78(d,J=8.8Hz,1H),7.56(d,J=8.4Hz,1H),4.67(s,2H),2.97(s,3H).

[0865] REJT-135 Synthesis

[0866] Step 1 Synthesis

[0867] 2,4-Dichloropyrimidine (15.0 g, 0.10 mol) was dissolved in dioxane (100 mL) and water (50 mL). (4-(trifluoromethyl)phenyl)boronic acid (19.1 g, 0.10 mol), [1,1′-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (3.7 g, 0.005 mol), and sodium carbonate (21.3 g, 0.20 mol) were added, and the mixture was stirred at 85 °C for 16 hours. The reaction mixture was concentrated, and the resulting crude oil was extracted with ethyl acetate (100 mL × 3), washed with water (100 mL × 2), and the organic layers were combined. The mixture was dried over magnesium sulfate and concentrated. The resulting crude oil was purified by silica gel column chromatography to give a grayish-white solid 2-chloro-4-(4-(trifluoromethyl)phenyl)pyrimidine (10.0 g, yield 38.7%).

[0868] MS(ESI)m / z = 258.9[M+H] + .

[0869] Second step of synthesis

[0870] 2-Chloro-4-(4-(trifluoromethyl)phenyl)pyrimidine (10.0 g, 0.039 mol) was dissolved in N,N-dimethylformamide (50 mL), and tetratetraphenylphosphine palladium (2.3 g, 0.0020 mol) and zinc cyanide (2.7 g, 0.023 mol) were added. The mixture was stirred in a microwave at 180 °C for 0.5 hours. The organic layer was washed with saturated brine, dried over MgSO4, and concentrated by column chromatography to give a grayish-white solid 4-(4-(trifluoromethyl)phenyl)pyrimidine-2-onitrile (5.8 g, yield 59.83%).

[0871] MS(ESI)m / z=249.9[M+H]+.

[0872] Third step of synthesis

[0873] 1.5 g (0.006 mol) of 4-(4-(trifluoromethyl)phenyl)pyrimidine-2-nitrile was dissolved in methanol (5 mL), and concentrated hydrochloric acid (5 mL) was added. The mixture was stirred at 85 °C for 5 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane (500 mL), and sodium carbonate solid was added with stirring. Water (500 mL) was added, and the mixture was transferred to a separatory funnel and shaken well (pH 10 of the aqueous phase). The aqueous phase was back-extracted with dichloromethane (200 mL), and the combined organic layers were dried over sodium sulfate, evaporated to an oily substance, dried, and solidified to give 7.6 g of product. Column chromatography gave 0.95 g (55.6%) of methyl 4-(4-trifluoromethyl)phenyl)pyrimidine-2-carboxylic acid, a white solid.

[0874] 1 H NMR (DMSO-d6, 400MHz): δ9.06 (d, J = 7.2Hz, 1H), 8.34 (d, J = 10.8Hz, 2H), 7.95 (d, J = 7.2Hz, 1H), 7.84 (d, J = 10.8Hz, 2H), 4.14 (s, 3H).

[0875] Fourth step synthesis

[0876] Methyl 4-(4-(trifluoromethyl)phenyl)pyrimidin-2-carboxylic acid (300.0 mg, 1.06 mmol) was dissolved in tetrahydrofuran (5 mL), and lithium borohydride (46.1 mg, 2.12 mmol) was added. The mixture was stirred for 6 hours. After the reaction was completed, the mixture was quenched with ammonium chloride aqueous solution, extracted with ethyl acetate (10 mL × 2), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a colorless oil (4-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)methanol (70 mg, yield 25.89%).

[0877] MS(ESI)m / z = 254.9[M+H] + .

[0878] Fifth step synthesis

[0879] (4-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)methanol (70.0 mg, 0.27 mmol) was dissolved in thionyl chloride (2 mL) and dichloromethane (2 mL), and the mixture was stirred at room temperature for 16 hours. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure, and then purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain a yellow solid 2-(chloromethyl)-4-(4-(trifluoromethyl)phenyl)pyrimidin (73 mg, yield 97.26%).

[0880] MS(ESI)m / z = 273.0[M+1] + .

[0881] Step 6 Synthesis

[0882] 2-(chloromethyl)-4-(4-(trifluoromethyl)phenyl)pyrimidine (35 mg, 0.13 mmol) was dissolved in acetonitrile (5 mL), and thiourea (11.7 mg, 0.15 mmol) was added. The mixture was stirred at 80 °C for 16 hours. After cooling, the reaction solution was filtered, and the resulting solid was purified by high performance liquid chromatography. After lyophilization, a yellow oily substance (4-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)methylthiourea trifluoroacetate (8.0 mg, yield 20.08%) was obtained.

[0883] MS(ESI)m / z = 313.0[M+H] + .

[0884] 1 H NMR (DMSO-d6, 400MHz): δ9.30 (s, 4H), 8.99 (d, J = 5.2Hz, 1H), 8.43 (d, J = 8.4Hz, 2H), 8.18 (d, J = 5.6Hz, 1H), 7.96 (d, J = 8.4Hz, 2H), 4.85 (s, 2H).

[0885] The compounds in Table 23 below were prepared using the same methods as in the examples described above, with the corresponding compounds.

[0886] Table 23

[0887] REJT-140 synthesis

[0888] 2-(chloromethyl)-4-(4-(trifluoromethyl)phenyl)pyrimidine (35 mg, 0.13 mmol) was dissolved in acetonitrile (5 mL), and 1-methylthiourea (13.8 mg, 0.15 mmol) was added. The mixture was stirred at 80 °C for 16 hours. After cooling, the reaction solution was filtered, and the resulting solid was purified by high performance liquid chromatography. After lyophilization, a yellow oily substance (4-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)methylmethylthiourea trifluoroacetate (30.0 mg, yield 71.85%) was obtained.

[0889] MS(ESI)m / z = 327.0 [M+H] + .

[0890] 1 H NMR (DMSO-d6, 400MHz): δ9.86 (s, 1H), 9.54 (s, 1H), 9.19 (s, 1H), 8.98 (d, J = 5.2Hz, 1H), 8.41 (d, J=8.4Hz,2H),8.18(d,J=5.2Hz,1H),7.97(d,J=8.4Hz,2H),4.85(s,2H),2.94(d,J=4.8Hz,3H).

[0891] The synthesis of REJT-152

[0892] Step 1 Synthesis

[0893] 2,2-Dimethoxyethanol (2.0 g, 18.84 mmol) was added to a 20 mL solution of tetrahydrofuran containing sodium hydrogen (412 mg, 17.92 mmol). After stirring at room temperature for 2 hours, 1-methyl-2-(methylthio)-4,5-dihydro-1H-imidazole (2.2 g, 16.96 mmol) was added, and the mixture was stirred overnight at 90 °C. The reaction solution was concentrated under vacuum and purified by silica gel column chromatography to give a yellow oily substance, 2-(2,2-dimethoxyethoxy)-1-methyl-4,5-dihydro-1H-imidazole (560 mg, yield 15.79%).

[0894] MS(ESI)m / z = 188.9[M+H] + .

[0895] Second step of synthesis

[0896] 2-(2,2-dimethoxyethoxy)-1-methyl-4,5-dihydro-1H-imidazole (500 mg, 2.65 mmol) and 4-chlorophenyl-1,2-diamine (471 mg, 2.66 mmol) were dissolved in 6N hydrochloric acid (5 mL) and stirred at room temperature for 16 hours. The reaction solution was cooled and concentrated under reduced pressure, purified by high performance liquid chromatography, and lyophilized to give a brown oily substance 5-chloro-2-(((1-methyl-4,5-dihydro-1H-imidazol-2-yl)oxy)methyl)-1H-benzo[d]imidazole (9.79 mg, yield 2.51%).

[0897] MS(ESI)m / z = 265.0 [M+H] + .

[0898] 1H NMR (DMSO-d6, 400MHz): δ7.71(d,J=1.6Hz,1H),7.64(d,J=8.8Hz,1H),7.30-7.27(m,1H),5.70(s,2H),4.88(s,1H),3.82-3.79(m,4H),2.92(s,3H).

[0899] Synthesis of REJT-157

[0900] Step 1 Synthesis

[0901] Methyl 3-bromobenzoate (2.15 g, 10.0 mmol) was dissolved in dioxane (20 mL) and water (10 mL), followed by the addition of (4-(trifluoromethyl)phenyl)boronic acid (1.90 g, 10.0 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (370.0 mg, 0.50 mmol), and sodium carbonate (2.12 g, 20.0 mmol). The reaction was stirred at 85 °C for 16 hours under nitrogen protection. After the reaction was completed and cooled, the reaction solution was diluted with water (100 mL) and ethyl acetate (100 mL). The solution was extracted with ethyl acetate (100 mL × 2), and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a brown solid, methyl 4'-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxylate (1.50 g, yield 51.0%).

[0902] 1 H NMR (CDCl3, 300MHz): δ8.34(s,1H),8.14(d,J=7.8Hz,1H),7.85(d,J=7.8Hz,1H),7.78(s,4H),7.61(t,J=7.8Hz,1H),4.02(s,3H).

[0903] Second step of synthesis

[0904] Methyl 4'-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxylate (800.0 mg, 2.85 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium borohydride solution (2 M in THF, 2.85 mL, 5.71 mmol) was slowly added dropwise at 0°C. The reaction mixture was stirred at 20°C for 16 hours. After the reaction was completed, the reaction solution was diluted with saturated ammonium chloride solution (50 mL) and ethyl acetate (50 mL), extracted with ethyl acetate (50 mL × 2), and the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a white solid 4'-(trifluoromethyl)-[1,1'-biphenyl]-3-methanol (540.0 mg, yield 67.50%).

[0905] 1 H NMR (CDCl3, 300MHz): δ7.75(s,4H),7.67(s,1H),7.60-7.45(m,3H),4.84(s,2H).

[0906] Third step of synthesis

[0907] 4'-(trifluoromethyl)-[1,1'-biphenyl]-3-methanol (190.0 mg, 0.75 mmol) was dissolved in tetrahydrofuran (3 mL), followed by the slow addition of thionyl chloride (268.9 mg, 2.26 mmol), and then 2 drops of N,N-dimethylformamide were added dropwise. The reaction was then carried out under nitrogen protection at 20 °C with stirring for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a light brown solid 3-(chloromethyl)-4'-(trifluoromethyl)-1,1'-biphenyl (165.0 mg, yield 52.6%), which was used directly in the next step.

[0908] Fourth step synthesis

[0909] 3-(chloromethyl)-4'-(trifluoromethyl)-1,1'-biphenyl (200.0 mg, 0.74 mmol) was dissolved in acetonitrile (5 mL), and imidazolidin-2-thione (150.1 mg, 1.48 mmol) was added. The mixture was stirred at 80 °C for 16 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a brown oily substance. This substance was then purified by high performance liquid chromatography and lyophilized to give a white solid, 2-(((4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methyl)thio)-4,5-dihydro-1H-imidazolium trifluoroacetate (182.01 mg, yield 72.62%).

[0910] MS(ESI)m / z = 337.0 [M+H] + .

[0911] 1 H NMR (DMSO-d6, 400MHz): δ10.26 (s, 2H), 7.91-7.84 (m, 5H), 7.73 (d, J = 7.2Hz, 1H), 7.57-7.51 (m, 2H), 4.59 (s, 2H), 3.88 (s, 4H).

[0912] The compounds in Table 24 below were prepared using the same methods as in the examples described above.

[0913] Table 24

[0914] REJT-160 synthesis

[0915] Step 1 Synthesis

[0916] 1H-pyrazole-4-carboxylic acid methyl ester (600.0 mg, 4.77 mmol) was dissolved in N,N-dimethylformamide (15 mL), and 1-iodo-4-(trifluoromethyl)benzene (1558.6 mg, 5.71 mmol), copper (30.2 mg, 0.48 mmol), acetylacetone iron(III) (168.0 mg, 0.48 mmol), and cesium carbonate (4650.3 mg, 14.27 mmol) were added. The mixture was stirred at 100 °C for 16 hours. After the reaction was completed, the mixture was diluted with ethyl acetate and filtered. The solution was extracted with ethyl acetate (10 mL × 2), and the organic phase was washed with saturated brine (10 mL). After drying with anhydrous sodium sulfate, the solution was filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a brown solid 1-(4-trifluoromethyl)phenyl)-1H-pyrazole-4-carboxylic acid methyl ester (1030.0 mg, yield 79.82%).

[0917] MS(ESI)m / z = 271.0[M+H] + .

[0918] Second step of synthesis

[0919] Methyl 1-(4-trifluoromethyl)phenyl)-1H-pyrazole-4-carboxylate (500.0 mg, 1.84 mmol) was dissolved in tetrahydrofuran (5 mL), and lithium borohydride (80.3 mg, 3.69 mmol) was added. The mixture was stirred for 16 hours. After the reaction was completed, the mixture was quenched with ammonium chloride aqueous solution, extracted with ethyl acetate (10 mL * 2), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give a brown oily substance (1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-4-yl)methanol (235 mg, yield 52.41%).

[0920] MS(ESI)m / z = 243.0[M+H] + .

[0921] Third step of synthesis

[0922] (1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-4-yl)methanol (230.0 mg, 0.95 mmol) was dissolved in thionyl chloride (5 mL), and the mixture was stirred at room temperature for 16 hours. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain a yellow solid 4-(chloromethyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole (218 mg, yield 88.09%).

[0923] MS(ESI)m / z = 261.0[M+1] + .

[0924] Fourth step synthesis

[0925] 4-(chloromethyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole (218 mg, 0.83 mmol) was dissolved in acetonitrile (5 mL), and imidazolidin-2-thione (85.1 mg, 0.83 mmol) was added. The mixture was stirred at 80 °C for 16 hours. The reaction solution was concentrated under reduced pressure and purified by high performance liquid chromatography to obtain a white solid 4-(((4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole trifluoroacetate (110.0 mg, yield 40.3%).

[0926] MS(ESI)m / z = 327.0 [M+H] + .

[0927] 1 H NMR (DMSO-d6, 400MHz): δ10.313 (s, 2H), 8.69 (s, 1H), 8.05 (d, J = 8.4Hz, 2H), 7.90 (s, 2H), 7.88 (s, 1H), 4.49 (s, 2H), 3.90 (s, 4H).

[0928] The compounds in Table 25 below were prepared using the same methods as in the examples described above.

[0929] Table 25

[0930] The synthesis of REJT-163

[0931] Step 1 Synthesis

[0932] Methyl 3-bromo-1-methyl-1H-pyrazole-5-carboxylic acid ester (300.0 mg, 1.37 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL). (4-(trifluoromethyl)phenyl)boronic acid (312.2 mg, 1.64 mmol), tetratetraphenylphosphine palladium (158.3 mg, 0.14 mmol), and cesium carbonate (892.5 mg, 2.74 mmol) were added. The mixture was stirred at 80 °C for 16 hours under nitrogen protection. After the reaction was complete, the mixture was diluted with ethyl acetate and filtered. The solution was extracted with ethyl acetate (10 mL × 2). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a white solid, methyl 1-methyl-3-(4-(trifluoromethyl)phenyl)-1H-pyrazole-5-carboxylic acid ester (65.0 mg, yield 16.71%).

[0933] MS(ESI)m / z = 285.0 [M+H]+ .

[0934] Second step of synthesis

[0935] Methyl 1-methyl-3-(4-(trifluoromethyl)phenyl)-1H-pyrazole-5-carboxylic acid (65.0 mg, 2.23 mmol) was dissolved in tetrahydrofuran (5 mL), and lithium borohydride (9.96 mg, 0.46 mmol) was added. The mixture was stirred for 16 hours. After the reaction was completed, the mixture was quenched with ammonium chloride aqueous solution, extracted with ethyl acetate (10 mL × 2), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to give a white solid (1-methyl-3-(4-(trifluoromethyl)phenyl)-1H-pyrazole-5-yl)methanol (55 mg, yield 93.85%).

[0936] MS(ESI)m / z = 257.0 [M+H] + .

[0937] Third step of synthesis

[0938] (1-Methyl-3-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)methanol (55.0 mg, 0.21 mmol) was dissolved in thionyl chloride (5 mL), and the mixture was stirred at room temperature for 16 hours. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain a white solid 5-(chloromethyl)-1-methyl-3-(4-(trifluoromethyl)phenyl)-1H-pyrazol (33 mg, yield 55.94%).

[0939] MS(ESI)m / z = 275.0[M+1] + .

[0940] Fourth step synthesis

[0941] 5-(chloromethyl)-1-methyl-3-(4-(trifluoromethyl)phenyl)-1H-pyrazole (33 mg, 0.12 mmol) was dissolved in acetonitrile (5 mL), and imidazolidin-2-thione (14.7 mg, 0.14 mmol) was added. The mixture was stirred at 80 °C for 16 hours. The reaction solution was concentrated under reduced pressure, and the result was purified by high performance liquid chromatography. After lyophilization, a white solid 5-(((4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-1-methyl-3-(4-(trifluoromethyl)phenyl)-1H-pyrazole trifluoroacetate (30.0 mg, yield 73.36%) was obtained.

[0942] MS(ESI)m / z = 341.0[M+H] + .

[0943] 1H NMR (DMSO-d6, 400MHz): δ10.29(s,2H),7.98(d,J=8.0Hz,2H),7.76(d,J=8.0Hz,2H),6.89(s,1H),4.68(s,2H),3.90(s,4H),3.89(s,3H).

[0944] The synthesis of REJT-164

[0945] 2-(chloromethyl)-4-(4-(trifluoromethyl)phenyl)pyrimidine (100.0 mg, 0.37 mmol) was dissolved in acetonitrile (5 mL), and N-ethyl-imidazolidine-2-thione (57.3 mg, 0.44 mmol) was added. The mixture was stirred at 80 °C for 16 hours. After cooling, the reaction solution was concentrated under reduced pressure and dried to obtain a brown oily substance. This substance was then purified by high performance liquid chromatography and lyophilized to give a white solid, 2-(((1-ethyl-4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-4-(4-(trifluoromethyl)phenyl)pyrimidine trifluoroacetate (127.12 mg, yield 94.41%).

[0946] MS(ESI)m / z = 367.1 [M+H] + .

[0947] 1 H NMR (DMSO-d6, 400MHz): δ10.08(s,1H),8.99(d,J=5.2Hz,1H),8.42(d,J=8.0Hz,2H),8.20(d,J=5.2Hz,1H),7.99( d,J=8.8Hz,2H),4.95(s,2H),4.07-3.99(m,2H),3.89-3.84(m,2H),3.53(q,J=7.2Hz,2H),1.20(t,J=7.2Hz,3H).

[0948] The compounds in Table 26 below were prepared using the same methods as in the examples described above, with the corresponding compounds.

[0949] Table 26

[0950] The synthesis of REJT-166

[0951] Step 1 Synthesis

[0952] Cyclopropane isothiocyanate (200.0 mg, 0.37 mmol) was dissolved in dichloromethane (5 mL), and N-methylcyclopropane (90.0 mg, 0.37 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure. After vacuum concentration, the solution was purified by silica gel column chromatography to obtain a colorless oily substance, 1,3-dicyclopropyl-1-methylthiourea (300.0 mg, yield 87.35%).

[0953] MS(ESI)m / z = 171.1[M+1] + .

[0954] Second step of synthesis

[0955] 2-(chloromethyl)-4-(4-(trifluoromethyl)phenyl)pyrimidine (100.0 mg, 0.37 mmol) was dissolved in acetonitrile (5 mL), and 1,3-dicyclopropyl-1-methylthiourea (75.0 mg, 0.44 mmol) was added. The mixture was stirred at 80 °C for 16 hours. After cooling, the reaction solution was filtered, and the resulting solid was purified by high performance liquid chromatography. After lyophilization, a yellow oily substance (4-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)methyl(Z)-N,N'-dicyclopropyl-N-methylthiourea trifluoroacetate (70.0 mg, yield 46.48%) was obtained.

[0956] MS(ESI)m / z = 407.1 [M+H] + .

[0957] 1 H NMR (DMSO-d6, 400MHz): δ9.73 (s, 1H), 8.99 (d, J = 5.2Hz, 1H), 8.43 (d, J = 8.4Hz, 2H), 8.19 (d, J = 5.6Hz, 1H), 7.9 8(d,J=8.4Hz,2H),4.74(s,2H),3.46(s,1H),3.33(s,3H),3.09(s,1H),0.91-0.83(m,4H),0.69-0.67(m,4H).

[0958] The compounds in Table 27 below were prepared using the same methods as in the examples described above.

[0959] Table 27

[0960] REJT-180 synthesis

[0961] Step 1 Synthesis

[0962] Diethyl oxalate (737.9.0 mg, 5.05 mmol) was dissolved in tetrahydrofuran (10 mL), and a methanol solution of sodium methoxide (30% w / t, 1.8 mL, 10.10 mmol) was slowly added. Under nitrogen protection, the mixture was stirred for ten minutes, followed by the slow dropwise addition of 4-trifluoromethylacetophenone (950.0 mg, 5.05 mmol). The reaction phase was stirred at 20 °C for 16 hours. After the reaction was complete, 50 mL of water was added to quench the reaction, and the pH was adjusted to 6 with 1 M HCl solution. The mixture was extracted with ethyl acetate (50 mL × 2), and the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a colorless, transparent oil, ethyl 2,4-dioxo-4-(4-(trifluoromethyl)phenyl)butyrate (200.0 mg, yield 13.70%).

[0963] 1 H NMR (CDCl3, 400MHz): δ8.09 (dd, J1=8.0, J2=2.8Hz, 2H), 7.76 (dd, J1=8.0, J2=2.8Hz, 2H), 4.41-4.34 (m, 2H), 3.97-3.91 (m, 2H), 1.44-1.37 (m, 3H).

[0964] Second step of synthesis

[0965] Ethyl 2,4-dioxo-4-(4-(trifluoromethyl)phenyl)butyrate (100.0 mg, 0.38 mmol) was dissolved in glacial acetic acid (10 mL), and hydrazine hydrate (38.5 mg, 0.77 mmol) was added. The mixture was stirred at 20 °C for 16 hours. After the reaction was completed, the acetic acid was removed by concentration under reduced pressure. The residue was extracted with ethyl acetate (10 mL × 2), and the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to give ethyl 5-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylate (70.0 mg, yield 54.46%) as a white solid.

[0966] MS(ESI)m / z = 285.1 [M+H] + .

[0967] Third step of synthesis

[0968] Ethyl 5-(4-trifluoromethylphenyl)-1H-pyrazole-3-carboxylate (300.0 mg, 1.06 mmol) was dissolved in tetrahydrofuran (5 mL), and lithium borohydride (96.4 mg, 4.42 mmol) was added. The mixture was stirred for 16 hours. After the reaction was completed, the mixture was quenched with ammonium chloride aqueous solution, extracted with ethyl acetate (10 mL × 2), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to give a white solid (5-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-yl)methanol (215.0 mg, yield 84.0%).

[0969] Fourth step synthesis

[0970] (5-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-yl)methanol (150.0 mg, 0.62 mmol) was dissolved in thionyl chloride (5 mL), and the mixture was stirred at room temperature for 16 hours. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain a yellow oily substance 3-(chloromethyl)-5-(4-(trifluoromethyl)phenyl)-1H-pyrazole (70.0 mg, yield 42.94%).

[0971] MS(ESI)m / z = 261.0[M+1] + .

[0972] Fifth step synthesis

[0973] 3-(chloromethyl)-5-(4-(trifluoromethyl)phenyl)-1H-pyrazole (100 mg, 0.38 mmol) was dissolved in acetonitrile (5 mL), and imidazolidin-2-thione (39.2 mg, 0.38 mmol) was added. The mixture was stirred at 80 °C for 16 hours. The reaction solution was concentrated under reduced pressure and purified by high performance liquid chromatography (mobile phase: acetonitrile / water (0.05% trifluoroacetic acid)). After lyophilization, a white solid 5-(((4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazole trifluoroacetate (60.0 mg, yield 47.43%) was obtained.

[0974] MS(ESI)m / z = 327.0 [M+H] + .

[0975] 1 H NMR(DMSO-d6,400MHz): δ13.62(s,1H),10.28(s,1H),10.25(s,1H),7.98(d, J=8.0Hz,2H),7.82(d,J=8.0Hz,2H),6.87(s,1H),4.57(s,2H),3.90(s,4H).

[0976] The synthesis of REJT-184

[0977] Step 1 Synthesis

[0978] 4-Trifluoromethylbenzonitrile (3.0 g, 0.0175 mol) was dissolved in ethanol (20 mL), and chloroacetyl (10.72 g, 0.1365 mol) was slowly added dropwise under ice bath. After the addition was complete, the reaction phase was stirred at 20 °C for 16 hours. After the reaction was completed, saturated sodium bicarbonate solution was added under ice bath, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a gray solid ethyl 4-(trifluoromethyl)benzoimide (2.1 g, yield 46.86%).

[0979] Second step of synthesis

[0980] Ethyl 4-(trifluoromethyl)benzylimine (1.0 g, 4.60 mmol) was dissolved in acetonitrile (20 mL), and 2-hydroxyacetylhydrazine (410.0 mg, 4.60 mmol) was added. The reaction mixture was stirred at 50 °C for 16 hours. Subsequently, the temperature was raised to 105 °C and the reaction was continued with stirring for 24 hours. After the reaction was completed, the crude oil obtained by vacuum concentration was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 8 / 1) to give a yellow solid (5-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)methanol (1.1 g, yield 89.13%).

[0981] MS(ESI)m / z = 244.4[M+H] + .

[0982] Third step of synthesis

[0983] (5-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)methanol (150.0 mg, 0.62 mmol) was dissolved in thionyl chloride (5 mL), and the mixture was stirred at room temperature for 16 hours. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain a yellow solid 3-(chloromethyl)-5-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole (112 mg, yield 69.41%).

[0984] MS(ESI)m / z = 262.0[M+1] + .

[0985] Fourth step synthesis

[0986] 3-(chloromethyl)-5-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole (110 mg, 0.42 mmol) was dissolved in acetonitrile (5 mL), and imidazolidine-2-thione (43.0 mg, 0.42 mmol) was added. The mixture was stirred at 80 °C for 16 hours. The reaction solution was concentrated under reduced pressure, purified by high performance liquid chromatography, and lyophilized to give a white solid 3-(((4,5-dihydro-1H-imidazol-2-yl)thio)methyl)-5-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole trifluoroacetate (30.0 mg, yield 21.81%).

[0987] MS(ESI)m / z = 328.0 [M+H] + .

[0988] 1 H NMR (DMSO-d6, 400MHz): δ14.86 (s, 1H), 10.34 (s, 2H), 8.20 (d, J = 8.4Hz, 2H), 7.91 (d, J = 6.8Hz, 2H), 4.69 (s, 2H), 3.92 (s, 4H).

[0989] Synthesis of REJT-186

[0990] Step 1 Synthesis

[0991] 15.0 g (0.0797 mol) of 4-trifluoromethylacetophenone was dissolved in 50 mL of anhydrous methanol. Sodium methoxide (8.6 g, 0.1594 mol) was slowly added under ice bath conditions, and the mixture was stirred at room temperature for 1 hour. Then, a solution of dimethyl oxalate (18.8 g, 0.1594 mol) diluted in methanol (20 mL) was added. The reaction was carried out under nitrogen protection at 20 °C with stirring for 24 hours. After the reaction was completed, the mixture was filtered. The resulting filter cake was washed with ice-cold methanol and ethyl acetate, and dried under vacuum to give methyl 2,4-dioxane-4-[4-(trifluoromethyl)phenyl]butyrate (14.2 g, yield 65.12%) as a white solid.

[0992] Second step of synthesis

[0993] Methyl 2,4-dioxane-4-[4-(trifluoromethyl)phenyl]butyrate (10.0 g, 0.0406 mol) and N-methylhydrazine sulfate (4.47 g, 0.0406 mol) were dissolved in glacial acetic acid (150 mL) and reacted at 105 °C for 1 hour under nitrogen protection. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the mixture was extracted with ethyl acetate (200 mL × 2). The organic phase was washed with saturated sodium bicarbonate aqueous solution (200 mL) and saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain methyl 1-methyl-3-(4-(trifluoromethyl)phenyl)-1H-pyrazole-5-carboxylate (1.6 g, yield 12.56%).

[0994] 1 H NMR (CDCl3, 400MHz): δ7.76 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 6.92 (s, 1H), 3.98 (s, 3H), 3.96 (s, 3H).

[0995] Third step of synthesis

[0996] Methyl 1-methyl-3-(4-(trifluoromethyl)phenyl)-1H-pyrazole-5-carboxylic acid (650.0 mg, 2.27 mmol) was dissolved in tetrahydrofuran (5 mL), and lithium borohydride (100.0 mg, 4.57 mmol) was added. The mixture was stirred for 16 hours. After the reaction was completed, the mixture was quenched with ammonium chloride aqueous solution, extracted with ethyl acetate (10 mL × 2), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a colorless oil (1-methyl-3-(4-(trifluoromethyl)phenyl)-1H-pyrazole-5-yl)methanol (450.0 mg, yield 76.80%).

[0997] MS(ESI)m / z = 257.0 [M+H] + .

[0998] Fourth step synthesis

[0999] (1-Methyl-3-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)methanol (450.0 mg, 1.76 mmol) was dissolved in thionyl chloride (5 mL), and the mixture was stirred at room temperature for 16 hours. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain a white solid 5-(chloromethyl)-1-methyl-3-(4-(trifluoromethyl)phenyl)-1H-pyrazol (335 mg, yield 69.44%).

[1000] MS(ESI)m / z = 275.0[M+1] + .

[1001] Fifth step synthesis

[1002] 5-(chloromethyl)-1-methyl-3-(4-(trifluoromethyl)phenyl)-1H-pyrazole (100.0 mg, 0.36 mmol) was dissolved in acetonitrile (5 mL), and thiourea (27.7 mg, 0.36 mmol) was added. The mixture was stirred at 80 °C for 16 hours. The reaction solution was concentrated under reduced pressure, and the result was purified by high performance liquid chromatography. After lyophilization, a white solid (1-methyl-3-(4-(trifluoromethyl)phenyl)-1H-pyrazole-5-yl)methylthiourea trifluoroacetate (90.0 mg, yield 77.86%) was obtained.

[1003] MS(ESI)m / z = 315.1[M+H] + .

[1004] 1 H NMR (DMSO-d6, 400MHz): δ9.36-9.30 (m, 4H), 7.97 (d, J = 8.0Hz, 2H), 7.76 (d, J = 8.0Hz, 2H), 6.85 (s, 1H), 4.66 (s, 2H), 3.91 (s, 3H).

[1005] REJT-185 Synthesis

[1006] 5-(chloromethyl)-1-methyl-3-(4-(trifluoromethyl)phenyl)-1H-pyrazole (100.0 mg, 0.36 mmol) was dissolved in acetonitrile (5 mL), and 1-methylthiourea (32.8 mg, 0.36 mmol) was added. The mixture was stirred at 80 °C for 16 hours. The reaction solution was concentrated under reduced pressure, and the result was purified by high performance liquid chromatography (mobile phase: acetonitrile / water (0.05% trifluoroacetic acid)). After lyophilization, a white solid (1-methyl-3-(4-(trifluoromethyl)phenyl)-1H-pyrazole-5-yl)methylmethylthiourea trifluoroacetate salt (88.0 mg, yield 72.91%) was obtained.

[1007] MS(ESI)m / z = 329.0 [M+H] + .

[1008] 1 H NMR (DMSO-d6, 400MHz): δ9.90 (s, 1H), 9.55 (s, 1H), 9.23 (s, 1H), 7.97 (d, J = 8.0Hz, 2H) ,7.76(d,J=8.0Hz,2H),6.81(s,1H),4.67(s,2H),3.91(s,3H),2.91(d,J=4.8Hz,3H).

[1009] The compounds in Table 28 below were prepared using the same methods as in the examples described above, with the corresponding compounds.

[1010] Table 28

[1011] Synthesis of REJT-188

[1012] 2-(chloromethyl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine (100.0 mg, 0.42 mmol) was dissolved in acetonitrile (5 mL), and thiourea (32.3 mg, 0.42 mmol) was added. The mixture was stirred at 80 °C for 16 hours. The reaction solution was concentrated under reduced pressure, purified by high performance liquid chromatography, and lyophilized to give a white solid (6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl)methylthiourea trifluoroacetate (85.0 mg, yield 72.01%).

[1013] MS(ESI)m / z = 276.1 [M+H] + .

[1014] 1 H NMR (DMSO-d6, 400MHz): δ13.79(s,1H),9.40(s,4H),8.74(s,1H),8.46(s,1H),4.81(s,2H).

[1015] Synthesis of REJT-193

[1016] Step 1 Synthesis

[1017] Triethylamine (57.0 mg, 0.56 mmol) was added to a 1,2-dichloroethane solution (20 mL) of 6-(trifluoromethyl)pyridine-3,4-diamine (100.0 mg, 0.56 mmol), followed by slow dropwise addition of chloroacetyl chloride (63.8 mg, 0.56 mmol) under ice bath conditions. The reaction mixture was allowed to react overnight at room temperature. The reaction solution was extracted three times with dichloromethane (50 mL × 3), washed three times with water (50 mL × 3), and the resulting pale yellow oily substance was concentrated under vacuum and dissolved in 10 mL of glacial acetic acid. The mixture was stirred at 70 °C for 2 hours under nitrogen protection. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure. The resulting oil was extracted three times with dichloromethane (50 mL × 3), washed three times with water (50 mL × 3), dried with magnesium sulfate, and the solvent was removed by rotary evaporation. The resulting light brown oil, 2-(chloromethyl)-6-(trifluoromethyl)-1H-imidazolium(5,6-naphthyl)pyridine, was directly used in the next step of the reaction (90.0 mg, yield 60.89%).

[1018] MS(ESI)m / z = 235.9[M+H] + .

[1019] Second step of synthesis

[1020] 2-(chloromethyl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine (60.0 mg, 0.25 mmol) was dissolved in acetonitrile (5 mL), and 1-methylthiourea (23.0 mg, 0.25 mmol) was added. The mixture was stirred at 80 °C for 16 hours. The reaction solution was concentrated under reduced pressure, purified by high performance liquid chromatography, and lyophilized to give a yellow solid (5-(trifluoromethyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl methylthiourea trifluoroacetate (59.0 mg, yield 81.90%).

[1021] MS(ESI)m / z = 290.0[M+H] + .

[1022] 1 H NMR(DMSO-d6,400MHz): δ13.68(s,1H),9.98(s,1H),9.68(s,1H),9.26(s,1 H),8.25(d,J=8.0Hz,1H),7.76(d,J=8.0Hz,1H),4.83(s,2H),2.94(s,3H).

[1023] The compounds in Table 29 below were prepared using the same methods as in the examples described above, with the corresponding compounds.

[1024] Table 29

[1025] The synthesis of REJT-195

[1026] 2-(chloromethyl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine (100.0 mg, 0.42 mmol) was dissolved in acetonitrile (5 mL), and 1-methylthiourea (38.3 mg, 0.42 mmol) was added. The mixture was stirred at 80 °C for 16 hours. The reaction solution was concentrated under reduced pressure, purified by high performance liquid chromatography, and lyophilized to give a yellow solid (6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl)methyl methylthiourea trifluoroacetate (20.0 mg, yield 16.11%).

[1027] MS(ESI)m / z = 290.0[M+H] + .

[1028] 1H NMR (DMSO-d6, 400MHz): δ10.02(s,1H),9.69(s,1H),9.30(s,1H),8.74(d,J=1.6Hz,1H),8.45(d,J=1.6Hz,1H),4.83(s,2H),2.94(s,3H).

[1029] Synthesis of REJT-206

[1030] Step 1 Synthesis

[1031] 4-Trifluoromethylbenzamide (2.00 g, 0.0106 mol), 1,3-dihydroxyacetone dimer (0.95 g, 0.0106 mol), and ammonium chloride (2.27 g, 0.0424 mol) were suspended in 35% ammonia water (40 mL). The reaction mixture was stirred at 45 °C for 48 hours. After the reaction was completed, the mixture was extracted with ethyl acetate (100 mL × 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the crude oil obtained by vacuum concentration was purified by silica gel column chromatography to give a gray solid (2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)methanol (1.30 g, yield 45.28%).

[1032] MS(ESI)m / z = 243.2[M+H] + .

[1033] Second step of synthesis

[1034] (2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)methanol (350.0 mg, 1.45 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the addition of iodomethane (205.2 mg, 1.45 mmol) and potassium hydroxide (570.8 mg, 7.23 mmol). The mixture was stirred at 50 °C for 16 hours. After the reaction was complete, dichloromethane (50 mL) and water (50 mL) were added to the reaction phase. The aqueous phase was extracted with dichloromethane (50 mL × 2) after separation. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The resulting crude oily product was purified by silica gel column chromatography to obtain a light brown solid (1-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-5-yl)methanol (280.0 mg, yield 68.06%).

[1035] 1 H NMR (DMSO-d6, 400MHz): δ7.76 -7.70(m,4H),7.07-6.97(m,1H),4.70-4.64(m,2H),3.77-3.74(m,3H).

[1036] Third step of synthesis

[1037] (1-Methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-5-yl)methanol (140.0 mg, 0.55 mmol) was dissolved in thionyl chloride (3 mL) and stirred at 50 °C for 16 hours. After the reaction was completed and cooled, the reaction solution was concentrated under reduced pressure. After vacuum concentration, without further purification, a yellow oily substance 5-(chloromethyl)-1-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazolium (150.0 mg, yield 44.99%) was obtained.

[1038] MS(ESI)m / z = 257.2[M+H-18] + .

[1039] Fourth step synthesis

[1040] 5-(chloromethyl)-1-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazolium (100 mg, 0.36 mmol) was dissolved in acetonitrile (5 mL), and imidazolidine-2-thione (55.8 mg, 0.55 mmol) was added. The mixture was stirred at 80 °C for 16 hours. The reaction solution was concentrated under reduced pressure, purified by high performance liquid chromatography, and lyophilized to obtain a colorless oily substance, 5-(((4,5-dihydroxy-1H-imidazol-2-yl)thio)methyl)-1-methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazolium trifluoroacetate (46.22 mg, yield 37.08%).

[1041] MS(ESI)m / z = 341.1[M+H] + .

[1042] 1 H NMR (DMSO-d6, 400MHz): δ10.33(s,2H),7.95-7.93(m,4H),7.43(s,1H),4.73(s,2H),3.91(s,4H),3.76(s,3H).

[1043] Synthesis of REJT-208

[1044] Step 1 Synthesis

[1045] 2-Iodo-4-(trifluoromethyl)aniline (1.0 g, 3.50 mmol) was dissolved in toluene (20 mL), and 3-hydroxypyrrolidone-2-one (390.0 mg, 38.5 mmol), potassium carbonate (961.7 mg, 6.97 mmol), cuprous iodide (130.0 mg, 0.70 mmol), and N,N-dimethylethylenediamine (60.0 mg, 0.70 mmol) were added. The mixture was stirred at 110 °C for 24 hours under nitrogen protection. After the reaction was complete, water was added for dilution, and the mixture was extracted with dichloromethane (50 mL x 2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a brown solid 7-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-ol (140 mg, yield 11.43%).

[1046] MS(ESI)m / z = 243.0[M+H] + .

[1047] Second step of synthesis

[1048] 7-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-ol (70.0 mg, 0.29 mmol) was dissolved in thionyl chloride (5 mL) and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain a yellow oily substance 3-chloro-7-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol (75 mg, yield 94.6%).

[1049] MS(ESI)m / z = 260.9[M+1] + .

[1050] Third step of synthesis

[1051] 3-Chloro-7-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazolium (70 mg, 0.27 mmol) was dissolved in acetonitrile (5 mL), and imidazolidine-2-thione (30.2 mg, 0.30 mmol) was added. The mixture was stirred at 70 °C for 16 hours. After cooling, the reaction solution was concentrated, and the resulting solid was purified by high performance liquid chromatography (mobile phase: acetonitrile / water (0.01% trifluoroacetic acid)). After lyophilization, a white solid 3-((4,5-dihydro-1H-imidazol-2-yl)thio)-7-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazolium trifluoroacetate (24.6 mg, 27.77% yield) was obtained.

[1052] MS(ESI)m / z=327.0[M+H]+.

[1053] 1 H NMR (DMSO-d6, 400MHz): δ10.58(s,2H),8.10(s,1H),7.86(d,J=8.4Hz,1H),7.57(d,J=8.4,1H),5.5 1(dd,J1=8.4,J2=4.8Hz,1H),4.39-4.33(m,2H),3.98(s,4H),3.39-3.35(m,1H),2.81-2.77(m,1H).

[1054] The compounds of the examples listed in Table 30 below were prepared using the same methods as in the examples described above, with the corresponding compounds.

[1055] Table 30

[1056] Synthesis of REJT-209

[1057] Step 1 Synthesis

[1058] 4-(tert-butyl)-2-iodoaniline (800.0 mg, 2.91 mmol) was dissolved in acetonitrile (10 mL), and 3-hydroxypyrrolidone-2-one (441.0 mg, 4.36 mmol), DMEDA (51.3 mg, 0.58 mmol), cuprous iodide (110.8 mg, 0.58 mmol), and potassium carbonate (803.8 mg, 5.81 mmol) were added. The mixture was refluxed at 90 °C and stirred for 48 hours under nitrogen protection. After the reaction was completed, the mixture was extracted with ethyl acetate (50 mL x 2), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a brown solid 1-(2-amino-5-(tert-butyl)phenyl)-3-hydroxypyrrolidone (410 mg, yield 51.11%).

[1059] MS(ESI)m / z = 249.1 [M+H] + .

[1060] Second step of synthesis

[1061] 1-(2-amino-5-(tert-butyl)phenyl)-3-hydroxypyrrole-2-one (410.0 mg, 1.65 mmol) was dissolved in acetic acid (20 mL), and the mixture was stirred at 90 °C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under vacuum, and the resulting oil was purified by silica gel column chromatography to obtain a brownish-gray oily substance, 7-(tert-butyl)-2,3-dihydro-1H-phenyl[a]pyrrole[1,2-a]imidazol-3-ol (280.0 mg, yield 62.6%).

[1062] MS(ESI)m / z = 231.4[M+H] + .

[1063] Third step of synthesis

[1064] 7-(tert-butyl)-2,3-dihydro-1H-phenyl[no]pyrrole[1,2-a]imidazol-3-ol (280.0 mg, 1.22 mmol) was dissolved in thionyl chloride (5 mL), and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was concentrated under vacuum, extracted with methanol, and purified by silica gel column chromatography to obtain an orange solid 7-(tert-butyl)-3-chloro-2,3-dihydro-1H-phenyl[no]pyrrole[1,2-a]imidazol (190.0 mg, 90% purity, yield 56.5%).

[1065] MS(ESI)m / z = 249.0 [M+H] + .

[1066] Fourth step synthesis

[1067] 7-(tert-butyl)-3-chloro-2,3-dihydro-1H-phenyl[d]pyrrole[1,2-a]imidazole (70.0 mg, 0.28 mmol) was dissolved in acetonitrile (5 mL), and imidazolidin-2-thione (43.1 mg, 0.42 mmol) was added. The mixture was stirred at 80 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated at room temperature and purified by high performance liquid chromatography (mobile phase: acetonitrile / water (0.02% trifluoroacetic acid)). After lyophilization, a white solid trifluoroacetate of 7-(tert-butyl)-3-((4,5-dihydro-1H-imidazol-2-yl)thio)-2,3-dihydro-1H-phenyl[d]pyrrole[1,2-a]imidazole (25.20 mg, 28.36% yield) was obtained.

[1068] MS(ESI)m / z = 315.1[M+H] + .

[1069] 1 H NMR(DMSO-d6,400MHz): δ10.60(brs,2H),7.60-7.56(m,2H),7.36(d,J=8.8Hz,1H),5.46(dd,J=8.4,4.4Hz ,1H),4.29(t,J=5.6Hz,2H),3.98(s,4H),3.34(td,J=14.4,8.0Hz,1H),2.76(d,J=5.6Hz,1H),1.35(s,9H).

[1070] The synthesis of REJT-210

[1071] Step 1 Synthesis

[1072] 2-Bromo-6-(trifluoromethyl)pyridine-3-amine (500.0 mg, 2.07 mmol) was dissolved in anhydrous toluene (10 mL), and 3-hydroxypyrrolidone-2-one (229.8 mg, 2.27 mmol), DMEDA (36.4 mg, 0.41 mmol), cuprous iodide (78.7 mg, 0.41 mmol), and potassium carbonate (571.1 mg, 4.13 mmol) were added. The mixture was refluxed and stirred for 16 hours under nitrogen protection. After the reaction was completed, the mixture was extracted with ethyl acetate, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to give a yellow solid 2-(trifluoromethyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine-6-ol (75 mg, yield 14.12%).

[1073] MS(ESI)m / z = 244.0[M+H] + .

[1074] Second step of synthesis

[1075] 2-(trifluoromethyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine-6-ol (75.0 mg, 0.31 mmol) was dissolved in thionyl chloride (5 mL) and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was concentrated under vacuum, extracted with methanol, and purified by silica gel column chromatography (eluent: dichloromethane / methanol = 5 / 1) to give a brown oily substance, 6-chloro-2-(trifluoromethyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine (65.0 mg, yield 75.8%).

[1076] Third step of synthesis

[1077] 6-Chloro-2-(trifluoromethyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine (35.0 mg, 0.13 mmol) was dissolved in acetonitrile (5 mL), and imidazoline-2-thione (16.3 mg, 0.20 mmol) was added. The mixture was stirred at 70 °C for 72 hours. After the reaction was completed, the reaction solution was concentrated at room temperature and purified by high performance liquid chromatography (mobile phase: acetonitrile / water (0.02% trifluoroacetic acid)). After lyophilization, a white solid 6-((4,5-dihydro-1H-imidazo-2-yl)thio)-2-(trifluoromethyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine trifluoroacetate (28.35 mg, 64.14% yield) was obtained.

[1078] MS(ESI)m / z = 328.0 [M+H] + .

[1079] 1 H NMR (DMSO-d6, 400MHz): δ10.55 (s, 2H), 8.35 (d, J = 8.4Hz, 1H), 7.82 (d, J = 8.4Hz, 1H), 5. 57-5.53(m,1H),4.39-4.34(m,2H),3.97(s,4H),3.44-3.35(m,1H),2.86-2.78(m,1H).

[1080] Synthesis of REJT-213

[1081] Step 1 Synthesis

[1082] 4-(trifluoromethyl)-2-iodoaniline (300.0 mg, 1.05 mmol) was dissolved in acetonitrile (10 mL), and 3-hydroxypiperidin-2-one (180.5 mg, 1.57 mmol), DMEDA (19.2 mg, 0.22 mmol), cuprous iodide (41.6 mg, 0.22 mmol), and potassium carbonate (301.4 mg, 2.18 mmol) were added. The mixture was refluxed at 90 °C and stirred for 48 hours under nitrogen protection. After the reaction was completed, the mixture was extracted with ethyl acetate, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give a brown solid 8-(trifluoromethyl)-1,2,3,4-tetrahydrophenyl[4,5]imidazol[1,2-a]pyridin-4-ol (85.0 mg, yield 26.98%).

[1083] MS(ESI)m / z = 257.0 [M+H] + .

[1084] Second step of synthesis

[1085] 8-(trifluoromethyl)-1,2,3,4-tetrahydrophenyl[4,5]imidazol[1,2-a]pyridine-4-ol (85.0 mg, 0.33 mmol) was dissolved in thionyl chloride (5 mL), and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was concentrated under vacuum, extracted with methanol, and purified by silica gel column chromatography to obtain an orange solid 4-chloro-8-(trifluoromethyl)-1,2,3,4-tetrahydrophenyl[4,5]imidazol[1,2-a]pyridine (30.0 mg, yield 27.98%).

[1086] MS(ESI)m / z = 275.0 [M+H] + .

[1087] Third step of synthesis

[1088] 4-Chloro-8-(trifluoromethyl)-1,2,3,4-tetrahydrophenyl[4,5]imidazol[1,2-a]pyridine (30.0 mg, 0.11 mmol) was dissolved in acetonitrile (5 mL), and imidazolidine-2-thione (16.7 mg, 0.16 mmol) was added. The mixture was stirred at 70 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated at room temperature and purified by high performance liquid chromatography (mobile phase: acetonitrile / water (0.02% trifluoroacetic acid)). After lyophilization, a pale yellow oily substance, 4-((4,5-dihydro-1H-imidazol-2-yl)thio)-8-(trifluoromethyl)-1,2,3,4-tetrahydrophenyl[4,5]imidazol[1,2-a]pyridine trifluoroacetate (10.95 mg, 28.02% yield) was obtained.

[1089] MS(ESI)m / z = 340.9[M+H] + .

[1090] 1 H NMR (DMSO-d6, 400MHz): δ10.60 (s, 2H), 8.07 (s, 1H), 7.87 (d, J = 8.4Hz, 1H), 7. 60(d,J=8.4Hz,1H),5.45(s,1H),4.29(s,2H),3.98(s,4H),2.23-2.18(m,4H).

[1091] Synthesis of REJT-214

[1092] Step 1 Synthesis

[1093] 2-Iodo-5-(trifluoromethyl)aniline (572.0 mg, 2.00 mmol) was dissolved in anhydrous toluene (10 mL), and 3-hydroxypyrrolidone-2-one (203.0 mg, 2.00 mmol), DMEDA (36.4 mg, 0.41 mmol), cuprous iodide (78.7 mg, 0.41 mmol), and potassium carbonate (571.1 mg, 4.13 mmol) were added. The mixture was refluxed and stirred for 16 hours under nitrogen protection. After the reaction was completed, the mixture was extracted with ethyl acetate (30 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a brown solid 6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-ol (80 mg, yield 14.80%).

[1094] Second step of synthesis

[1095] 6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-ol (70.0 mg, 0.29 mmol) was dissolved in thionyl chloride (5 mL), and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was concentrated under vacuum, extracted with methanol, and purified by silica gel column chromatography (eluent: dichloromethane / methanol = 5 / 1) to give a brown oily substance 3-chloro-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol (75.0 mg, yield 94.61%).

[1096] MS(ESI)m / z = 261.0[M+H] + .

[1097] Third step of synthesis

[1098] 3-Chloro-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazolium (75.0 mg, 0.29 mmol) was dissolved in acetonitrile (5 mL), and imidazolidine-2-thione (29.3 mg, 0.29 mmol) was added. The mixture was stirred at 70 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated at room temperature and purified by high performance liquid chromatography (mobile phase: acetonitrile / water (0.02% trifluoroacetic acid)). After lyophilization, a pale yellow oily substance, 3-((4,5-dihydro-1H-imidazol-2-yl)thio)-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazolium trifluoroacetate (75.0 mg, 75.96% yield), was obtained.

[1099] MS(ESI)m / z = 327.1 [M+H] + .

[1100] 1 H NMR (DMSO-d6, 400MHz): δ10.60 (s, 2H), 8.05 (s, 1H), 7.81 (d, J = 8.4Hz, 1H), 7.63 (d, J = 8.4Hz, 1H), 5. 51(dd,J1=8.4,J2=4.8Hz,1H),4.36-4.31(m,2H),3.98(s,4H),3.39-3.36(m,1H),2.87-2.73(m,1H).

[1101] The synthesis of REJT-217

[1102] Step 1 Synthesis

[1103] 4,5-Difluoro-2-iodoaniline (800.0 mg, 3.14 mmol) was dissolved in acetonitrile (10 mL), and 3-hydroxypyrrolidone-2-one (380.6 mg, 3.76 mmol), DMEDA (110.6 mg, 1.25 mmol), cuprous iodide (239.0 mg, 1.25 mmol), and potassium carbonate (867.2 mg, 6.27 mmol) were added. The mixture was refluxed at 90 °C and stirred for 48 hours under nitrogen protection. After the reaction was complete, the mixture was extracted with ethyl acetate (50 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give a brown solid 1-(2-amino-4,5-difluorophenyl)-3-hydroxypyrrolidone-2-one (370 mg, yield 41.35%).

[1104] MS(ESI)m / z = 229.0 [M+H] + .

[1105] Second step of synthesis

[1106] 1-(2-amino-4,5-difluorophenyl)-3-hydroxypyrrole-2-one (370.0 mg, 1.62 mmol) was dissolved in acetic acid (5 mL), and the mixture was stirred at 90 °C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under vacuum, and the resulting oil was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give a brownish-gray solid 6-difluoro-2,3-dihydro-1H-phenyl[a]pyrrole[1,2-a]imidazol-3-ol (180.0 mg, 90% purity, yield 47.5%).

[1107] MS(ESI)m / z = 211.0[M+H] + .

[1108] Third step of synthesis

[1109] 6,7-Difluoro-2,3-dihydro-1H-phenyl[no]pyrrole[1,2-a]imidazol-3-ol (180.0 mg, 0.86 mmol) was dissolved in thionyl chloride (5 mL), and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was concentrated under vacuum, extracted with methanol, and purified by silica gel column chromatography (eluent: dichloromethane / methanol = 15 / 1) to give a light brown solid 6,7-difluoro-3-chloro-2,3-dihydro-1H-phenyl[no]pyrrole[1,2-a]imidazol (140.0 mg, 85% purity, yield 60.8%).

[1110] MS(ESI)m / z = 229.0 [M+H] + .

[1111] Fourth step synthesis

[1112] 6,7-Difluoro-3-chloro-2,3-dihydro-1H-phenyl[d]pyrrole[1,2-a]imidazole (70.0 mg, 0.31 mmol) was dissolved in acetonitrile (5 mL), and imidazolidin-2-thione (46.9 mg, 0.42 mmol) was added. The mixture was stirred at 70 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated at room temperature and purified by high performance liquid chromatography (mobile phase: acetonitrile / water (0.02% trifluoroacetic acid)). After lyophilization, a pale yellow oily substance, 6,7-difluoro-3-((4,5-dihydro-1H-imidazol-2-yl)thio)-2,3-dihydro-1H-phenyl[d]pyrrole[1,2-a]imidazole trifluoroacetate (46.94 mg, 51.18% yield) was obtained.

[1113] MS(ESI)m / z = 295.0 [M+H] + .

[1114] 1 H NMR(DMSO-d6,400MHz): δ10.55(s,2H),7.83-7.74(m,2H),5.45(dd,J=8.4,4.8Hz,1 H),4.25-4.21(m,2H),3.97(s,4H),3.34(dt,J=14.4,7.2Hz,1H),2.77-2.73(m,1H).

[1115] Synthesis of REJT-219

[1116] Step 1 Synthesis

[1117] 4-Amino-3-iodobenzonitrile (488.0 mg, 2.00 mmol) was dissolved in anhydrous toluene (10 mL), and 3-hydroxypyrrolidone-2-one (222.4 mg, 2.20 mmol), DMEDA (17.6 mg, 0.20 mmol), cuprous iodide (38.1 mg, 0.20 mmol), and potassium carbonate (552.8 mg, 4.00 mmol) were added. The mixture was refluxed and stirred for 16 hours under nitrogen protection. After the reaction was completed, the mixture was extracted with ethyl acetate (30 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography (eluent: dichloromethane / methanol = 5 / 1) to give a yellow oily substance 3-hydroxy-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-nitrile (75.0 mg, yield 17.89%).

[1118] MS(ESI)m / z = 200.1[M+H] + .

[1119] Second step of synthesis

[1120] 3-Hydroxy-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-onitrile (60.0 mg, 0.30 mmol) was dissolved in thionyl chloride (5 mL) and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was concentrated under vacuum, extracted with methanol, and purified by silica gel column chromatography (eluent: dichloromethane / methanol = 5 / 1) to give a brown oily substance 3-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-onitrile (25.0 mg, yield 36.22%).

[1121] MS(ESI)m / z = 218.1[M+H] + .

[1122] Third step of synthesis

[1123] 3-Chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-onitrile (25.0 mg, 0.11 mmol) was dissolved in acetonitrile (5 mL), and imidazolidine-2-thione (12.9 mg, 0.13 mmol) was added. The mixture was stirred at 70 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated at room temperature and purified by high performance liquid chromatography (mobile phase: acetonitrile / water (0.02% trifluoroacetic acid)). After lyophilization, a pale yellow oily substance, 3-((4,5-dihydro-1H-imidazol-2-yl)thio)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-onitrile trifluoroacetate (9.53 mg, 28.98% yield) was obtained.

[1124] MS(ESI)m / z = 284.0 [M+H] + .

[1125] 1 H NMR (DMSO-d6, 400MHz): δ10.56 (s, 2H), 8.25 (s, 1H), 7.84 (d, J = 8.4Hz, 1H), 7.64 (d, J = 8.4Hz, 1H), 5. 51(dd,J1=8.4,J2=4.8Hz,1H),4.34-4.28(m,2H),3.97(s,4H),3.89-3.35(m,1H),2.80-2.77(m,1H).

[1126] The synthesis of REJT-220

[1127] Step 1 Synthesis

[1128] 4-Fluoro-2-iodoaniline (700.0 mg, 2.95 mmol) was dissolved in acetonitrile (20 mL), and 3-hydroxypyrrolidone-2-one (447.9 mg, 4.43 mmol), DMEDA (104.1 mg, 1.18 mmol), cuprous iodide (225.0 mg, 1.18 mmol), and potassium carbonate (815.1 mg, 5.90 mmol) were added. The mixture was refluxed at 90 °C for 16 hours under nitrogen protection. After the reaction was complete, the mixture was extracted with ethyl acetate (50 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give a brown solid 1-(2-amino-5-fluorophenyl)-3-hydroxypyrrolidone-2-one (330 mg, yield 45.2%).

[1129] MS(ESI)m / z = 211.0[M+H] + .

[1130] Second step of synthesis

[1131] 1-(2-amino-5-fluorophenyl)-3-hydroxypyrrole-2-one (330.0 mg, 1.57 mmol) was dissolved in acetic acid (30 mL), and the mixture was stirred at 90 °C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under vacuum, and the resulting oil was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 15 / 1) to give a brownish-gray solid 7-fluoro-2,3-dihydro-1H-phenyl[a]pyrrole[1,2-a]imidazol-3-ol (100.0 mg, yield 32.8%).

[1132] MS(ESI)m / z = 193.1 [M+H] + .

[1133] Third step of synthesis

[1134] 7-Fluoro-2,3-dihydro-1H-phenyl[no]pyrrole[1,2-a]imidazol-3-ol (180.0 mg, 0.94 mmol) was dissolved in thionyl chloride (5 mL), and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was concentrated under vacuum, extracted with methanol, and purified by silica gel column chromatography (eluent: dichloromethane / methanol = 15 / 1) to give a light brown solid 7-fluoro-3-chloro-2,3-dihydro-1H-phenyl[no]pyrrole[1,2-a]imidazol (110.0 mg, yield 33.5%).

[1135] MS(ESI)m / z = 211.0[M+H] + .

[1136] Fourth step synthesis

[1137] 7-Fluoro-3-chloro-2,3-dihydro-1H-phenyl[d]pyrrole[1,2-a]imidazole (80.0 mg, 0.38 mmol) was dissolved in acetonitrile (5 mL), and imidazolidin-2-thione (58.2 mg, 0.57 mmol) was added. The mixture was stirred at 70 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated at room temperature and purified by high performance liquid chromatography (mobile phase: acetonitrile / water (0.02% trifluoroacetic acid)). After lyophilization, a colorless oily trifluoroacetate salt of 7-fluoro-3-((4,5-dihydro-1H-imidazol-2-yl)thio)-2,3-dihydro-1H-phenyl[d]pyrrole[1,2-a]imidazole (72.41 mg, 68.38% yield) was obtained.

[1138] MS(ESI)m / z = 277.0 [M+H] + .

[1139] 1 H NMR (DMSO-d6, 400MHz): δ10.59(s,2H),7.67(dd,J=8.8,4.8Hz,1H),7.51(dd,J=9.2,2.4Hz,1H),7.12(dd,J=10.0,2.4 Hz,1H),5.45(dd,J=8.4,4.8Hz,1H),4.29-4.21(m,2H),3.97(s,4H),3.34(td,J=14.4,8.4Hz,1H),2.77-2.72(m,1H).

[1140] Synthesis of REJT-216

[1141] Step 1 Synthesis

[1142] 3-Iodo-5-(trifluoromethyl)pyridine-2-amine (1.0 g, 3.46 mmol) was dissolved in N-methylpyrrolidone (5 mL), and 3-hydroxypyrrolidone-2-one (384.8 mg, 3.81 mmol), potassium carbonate (956.4 mg, 6.92 mmol), cuprous iodide (65.9 mg, 0.35 mmol), and ferric acetone acetate (122.1 mg, 0.35 mmol) were added. The mixture was stirred at 150 °C for 36 hours under nitrogen protection. After the reaction was completed, water was added for dilution, and the mixture was extracted with ethyl acetate (50 mL * 2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain a yellow solid 3-(trifluoromethyl)-7,8-dihydro-6H-pyrrolo[1',2':1,2]imidazo[4,5-b]pyridine-8-ol (275 mg, yield 30.92%).

[1143] MS(ESI)m / z = 244.3[M+H] + .

[1144] Second step of synthesis

[1145] 3-(trifluoromethyl)-7,8-dihydro-6H-pyrrolo[1',2':1,2]imidazo[4,5-b]pyridine-8-ol (60.0 mg, 0.25 mmol) was dissolved in thionyl chloride (5 mL) and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain a brown oily substance, 8-chloro-3-(trifluoromethyl)-7,8-dihydro-6H-pyrrolo[1',2':1,2]imidazo[4,5-b]pyridine (45 mg, yield 66.26%).

[1146] MS(ESI)m / z = 262.0[M+1] + .

[1147] Third step of synthesis

[1148] 8-Chloro-3-(trifluoromethyl)-7,8-dihydro-6H-pyrrolo[1',2':1,2]imidazo[4,5-b]pyridine (45 mg, 0.17 mmol) was dissolved in acetonitrile (5 mL), and imidazoline-2-thione (17.5 mg, 0.17 mmol) was added. The mixture was stirred at 70 °C for 16 hours. After cooling, the reaction solution was concentrated, and the resulting solid was purified by high performance liquid chromatography. After lyophilization, a colorless oily substance, 8-((4,5-dihydro-1H-imidazo-2-yl)thio)-3-(trifluoromethyl)-7,8-dihydro-6H-pyrrolo[1',2':1,2]imidazo[4,5-b]pyridine trifluoroacetate (10.31 mg, yield: 17.86%), was obtained.

[1149] MS(ESI)m / z = 328.0 [M+H] + .

[1150] 1 H NMR(DMSO-d6,400MHz): δ10.51(brs,2H),8.79(s,1H),8.62(s,1H),5.56(dd,J 8.4,4.8Hz,1H),4.39-4.36(m,2H),3.98(s,4H),3.36-3.33(m,1H),2.78-2.76(m,1H).

[1151] The compounds of the examples listed in Table 30 below were prepared using the same methods as in the examples described above, with the corresponding compounds.

[1152] Table 31

[1153] Example 2: Anti-apoptotic experiment of the compound on Jurkat cells

[1154] The main purpose of this embodiment is to investigate the inhibitory effect of the REJT series compounds in Example 1 on cell apoptosis.

[1155] Methods: Jurkat cells were plated and stabilized for 1 day. 50 nM Velcade was added to each group to induce apoptosis. At the same time, a compound with a concentration of 10 μM was added to each group, and the solvent of the compound was added to the model group. After 24 h of treatment, Cell Titer-Glo Luminescent (manufacturer: Promega) cell viability assay reagent was added, mixed, and incubated for 10 min. The assay was performed using a microplate reader with full wavelength scanning.

[1156] Results: As shown in Figures 1A, 1B, and 1C, the cell viability of each group treated with the REJT series compounds was significantly increased compared to the model group, indicating that the REJT series compounds of this application have a significant inhibitory effect on apoptosis. Furthermore, the results also showed that when ring A in Formula I and Formulas I-1 to I-3 contains a heteroatom, especially when ring A is associated with a heteroatom... When at least one heteroatom, such as N, S, and / or O, is present in the adjacent position of the connected ring atom, the efficacy of the resulting compound is significantly improved, indicating that ring A contains heteroatoms, especially those on ring A adjacent to the ring atom. The presence of at least one heteroatom (e.g., N, S, and / or O) in the adjacent position of the linked ring atoms is advantageous for improving the efficacy of the compound.

[1157] Example 3: Anti-inflammatory experiment of compound LPS stimulating BV2

[1158] The main purpose of this embodiment is to investigate the anti-inflammatory effect of the compound in Example 1 on BV2 cells stimulated by LPS.

[1159] Methods: BV2 cells were plated and, after reaching near confluence, REJT series compounds (5 μM) were added. The model group was incubated with the corresponding compound solvent for 1 h, followed by LPS (100 ng / mL). After 6 h of incubation, the cell supernatant was collected, and TNF-α expression was detected by ELISA. The kits used were purchased from Dakota Biotechnology Co., Ltd., and the ELISA assay was performed according to the manufacturer's instructions.

[1160] Results: As shown in Figures 2A, 2B and 2C, the expression levels of TNF-α in each group with added REJT series compounds were significantly lower than those in the model group, indicating that the REJT series compounds of this application have anti-inflammatory effects.

[1161] Example 4: Compound activates autophagy in HCE-T cells

[1162] The main purpose of this embodiment is to examine the activating effect of the compound in Example 1 on autophagy.

[1163] Methods: HCE-T cells were plated and stabilized for 1 day. Then, 3 μL of mRFP-GFP-LC3 adenovirus was added. After 2 hours, the medium was replaced with fresh medium. After 24 hours of transfection, the fluorescence intensity was observed under a microscope. After confirming successful transfection, 10 μM of REJT-1 was added. For the blank control group, the corresponding compound solvent was added. After 24 hours of incubation, the cells were fixed with 4% PFA and then stained with DAPI. After fixation, the cells were photographed using a laser confocal microscope.

[1164] Results: As shown in Figure 3, the REJT-1 group produced more autophagic vesicles than the blank group, indicating that the REJT series compounds of this application have a good efficacy in activating autophagy.

[1165] Example 5: The role of the compound in a dry eye model

[1166] The main purpose of this embodiment is to examine the efficacy of the compound in Example 1 in a dry eye model.

[1167] Methods: 0.2% BAC (benzalkonium chloride) was used to establish the model in male C57BL / 6 mice aged 6-8 weeks. The mice were administered the drug at the same time as the model was established. No model was established in the blank group. The model group was given the corresponding compound solvent as eye drops once a day at the same time as the model was established. The REJT-1 group was given 0.05 mg / mL REJT-1 as eye drops once a day. The tear production of mice was measured 8 days after administration.

[1168] Results: As shown in Figure 4, the tear production in the REJT-1 group was significantly increased compared with that in the model group, indicating that the REJT series compounds of this application can significantly alleviate dry eye syndrome in mice.

[1169] Example 6: The role of the compound in an osteoarthritis model

[1170] The main purpose of this embodiment is to examine the efficacy of the compound in Example 1 in an osteoarthritis model.

[1171] Methods: Model: C57BL / 6 mice, male, 12 weeks old; Modeling method: surgical DMM; Observation for 8 weeks after modeling; Drug administration frequency: drug administration started 1 week after surgery and continued for 7 weeks; Administration method: intra-articular injection, REJT-1 1 mg / kg; The model group and the blank group were given the compound solvent. After the drug administration was completed, the mouse joints were taken for SO staining and the OARSI score was used to assess the disease status of the mice.

[1172] Results: As shown in Figure 5, the OARSI score of the REJT-1 group was significantly lower than that of the model group, indicating that the REJT series compounds of this application can significantly alleviate arthritis-like symptoms in mice.

[1173] Example 7: The role of the compound in an ischemic stroke model

[1174] The main purpose of this embodiment is to examine the efficacy of the compound in Example 1 in a stroke model.

[1175] Methods: This study used a rat model of middle cerebral artery occlusion (MCA) established by the suture occlusion method. Male SD rats, 7-8 weeks old, were selected. After anesthetizing the rats, the common carotid artery (CCA), external carotid artery (ECA), and internal carotid artery (ICA) were isolated. Sutures were placed at the distal and proximal ends of the CCA and the ECA for later use. The ICA was temporarily closed with a carotid clamp, and then the CCA and ECA were ligated proximal to the heart. A suture occluded the ICA for 1.5 hours, after which it was removed. Drug administration was then performed via tail vein injection of REJT-1 and REJT-6 at a dose of 0.5 mg / kg. Brain tissue was collected 24 hours later for TTC staining to determine the infarct area and assess the disease progression. The efficacy of the drugs was evaluated by comparing the treated group with the model group and the sham-operated group.

[1176] Results: As shown in Figure 6, all compounds at a dose of 0.5 mg / kg reduced the infarct area in the rat stroke model, indicating that the REJT series compounds of this application can significantly alleviate the symptoms of ischemic stroke in rats.

[1177] Example 8: The role of the compound in the Parkinson's model

[1178] The main purpose of this embodiment is to examine the efficacy of the compound in Example 1 for the Parkinson's disease model.

[1179] Methods: A mouse Parkinson's disease model was induced using MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). Male C57BL / 6 mice, 7-8 weeks old, were intraperitoneally injected daily with 20 mg / kg of MPTP. Simultaneously, REJT-1 and REJT-6 were administered intraperitoneally at a dose of 0.5 mg / kg for 7 consecutive days. The expression level of TH was detected by Western blotting in the striatum of the mice to evaluate the efficacy of the drug.

[1180] Results: As shown in Figure 7, all compounds at 0.5 mg / kg were able to effectively protect the survival of neurons in the mouse Parkinson's disease model, indicating that the REJT series compounds of this application can significantly alleviate the symptoms in the mouse Parkinson's disease model.

[1181] Example 9: The role of the compound in an enteritis model

[1182] The main purpose of this embodiment is to examine the efficacy of the compound in Example 1 in an enteritis model.

[1183] Methods: A DSS-induced mouse inflammation model was used. Male C57BL / 6 mice, aged 6-8 weeks, were given 2.5% DSS solution via drinking water and fed for 7 days. They were weighed daily and simultaneously administered 3 mg / kg of REJT-1 daily. On day 8, the mice were sacrificed, and colon tissue was removed for length measurement to assess the disease incidence. The efficacy of the drug was evaluated by comparing the drug-treated group with the model group and the blank group.

[1184] Results: As shown in Figure 8, REJT-1 can significantly protect against colonic shortening induced by the modeling agent, indicating that the REJT series compounds can significantly alleviate the pathogenesis of mouse-related inflammatory bowel disease models.

[1185] Example 10: The role of the compound in an Alzheimer's disease model

[1186] The main purpose of this embodiment is to examine the efficacy of the compound in Example 1 in an Alzheimer's disease model.

[1187] Methods: Male B6.CgTg(5×FAD) transgenic mice were used to spontaneously establish an Alzheimer's disease model. Starting from 2 months of age, mice were intraperitoneally injected with compound REJT-1 at a dose of 0.5 mg / kg once daily for 8 weeks. The efficacy was evaluated using the Novel Object Recognition Index as the endpoint of drug administration.

[1188] Results: As shown in Figure 9, REJT-1 can significantly increase the cognitive index of new object recognition, indicating that the REJT series compounds of this application can significantly alleviate the symptoms in the 5×FAD mouse Alzheimer's disease model.

[1189] Example 11 Evaluation of the brain-penetrating properties of the compound

[1190] The main purpose of this embodiment is to examine the properties of the compound in Example 1 to cross the blood-brain barrier.

[1191] Methods: To test the cross-linking ability of relevant compounds across the blood-brain barrier, male SD rats aged 6-8 weeks (n=3 per group) were selected. The relevant compounds were administered via tail vein injection at a dose of 1 mg / kg. Blood samples were collected at 10 min, 30 min, and 2 h post-administration. Rats were then sacrificed, and residual blood in the brain vessels was washed away by perfusion. Brain tissue and plasma were collected, and the concentration of the compounds was determined using LC-MS-MS (limit of detection: 1 ng / ml).

[1192] Results: As shown in Table 30, the contents of Apt-1 and ICCB-19 in the brain were both below the detection limit, indicating that the two compounds were almost non-transparent to the brain. However, the brain-penetrating properties of the compounds involved in this patent are far superior to those of Apt-1 and ICCB-19, indicating that the improved brain-penetrating properties of the compounds in this application are an important breakthrough feature of the compounds in this application.

[1193] Table 32. Brain penetration of compounds

[1194] Note: BQL: Concentration below the detection limit, not detected.

[1195] The technical solutions of the present invention are not limited to the specific embodiments described above. Any technical modifications made in accordance with the technical solutions of the present invention fall within the protection scope of the present invention.

Claims

1. A nitrogen-containing compound, which is a compound of Formula I, or a solvate, tautomer, enantiomer, diastereomer, isotopically labeled compound (preferably deuterated), or pharmaceutically acceptable salt of a compound of Formula I: in, (1) R1 and R2 are each independently selected from hydrogen, deuterium, C1-C10 alkyl and C6-C20 aryl, or R1 and R2 are connected together with the nitrogen atom attached to them to form an unsaturated heterocycle, wherein the C1-C10 alkyl, C6-C20 aryl and the unsaturated heterocycle may optionally be substituted by one or more substituents selected from deuterium, hydroxyl, halogen, nitro, cyano, -NH2, NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, C1-C6 alkyl, C3-C10 cycloalkyl, C1-C6 alkoxy, -C(=O)OR, -C(=O)R, C6-C20 aryl, wherein R is selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl; Z1 is selected from O, S, and NR3; R3 is selected from hydrogen, deuterium, C1-C10 alkyl, C3-C10 cycloalkyl, and C6-C20 aryl, wherein the C1-C10 alkyl, C3-C10 cycloalkyl, and C6-C20 aryl may optionally be substituted by one or more substituents selected from deuterium, hydroxyl, halogen, nitro, cyano, -NH2, NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, C1-C6 alkyl, C3-C10 cycloalkyl, C1-C6 alkoxy, -C(=O)OR, -C(=O)R, and C6-C20 aryl, wherein R is selected from hydrogen, deuterium, C1-C6 alkyl, and C1-C6 haloalkyl; Z2 is selected from S, O, S(=O), S(=O)2, NR a and C1-C10 alkylene, R a The group is selected from hydrogen, deuterium, C1-C10 alkyl, C3-C10 cycloalkyl and C6-C20 aryl, wherein the C1-C10 alkyl, C3-C10 cycloalkyl and C6-C20 aryl may optionally be substituted by one or more substituents selected from deuterium, hydroxyl, halogen, nitro, cyano, -NH2, NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, C1-C6 alkyl, C3-C10 cycloalkyl, C1-C6 alkoxy, -C(=O)OR, -C(=O)R, C6-C20 aryl, wherein R is selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl; R4 and R5 are each independently selected from hydrogen, deuterium, C1-C10 alkyl, C3-C10 cycloalkyl, and C6-C20 aryl, or R4 and R5 are connected together with the carbon atoms they are attached to to form a saturated or unsaturated carbocyclic or heterocyclic ring, or R4 is selected from hydrogen, deuterium, C1-C10 alkyl, C3-C10 cycloalkyl, and C6-C20 aryl, and R5 is connected to a ring atom on ring A to form a saturated or unsaturated carbocyclic or heterocyclic ring fused with ring A, wherein the C1-C10 alkyl, C3-C10 cycloalkyl, and C6-C20 aryl are... The alkyl, C6-C20 aryl, and said saturated or unsaturated carbocyclic or heterocyclic groups may optionally be substituted by one or more substituents selected from deuterium, hydroxyl, halogen, nitro, cyano, -NH2, NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, C1-C6 alkyl, C3-C10 cycloalkyl, C1-C6 alkoxy, -C(=O)OR, -C(=O)R, C6-C20 aryl, wherein R is selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl; Ring A is selected from 4-7 membered monocyclic heteroaromatic rings, C7-C20 fused-ring heteroaromatic rings, C6-C20 aromatic rings and C1-C12 saturated or unsaturated heterocycles; n represents the number of substituents R6 on ring A, and n is 0, 1, 2, 3, 4, 5 or 6; R6 is independently selected from deuterium, hydroxyl, halogen, nitro, cyano, -NH2, NH-C1-C10 alkyl, -N(C1-C10 alkyl)2, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C3-C10 cycloalkyl, C6-C20 aryl, C3-C20 heteroaryl, -C(=O)OR, -C(=O)R, wherein the C1-C10 alkyl, C1-C10 alkoxy, C3-C... The 10-cycloalkyl, C6-C20 aryl, and C3-C20 heteroaryl groups may optionally be substituted with one or more substituents selected from deuterium, halogen, nitro, cyano, -NH2, NH-C1-C5 alkyl, -N(C1-C5 alkyl)2, C1-C5 alkyl, C1-C5 alkoxy, C1-C10 haloalkyl, -C(=O)OR, and -C(=O)R, wherein R is selected from hydrogen, deuterium, C1-C6 alkyl, and C1-C6 haloalkyl. Alternatively, (2) R1 and R2 are each independently selected from hydrogen, deuterium, C1-C10 alkyl and C6-C20 aryl, or R1 and R2 are connected together with the nitrogen atom attached to them to form an unsaturated heterocycle, wherein the C1-C10 alkyl, C6-C20 aryl and the unsaturated heterocycle may optionally be substituted by one or more substituents selected from deuterium, hydroxyl, halogen, nitro, cyano, -NH2, NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, C1-C6 alkyl, C3-C10 cycloalkyl, C1-C6 alkoxy, -C(=O)OR, -C(=O)R, C6-C20 aryl, wherein R is selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl; Z1 is selected from O, S, and NR3; R3 is selected from hydrogen, deuterium, C1-C10 alkyl, C3-C10 cycloalkyl, and C6-C20 aryl, wherein the C1-C10 alkyl, C3-C10 cycloalkyl, and C6-C20 aryl may optionally be substituted by one or more substituents selected from deuterium, hydroxyl, halogen, nitro, cyano, -NH2, NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, C1-C6 alkyl, C3-C10 cycloalkyl, C1-C6 alkoxy, -C(=O)OR, -C(=O)R, and C6-C20 aryl, wherein R is selected from hydrogen, deuterium, C1-C6 alkyl, and C1-C6 haloalkyl; or, when Z1 is NR3, R1 and R3 together with the N atom to which they are attached form a 4-8 membered heterocycle; Z2 is selected from S, O, S(=O), S(=O)2, NR a and C1-C10 alkylene, R a The group is selected from hydrogen, deuterium, C1-C10 alkyl, C3-C10 cycloalkyl and C6-C20 aryl, wherein the C1-C10 alkyl, C3-C10 cycloalkyl and C6-C20 aryl may optionally be substituted by one or more substituents selected from deuterium, hydroxyl, halogen, nitro, cyano, -NH2, NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, C1-C6 alkyl, C3-C10 cycloalkyl, C1-C6 alkoxy, -C(=O)OR, -C(=O)R, C6-C20 aryl, wherein R is selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl; R4 and R5 are each independently selected from hydrogen, deuterium, C1-C10 alkyl, C3-C10 cycloalkyl, and C6-C20 aryl, or R4 and R5 are connected together with the carbon atoms they are attached to to form a saturated or unsaturated carbocyclic or heterocyclic ring, or R4 is selected from hydrogen, deuterium, C1-C10 alkyl, C3-C10 cycloalkyl, and C6-C20 aryl, and R5 is connected to a ring atom on ring A to form a saturated or unsaturated carbocyclic or heterocyclic ring fused with ring A, wherein the C1-C10 alkyl, C3-C10 cycloalkyl, and C6-C20 aryl are... The alkyl, C6-C20 aryl, and said saturated or unsaturated carbocyclic or heterocyclic groups may optionally be substituted by one or more substituents selected from deuterium, hydroxyl, halogen, nitro, cyano, -NH2, NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, C1-C6 alkyl, C3-C10 cycloalkyl, C1-C6 alkoxy, -C(=O)OR, -C(=O)R, C6-C20 aryl, wherein R is selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl; Ring A is selected from 4-7 membered monocyclic heteroaromatic rings, C7-C20 fused-ring heteroaromatic rings, C6-C20 aromatic rings and C1-C12 saturated or unsaturated heterocycles; n represents the number of substituents R6 on ring A, and n is 0, 1, 2, 3, 4, 5 or 6; R6 is independently selected from deuterium, hydroxyl, halogen, nitro, cyano, -NH2, NH-C1-C10 alkyl, -N(C1-C10 alkyl)2, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C3-C10 cycloalkyl, C6-C20 aryl, C3-C20 heteroaryl, -C(=O)OR, -C(=O)R, wherein the C1-C10 alkyl, C1-C10 alkoxy, C3-C... The 10-cycloalkyl, C6-C20 aryl, and C3-C20 heteroaryl groups may optionally be substituted with one or more substituents selected from deuterium, halogen, nitro, cyano, -NH2, NH-C1-C5 alkyl, -N(C1-C5 alkyl)2, C1-C5 alkyl, C1-C5 alkoxy, C1-C10 haloalkyl, -C(=O)OR, and -C(=O)R, wherein R is selected from hydrogen, deuterium, C1-C6 alkyl, and C1-C6 haloalkyl. Preferably, R6 is independently selected from deuterium, halogen, nitro, cyano, amino, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C3-C10 cycloalkyl, C3-C10 cycloalkyl substituted with one or more C1-C10 haloalkyl, C6-C20 aryl, C6-C20 aryl substituted with one or more C1-C10 haloalkyl, C3-C20 heteroaryl, and C3-C20 heteroaryl substituted with one or more C1-C10 haloalkyl. Preferably, when ring A is a C6-C20 aromatic ring, R6 is independently selected from C3-C10 cycloalkyl, C3-C10 cycloalkyl substituted with one or more C1-C10 haloalkyl, C6-C20 aryl, C6-C20 aryl substituted with one or more C1-C10 haloalkyl, C3-C20 heteroaryl, and C3-C20 heteroaryl substituted with one or more C1-C10 haloalkyl.

2. The nitrogen-containing compound according to claim 1, characterized in that, R1 is selected from hydrogen, deuterium, and C1-C6 alkyl groups, preferably from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl, more preferably from hydrogen, deuterium, methyl, and ethyl; and / or, R2 is selected from hydrogen, deuterium, and C1-C6 alkyl groups, preferably from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl, more preferably from hydrogen, deuterium, methyl, and ethyl; and / or, R3 is selected from hydrogen, deuterium, C1-C6 alkyl and C3-C8 cycloalkyl, preferably from hydrogen, deuterium, C1-C4 alkyl and C3-C6 cycloalkyl; more preferably from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, more preferably from hydrogen, deuterium, methyl and cyclopropyl; Alternatively, R1 and R2, together with the nitrogen atom they are attached to, can form a 5-7 member unsaturated heterocycle.

3. The nitrogen-containing compound according to claim 1 or 2, characterized in that, The compound shown in Formula I has the structure shown in Formula II: Among them, R1, R2, R3, R4, R5, R6, Z2, ring A and n are defined as in formula I; or, R1 and R3 together with the N atoms they are attached to form 4-8 membered heterocycles; Preferably, the compound shown in Formula I has the structure shown in Formula III: Where m is 1, 2 or 3; Z2, R3, R4, R5, R6, ring A and n are defined as in equation I.

4. The nitrogen-containing compound according to any one of claims 1-3, characterized in that, The compound shown in Formula I has the structure shown in Formula I-1, Formula I-2, or Formula I-3: Where m is 1, 2 or 3; Z2, R4, R5, R6, ring A and n are defined as in equation I; Preferably, Z2 is O or S; More preferably, Z2 is S.

5. The nitrogen-containing compound according to any one of claims 1-4, characterized in that, The compound shown in Formula I has the structure shown in Formula IV: The definitions of R3, R4, R5, R6, ring A, and n are the same as those in equation I.

6. The nitrogen-containing compound according to any one of claims 1-5, characterized in that, R4 is selected from hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl substituted with C3-C8 cycloalkyl, C1-C6 alkyl substituted with C6-C12 aryl, and preferably from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, phenyl, and benzyl; more preferably from hydrogen, deuterium, methyl, ethyl, and benzyl; and / or, R5 is selected from hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl substituted with C3-C8 cycloalkyl, C1-C6 alkyl substituted with C6-C12 aryl, and C6-C12 aryl, preferably selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, phenyl, and benzyl, and more preferably selected from hydrogen, deuterium, methyl, and ethyl; Alternatively, R4 and R5, together with the carbon atoms they are attached to, form a 3-7 member saturated or unsaturated carbon ring or heterocycle; preferably, R4 and R5, together with the carbon atoms they are attached to, form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group. Alternatively, R4 is selected from hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl substituted with C3-C8 cycloalkyl, C1-C6 alkyl substituted with C6-C12 aryl, and C6-C12 aryl, preferably selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, phenyl, and benzyl. More preferably, R5 is selected from hydrogen, deuterium, methyl, ethyl, and benzyl, and is connected to a ring atom on ring A to form a 5-7 member saturated or unsaturated carbon ring or heterocycle fused with ring A; preferably, R5 is connected to a ring atom on ring A to form a 5- or 6 member nitrogen-containing heterocycle fused with ring A; more preferably, R5 is connected to a ring atom on ring A to form a pyrrole ring, dihydropyrrole ring, tetrahydropyrrole ring, pyrimidine ring, or piperidine ring fused with ring A.

7. The nitrogen-containing compound according to any one of claims 1-6, characterized in that, Ring A is selected from 5-6 membered monocyclic heteroaromatic rings, C7-C12 fused heteroaromatic rings, C6-C12 aromatic rings and C6-C12 saturated or unsaturated heterocycles; Preferably, ring A is selected from the group consisting of the following structures: Among them, X1, X2, X3, X4, X5, and X6 are each independently selected from N and CH, and Y is independently selected from NH, O, S, and CH2; t1 and t2 are each independently 0, 1, 2, 3, 4, 5, or 6; *— indicates ring A and The location of the connection; Preferably, when X1 is CH, X2 is not CH and Y is not CH2; Preferably, any one or two of X3, X4, X5 and X6 are N, or X3, X4, X5 and X6 are all CH.

8. The nitrogen-containing compound according to any one of claims 1-7, characterized in that, Ring A is selected from the group consisting of the following structures: Where X1 is independently selected from N and CH, and Y is independently selected from NH, O, and S; *- indicates ring A and The location of the connection; Preferably, ring A is selected from the group consisting of the following structures: More preferably, ring A is selected from the group consisting of the following structures:

9. The nitrogen-containing compound according to any one of claims 1-8, characterized in that, R6 is independently selected from deuterium, halogen, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl substituted with one or more C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted with one or more C1-C6 haloalkyl, C6-C12 aryl, C6-C12 aryl substituted with one or more C1-C6 haloalkyl, C3-C12 heteroaryl, and C3-C12 heteroaryl substituted with one or more C1-C6 haloalkyl. Preferably, R6 is independently selected from deuterium, fluorine, chlorine, nitro, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C3-C6 cycloalkyl, C1-C4 alkyl substituted with one or more C3-C6 cycloalkyl, phenyl, phenyl substituted with one or more C1-C4 haloalkyl, 5-6 heteroaryl, 5-6 heteroaryl substituted with one or more C1-C4 haloalkyl; Preferably, R6 is independently selected from deuterium, fluorine, chlorine, nitro, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, phenyl, trifluoromethyl-substituted phenyl, pyridyl and trifluoromethyl-substituted pyridyl. Preferably, R6 is independently selected from deuterium, fluorine, chlorine, nitro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, cyclopropyl, cyclopropylmethyl, phenyl, o-trifluoromethylphenyl, p-trifluoromethylphenyl and m-trifluoromethylphenyl; Preferably, n is 0, 1, 2 or 3.

10. The nitrogen-containing compound according to any one of claims 1-9, characterized in that, Selected from the group consisting of the following groups: Preferably, Selected from the group consisting of the following structures:

11. The nitrogen-containing compound according to any one of claims 1-10, characterized in that, The compound described in Formula I is selected from the group consisting of the following compounds:

12. A pharmaceutical composition comprising any one of the nitrogen-containing compounds according to claims 1-11 and one or more pharmaceutically acceptable excipients.

13. The pharmaceutical composition according to claim 12, characterized in that, The excipients include one or more of the following: diluents, fillers, binders, wetting agents, absorption promoters, surfactants, lubricants, and stabilizers.

14. The use of the nitrogen-containing compound of any one of claims 1-11 or the pharmaceutical composition of any one of claims 12-13 in the preparation of a medicament for the prevention or treatment of inflammation-related diseases and / or cell necrosis, apoptosis, and autophagy-related diseases.

15. The application according to claim 14, characterized in that, The central nervous system conditions or diseases with inflammation-related diseases and / or cell necrosis, apoptosis, or autophagy-related diseases as the main pathogenic mechanisms, such as stroke, Parkinson's disease, Alzheimer's disease, etc., or peripheral system conditions or diseases, such as dry eye syndrome, osteoarthritis, inflammatory bowel diseases such as ulcerative colitis, Crohn's disease, etc.

16. A method for preventing or treating acute or chronic central or peripheral system diseases related to inflammation and / or necroptosis, autophagy, comprising administering to a subject in need a nitrogen-containing compound as claimed in any one of claims 1-11 or a pharmaceutical composition as claimed in any one of claims 12-13.

17. A method for modulating inflammation, apoptosis, and autophagy in cells or a subject, the method comprising contacting cells with a nitrogen-containing compound according to any one of claims 1-11 or a pharmaceutical composition according to any one of claims 12-13; or administering to a subject a nitrogen-containing compound according to any one of claims 1-11 or a pharmaceutical composition according to any one of claims 12-13.

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