SEH inhibitor compound, pharmaceutical composition as well as preparation method and application of sEH inhibitor compound

Abstract

The compound as shown in the formula (I), the tautomer, the stereoisomer, the hydrate, the solvate, the pharmaceutically acceptable salt or the prodrug thereof have an excellent sEH inhibition effect, and can be used for preventing and / or treating sEH inhibition related diseases, such as inflammation.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and particularly relates to a class of sEH inhibitor compounds, pharmaceutical compositions and preparation methods and applications thereof. BACKGROUND

[0002] Inflammation is the first alarm signal of the human body in response to the invasion of microorganisms and pathogens, and long-term, chronic inflammation can lead to the occurrence of various diseases, such as cardiovascular disease, cancer, Alzheimer's disease, senile dementia, asthma, rheumatoid arthritis, etc. Arachidonic acid (AA) is a polyunsaturated fatty acid, and existing studies have shown that arachidonic acid pathway produces active mediators, which regulate a series of different inflammatory processes. Arachidonic acid can be metabolized through the cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (CYP) pathways, among which the COX and LOX pathways are mainly responsible for the production of pro-inflammatory mediators such as prostaglandins and leukotrienes. In clinical practice, COX inhibitors as non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat inflammatory diseases. This class of representative drugs includes celecoxib, rofecoxib and etoricoxib, etc. Celecoxib is the first selective COX-2 inhibitor approved by FDA, which is known to have gastrointestinal and cardiovascular side effects. Rofecoxib and etoricoxib have been withdrawn from the market due to the possibility of causing serious cardiovascular side effects, such as heart attack and stroke. Therefore, there is an urgent need for an effective and safe method for treating inflammatory diseases. In contrast, CYP2C and CYP2J enzymes in the CYP pathway can convert arachidonic acid into anti-inflammatory mediators epoxyeicosatrienoic acids (EETs), which are important signal molecules in the body, and have the effects of mediating vasodilation, reducing inflammatory response and analgesia, etc. However, EETs will be metabolized by soluble epoxide hydrolase (sEH) into corresponding pro-inflammatory factors dihydroxyeicosatrienoic acids (DHETs). Previous studies have shown that inhibition of sEH can significantly reduce the conversion of EETs to corresponding DHETs, thereby reducing the state of inflammation and pain. This indicates that sEH can be used as a pharmacological target for the treatment of inflammatory diseases and pain.

[0003] A large number of compounds in natural products show inhibitory effect on sEH, but the IC 50 values are all in the micromolar level, which do not have the value of further preclinical research. So far, synthetic compounds AR9281, GSK2256294 and EC5026 have entered the clinical trial stage, but there is no sEH inhibitor drug on the market at present.

[0004] Therefore, for the anti-inflammatory target soluble epoxide hydrolase, there is an urgent need for a new skeleton soluble epoxide hydrolase inhibiting compound with IC 50 values in the nanomolar level. SUMMARY

[0005] The present application provides a compound represented by the following formula (I), a tautomer, a stereoisomer, an isotopically labeled material, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof:

[0006]

[0007] wherein ring B is selected from a 5-6 membered heterocyclic ring, a 5-6 membered heteroaromatic ring;

[0008] R1is selected from the following groups, which are unsubstituted or optionally substituted by one, two or more R 11 substituents: C 1-10 alkyl, 3-14 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl; each R 11 is the same or different, independently of one another, selected from H, CN, halogen, the following groups, which are unsubstituted or optionally substituted by one, two or more R 12 substituents: C 1-10 alkyl, C 3-10 alkoxy, C 1-10 cycloalkyl, C 6-14 alkyl-C(=O)-, 3-14 membered heterocyclyl, C 12 aryl, 5-14 membered heteroaryl; each R 13 is the same or different, independently of one another, selected from H, CN, halogen, the following groups, which are unsubstituted or optionally substituted by one, two or more R 1-10 substituents: C 1-10 alkyl, C 1-10 alkoxy, C 1-10 alkyl-C(=O)-, C 3-10 alkoxy-C(=O)-, C 1-10 cycloalkyl-C(=O)-, C 13 alkyl-S(=O)2-, H2N-S(=O)2-; each R 1-10 is the same or different, independently of one another, selected from H, halogen, C 1-10 alkyl, C 6-14 alkoxy, C 1-10 aryl;

[0009] each R2is the same or different, independently of one another, selected from H, C 1-10 alkyl, C 31 alkoxy;

[0010] each R3is the same or different, independently of one another, selected from H, CN, the following groups, which are unsubstituted or optionally substituted by one, two or more R 1-10 substituents: amino, C 1-10 alkyl, C 1-10Alkyl-S(=O)2-, H2N-S(=O)2-, C 1-10 Alkyl-C(O)NH-; each R 31 They are either the same or different, and are independently selected from H, halogens, oxometalates (=O), and C. 1-10 Alkyl, C 1-10 Alkoxy, -NH(C 1-10 alkyl), N(C) 1-10 Alkyl)(C 1-10 Alkyl groups, 5-14 membered heteroaryl groups, and halogenated 5-14 membered heteroaryl groups;

[0011] Alternatively, two adjacent R3 atoms and their respective attached atoms form an unsubstituted or optionally substituted arrangement with one, two or more R3 atoms. 32 Substituted 3-14 membered heterocyclic groups; each R 32 Whether the two are the same or different, they are selected independently from H and C. 1-10 Alkyl, C 1-10 Alkoxy;

[0012] Each R b Whether the two are the same or different, they are selected independently from H and C. 1-10 Alkyl, C 1-10 Alkoxy;

[0013] m is selected from 0, 1, 2, or 3;

[0014] n is selected from 0, 1, 2, 3, 4 or 5;

[0015] p is selected from 0, 1, or 2.

[0016] According to an embodiment of the present invention, ring B is selected from 5-membered nitrogen-containing heterocycles, 5-membered nitrogen-containing heteroaromatic rings, 6-membered nitrogen-containing heterocycles, and 6-membered nitrogen-containing heteroaromatic rings;

[0017] According to an embodiment of the present invention, ring B is selected from imidazole ring, pyrrole ring, pyridine ring or piperidine ring.

[0018] According to an embodiment of the present invention, Selected from

[0019] According to an embodiment of the present invention, Selected from

[0020] According to embodiments of the present invention, R1 is selected from unsubstituted or optionally replaced by one, two or more R1s. 11 The following groups are substituted: C 1-6 Alkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl; each R 11They may be the same or different, and are independently selected from H, without substitution, or optionally by one, two, or more R. 12 The following groups are substituted: C 1-6 Alkoxy, C 3-8 cycloalkyl, C 1-6 Alkyl-C(=O)-, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl; each R 12 They may be identical or different, and are independently selected from H, CN, halogens, unsubstituted, or optionally substituted by one, two, or more R groups. 13 The following groups are substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C(=O)-, C 1-6 Alkoxy-C(=O)-, C 3-8 Cycloalkyl-C(=O)-, C 1-6 Alkyl-S(=O)2-, H2N-S(=O)2-; each R 13 They may be the same or different, and are independently selected from H, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl;

[0021] According to embodiments of the present invention, R1 is selected from unsubstituted or optionally replaced by one, two or more R1s. 11 The following groups are substituted: C 1-6 Alkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl; each R 11 Whether the two are the same or different, they are selected independently from H and C. 1-6 Alkyl-C(=O)-, Halogenated C 1-6 Alkoxy, unsubstituted, or optionally with one, two, or more R groups 12 The following groups are substituted: C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl; each R 12 They are either the same or different, and are independently selected from H, CN, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl-C(=O)-, Halogenated C 1-6 Alkyl-C(=O)-, C 1-6 Alkoxy-C(=O)-, C 6-10 Aryl-C 1-6 Alkoxy-C(=O)-, C 3-8 Cycloalkyl-C(=O)-, C 1-6alkyl-S(=0)2-, H2N-S(=0)2-;

[0022] According to an embodiment of the present application, R1is selected from -CH2-R 11 .

[0023] According to an embodiment of the present application, each R 11 is selected independently from each other, identically or differently, from trifluoromethoxy, unsubstituted or optionally substituted by one, two or more R 12 selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, cyclohexyl, piperidinyl, phenyl.

[0024] According to an embodiment of the present application, each R 11 is selected independently from each other, identically or differently, from

[0025] According to an embodiment of the present application, each R 12 is selected independently from each other, identically or differently, from H, CN, methoxy, -C(0)OCH3, benzyloxycarbonyl, trifluoromethoxy, difluoromethoxy, trifluoromethyl, methylsulfonyl, aminosulfonyl,

[0026] According to an embodiment of the present application, R1is selected from C 1-6 alkyl, 5-6 membered heterocyclyl-C 1-3 alkyl, C 1-6 alkyl-C(=0)-piperidinyl, haloC 1-3 alkoxyphenyl, C 1-3 alkoxy-C(=0)-cyclohexyl-C 1-3 alkyl, C 1-3 alkyl-C(=0)-piperidinyl-C 1-3 alkyl, haloC 1-3 alkyl-C(=0)-piperidinyl-C 1-3 alkyl, C 3-6 cycloalkyl-C(=0)-piperidinyl-C 1-3 alkyl, phenylC 1-3 alkyl-C(=0)-piperidinyl-C 1-3 alkyl, C 1-3 alkoxyphenylC 1-3 alkyl, haloC 1-3 alkoxyphenylC 1-3 alkyl, haloC 1-3 alkylphenylC 1-3 alkyl, cyanophenylC 1-3 alkyl, H2N-S(O)2-phenylC 1-3 alkyl, C 1-3alkyl-S(=0)2-phenyl C 1-3 alkyl, pyridinyl C 1-3 alkyl;

[0027] According to an embodiment of the present application, R1is selected from

[0028] According to an embodiment of the present application, each R2is the same or different, independently of one another, selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkoxy.

[0029] According to an embodiment of the present application, each R3is the same or different, independently of one another, selected from the group consisting of H, CN, C 31 substituted amino, C 1-6 alkyl, C 1-6 alkoxy, 3-8 membered heterocyclyl, C 1-6 alkyl-S(=0)2-, H2N-S(=0)2-, C 1-6 alkyl-C(O)NH-; each R 31 is the same or different, independently of one another, selected from the group consisting of H, halogen, oxo (=0), C 1-6 alkyl, C 1-6 alkoxy, -NH(C 1-6 alkyl), N(C 1-6 alkyl)(C 1-6 alkyl), 5-10 membered heteroaryl, halogenated 5-10 membered heteroaryl;

[0030] Alternatively, two adjacent R3form, with the atoms to which they are each attached, a 3-8 membered heterocyclyl which is unsubstituted or optionally substituted by one, two or more R 32 substituted 3-8 membered heterocyclyl; each R 32 is the same or different, independently of one another, selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkoxy.

[0031] According to an embodiment of the present application, each R 31 is the same or different, independently of one another, selected from the group consisting of H, halogen, oxo (=0), C 1-3 alkyl, C 1-3 alkoxy, -NH(C 1-3 alkyl), N(C 1-3 alkyl)(C 1-3 alkyl), pyridinyl, halogenated pyridinyl.

[0032] According to an embodiment of the present application, each R3is the same or different, independently of one another, selected from the group consisting of H, CN, C 1-6 alkyl, C 1-6alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, C 1-6 alkyl-C(O)-, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)(C 1-6 alkyl), -C 1-6 alkyl-NH(C 1-6 alkyl), -C 1-6 alkyl-N(C 1-6 alkyl)(C 1-6 alkyl), C 1-6 alkyl-3-8 membered heterocyclyl, C 1-6 alkyl-S(=O)2-, H2N-S(=O)2-, 5-10 membered heteroaryl-C 1-6 alkyl-C(O)NH-, halo 5-10 membered heteroaryl-C 1-6 alkyl-C(O)NH-;

[0033] Alternatively, two adjacent R3form, with the atoms to which they are each attached, a 3-8 membered heterocyclyl.

[0034] According to an embodiment of the present application, R3is selected from H, CN, amino, methyl, methoxy, trifluoromethoxy, acetyl, dimethylamino,

[0035]

[0036] Alternatively, two adjacent R3form, with the atoms to which they are each attached, a

[0037] According to an embodiment of the present application, is selected from

[0038] According to an embodiment of the present application, each R b are the same or different, each independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkoxy.

[0039] According to an embodiment of the present application, the compound of formula (I) has the structure as shown below:

[0040]

[0041]

[0042] wherein R1, R2, R3, R b , m, n, p each independently have the definitions described above.

[0043] According to an embodiment of the present application, the compound of formula (I) has the structure shown below:

[0044]

[0045] wherein ring B, R1, R2, R 31 , R b , m, p are each independently as defined above.

[0046] According to an embodiment of the present application, the compound of formula (I) has the structure shown below:

[0047]

[0048] wherein ring B, R2, R3, R 12 , R b , m, p are each independently as defined above.

[0049] According to an embodiment of the present application, the compound of formula (I) has the structure shown below:

[0050]

[0051] wherein ring B, R2, R3, R 11 , R b , m, n, p are each independently as defined above. According to an embodiment of the present application, the compound of formula (I) has the structure shown below:

[0052]

[0053] wherein R3, R 12 are each independently as defined above.

[0054] According to an exemplary embodiment of the present application, the compound of formula (I) can have one of the following structures:

[0055]

[0056]

[0057] The present application also provides a method for preparing a compound of formula (I), a tautomer, stereoisomer, isotopically-labeled, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, comprising the step of reacting compound a with compound b in the presence of carbonyldiimidazole to obtain a compound of formula (I);

[0058]

[0059] wherein ring B, R1, R2, R3, R b , m, n, p have independently of each other the definitions described above.

[0060] According to embodiments of the present application, the preparation method can be carried out in the presence of a solvent, such as an organic solvent. For example, the organic solvent can be selected from at least one of the following: alcohols, such as methanol, ethanol, isopropanol, n-butanol; ethers, such as ethyl propyl ether, n-butyl ether, anisole, phenyl ethyl ether, cyclohexyl methyl ether, dimethyl ether, diethyl ether, dimethyl glycol, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, dioxane, dichlorodiethyl ether, and polyethers of ethylene oxide and / or propylene oxide; aliphatic, cycloaliphatic or aromatic hydrocarbons, such as pentane, hexane, heptane, octane, nonane, and the like that can be substituted with fluorine and chlorine atoms, such as methylene chloride, dichloromethane, trichloromethane, carbon tetrachloride, fluorobenzene, chlorobenzene or dichlorobenzene; cyclohexane, methylcyclohexane, petroleum ether, octane, benzene, toluene, chlorobenzene, bromobenzene, xylene; esters such as methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate, and dimethyl carbonate, dibutyl carbonate or ethylene carbonate.

[0061] The present application also provides a pharmaceutical composition, wherein the pharmaceutical composition comprises the compound represented by formula (I), a tautomer, a stereoisomer, an isotopically labeled material, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof.

[0062] According to embodiments of the present application, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0063] The present application also provides the use of the compound represented by formula (I), a tautomer, a stereoisomer, an isotopically labeled material, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, or the pharmaceutical composition in the preparation of a medicament.

[0064] According to embodiments of the present application, the pharmaceutical composition or the medicament is used for treating diseases related to sEH inhibition, such as for treating inflammation (such as foot swelling inflammation, pancreatitis, neuroinflammation), analgesia, myocardial ischemia, fibrosis, renal failure, diabetes, hypertension and cardiovascular diseases.

[0065] The present application also provides a compound represented by formula (I), a tautomer, a stereoisomer, an isotopically labeled material, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, or the pharmaceutical composition for use in the prevention and / or treatment of diseases related to sEH inhibition.

[0066] According to embodiments of the present application, the sEH-inhibition related disease is selected from the group consisting of inflammation (e.g., inflammation of foot swelling, pancreatitis, neuroinflammation), analgesia, myocardial ischemia, fibrosis, renal failure, diabetes, hypertension, and cardiovascular disease.

[0067] The present application also provides a method for preventing and / or treating a sEH-inhibition related disease, comprising administering to a patient a therapeutically effective amount of at least one of the compound represented by Formula (I), a tautomer, a stereoisomer, an isotopically-labeled material, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, or the pharmaceutical composition.

[0068] According to embodiments of the present application, the sEH-inhibition related disease is selected from the group consisting of inflammation (e.g., inflammation of foot swelling, pancreatitis, neuroinflammation), analgesia, myocardial ischemia, fibrosis, renal failure, diabetes, hypertension, and cardiovascular disease.

[0069] The therapeutically effective amount or dosage according to the present application will vary depending on factors such as the chosen route of administration, the formulation of the composition, the patient's response, the severity of the condition, the subject's body weight, and the judgment of the prescribing physician, for example, 1-200 mg / kg, 40-150 mg / kg, such as 50 mg / kg. The dosage can be increased or decreased over time, as the individual patient needs. In some cases, the patient is initially given a low dose and then the dose is increased to an effective dose that the patient can tolerate. In addition, the patient can be given multiple doses over a defined period of time, particularly time increments (e.g., daily, weekly, biweekly, monthly, quarterly, biannually, or the like).

[0070] Beneficial effects

[0071] The compound represented by Formula (I), a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof according to the present application has an excellent sEH-inhibition effect, and can be used for preventing and / or treating a sEH-inhibition related disease. BRIEF DESCRIPTION OF DRAWINGS

[0072] Figure 1 Pancreatic sections after pancreatitis and inflammation infiltrate score for Compound C17 for treating pancreatitis.

[0073] Figure 2 Inflammatory factor levels in plasma after pancreatitis for Compound C17 for treating pancreatitis.

[0074] Figure 3 Analgesic effect of Compounds C5, C9, C17 and C30 in a mouse acetic acid writhing test.

[0075] Definitions and explanations of terms

[0076] Unless otherwise indicated, the definitions of groups and terms in the specification and claims hereof include definitions that are incorporated herein by reference, definitions that are exemplified in the examples of specific compounds, definitions that are set forth in tables, definitions that are set forth in the specification and / or claims, and the like. Group definitions and compound structures that result from such combinations and permutations should be understood to be within the scope of the specification and / or claims.

[0077] Unless otherwise indicated, numerical ranges expressed in the specification and claims herein are intended to include every integer value within that range. For example, "a range of 1 to 10" is intended to include each integer from 1 to 10, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0078] It should be understood that, in describing one, two, or more items, "more" should be taken to mean greater than 2, e.g., an integer greater than or equal to 3, e.g., 3, 4, 5, 6, 7, 8, 9, or 10.

[0079] The term "C 1-10 "alkyl" denotes straight chain or branched chain saturated hydrocarbon groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The C 1-10 "alkyl" includes C 1-3 "alkyl", C 1-6 "alkyl", C 3-6 "alkyl" denotes straight chain and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms, "C 1-10 "alkyl" denotes straight chain and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms, "C 1-8 "alkyl" denotes straight chain and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms, "C 1-6 "alkyl" denotes straight chain and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms, "C

[0080] The term "C 3-10 "Cycloalkyl" denotes saturated, monovalent monocyclic, bicyclic (e.g., fused, bridged, spirocyclic) hydrocarbon rings or tricyclic cycloalkanes having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The C 3-10 "Cycloalkyl" includes C3-8 cycloalkyl, C 3-5 cycloalkyl, C 6-8 cycloalkyl, C 3-4 cycloalkyl, C 5-6 Cycloalkyl, C6 cycloalkyl, etc. The C... 3-10 Cycloalkyl groups can be monocyclic hydrocarbon groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl; or bicyclic hydrocarbon groups, such as borneolyl, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonyl, 2,6-diazaspiro[3,4]octyl; or tricyclic hydrocarbon groups, such as adamantyl.

[0081] The term "3-14 membered heterocyclic group" refers to a saturated or unsaturated non-aromatic ring or ring system containing at least one heteroatom selected from O, S, and N. The heterocyclic group can be connected to the remainder of the molecule via any one of the carbon atoms or a nitrogen atom (if present). The heterocyclic group can include fused or bridged rings and spirocyclic rings. Specifically, the heterocyclic group can include, but is not limited to: 3-membered rings, such as azirropropyl or oxacyclopropyl; 4-membered rings, such as azirrobutyl or oxacyclobutyl; 5-membered rings, such as tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoalkyl, pyrazolyl, or pyrrololinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazinyl, or trithiaalkyl; or 7-membered rings, such as diazacycloheptyl. Optionally, the heterocyclic group can be benzofused. The heterocyclic group can be bicyclic, such as, but not limited to, a 5,5-membered ring, like a hexahydrocyclopentano[c]pyrrole-2(1H)-yl ring, or a 5,6-membered bicyclic ring, like a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The heterocyclic group can be partially unsaturated, meaning it can contain one or more double bonds, such as, but not limited to, dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrroleyl, 4H-[1,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl, or 4H-[1,4]thiazinyl, or it can be benzofused, such as, but not limited to, dihydroisoquinolinyl. When the 3-14-membered heterocyclic group is linked to other groups to form the compounds of the present invention, the carbon atom on the 3-14-membered heterocyclic group can be linked to other groups, or a heterocyclic atom (such as a nitrogen atom) on the 3-14-membered heterocyclic group ring can be linked to other groups. For example, when the 3-14 membered heterocyclic group is selected from piperazine or tetrahydropyrrole, the nitrogen atom or carbon atom on the piperazine group can be attached to other groups. Or when the 3-14 membered heterocyclic group is selected from piperidinyl, the nitrogen atom on the piperidinyl ring or the carbon atom at the ortho, meta, or para position can be attached to other groups.

[0082] Term "C" 6-14 "Aryl" should be understood to preferably represent a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring ("C") having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms. 6-14 Aryl), particularly a ring with 6 carbon atoms (“C6 aryl”), such as phenyl; or biphenyl, or a ring with 9 carbon atoms (“C9 aryl”), such as indenyl or indenyl, or a ring with 10 carbon atoms (“C9 aryl”). 10 Aryl groups, such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl, or rings with 13 carbon atoms (“C”). 13 Aryl groups, such as fluorene groups, or rings with 14 carbon atoms (“C”). 14 Aryl), for example, anthracene. When the C6-20 When substituted, the aryl group can be mono- or poly-substituted. Also, the substitution position is not limited, and can be, for example, ortho-, para- or meta-substitution.

[0083] The term "5-14 membered heteroaryl" means a monovalent or multivalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, and of which the ring atoms include 1 to 5 heteroatoms independently selected from N, O and S, and the bicyclic and tricyclic aromatic ring systems can be fused, spiro or bridged. The 5-14 membered heteroaryl group includes 1 to 5, preferably 1 to 3 heteroatoms. In addition, the 5-14 membered heteroaryl group can be benzo-fused in each instance. The 5-14 membered heteroaryl group includes 5-8 membered heteroaryl, 5-9 membered heteroaryl, 5-10 membered heteroaryl, 5-6 membered heteroaryl, 8-10 membered heteroaryl, 6 membered heteroaryl, and the like. Examples of heteroaryl include, but are not limited to: 5 membered rings such as oxazolyl, pyrazolyl, thienyl, thiazolyl, triazolyl, imidazolyl, and the like; 6 membered rings such as pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and the like. The heterocyclyl group can be bicyclic, including but not limited to: 5,5 membered rings such as tetrahydrocyclopentapyrazole; 5,6 membered rings such as tetrahydroindole, tetrahydropyrazolopyridine, tetrahydroimidazopyridine, tetrahydrobenzisoxazole, tetrahydrobenzoxazole, tetrahydrobenzothiazole, tetrahydrobenzisothiazole, dihydrofuropyrazole, tetrahydrobenzofuran, dihydrobenzofuran, tetrahydrobenzothiophene; 6,6 membered rings such as tetrahydroquinoline; 5,7 membered rings such as tetrahydrocycloheptylthiazole, tetrahydrocycloheptylfuran. The heterocyclyl group can be tricyclic, including but not limited to: 6,7-dihydrospiro[cyclopropane-l,5-pyrrolo[l,2-c]imidazole]. When the 5-14 membered heteroaryl group is substituted, it can be mono- or poly-substituted. Also, the substitution position is not limited, and can be, for example, substitution of a hydrogen attached to a carbon atom on the heteroaryl ring, or substitution of a hydrogen attached to a heteroatom on the heteroaryl ring.

[0084] The term "spiro ring" means a ring system in which two rings share one ring atom.

[0085] The term "fused ring" means a ring system in which two rings share two ring atoms.

[0086] The term "bridged ring" means a ring system in which two rings share three or more ring atoms.

[0087] The term "halogen" means fluorine, chlorine, bromine or iodine.

[0088] "halo" means substituted with one or more halogens.

[0089] The term "oxo (=0)" means substitution of a hydrogen or lone pair on a non-oxygen atom with oxygen, for example, after oxo is after oxidation

[0090] The term "haloC 1-10 alkyl" means an alkyl group as defined above, which is substituted by one or more halogen as defined above, preferably "haloC 1-6 alkyl". Said haloalkyl groups include, but are not limited to monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl and the like.

[0091] Unless otherwise indicated, the definition of a term herein also applies to the definition of that term throughout this specification and claims for example, C 1-10 alkyl" means an alkyl group as defined above, which is substituted by one or more halogen as defined above, preferably "haloC 1-10 alkyl" means an alkyl group as defined above, which is substituted by one or more halogen as defined above, preferably "haloC 1-10 alkyl" means an alkyl group as defined above, which is substituted by one or more halogen as defined above, preferably "haloC 1-10 alkyl" means an alkyl group as defined above, which is substituted by one or more halogen as defined above, preferably "haloC 1-10 alkyl" means an alkyl group as defined above, which is substituted by one or more halogen as defined above, preferably "haloC 1-10 alkyl" means an alkyl group as defined above, which is substituted by one or more halogen as defined above, preferably "haloC

[0092] Crystallization often produces solvates of the compounds of the present application, and the term "solvate" as used herein means a combination of one or more molecules of a compound of the present application with one or more molecules of solvent.

[0093] The solvent can be water, in which case the solvate is a hydrate. Alternatively, the solvent can be an organic solvent. Thus, the compounds of the present application can exist as a hydrate, including a monohydrate, a dihydrate, a hemihydrate, a trihydrate, a tetrahydrate, and the like, as well as the corresponding solvated forms. The compounds of the present application can be true solvates, but in other cases the compounds of the present application can only adventitiously retain solvent or a mixture of solvents after their removal. The compounds of the present application can be reacted in one solvent or precipitated or crystallized from one solvent. Solvates of the compounds of the present application are also within the scope of the present application.

[0094] The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effects on the general health of the subject being treated.

[0095] The term "pharmaceutically acceptable" as used herein means a substance that does not affect the biological activity or properties of the compounds of the present application, and is relatively nontoxic, i.e., the substance can be administered to an individual without causing any undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0096] As will be understood by those skilled in the art, the compounds of the present application can exist in various pharmaceutically acceptable salt forms. If the compounds have a basic center, they can form acid addition salts; if the compounds have an acidic center, they can form base addition salts; and if the compounds contain both an acidic center (e.g., carboxyl) and a basic center (e.g., amino), they can also form inner salts.

[0097] The term "tautomer" refers to isomeric forms of a functional group resulting from the movement of a proton between two positions in a molecule. The compounds of the present application can exhibit tautomerism. Compounds that tautomerize can exist in two or more interconvertible forms. Proton-shift tautomers result from the migration of a hydrogen atom covalently bonded between two atoms. Tautomers generally exist in equilibrium and attempts to isolate a single tautomer usually result in a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates; in phenols, the enol form predominates. The present application encompasses all tautomeric forms of the compounds.

[0098] Depending on their molecular structure, the compounds of the present application can be chiral and, therefore, can exist in various enantiomeric forms. The compounds can thus exist in racemic or optically active forms. The compounds of the present application encompass the isomers of each chiral carbon in the R or S configuration or mixtures thereof, racemates. The compounds of the present application or intermediates thereto can be separated into the individual enantiomeric compounds by chiral phase chromatography or by other methods known to those skilled in the art, or used in the synthesis in this form. In the case of racemic amines, the diastereomeric amines are prepared from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, the appropriate N-protected amino acids, for example N-benzoylproline or N-benzenesulfonylproline, or the various optically active camphorsulfonic acids. Enantiomeric resolution by chromatography is also advantageously performed with optically active stationary phases, for example dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatizing reagents, fixed on silica gel. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example hexane / isopropanol / acetonitrile.

[0099] In the present application, "pharmaceutical composition" means a preparation of a compound of the present application with a medium generally accepted in the art for the delivery of a biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate administration of the active ingredient to the organism for the purpose of absorption and thereby exerting a biological activity.

[0100] In the present application, "pharmaceutically acceptable excipient" includes any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsor that is useful in preparing a pharmaceutical composition given the relevant government regulatory approvals for use in humans or in animals.

[0101] In the present application, the term "solvate" refers to a compound of the present application or a salt thereof, including stoichiometric or non-stoichiometric amounts of solvent, which is bound by intermolecular non-covalent forces, where the solvent is water, then it is a hydrate.

[0102] In the present application, the term "prodrug" refers to a compound of the present application that can be converted to a biologically active compound of the present application under physiological conditions or by solvolysis. A prodrug of the present application is prepared by modifying functional groups present in the compound in a manner known in the art, which modification can be either a conventional manipulation or in vivo. A prodrug includes a compound of the present application in which a hydroxyl or amino group is attached to any group, which when the prodrug of the present application is administered to a mammalian subject, the prodrug is cleaved to form the free hydroxyl, free amino group, respectively.

[0103] "Isotopes" are atoms of the elements that occur in the compounds of the present application. Isotopes include those atoms having the same atomic number but different mass numbers. Examples of isotopes suitable for inclusion in the compounds of the present application are hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, for example, and include without limitation 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 31 P, 32 P, 35 S, 18 F and 36 C1. Isotopically-labeled compounds of the present application can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described in the accompanying Examples using an appropriate isotopically-labeled reagent in place of the non- isotopically labeled reagent. Such compounds are useful in, e.g., determination of biological activity. In the case of stable isotopes, such compounds are useful in, e.g., providing improved bioavailability or improved pharmacokinetic properties.

[0104] In the present application, the term "tumor" includes benign tumors and malignant tumors (e.g., cancer).

[0105] The terms "treat" and other similar synonymous terms as used herein include the following meanings:

[0106] (i) preventing the disease or condition from occurring in a mammal, in particular, when such mammal is predisposed or at risk to developing the disease or condition but has not yet been diagnosed as having it;

[0107] (ii) inhibiting the disease or condition, i.e., arresting its development;

[0108] (iii) relieving the disease or condition, i.e., causing regression of the state of the disease or condition; or

[0109] (iv) relieving the symptoms of the disease or condition.

[0110] The term "patient" means any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, most preferably humans.

[0111] The term "therapeutically effective amount" means the amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician, and includes one or more of the following: (1) preventing the disease: for example, preventing a disease, disorder or condition from occurring in an individual that is predisposed or at risk to developing the disease, disorder or condition but has not yet been diagnosed with a pathology or symptoms of the disease; (2) inhibiting the disease: for example, arresting the development of a disease, disorder or condition in an individual that is already experiencing or has already been diagnosed with a pathology or symptoms of the disease, disorder or condition (i.e., halting further progression of the pathology and / or symptoms); (3) relieving the disease: for example, relieving a disease, disorder or condition in an individual that is already experiencing or has already been diagnosed with a pathology or symptoms of the disease, disorder or condition (i.e., reversing the pathology and / or symptoms). DETAILED DESCRIPTION

[0112] The technical solutions of the present application will be further described in detail below in combination with specific examples. It should be understood that the following examples are only illustratively and explain the present application, and should not be interpreted as limiting the scope of protection of the present application. Any technology realized based on the above description of the present application is covered within the scope intended to be protected by the present application.

[0113] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0114] The synthesis method of the quinoline skeleton compound of the present application is briefly described below. In the synthesis examples listed below, the synthesis of intermediates mainly involves Suzuki reaction, reduction reaction and acylation reaction, etc.

[0115] Specifically, the synthesis method of representative specific compounds of the present application is given below.

[0116] Method for preparing intermediates

[0117] The synthetic route of compound 1 in Preparation Example 1 is as follows:

[0118]

[0119] Compound 1 (1.13 g, 4.48 mmol, yield 78%) was obtained by dissolving 7-nitroquinoline (1.0 g, 5.75 mmol) in 20 mL of acetic acid, adding N-bromosuccinimide (NBS) (1.225 g, 6.90 mmol, 1.2 eq), and reacting at 80 °C for 10 h. After the reaction was completed, the solution was placed in ice water to precipitate a large amount of white solid, which was filtered. 1 H NMR (400 MHz, CDC13) δ 9.07 (d, J = 2.2 Hz, 1H), 8.99 (d, J = 2.3 Hz, 1H), 8.45 (d, J = 2.3 Hz, 1H), 8.37 (dd, J = 9.0, 2.3 Hz, 1H), 7.92 (d, J = 9.0 Hz, 1H). HRMS-ESI: calculated value C9H6BrN2O2 [M+H] + 252.9613, experimental value: 252.9605.

[0120] The synthetic route of compound 2 in Preparation Example 2 is as follows:

[0121]

[0122] Compound 2 (0.529 g, yield 90%) was obtained by dissolving compound 1 (0.5 g, 2 mmol) in 15 mL of ethylene glycol dimethyl ether, adding 3,4-methylenedimethoxybenzene boronic acid (0.396 g, 2.4 mmol, 1.2 eq), tetrakis triphenylphosphine palladium (0.346 g, 0.3 mmol, 0.15 eq), sodium carbonate (0.318 g, 3 mmol, 1.5 eq), and 5 mL of water, and reacting at 80 °C for 1.5 h under argon protection. After the reaction was completed, dichloromethane and water were added to the reaction solution, and the organic phase was washed with water and saturated brine after extraction, concentrated by rotary evaporation, dried to obtain a solid, and column chromatography (100-200 mesh silica gel, mobile phase V(petroleum ether):V(ethyl acetate)=10:1) was used to obtain compound 2 (0.529 g, yield 90%).

[0123] The synthetic route of compound 3 in Preparation Example 3 is as follows:

[0124]

[0125] Compound 2 (0.470 g, 1.6 mmol) was dissolved in 20 mL of ethanol, iron powder (0.313 g, 5.6 mmol, 3.5 eq) and aqueous ammonium chloride solution 5 mL (0.428 g, 8 mmol, 5 eq) were added, and the reaction was carried out at 90°C for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature, ammonia water was added to adjust the pH to 9, diatomite was added for filtration, the filtrate was extracted with dichloromethane and water three times, the organic phase was collected and concentrated by rotary evaporation, and the solid was dried to obtain compound 3 (0.363 g, yield 86%) by column chromatography (100-200 mesh silica gel, mobile phase V(dichloromethane):V(methanol):V(ammonia water)=10:0.1:0.05).

[0126] The synthetic route of compound 4 in Preparation Example 4 is shown below:

[0127]

[0128] Compound 1 (0.5 g, 2 mmol) was dissolved in 15 mL of ethylene glycol dimethyl ether, 3,4-dimethoxybenzeneboronic acid (0.437 g, 2.4 mmol, 1.2 eq), tetrakis triphenylphosphine palladium (0.346 g, 0.3 mmol, 0.15 eq), sodium carbonate (0.318 g, 3 mmol, 1.5 eq) and water 5 mL were added. Stirring was carried out at 80°C for 1.5 h under argon protection. After the reaction was completed, extraction was carried out with dichloromethane and water, the organic phase was washed with water and saturated brine in turn, concentrated by rotary evaporation, and dried to obtain a yellowish powder of compound 4 (0.520 g, yield 80%) by column chromatography (100-200 mesh silica gel, mobile phase V(petroleum ether):V(ethyl acetate)=10:1).

[0129] The synthetic route of compound 5 in Preparation Example 5 is shown below:

[0130]

[0131] Compound 4 was dissolved in 20 mL of ethanol, iron powder (0.620 g, 11.1 mmol, 7 eq) and aqueous ammonium chloride solution 5 mL (0.850 g, 15.9 mmol, 10 eq) were added, and the reaction was carried out at 90°C for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature, ammonia water was added to adjust the pH to 9, diatomite was added for filtration, the filtrate was extracted with dichloromethane and water three times, the organic phase was collected and concentrated by rotary evaporation, and the solid was dried to obtain compound 5 (0.380 g, yield 85%) by column chromatography (100-200 mesh silica gel, mobile phase V(dichloromethane):V(methanol):V(ammonia water)=10:0.1:0.05).

[0132] The synthetic route of compound 6 in Preparation Example 6 is shown below:

[0133]

[0134] Compound 1 (0.5 g, 2 mmol) was dissolved in 15 mL of ethylene glycol dimethyl ether, 3,5-dimethoxybenzeneboronic acid (0.437 g, 2.4 mmol, 1.2 eq), tetrakis triphenylphosphine palladium (0.346 g, 0.3 mmol, 0.15 eq), sodium carbonate (0.318 g, 3 mmol, 1.5 eq) and 5 mL of water were added. The reaction was stirred at 80 °C for 1.5 h under argon protection. After the reaction was completed, the reaction solution was extracted with dichloromethane and water, and the organic phase was washed with water and saturated brine successively. The organic phase was concentrated by rotary evaporation and dried to obtain a solid. The solid was purified by column chromatography (100-200 mesh silica gel, mobile phase: petroleum ether / ethyl acetate = 10:1) to obtain compound 6 (0.564 g, yield 90.9%) as a light yellow powder. HRMS-ESI: calculated value C 17 H 15 N2O4[M+H] + 311.1032, experimental value: 311.1022. 1 H NMR (400 MHz, CDC13) δ 9.33 (d, J = 2.3 Hz, 1H), 9.06 (d, J = 2.3 Hz, 1H), 8.52 - 8.30 (m, 2H), 8.05 (d, J = 9.0 Hz, 1H), 6.86 (d, J = 2.2 Hz, 2H), 6.61 (d, J = 2.3 Hz, 1H), 3.92 (s, 6H).

[0135] The synthetic route of compound 7 in Preparation Example 7 is as follows:

[0136]

[0137] Compound 6 (0.5 g, 1.6 mmol) was dissolved in 20 mL of ethanol, iron powder (0.625 g, 11.2 mmol, 7 eq) and aqueous ammonium chloride solution (5 mL, 0.856 g, 16 mmol, 10 eq) were added, and the reaction was carried out at 90 °C for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature, and the pH was adjusted to 9 by adding ammonia water. Silica was added to the solution, and the solution was filtered. The filtrate was extracted with dichloromethane and water three times, and the organic phase was concentrated by rotary evaporation and dried to obtain a solid. The solid was purified by column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / methanol / ammonia water = 10:0.1:0.05) to obtain compound 7 (0.380 g, yield 85%) as a light yellow solid. 1H NMR (400 MHz, CD3OD) δ 8.81 (d, J = 2.3 Hz, 1H), 8.23 (d, J = 2.2 Hz, 1H), 7.68 (d, J = 9.4 Hz, 1H), 7.10 (dd, J = 9.4, 2.4 Hz, 1H), 7.08 (d, J = 1.0 Hz, 1H), 6.80 (d, J = 2.2 Hz, 2H), 6.49 (t, J = 2.2 Hz, 1H), 3.83 (s, 6H). HRMS-ESI: Calcd for C 17 H 17 N2O2[M+H] + 281.1290, Found: 281.1280.

[0138] The synthetic route of compound 8 in Preparation Example 8 is as follows:

[0139]

[0140] Compound 1 (0.4 g, 1.6 mmol) was dissolved in 20 mL of ethanol, iron powder (0.625 g, 11.2 mmol, 7 eq) and aqueous ammonium chloride solution 5 mL (0.856 g, 16 mmol, 10 eq) were added, and the reaction was carried out at 90°C for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature, ammonia water was added to adjust the pH to 9, diatomite was added for filtration, and the filtrate was extracted with dichloromethane and water three times, and the organic phase was collected and concentrated by rotary evaporation to obtain a solid, which was dried and column chromatographed (100-200 mesh silica gel, mobile phase V(dichloromethane):V(methanol):V(ammonia water)=10:0.1:0.05) to obtain yellowish solid compound 8 (0.293 g, yield 82%). 1 H NMR (400 MHz, CD3OD) δ 8.81 (d, J = 2.3 Hz, 1H), 8.23 (d, J = 2.2 Hz, 1H), 7.68 (d, J = 9.4 Hz, 1H), 7.10 (dd, J = 9.4, 2.4 Hz, 1H), 7.08 (d, J = 1.0 Hz, 1H), 6.80 (d, J = 2.2 Hz, 2H), 6.49 (t, J = 2.2 Hz, 1H), 3.83 (s, 6H). HRMS-ESI: Calcd for C + 222.9871, Found: 222.9859.

[0141] The synthetic route of compound 9 in Preparation Example 9 is as follows:

[0142]

[0143] Compound 8 (0.1 g, 0.36 mmol) was dissolved in 15 mL of dichloromethane, carbonyldiimidazole (CDI, 0.065 g, 0.43 mmol, 1.2 eq) was added, and the reaction was allowed to proceed at room temperature for 12 h. 4-aminomethyltetrahydropyran (0.54 mmol, 1.5 eq) was added to the reaction solution, and the reaction was allowed to proceed at room temperature for 0.5 h. After the reaction was completed, the organic phase was washed with saturated ammonium chloride, the organic phase was collected, and concentrated by rotary evaporation. Column chromatography (V(dichloromethane):V(methanol):V(ammonia water)=10:0.15:0.05) was performed to obtain solid compound 9. Yellow powder, yield 86%. 1 H NMR (400 MHz, CD3OD) δ 8.75 (d, J = 2.3 Hz, 1H), 8.43 (dd, J = 2.3, 0.8 Hz, 1H), 8.12 (d, J = 2.1 Hz, 1H), 7.78 (d, J = 8.9 Hz, 1H), 7.67 (dd, J = 8.9, 2.2 Hz, 1H), 4.02-3.92 (m, 2H), 3.43 (td, J = 11.8, 2.1 Hz, 2H), 3.16 (d, J = 6.7 Hz, 2H), 1.88-1.73 (m, 1H), 1.72-1.63 (m, 2H), 1.41-1.27 (m, 2H). HRMS-ESI: calculated value C 16 H 19 N3O2Br[M+H] + 364.0661, experimental value: 364.0653.

[0144] The synthetic route of compound 10 of Preparation Example 10 is as follows:

[0145]

[0146] Compound 9 (0.5 g, 1.37 mmol) was dissolved in 15 mL of ethylene glycol dimethyl ether, 3-aminobenzeneboronic acid (0.226 g, 1.65 mmol, 1.2 eq), tetrakis(triphenylphosphine)palladium (0.238 g, 0.206 mmol, 0.15 eq), sodium carbonate (0.217 g, 2.06 mmol, 1.5 eq), and 5 mL of water were added, and the mixture was stirred at 80°C for 1.5 h under argon protection. After the reaction was completed, the mixture was extracted with dichloromethane and water, the organic phase was washed with water and saturated brine, concentrated by rotary evaporation, dried, and column chromatography (V(dichloromethane):V(methanol):V(ammonia water)=10:0.2:0.1) was performed to obtain white powder compound 10 (0.564 g, yield 90.9%).

[0147] The synthetic route of compound 11 of Preparation Example 11 is as follows:

[0148]

[0149] Compound 8 (0.1 g, 0.36 mmol) was dissolved in 15 mL of dichloromethane, carbonyldiimidazole (0.065 g, 0.43 mmol, 1.2 eq) was added, and the reaction was carried out at room temperature for 12 h. 4-aminomethylpivaloylpiperidine (0.54 mmol, 1.5 eq) was added to the reaction solution, and the reaction was continued at room temperature for 0.5 h. After the reaction was completed, the organic phase was washed with saturated ammonium chloride, and the organic phase was collected and concentrated by rotary evaporation, and column chromatography on silica gel (V(dichloromethane):V(methanol):V(ammonia water)=10:0.15:0.05) gave solid compound 11. Yellow powder, yield 71%. 1 H NMR (400 MHz, CDC13) δ 8.76 (d, J = 2.3 Hz, 1H), 8.66 (s, 1H), 8.16 (d, J = 2.3 Hz, 1H), 7.97 (dd, J = 9.0, 2.1 Hz, 1H), 7.78 (d, J = 2.1 Hz, 1H), 7.61 (d, J = 9.0 Hz, 1H), 6.33 (t, J = 6.1 Hz, 1H), 4.66-4.52 (m, 1H), 3.92-3.77 (m, 1H), 3.43-3.25 (m, 1H), 3.16-3.06 (m, 1H), 2.98 (td, J = 13.1, 2.4 Hz, 1H), 2.53 (td, J = 12.8, 2.5 Hz, 1H), 2.41-2.22 (m, 2H), 1.83-1.57 (m, 3H), 1.14 (t, J = 7.4 Hz, 3H), 1.17-1.07 (m, 2H). HRMS-ESI: Calcd for C 19 H 24 N4O2Br[M+H] + 419.1083, Found: 419.1081.

[0150] The synthetic route of compound 12 of Preparation Example 12 is as follows:

[0151]

[0152] Compound 8 (0.1 g, 0.36 mmol) was dissolved in 15 mL of dichloromethane, carbonyldiimidazole (0.065 g, 0.43 mmol, 1.2 eq) was added, and the reaction was carried out at room temperature for 12 h. 4-aminomethylpivaloylpiperidine (0.54 mmol, 1.5 eq) was added to the reaction solution, and the reaction was continued at room temperature for 0.5 h. After the reaction was completed, the organic phase was washed with saturated ammonium chloride, and the organic phase was collected and concentrated by rotary evaporation, and column chromatography on silica gel (V(dichloromethane):V(methanol):V(ammonia water)=10:0.15:0.05) gave solid compound 11. Yellow powder, yield 71%. 1H NMR (400 MHz, CD3OD) δ 8.78 (d, J = 2.4 Hz, 1H), 8.46 (dd, J = 2.4, 0.8 Hz, 1H), 8.16 (d, J = 2.1 Hz, 1H), 7.81 (d, J = 8.9 Hz, 1H), 7.71 (dd, J = 8.9, 2.2 Hz, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.26 (d, J = 7.7 Hz, 1H), 4.48 (s, 2H). HRMS-ESI: Calcd for C 18 H 14 N3O2F3Br[M+H] + 440.0221, Found: 440.0223.

[0153] The synthesis method of compound 13 of Preparation Example 13 is as follows:

[0154]

[0155] 6-nitroquinoline (1.0 g, 5.75 mmol) was dissolved in 20 mL of acetic acid, and NBS (1.225, 6.90 mmol, 1.2 eq) was added, and the reaction was performed at 80°C for 10 h. After the reaction was completed, the solution was placed in ice water to precipitate a large amount of white solid, and filtration gave 3-bromo-6-nitroquinoline compound 13 (1.13 g, 4.48 mmol, yield 75%). 1 H NMR (400 MHz, DMSO-d6) δ 9.18 (d, J = 2.4 Hz, 1H), 9.07 (d, J = 2.4 Hz, 1H), 9.04 (d, J = 2.6 Hz, 1H), 8.50 (dd, J = 9.2, 2.6 Hz, 1H), 8.25 (d, J = 9.2 Hz, 1H). HRMS-ESI: Calcd for C9H6BrN2O2[M+H] + 252.9613, Found: 252.9599.

[0156] The synthesis method of compound 14 of Preparation Example 14 is as follows:

[0157]

[0158] Compound 13 (0.5 g, 2 mmol) was dissolved in 15 mL of ethylene glycol dimethyl ether, 3,4-(methylenedioxy)benzoic acid (0.437 g, 2.4 mmol, 1.2 eq), tetrakis triphenylphosphine palladium (0.346 g, 0.3 mmol, 0.15 eq), sodium carbonate (0.318 g, 3 mmol, 1.5 eq) and 5 mL of water were added. Stirring was carried out under argon protection at 80 °C for 1.5 h. After the reaction was completed, extraction was carried out with dichloromethane and water, and the organic phase was washed with water and saturated brine successively. Concentration was carried out by rotary evaporation, and a solid was obtained after drying. Column chromatography (100-200 mesh silica gel, mobile phase V(petroleum ether):V(ethyl acetate) = 10:1) gave compound 14 (0.520 g, yield 83%) as a light yellow powder.

[0159] The synthetic route of compound 15 in Preparation Example 16 is as follows:

[0160]

[0161] Compound 14 (0.5 g, 1.6 mmol) was dissolved in 20 mL of ethanol, iron powder (0.625 g, 11.2 mmol, 7 eq) and aqueous ammonium chloride solution (5 mL, 0.856 g, 16 mmol, 10 eq) were added, and reaction was carried out at 90 °C for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature, ammonia water was added to adjust the pH to 9, and diatomite was added for filtration. The filtrate was extracted with dichloromethane and water three times, and the organic phase was collected and concentrated by rotary evaporation. A solid was obtained after drying, and column chromatography (100-200 mesh silica gel, mobile phase V(dichloromethane):V(methanol):V(ammonia water) = 10:0.1:0.05) gave compound 15 (0.358 g, yield 81%) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J = 2.3 Hz, 1H), 8.10 (d, J = 2.3 Hz, 1H), 7.69 (d, J = 9.0 Hz, 1H), 7.41 (d, J = 1.8 Hz, 1H), 7.30 (dd, J = 8.1, 1.8 Hz, 1H), 7.13 (dd, J = 9.0, 2.5 Hz, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.84 (d, J = 2.5 Hz, 1H), 6.09 (s, 2H), 5.61 (s, 2H). HRMS-ESI: calculated C 16 H 13 N2O2[M+H] + 265.0977, found: 265.0967.

[0162] The synthetic route of compound 16 in Preparation Example 16 is as follows:

[0163]

[0164] Dissolve m-nitrobenzaldehyde (39.70 mmol, 6.00 g) in 100 mL of toluene, add ethylene glycol (79.41 mmol, 4.34 mL), p-toluenesulfonic acid (1.19 mmol, 0.23 g), and react at 120 °C for 2 h. After the reaction is completed, wash with saturated sodium bicarbonate solution and saturated sodium chloride solution, respectively, dry and concentrate to obtain a yellow oil (7.75 g, yield 100%). This intermediate is pure and can be used in the next reaction without purification. Add 100 mL of a methanol solution of the yellow oil (39.70 mmol, 7.75 g) to a high-pressure reactor, and add palladium-carbon (0.77 g). After three times of hydrogen gas replacement and circulation, react at a hydrogen pressure of 60 psi for 24 h. After the reaction is completed, filter, collect the organic phase, and concentrate by rotary evaporation. Purify by silica gel column chromatography (V(petroleum ether):V(ethyl acetate) = 5:1) to obtain compound 16 as a light yellow oil (5.97 g, yield 91%). 1 H NMR (400 MHz, DMSO-d6) δ 7.00 (t, J = 7.7 Hz, 1H), 6.65 (t, J = 2.0 Hz, 1H), 6.59 - 6.51 (m, 2H), 5.55 (s, 1H), 5.10 (s, 2H), 4.04 - 3.82 (m, 4H).

[0165] The synthetic route of compound 18 is as follows:

[0166]

[0167] Dissolve compound 16 (12.11 mmol, 2.00 g) in anhydrous DMF, and add NBS (13.32 mmol, 2.37 g) in batches under ice bath, and react at room temperature under argon atmosphere for 18 h. After the reaction is completed, add water to terminate the reaction, extract with ethyl acetate for several times, wash the combined organic phase with half-saturated sodium chloride solution, collect the organic phase, concentrate by rotary evaporation, and purify by silica gel column chromatography (V(petroleum ether):V(ethyl acetate) = 5:1) to obtain compound 17 as a light yellow oil (2.31 g, yield 78%). 1 H NMR (400 MHz, DMSO-d6) δ 7.00 (t, J = 7.7 Hz, 1H), 6.65 (t, J = 2.0 Hz, 1H), 6.59 - 6.51 (m, 2H), 5.55 (s, 1H), 5.10 (s, 2H), 4.04 - 3.82 (m, 4H).

[0168] The synthetic route of compound 18 is as follows:

[0169]

[0170] To a solution of compound 17 (8.19 mmol, 2.00 g) in anhydrous DCM was added pyridine (24.58 mmol, 1.98 mL), DMAP (0.82 mmol, 0.10 g) and acetic anhydride (12.29 mmol, 1.15 mL) successively, and the reaction was carried out at room temperature for 30 min under argon atmosphere. After the reaction was completed, the organic phase was washed successively with saturated ammonium chloride solution, water, saturated sodium bicarbonate solution, saturated brine, and the organic phase was collected and concentrated by rotary evaporation, and purified by slurry with dichloromethane and n-hexane to obtain compound 18 (2.13 g, yield 91%) as a white solid. 1 H NMR (400 MHz, CDC13) δ 7.63 - 7.52 (m, 2H), 7.49 (d, J = 8.4 Hz, 1H), 7.35 - 7.30 (m, 1H), 6.05 (s, 1H), 4.22 - 3.98 (m, 4H), 2.15 (s, 3H). 13 C NMR (100 MHz, CDC13) δ 168.35, 137.42, 137.10, 133.49, 122.01, 118.89, 117.05, 102.34, 65.49, 24.59. HRMS-ESI: Calcd for C 11 H 12 BrNNaO3[M+Na] + 307.9893, Found: 307.9893.

[0171] The synthetic route of compound 19 in Preparation Example 19 is as follows:

[0172]

[0173] Compound 18 (1.40 mmol, 0.40 g), 3,5-dimethoxyacetophenone (2.80 mmol, 0.51 g) were dissolved in 20 mL of tetrahydrofuran, and palladium acetate (0.07 mmol, 0.016 g), Xantphos (0.14 mmol, 0.081 g) and potassium phosphate (2.80 mmol, 0.61 g) were added successively, and the reaction system was replaced with argon for 3 times and reacted at 90 °C for 48 h. After the reaction was completed, the organic phase was filtered and concentrated by rotary evaporation, and purified by silica gel column chromatography (silica gel 200-300 mesh, V(petroleum ether):V(ethyl acetate)=1:1) to obtain compound 19 (0.52 g, 96%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 7.67 (d, J = 2.3 Hz, 1H), 7.59 (dd, J = 8.2, 2.3 Hz, 1H), 7.13 (d, J = 2.3 Hz, 2H), 7.09 (d, J = 8.3 Hz, 1H), 6.77 (t, J = 2.3 Hz, 1H), 5.74 (s, 1H), 4.41 (s, 2H), 3.97 - 3.82 (m, 4H), 3.80 (s, 6H), 2.03 (s, 3H).

[0174] The synthetic route of the compound 20 of Preparation Example 21 is as follows:

[0175]

[0176] The compound 20 (0.31 g, yield 65%) was obtained as a yellow oil by adding compound 19 (1.69 mmol, 0.65 g) and ammonium chloride (1.07 g) in a pressure-resistant bottle in 20 / 10 mL of an ethanol / water solution, reacting at 90°C for 48 h in a closed system, and then continuing to react at 120°C for 48 h. After the reaction was completed, the reaction solution was diluted with ethyl acetate, and the organic phase was washed with a saturated sodium bicarbonate solution. The organic phase was collected and concentrated by rotary evaporation, and was subjected to silica gel column chromatography (V(dichloromethane):V(tetrahydrofuran):V(ammonia water)=10:0.2:0.05) to obtain the compound 20 (0.31 g, yield 65%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 7.67 (d, J = 2.3 Hz, 1H), 7.59 (dd, J = 8.2, 2.3 Hz, 1H), 7.13 (d, J = 2.3 Hz, 2H), 7.09 (d, J = 8.3 Hz, 1H), 6.77 (t, J = 2.3 Hz, 1H), 5.74 (s, 1H), 4.41 (s, 2H), 3.97 - 3.82 (m, 4H), 3.80 (s, 6H), 2.03 (s, 3H).

[0177] The synthetic route of the compound 20 of Preparation Example 21 is as follows:

[0178]

[0179] Into a 100 mL round bottom flask, 4-nitro-o-phenylenediamine (0.766 g, 5.00 mmol) and piperonal (0.750 g, 5.00 mmol, 1 eq) were dissolved in 25 mL of absolute ethanol as solvent, stirred and dissolved under argon protection, stirred at 80 °C for 24 h. After the reaction was completed, the reaction liquid was cooled to room temperature, and the reaction mixture was concentrated to half of the initial volume, and the precipitated crude product was recrystallized with petroleum ether (30 mL) to obtain the Schiff base compound (0.998 g, yield 70.0%). The intermediate was dissolved in 25 mL of absolute ethanol, then nitrobenzene (1 mL) was added, stirred at 80 °C for 24 h under argon protection. After the reaction was completed, the reaction liquid was cooled to room temperature, the reaction mixture was concentrated to half of the initial volume, and the precipitated crude product was filtered to obtain compound 21 (0.496 g, yield 50%). 1 H NMR (400 MHz, Methanol-d4) δ 8.47 (d, J = 2.2 Hz, 1H), 8.19 (dd, J = 8.8, 2.2 Hz, 1H), 7.68 (dd, J = 8.1, 1.7 Hz, 2H), 7.59 (d, J = 1.8 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.09 (s, 2H). HRMS-ESI: calculated value C 14 H 10 N3O4[M+H] + 284.0671, experimental value: 284.0659.

[0180] The synthetic route of compound 22 of Preparation Example 22 is as follows:

[0181]

[0182] Compound 21 (0.181 g, 0.638 mmol) was dissolved in 12 mL of ethanol, and iron powder (0.274 g, 4.9 mmol, 7 eq), 5 mL of aqueous ammonium chloride solution (0.350 g, 6.38 mmol, 10 eq) were added in turn, and reacted at 80 °C for 2 h. After the reaction was completed, the reaction liquid was cooled to room temperature, ammonia was added to adjust the pH to 9, diatomite was added for filtration, and ethyl acetate was added to the filtrate and washed with saturated sodium bicarbonate solution (30 mL), water (30 mL), and saturated sodium chloride solution (30 mL) in turn. The organic phase was concentrated by rotary evaporation, and column chromatography (100-200 mesh silica gel, mobile phase V(petroleum ether):V(ethyl acetate) = 1:1) was performed to obtain the reduced compound 22 (0.121 g, yield 75.0%).

[0183] The synthetic route of compound 23 of Preparation Example 23 is as follows:

[0184]

[0185] Dissolve piperonal (0.500 g, 3.33 mmol) and 2,4-dinitrotoluene (0.606 g, 3.33 mmol, 1 eq) in 30 mL of toluene, add piperidine (0.07 mL, 0.666 mmol, 0.2 eq), react at 110 °C for 24 h. After the reaction is completed, the organic phase is concentrated by rotary evaporation, then ethanol is added, a large amount of yellow solid is precipitated, and the intermediate (0.909 g, yield 87%) is obtained by filtration. 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 2.4 Hz, 1H), 8.46 (dd, J = 8.8, 2.5 Hz, 1H), 8.20 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 16.1 Hz, 1H), 7.37 (s, 1H), 7.34 - 7.29 (m, 1H), 7.16 (d, J = 8.1 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 6.09 (s, 2H). HRMS-ESI: calculated value C 15 H 11 N2O6[M+H] + 315.0617, experimental value: 315.0617. Dissolve the intermediate (0.500 g, 1.6 mmol) in 20 mL of ethylene glycol dimethyl ether (DME), add iron acetate (0.0152 g, 0.08 mmol, 0.05 eq), phenanthroline (0.02 g, 0.08 mmol, 0.05 eq), phenylsilane (0.6 mL, 9.6 mmol, 6 eq), react at 85 °C for 15 h. After the reaction is completed, the organic phase is concentrated by rotary evaporation, and then the pure compound 23 (0.171 g, yield 38%) is obtained by silica gel column chromatography V (dichloromethane): V (methanol) = 10:0.05). 1 H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 8.24 (d, J = 2.1 Hz, 1H), 7.89 (dd, J = 8.8, 2.2 Hz, 1H), 7.66 (d, J = 8.7 Hz, 1H), 7.53 (s, 1H), 7.47 (dd, J = 8.1, 1.8 Hz, 1H), 7.09 (d, J = 8.1 Hz, 1H), 7.05 (s, 1H), 6.12 (s, 2H). HRMS-ESI: calculated value C 15 H 12 N2O4[M+H] + 283.0719, experimental value: 283.0713.

[0186] The synthetic route of compound 24 of Preparation Example 24 is as follows:

[0187]

[0188] Compound 23 (0.200 g, 0.7 mmol) was dissolved in 20 mL of ethanol, iron powder (0.274 g, 4.9 mmol, 7 eq) and aqueous ammonium chloride solution 5 mL (0.374 g, 7 mmol, 10 eq) were added, and the reaction was carried out at 90 °C for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature, ammonia water was added to adjust the pH to 9, diatomite was added for filtration, and the filtrate was extracted with dichloromethane and water three times. The organic phase was collected and concentrated by rotary evaporation, and dried to obtain a solid. Column chromatography (100-200 mesh silica gel, mobile phase V(dichloromethane):V(methanol):V(ammonia water)=10:0.1:0.05) was used to obtain compound 24 (0.139 g, yield 79%) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 7.32 (d, J = 1.8 Hz, 1H), 7.23 (dd, J = 8.2, 1.8 Hz, 1H), 7.13 (d, J = 8.3 Hz, 1H), 6.94 (s, 1H), 6.55 (d, J = 2.2 Hz, 2H), 6.37 (dd, J = 8.3, 1.8 Hz, 1H), 6.03 (s, 2H), 4.79 (s, 1H). HRMS-ESI: calculated value C 15 H 14 N2O2[M+H] + 253.0977, experimental value: 253.0964.

[0189] Compound preparation method

[0190] The synthesis route of compound C1 of Example 1 is as follows:

[0191]

[0192] Compound 3 (0.1 g, 0.38 mmol) was dissolved in 15 mL of dichloromethane, carbonyldiimidazole (0.065 g, 0.45 mmol, 1.2 eq) was added, and the reaction was carried out at room temperature for 12 h. Isobutylamine (0.054 mL, 0.57 mmol, 1.5 eq) was added to the reaction solution, and the reaction was continued at room temperature for 0.5 h. After the reaction was completed, the organic phase was washed with saturated ammonium chloride, and the organic phase was collected and concentrated by rotary evaporation. Column chromatography on silica gel (V(dichloromethane):V(methanol):V(ammonia water)=10:0.15:0.05) was used to obtain compound C1 (0.116 g, yield 85%). m.p. 235.4-236.8 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.06 (d, J = 2.4 Hz, 1H), 8.82 (s, 1H), 8.40 (d, J = 2.4 Hz, 1H), 8.17 (d, J = 2.1 Hz, 1H), 7.85 (d, J = 8.9 Hz, 1H), 7.55 (dd, J = 8.9, 2.2 Hz, 1H), 7.44 (d, J = 1.8 Hz, 1H), 7.32 (dd, J = 8.1, 1.8 Hz, 1H), 7.06 (d, J = 8.1 Hz, 1H), 6.34 (t, J = 5.8 Hz, 1H), 6.09 (s, 2H), 2.98 (t, J = 6.3 Hz, 2H), 1.75 - 1.72 (m, 1H), 0.90 (d, J = 6.7 Hz, 6H). 13 C NMR (100 MHz, DMSO-d6) δ 155.6, 149.9, 148.7, 148.2, 147.6, 141.9, 132.3, 132.1, 130.8, 128.9, 123.3, 120.9, 120.6, 113.4, 109.4, 107.7, 101.7, 47.1, 28.9, 20.5. HRMS-ESI: calc. C21H22N3O3 [M+H]+364.1661, found: 364.1660.

[0193] The synthetic route of compound C2 of Example 2 is as follows:

[0194]

[0195] Using 3-(3,4-dimethoxyphenyl)quinolin-7-amine (compound 5, 0.1 g, 0.36 mmol) and isobutylamine (0.54 mmol, 1.5 eq) as raw materials, reacting according to the synthetic method of Example 1, and purifying the product by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia water) = 10:0.15:0.05) to obtain compound C2 yellow oil (0.051 g, 37%). 1 H NMR (400 MHz, CD3OD) δ 8.98 (d, J = 2.3 Hz, 1H), 8.36 (d, J = 2.3 Hz, 1H), 8.10 (d, J = 2.1 Hz, 1H), 7.85 (d, J = 8.9 Hz, 1H), 7.65 (dd, J = 8.9, 2.2 Hz, 1H), 7.34 - 7.29 (m, H), 7.28 (d, J = 2.2 Hz, 1H), 7.08 (d, J = 8.2 Hz, 1H), 3.94 (s, 3H), 3.88 (s, 3H), 3.08 (d, J = 6.7 Hz, 2H), 1.94 - 1.75 (m, 1H), 0.97 (d, J = 6.7 Hz, 6H).13 C NMR (100 MHz, DMSO-d6) δ 155.7, 149.8, 149.4, 149.0, 146.9, 142.6, 133.3, 130.9, 130.1, 129.1, 123.5, 120.9, 119.6, 112.9, 111.9, 111.0, 56.2, 56.1, 47.0, 28.9, 20.5. HRMS-ESI: Calcd for C 22 H 26 N3O3[M+H] + 380.1974, found: 380.1960.

[0196] The synthetic route of compound C3 in Example 3 is as follows:

[0197]

[0198] Compound 7 (0.1 g, 0.36 mmol) was dissolved in 15 mL of dichloromethane, then carbonyldiimidazole (0.065 g, 0.43 mmol, 1.2 eq) was added, and the reaction was carried out at room temperature for 12 h. After compound 7 was completely reacted, isobutylamine (0.054 mL, 0.54 mmol, 1.5 eq) was added to the above reaction solution, and the reaction was continued at room temperature for 0.5 h. After the reaction was completed, the reaction solution was washed with saturated ammonium chloride 3 times, and the organic phase was collected and concentrated by rotary evaporation, and compound C3 (0.116 g, yield 85%) was obtained by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia water)=10:0.15:0.05). mp. 116.8-118.2℃. 1 H NMR (400 MHz, CD3OD) δ 8.93 (d, J = 2.3 Hz, 1H), 8.33 (d, J = 2.3 Hz, 1H), 8.10 (d, J = 2.1 Hz, 1H), 7.83 (d, J = 8.9 Hz, 1H), 7.63 (dd, J = 8.9, 2.1 Hz, 1H), 6.81 (d, J = 2.2 Hz, 2H), 6.50 (t, J = 2.2 Hz, 1H), 3.84 (s, 6H), 3.07 (d, J = 6.8 Hz, 2H), 1.81 (dt, J = 13.4, 6.7 Hz, 1H), 0.97 (d, J = 6.7 Hz, 6H). 13 C NMR (176 MHz, DMSO-d6) δ 161.6, 155.6, 148.6, 143.2, 139.3, 130.8, 129.5, 123.5, 121.1, 105.4, 100.4, 47.00 28.9, 20.5. HRMS-ESI: Calcd for C 22 H 26 N3O3[M+H]+ 380.1974, found: 380.1959.

[0199] The synthetic route of compound C4 is as follows:

[0200]

[0201] Using compound 7 (0.1 g, 0.36 mmol) and (S)-(tetrahydrofuran-2-yl)methanamine (0.54 mmol, 1.5 eq) as raw materials, reacting according to the synthetic method of Example 1, the product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia water) = 10:0.15:0.05) to obtain compound C4 yellow oil (0.069 g, 52%). 1 H NMR (400 MHz, CD3OD) δ 8.94 (d, J = 2.3 Hz, 1H), 8.33 (d, J = 1.5 Hz, 1H), 8.11 (d, J = 2.1 Hz, 1H), 7.83 (d, J = 8.9 Hz, 1H), 7.63 (dd, J = 8.9, 2.2 Hz, 1H), 6.82 (d, J = 2.2 Hz, 2H), 6.51 (t, J = 2.2 Hz, 1H), 4.05-3.99 (m, 1H), 3.90 (dt, J = 8.2, 6.7 Hz, 1H), 3.84 (s, 6H), 3.80-3.74 (m, 1H), 3.42 (dd, J = 13.8, 4.0 Hz, 1H), 3.26 (dd, J = 13.8, 6.6 Hz, 1H), 1.88-2.08 (m, 3H), 1.62-1.69 (m, 1H). 13 CNMR (100 MHz, CD3OD) δ 161.6, 149.0, 147.5, 141.6, 139.4, 133.5, 132.0, 128.6, 123.9, 120.6, 113.1, 104.9, 99.5, 78.1, 67.7, 54.5, 43.3, 28.1, 25.4. HRMS-ESI: Calcd for C 23 H 26 N3O4[M+H] + 408.1923, found: 408.1920.

[0202] The synthetic route of compound C5 is as follows:

[0203]

[0204] Compound 7 (0.1 g, 0.36 mmol) and 4-aminomethyltetrahydropyran (0.54 mmol, 1.5 eq) were used as starting materials, and the reaction was carried out according to the synthetic method of Example 1. The product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia water) = 10:0.15:0.05) to obtain compound C5 (0.114 g, 75%) as a white powder. m.p. 115.2-117.0 °C. 1 H NMR (400 MHz, DMSO-d6) δ 9.12 (d, J = 2.3 Hz, 1H), 8.86 (s, 1H), 8.50 (d, J = 2.3 Hz, 1H), 8.20 (d, J = 2.1 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.57 (dd, J = 8.9, 2.2 Hz, 1H), 6.98 (d, J = 2.2 Hz, 2H), 6.56 (t, J = 2.2 Hz, 1H), 6.40 (t, J = 5.9 Hz, 1H), 3.91 - 3.86 (m, 2H), 3.85 (s, 6H), 3.29 - 3.23 (m, 2H), 3.06 (t, J = 6.3 Hz, 2H), 1.77 - 1.67 (m, 1H), 1.62 - 1.55 (m, 2H), 1.31 - 1.13 (m, 2H). 13 C NMR (100 MHz, CD3OD) δ 161.6, 156.5, 149.1, 147.5, 141.7, 139.5, 133.6, 132.1, 128.6, 123.9, 120.7, 113.1, 104.9, 99.5, 67.4, 54.5, 45.1, 35.6, 30.3. HRMS-ESI: Calcd for C 24 H 28 N3O4[M+H] + 422.2080, Found: 422.2071.

[0205] The synthetic route of compound C6 is as follows:

[0206]

[0207] Compound 7 (0.1 g, 0.36 mmol) and 4-(2-aminomethyl)tetrahydropyran (0.54 mmol, 1.5 eq) were used as starting materials, and the reaction was carried out according to the synthetic method of Example 1. The product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia water) = 10:0.15:0.05) to obtain compound C6 (0.114 g, 75%) as a white powder. m.p. 165.6-167.5 °C. 1H NMR (400 MHz, CDC13) δ 8.99 (d, J = 2.3 Hz, 1H), 8.37 (s, 1H), 8.12 (d, J = 2.3 Hz, 1H), 7.95 (dd, J = 8.9, 2.1 Hz, 1H), 7.80 (d, J = 2.1 Hz, 1H), 7.72 (d, J = 8.9 Hz, 1H), 6.73 (d, J = 2.2 Hz, 2H), 6.49 (t, J = 2.2 Hz, 1H), 5.72 (t, J = 5.5 Hz, 1H), 3.92 - 3.82 (m, 8H), 3.34 - 3.17 (m, 4H), 1.53 - 1.32 (m, 5H), 1.28 - 1.25 (m, 2H). 13 C NMR (100 MHz, CDC13) δ 161.4, 155.9, 149.8, 147.9, 141.3, 139.7, 133.3, 132.2, 128.9, 124.1, 121.4, 114.7, 105.5, 99.7, 67.9, 55.5, 37.5, 37.1, 32.8, 32.6. HRMS-ESI: calcd for C 25 H 30 N3O4[M+H] + 436.2236, found: 436.2216.

[0208] The synthetic route of compound C7 is as follows:

[0209]

[0210] Using compound 7 (0.1 g, 0.36 mmol) and methyl 4-(aminomethyl)cyclohexane-1- carboxylate (0.54 mmol, 1.5 eq) as raw materials, the reaction was carried out according to the synthetic method of Example 1, and the product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia water) = 10:0.15:0.05) to obtain compound C7 yellow powder (0.134 g, 78%). m.p. 217.1-218.5 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.12 (d, J = 2.3 Hz, 1H), 8.84 (s, 1H), 8.50 (d, J = 2.4 Hz, 1H), 8.20 (d, J = 2.1 Hz, 1H), 7.89 (d, J = 8.9 Hz, 1H), 7.55 (dd, J = 8.8, 2.1 Hz, 1H), 6.98 (d, J = 2.2 Hz, 2H), 6.56 (d, J = 2.2 Hz, 1H), 6.37 (t, J = 5.9 Hz, 1H), 3.85 (s, 6H), 3.59 (s, 3H), 3.01 (t, J = 6.2 Hz, 2H), 2.34 - 2.22 (m, 1H), 2.02 - 1.90 (m, 2H), 1.84 - 1.75 (m, 2H), 1.46 - 1.38 (m, 0H), 1.36 - 1.28 (m, 2H), 1.09 - 0.89 (m, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 175.9, 161.5, 155.6, 150.0, 148.7, 142.2, 139.9, 133.1, 130.9, 129.2, 123.2, 120.6, 113.3, 105.4, 100.2, 55.9, 51.7, 45.3, 42.8, 37.9, 29.7, 28.7. HRMS-ESI: Calcd for C 27 H 32 N3O5[M+H] + 478.2342, Found: 478.2335.

[0211] The synthetic route of compound C8 is as follows:

[0212]

[0213] Using compound 7 (0.1 g, 0.36 mmol) and 4-amino-1-propionylpiperidine (0.54 mmol, 1.5 eq) as raw materials, the reaction was carried out according to the synthetic method of Example 1, and the product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia water) = 10:0.3:0.05) to obtain compound C8 yellow powder (0.113 g, 68%). m.p. 236.2-236.8 °C. 1H NMR (400 MHz, CD3OD) δ 8.96 (d, J = 2.3 Hz, 1H), 8.36 (d, J = 2.3 Hz, 1H), 8.12 (d, J = 2.1 Hz, 1H), 7.85 (d, J = 8.9 Hz, 1H), 7.61 (dd, J = 8.9, 2.1 Hz, 1H), 6.84 (d, J = 2.2 Hz, 2H), 6.52 (t, J = 2.2 Hz, 1H), 4.44 - 4.34 (m, 1H), 3.96 - 3.87 (m, 2H), 3.85 (s, 6H), 3.30 - 3.18 (m, 1H), 2.97 - 2.83 (m, 1H), 2.41 (q, J = 7.5 Hz, 2H), 2.13 - 1.93 (m, 2H), 1.53 - 1.31 (m, 2H), 1.12 (t, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, CD3OD) δ 173.3, 161.6, 155.6, 148.9, 147.4, 141.5, 139.4, 133.7, 132.0, 128.6, 124.0, 120.7, 113.0, 104.9, 99.5, 54.6, 46.8, 44.1, 40.4, 32.6, 31.7, 25.9, 8.6. HRMS-ESI: calcd for C 26 H 31 N4O4[M+H] + 463.2345, found: 463.2347.

[0214] The synthetic route of compound C9 is as follows:

[0215]

[0216] Using compound 7 (0.1 g, 0.36 mmol) and 4-(aminomethyl)-1-piperidinepropanoic acid (0.54 mmol, 1.5 eq) as raw materials, the reaction was carried out according to the synthetic method of Example 1, and compound C9 yellow powder (0.096 g, 56%) was obtained by silica gel column chromatography purification (V(dichloromethane):V(methanol):V(ammonia)=10:0.3:0.05). m.p. 91.7-93.2 °C. 1HNMR (400 MHz, CD3OD) δ 8.97 (d, J = 2.3 Hz, 1H), 8.40 (d, J = 2.3 Hz, 1H), 8.13 (d, J = 2.1 Hz, 1H), 7.88 (d, J = 8.9 Hz, 1H), 7.66 (dd, J = 8.9, 2.1 Hz, 1H), 6.86 (d, J = 2.2 Hz, 2H), 6.53 (t, J = 2.2 Hz, 1H), 4.56-4.52 (m, 1H), 3.99-3.95 (m, 1H), 3.86 (s, 6H), 3.17 (t, J = 6.5 Hz, 2H), 3.11-3.07 (m, 1H), 2.63 (td, J = 12.8, 2.7 Hz, 1H), 2.40 (q, J = 7.5 Hz, 2H), 1.86-1.78 (m, 3H), 1.22-1.14 (m, 2H), 1.11 (t, J = 7.5 Hz, 4H). 13 C NMR (100 MHz, CD3OD) δ 174.7, 163.1, 157.9, 150.4, 148.8, 143.1, 140.9, 135.2, 133.5, 130.0, 125.4, 122.2, 114.4, 106.3, 101.0, 56.0, 46.8, 46.0, 42.9, 38.2, 31.5, 30.7, 27.4, 10.1. HRMS-ESI: Calcd for C 27 H 33 N4O4[M+H] + 477.2502, Found: 477.2502.

[0217] The synthetic route of compound C10 is as follows:

[0218]

[0219] Using compound 7 (0.1 g, 0.36 mmol) and 4-aminoethyl-1-piperidinepropanoate (0.54 mmol, 1.5 eq) as raw materials, the reaction was carried out according to the synthetic method of Example 1, and compound C10 was obtained as a yellow oil (0.104 g, 59%) by purification on a silica gel column (V(dichloromethane):V(methanol):V(ammonia)=10:0.3:0.05). 1H NMR (400 MHz, CD3OD) δ 8.97 (d, J = 2.3 Hz, 1H), 8.39 (d, J = 2.3 Hz, 1H), 8.13 (d, J = 2.1 Hz, 1H), 7.87 (d, J = 8.9 Hz, 1H), 7.64 (dd, J = 8.9, 2.1 Hz, 1H), 6.85 (d, J = 2.2 Hz, 2H), 6.52 (t, J = 2.2 Hz, 1H), 4.51 (d, J = 13.2 Hz, 1H), 3.92 (d, J = 13.7 Hz, 1H), 3.85 (s, 6H), 3.28 (d, J = 7.2 Hz, 2H), 3.05 (dt, J = 13.0, 2.7 Hz, 1H), 2.60 (dt, J = 12.9, 2.9 Hz, 1H), 2.38 (q, J = 7.5 Hz, 2H), 1.85 - 1.80 (m, 2H), 1.65 - 1.63 (m, 1H), 1.51 (q, J = 7.0 Hz, 2H), 1.26 - 1.06 (m, 5H). 13 C NMR (100 MHz, CD3OD) δ 161.6, 112.9, 104.8, 99.5, 54.5, 48.2, 48.0, 47.8, 47.6, 47.4, 47.2, 46.9, 41.8, 36.9, 36.3, 33.4, 31.6, 25.9. HRMS-ESI: Calcd for C 28 H 35 N4O4[M+H] + 491.2658, Found: 491.2639.

[0220] The synthetic route of compound C11 is as follows:

[0221]

[0222] Using compound 7 (0.1 g, 0.36 mmol) and 4-aminomethyl-1-acetylpiperidine (0.54 mmol, 1.5 eq) as raw materials, the reaction was carried out according to the synthetic method of Example 1, and compound C11 yellow powder (0.125 g, 75%) was obtained by silica gel column chromatography purification (V(dichloromethane):V(methanol):V(ammonia)=10:0.2:0.05). m.p. 65.5-66.2 °C. 1H NMR (400 MHz, CD3OD) δ 8.96 (d, J = 2.3 Hz, 1H), 8.37 (d, J = 1.9 Hz, 1H), 8.12 (d, J = 2.1 Hz, 1H), 7.86 (d, J = 8.9 Hz, 1H), 7.64 (dd, J = 8.9, 2.2 Hz, 1H), 6.84 (d, J = 2.2 Hz, 2H), 6.52 (t, J = 2.2 Hz, 1H), 4.55 - 4.51 (m, 1H), 3.95 - 3.91 (m, 1H), 3.85 (s, 6H), 3.21 - 3.06 (m, 3H), 2.62 (td, J = 12.9, 2.7 Hz, 1H), 2.09 (s, 3H), 1.85 - 1.77 (m, 3H), 1.27 - 1.11 (m, 2H). 13 C NMR (100 MHz, CD3OD) δ 170.0, 161.6, 156.5, 149.1, 147.5, 141.6, 139.4, 133.6, 132.0, 128.6, 123.9, 120.7, 113.1, 104.9, 99.5, 54.6, 46.2, 44.6, 41.4, 36.6, 29.9, 29.2, 19.9. HRMS-ESI: calcd for C 26 H 31 N4O4[M+H] + 463.2345, found: 463.2338.

[0223] The synthetic route of compound C12 is as follows:

[0224]

[0225] Using compound 7 (0.1 g, 0.36 mmol) and 4-aminomethyl-1-trifluoroacetyl piperidine (0.54 mmol, 1.5 eq) as raw materials, reacting according to the synthetic method of Example 1, the product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia)=10:0.2:0.05) to obtain compound C12 yellow oil (0.134 g, 72%). 1H NMR (400 MHz, CD3OD) δ 8.98 (d, J = 2.3 Hz, 1H), 8.42 (dd, J = 2.3, 0.8 Hz, 1H), 8.14 (d, J = 2.1 Hz, 1H), 7.89 (d, J = 8.9 Hz, 1H), 7.66 (dd, J = 8.9, 2.2 Hz, 1H), 6.87 (d, J = 2.2 Hz, 2H), 6.54 (t, J = 2.2 Hz, 1H), 4.53 - 4.44 (m, 1H), 4.08 - 3.97 (m, 1H), 3.86 (s, 6H), 3.25 (ddd, J = 14.1, 12.5, 2.4 Hz, 1H), 3.18 (dd, J = 6.3, 1.2 Hz, 2H), 2.89 (t, J = 12.6 Hz, 1H), 1.98 - 1.84 (m, 3H), 1.37 - 1.13 (m, 3H). 13 C NMR (100 MHz, CD3OD) δ 161.7, 156.4, 148.5, 146.8, 141.9, 139.2, 134.3, 132.1, 128.7, 124.1, 120.9, 112.3, 104.9, 99.6, 54.6, 45.5, 44.3, 43.3, 36.4, 29.9, 28.9. HRMS-ESI: calcd for C 26 H 28 N4O4F3[M+H] + 517.2063, found: 517.2050.

[0226] The synthetic route of compound C13 is as follows:

[0227]

[0228] Using compound 7 (0.1 g, 0.36 mmol) and 4-aminomethyl-1- cyclopropylacylpiperidine (0.54 mmol, 1.5 eq) as raw materials, the reaction was carried out according to the synthetic method of Example 1, and the product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia)=10:0.2:0.05) to obtain compound C13 yellow oil (0.120 g, 68%). 1H NMR (400 MHz, CD3OD) δ 8.96 (d, J = 2.2 Hz, 1H), 8.38 (d, J = 2.3 Hz, 1H), 8.13 (d, J = 2.1 Hz, 1H), 7.87 (d, J = 8.9 Hz, 1H), 7.65 (dd, J = 8.9, 2.1 Hz, 1H), 6.85 (d, J = 2.2 Hz, 2H), 6.53 (t, J = 2.4 Hz, 1H), 4.56 - 4.48 (m, 1H), 4.44 - 4.27 (m, 1H), 3.85 (s, 6H), 3.25 - 3.08 (m, 3H), 2.66 (t, J = 12.6 Hz, 1H), 2.05 - 1.90 (m, 1H), 1.90 - 1.69 (m, 3H), 1.36 - 0.98 (m, 3H), 0.90 - 0.81 (m, 2H), 0.81 - 0.71 (m, 2H). 13 CNMR (100 MHz, CDC13) δ 172.3, 161.4, 156.0, 149.7, 147.8, 141.8, 139.9, 133.5, 132.1, 128.8, 123.9, 121.3, 114.1, 105.5, 99.8, 55.5, 45.8, 44.9, 42.7, 30.4, 29.3, 11.2, 7.5. HRMS-ESI: Calcd for C 28 H 33 N4O4[M+H] + 489.2502, Found: 489.2489.

[0229] The synthetic route of compound C14 is as follows:

[0230]

[0231] Using compound 7 (0.1 g, 0.36 mmol) and 4-(aminomethyl)piperidine-1-carboxylic acid benzyl ester (0.54 mmol, 1.5 eq) as raw materials, the reaction was carried out according to the synthetic method of Example 1, and compound C14 (0.148 g, 74%) was obtained by silica gel column chromatography purification (V(dichloromethane): V(methanol): V(ammonia water) = 10:0.2:0.05). m.p. 189.5-191.0 °C. 1H NMR (400 MHz, CDC13) δ 9.00 (d, J = 2.2 Hz, 1H), 8.14 (d, J = 2.3 Hz, 1H), 7.99 (dt, J = 9.0, 2.3 Hz, 1H), 7.78 - 7.69 (m, 2H), 7.36 - 7.18 (m, 5H), 6.75 (d, J = 2.2 Hz, 2H), 6.49 (t, J = 2.2 Hz, 1H), 5.09 (s, 2H), 4.13 (s, 2H), 3.84 (s, 6H), 3.16 (d, J = 5.6 Hz, 2H), 2.70 (s, 2H), 1.66 - 1.63 (m, 3H), 1.19 - 1.07 (m, 2H). 13 C NMR (100 MHz, CDC13) δ 161.4, 155.9, 155.9, 155.5, 149.9, 147.9, 141.4, 141.3, 139.8, 136.7, 133.3, 132.2, 128.9, 128.5, 128.0, 127.7, 124.0, 123.9, 121.2, 121.1, 114.6, 114.4, 105.5, 99.7, 67.2, 55.5, 45.2, 45.1, 43.9, 36.7, 29.6. HRMS-ESI: Calcd for C 32 H 35 N4O5[M+H] + 555.2607, found: 555.2584.

[0232] The synthetic route of compound C15 is as follows:

[0233]

[0234] Using compound 7 (0.1 g, 0.36 mmol) and (S)-1-(4-aminopiperidin-1-yl)-2- methylbutan-1-one (0.54 mmol, 1.5 eq) as raw materials, reacting according to the synthetic method of Example 1, the product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia)=10:0.2:0.05) to obtain compound C15 yellow oil (0.097 g, 55%). 1H NMR (400 MHz, CD3OD) δ 8.97 (d, J = 2.3 Hz, 1H), 8.38 (d, J = 2.1 Hz, 1H), 8.14 (d, J = 2.3 Hz, 1H), 7.87 (d, J = 8.9 Hz, 1H), 7.63 (dd, J = 8.9, 2.2 Hz, 1H), 6.85 (d, J = 2.3 Hz, 2H), 6.53 (t, J = 2.2 Hz, 1H), 4.49 - 4.36 (m, 1H), 4.08 - 4.00 (m, 1H), 3.92 - 3.87 (m, 1H), 3.85 (s, 6H), 3.31 - 3.27 (m, 1H), 2.92 - 2.89 (m, 1H), 2.81 - 2.77 (m, 1H), 2.09 - 2.06 (m, 1H), 2.03 - 1.93 (m, 1H), 1.67 - 1.64 (m, 1H), 1.44 - 1.38 (m, 3H), 1.08 (t, J = 7.8 Hz, 3H), 0.89 (dt, J = 10.8, 7.3 Hz, 3H). 13 C NMR (100 MHz, CD3OD) δ 175.94, 175.9, 161.6, 155.6, 149.0, 147.4, 141.5, 139.4, 133.7, 132.1, 128.6, 124.0, 120.7, 113.0, 104.9, 99.5, 54.6, 48.3, 48.0, 47.8, 47.6, 47.4, 47.2, 46.9, 46.9, 44.2, 44.1, 40.6, 40.5, 36.6, 33.0, 32.0, 31.8, 26.8, 26.8, 16.4, 16.3, 10.9, 10.7. HRMS-ESI: calc C 28 H 35 N4O4[M+H] + 491.2658, found: 491.2654.

[0235] The synthetic route of compound C16 in Example 16 is as follows:

[0236]

[0237] Compound 7 (0.1 g, 0.36 mmol) was dissolved in 15 mL of dichloromethane, and carbonyldiimidazole (0.065 g, 0.43 mmol, 1.2 eq) was added, and the reaction was allowed to proceed at room temperature for 12 h. Then 4-trifluoromethoxy aniline (0.54 mmol, 1.5 eq) was added to the reaction solution, and the reaction was allowed to proceed at room temperature for 0.5 h. After the reaction was completed, the reaction solution was washed with saturated ammonium chloride, and the organic phase was collected and concentrated by rotary evaporation, and compound C16 was obtained as a light yellow powder (0.097 g, 56%) by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia water)=10:0.1:0.05). m.p. 216.6-217.9 °C. 1 H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 9.19 (d, J = 2.3 Hz, 1H), 9.09 (s, 1H), 8.59 (d, J = 2.4 Hz, 1H), 8.30 (d, J = 2.1 Hz, 1H), 7.99 (d, J = 8.9 Hz, 1H), 7.66 (dd, J = 8.9, 2.2 Hz, 1H), 7.62 (d, J = 9.0 Hz, 2H), 7.33 (d, J = 8.7 Hz, 2H), 7.01 (d, J = 2.3 Hz, 2H), 6.58 (t, J = 2.2 Hz, 1H), 3.86 (s, 6H). 13 C NMR (176 MHz, DMSO) δ 161.6, 152.9, 152.8, 150.1, 143.3, 141.3, 139.7, 139.2, 133.5, 131.3, 129.4, 123.8, 122.3, 121.4, 120.9, 120.1, 119.9, 114.2, 105.4, 100.33, 55.9. HRMS-ESI: Calcd for C 25 H 21 N3O4F3[M+H] + 484.1484, Found: 484.1485.

[0238] The synthetic route of compound C17 is as follows:

[0239]

[0240] Compound 7 (0.1 g, 0.36 mmol) and 4-trifluoromethoxy benzylamine (0.54 mmol, 1.5 eq) were used as raw materials, and the reaction was carried out according to the synthesis method of Example 1, and the product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia water)=10:0.1:0.05) to obtain compound C17 as a yellow powder (0.134 g, 75%). m.p. 186.7-187.7 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.13 (d, J = 2.4 Hz, 1H), 9.11 (s, 1H), 8.50 (d, J = 2.4 Hz, 1H), 8.22 (d, J = 2.1 Hz, 1H), 7.91 (d, J = 8.9 Hz, 1H), 7.61 (dd, J = 8.9, 2.1 Hz, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 6.98 (d, J = 2.2 Hz, 2H), 6.91 (t, J = 6.0 Hz, 1H), 6.56 (t, J = 2.2 Hz, 1H), 4.39 (d, J = 5.9 Hz, 2H), 3.85 (s, 6H). 13 C NMR (176 MHz, DMSO-d6) δ 161.5, 155.9, 150.0, 148.7, 147.6, 142.23, 140.5, 139.9, 133.1, 130.8, 129.3, 129.1, 123.2, 121.4, 120.5, 113.2, 105.3, 100.2, 55.9, 42.4. HRMS-ESI: calc. for C 26 H 23 N3O4F3[M+H] + 498.1641, found: 498.1649.

[0241] The synthetic route of compound C18 is as follows:

[0242]

[0243] Using compound 7 (0.1 g, 0.36 mmol) and 3-trifluoromethoxybenzylamine (0.54 mmol, 1.5 eq) as raw materials, reacting according to the synthetic method of Example 1, the product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia water) = 10:0.1:0.05) to obtain compound C18 yellow powder (0.118 g, 66%). m.p. 176.2-178.1 °C. 1H NMR (400 MHz, CD3OD) δ 9.00 (d, J = 2.4 Hz, 1H), 8.44 (s, 1H), 8.16 (s, 1H), 7.92 (d, J = 8.9 Hz, 1H), 7.71 (dd, J = 8.9, 2.2 Hz, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.37 (d, J = 7.7 Hz, 1H), 7.29 (s, 1H), 7.17 (d, J = 9.5 Hz, 1H), 6.89 (d, J = 2.3 Hz, 2H), 6.55 (t, J = 2.3 Hz, 1H), 4.49 (s, 2H), 3.87 (s, 6H). 13 CNMR (100 MHz, DMSO-d6) δ 161.6, 155.6, 150.1, 149.0, 148.6, 143.9, 142.0, 139.9, 133.1, 131.0, 130.7, 129.2, 126.7, 123.4, 120.7, 119.9, 119.6, 113.7, 105.4, 100.3, 55.9, 42.8. HRMS-ESI: Calcd for C 26 H 23 N3O4F3[M+H] + 498.1641, Found: 498.1637.

[0244] The synthetic route of compound C19 is as follows:

[0245]

[0246] Using compound 7 (0.1 g, 0.36 mmol) and 4-difluoromethoxybenzylamine (0.54 mmol, 1.5 eq) as starting materials, the reaction was carried out according to the synthetic method of Example 1, and the product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia)=10:0.1:0.05) to obtain compound C19 white powder (0.116 g, 67%). m.p. 205.1-206.9 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.13 (d, J = 2.3 Hz, 1H), 9.06 (s, 1H), 8.51 (d, J = 2.4 Hz, 1H), 8.22 (d, J = 2.1 Hz, 1H), 7.90 (d, J = 8.9 Hz, 1H), 7.59 (dd, J = 8.9, 2.2 Hz, 1H), 7.40 (d, J = 8.6 Hz, 2H), 7.20 (t, J = 72 Hz, 1H), 7.16 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 2.2 Hz, 2H), 6.84 (t, J = 6.0 Hz, 1H), 6.56 (t, J = 2.2 Hz, 1H), 4.35 (d, J = 5.9 Hz, 2H), 3.85 (s, 6H). 13 C NMR (100 MHz, DMSO-d6) δ 160.9, 154.9, 149.6, 148.1, 141.4, 139.4, 137.3, 132.5, 130.4, 128.7, 122.8, 120.1, 118.9, 116.3, 113.8, 113.1, 104.8, 99.7, 55.3, 42.1. HRMS-ESI: calcd for C 26 H 24 N3O4F2[M+H] + 480.1735, found: 480.1728.

[0247] The synthetic route of compound C20 is as follows:

[0248]

[0249] Using compound 7 (0.1 g, 0.36 mmol) and 4-trifluoromethylbenzylamine (0.54 mmol, 1.5 eq) as raw materials, reacting according to the synthetic method of Example 1, the product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia water) = 10:0.1:0.05) to obtain compound C20 white powder (0.109 g, 63%). m.p. 223.0-224.1 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 9.13 (d, J = 1.7 Hz, 1H), 8.51 (d, J = 2.4 Hz, 1H), 8.22 (s, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.61 (dd, J = 9.0, 2.1 Hz, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.03 - 6.90 (m, 3H), 6.56 (t, J = 2.2 Hz, 1H), 4.45 (d, J = 5.9 Hz, 2H), 3.85 (s, 6H). 13 C NMR (100 MHz, DMSO-d6) δ 160.9, 154.9, 149.4, 147.9, 145.1, 141.3, 139.2, 132.4, 130.3, 128.5, 127.5, 127.3, 124.9, 124.9, 124.9, 122.7, 120.0, 113.1, 104.7, 99.5, 55.2, 42.2. HRMS-ESI: calcd for C 26 H 23 N3O3F3[M+H] + 482.1692, found: 482.1687.

[0250] The synthetic route of compound C21 is as follows:

[0251]

[0252] Using compound 7 (0.1 g, 0.36 mmol) and 4-methoxybenzylamine (0.54 mmol, 1.5 eq) as raw materials, reacting according to the synthetic method of Example 1, and purifying the product by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia water) = 10:0.1:0.05) to obtain compound C21 white powder (0.129 g, 81%). m.p. 200.9-201.4 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.17 (d, J = 2.3 Hz, 1H), 9.07 (s, 1H), 8.61 (s, 1H), 8.27 (d, J = 2.2 Hz, 1H), 7.94 (d, J = 8.9 Hz, 1H), 7.60 (dd, J = 8.8, 2.2 Hz, 1H), 7.28 (d, J = 8.7 Hz, 2H), 7.00 (d, J = 2.2 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 6.77 (t, J = 5.9 Hz, 1H), 6.57 (t, J = 2.2 Hz, 1H), 4.29 (d, J = 5.5 Hz, 2H), 3.85 (s, 6H), 3.74 (s, 3H). 13 C NMR (176 MHz, DMSO-d6) δ 161.6, 158.7, 155.3, 132.4, 130.9, 129.6, 129.1, 123.7, 114.2, 105.5, 100.5, 55.9, 55.6, 42.8. HRMS-ESI: Calcd for C 26 H 26 N3O4[M+H] + 444.1923, Found: 444.1915.

[0253] The synthetic route of compound C22 is as follows:

[0254]

[0255] Using compound 7 (0.1 g, 0.36 mmol) and 4-cyanobenzylamine (0.54 mmol, 1.5 eq) as raw materials, reacting according to the synthetic method of Example 1, and purifying the product by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia)=10:0.1:0.05) to obtain compound C22 white powder (0.131 g, 83%). m.p. 219.1-220.7 °C. 1 H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 9.14 (d, J = 2.4 Hz, 1H), 8.51 (d, J = 2.4 Hz, 1H), 8.22 (d, J = 2.1 Hz, 1H), 7.91 (d, J = 8.9 Hz, 1H), 7.83 (d, J = 8.3 Hz, 2H), 7.61 (dd, J = 8.9, 2.2 Hz, 1H), 7.54 (d, J = 8.1 Hz, 2H), 6.98 (d, J = 2.3 Hz, 2H), 6.95 (t, J = 6.1 Hz, 1H), 6.56 (t, J = 2.2 Hz, 1H), 4.45 (s, 2H), 3.85 (s, 6H). 13C NMR (176 MHz, DMSO-d6) δ 161.5, 155.6, 150.1, 148.6, 146.9, 141.9, 139.9, 133.1, 132.8, 131.0, 129.2, 128.4, 123.4, 120.7, 119.4, 113.7, 109.9, 105.4, 100.2, 55.7, 43.1. HRMS-ESI: calculated for C 26 H 23 N4O3[M+H] + 439.1770, found: 439.1768.

[0256] The synthetic route of compound C23 is as follows:

[0257]

[0258] Using compound 7 (0.1 g, 0.36 mmol) and 4-sulfonamidobenzylamine (0.54 mmol, 1.5 eq) as raw materials, the reaction was carried out according to the synthetic method of Example 1, and the product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia water) = 10:0.2:0.05) to obtain compound C23 yellow powder (0.063 g, 36%). m.p. 235.5-236.1 °C. 1 H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 9.14 (d, J = 2.3 Hz, 1H), 8.52 (d, J = 2.4 Hz, 1H), 8.23 (d, J = 2.1 Hz, 1H), 7.91 (d, J = 8.9 Hz, 1H), 7.81 (d, J = 8.2 Hz, 2H), 7.61 (dd, J = 8.9, 2.2 Hz, 1H), 7.52 (d, J = 8.1 Hz, 2H), 7.32 (s, 2H), 7.02 - 6.87 (m, 3H), 6.56 (t, J = 2.2 Hz, 1H), 4.44 (d, J = 5.8 Hz, 2H), 3.85 (s, 6H). 13 C NMR (100 MHz, DMSO-d6) δ 161.5, 155.6, 150.1, 148.6, 144.9, 143.0, 142.0, 139.9, 133.1, 130.9, 129.2, 127.8, 123.4, 120.7, 113.7, 105.4, 100.2, 55.9, 42.9. HRMS-ESI: calculated for C 25 H 25 N4O5S[M+H] + 493.1546, found: 493.1540.

[0259] The synthetic route of compound C24 is as follows:

[0260]

[0261] Using compound 7 (0.1 g, 0.36 mmol) and 4-methylsulfonamidobenzylamine (0.54 mmol, 1.5 eq) as raw materials, the reaction was carried out according to the synthetic method of Example 1, and the product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia water) = 10:0.1:0.05) to obtain compound C24 white powder (0.067 g, 38%). m.p. 184.3-185.6 °C. 1 H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 9.14 (d, J = 2.4 Hz, 1H), 8.51 (d, J = 2.4 Hz, 1H), 8.22 (d, J = 2.1 Hz, 1H), 7.92 (d, J = 8.4 Hz, 3H), 7.61 (d, J = 8.3 Hz, 3H), 7.01-6.90 (m, 3H), 6.56 (t, J = 2.2 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 3.85 (s, 6H), 3.20 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 161.6, 155.6, 150.1, 148.6, 147.1, 141.9, 139.9, 139.7, 133.1, 131.0, 129.2, 128.3, 127.6, 123.4, 120.7, 113.7, 100.2, 55.9, 44.1, 42.9. HRMS-ESI: Calcd for C 26 H 26 N3O5S [M+H] + 492.1593, Found: 492.1588.

[0262] The synthetic route of compound C25 is as follows:

[0263]

[0264] Using compound 7 (0.1 g, 0.36 mmol) and 4-aminomethylpyridine (0.54 mmol, 1.5 eq) as raw materials, the reaction was carried out according to the synthetic method of Example 1, and the product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia water) = 10:0.1:0.05) to obtain compound C25 yellow powder (0.092 g, 62%). m.p. 205.3-207.1 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 9.13 (d, J = 2.4 Hz, 1H), 8.53 (d, J = 6.1 Hz, 2H), 8.51 (d, J = 2.4 Hz, 1H), 8.22 (d, J = 2.1 Hz, 1H), 7.91 (d, J = 8.9 Hz, 1H), 7.62 (dd, J = 8.8, 2.2 Hz, 1H), 7.34 (d, J = 6.1 Hz, 2H), 6.98 (d, J = 2.2 Hz, 2H), 6.93 (t, J = 6.1 Hz, 1H), 6.56 (t, J = 2.2 Hz, 1H), 4.40 (d, J = 6.0 Hz, 2H), 3.85 (s, 6H). 13 C NMR (100 MHz, DMSO-d6) δ 161.6, 155.7, 150.1, 150.0, 149.9, 148.6, 141.9, 139.9, 133.1, 131.0, 129.2, 123.4, 122.5, 120.7, 113.8, 105.4, 100.3, 55.9, 42.4. HRMS-ESI: Calcd for C 24 H 23 N4O3[M+H] + 415.1770, Found: 415.1770.

[0265] The synthetic route of compound C26 is as follows:

[0266]

[0267] Compound 5 (0.1 g, 0.36 mmol) was dissolved in 15 mL of dichloromethane, carbonyldiimidazole (0.065 g, 0.43 mmol, 1.2 eq) was added, and the reaction was carried out at room temperature for 12 h. 4-sulfonamidobenzylamine (0.54 mmol, 1.5 eq) was added to the reaction solution, and the reaction was continued at room temperature for 0.5 h. After the reaction was completed, the organic phase was washed with saturated ammonium chloride, and the organic phase was collected and concentrated by rotary evaporation, and was subjected to silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia water) = 10:0.25:0.05) to obtain compound C26 as a yellow powder (0.074 g, 42%). m.p. 224.1-225.3 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 2H), 8.46 (d, J = 2.4 Hz, 1H), 8.21 (d, J = 2.1 Hz, 1H), 7.89 (d, J = 8.9 Hz, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.60 (dd, J = 8.8, 2.2 Hz, 1H), 7.52 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 2.2 Hz, 1H), 7.38 (dd, J = 8.3, 2.1 Hz, 1H), 7.32 (s, 2H), 7.10 (d, J = 8.4 Hz, 1H), 6.94 (t, J = 6.0 Hz, 1H), 4.44 (s, 1H), 4.43 (s, 1H), 3.89 (s, 3H), 3.82 (s, 3H). 13 C NMR (176 MHz, DMSO) δ 155.6, 150.08, 150.06, 149.8, 149.3, 148.1, 145.0 144.7, 143.0, 141.6, 132.0, 131.1, 130.5, 129.8, 128.9, 127.8, 126.2, 123.5, 120.6, 119.5, 113.8, 112.8, 110.9, 56.1, 56.1, 42.9. HRMS-ESI: calc. for C 25 H 25 N4O5S [M+H] + 493.1546, found: 493.1545.

[0268] The synthetic route of compound C27 is as follows:

[0269]

[0270] Using compound 5 (0.1 g, 0.36 mmol) and 4-difluoromethoxybenzylamine (0.54 mmol, 1.5 eq) as starting materials, the reaction was carried out according to the synthetic method of Example 26, and the product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia)=10:0.15:0.05) to obtain compound C27 white powder (0.119 g, 67%). m.p. 181.1-182.0 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.14 (d, J = 2.3 Hz, 1H), 9.02 (s, 1H), 8.45 (d, J = 2.4 Hz, 1H), 8.20 (d, J = 2.1 Hz, 1H), 7.89 (d, J = 8.9 Hz, 1H), 7.58 (dd, J = 8.8, 2.2 Hz, 1H), 7.40 (d, J = 8.2 Hz, 3H), 7.21 (t, J = 72 Hz, 1H), 7.17 (d, J = 8.6 Hz, 2H), 7.10 (d, J = 8.4 Hz, 1H), 6.83 (t, J = 6.0 Hz, 1H), 4.36 (s, 1H), 4.34 (s, 1H), 3.90 (s, 3H), 3.82 (s, 3H). 13 C NMR (176 MHz, DMSO) δ 155.6, 150.2, 150.2, 150.2, 150.0, 149.8, 149.3, 148.1, 141.6, 137.9, 132.1, 131.1, 130.5, 129.3, 128.9, 123.5, 120.6, 119.5, 119.3, 118.4, 116.9, 115.4 (F-C), 113.7, 112.8, 110.9, 56.1 56.1, 55.4, 42.6. HRMS-ESI: Calcd for C 26 H 24 N3O4F2[M+H] + 480.1735, Found: 480.1735.

[0271] The synthetic route of compound C28 is as follows:

[0272]

[0273] Compound 9 (0.073 g, 0.2 mmol) was dissolved in 15 mL of ethylene glycol dimethyl ether, 3,4-(methylenedioxy)benzeneboronic acid (0.04 g, 0.24 mmol, 1.2 eq), tetrakis triphenylphosphine palladium (0.035 g, 0.03 mmol, 0.15 eq), sodium carbonate (0.32 g, 0.3 mmol, 1.5 eq) and 5 mL of water were added. Stirring was carried out under argon protection at 80 °C for 1.5 h. After the reaction was completed, extraction was carried out with dichloromethane and water, and the organic phase was washed with water, saturated brine in turn, concentrated by rotary evaporation, and dried to obtain a solid, which was subjected to silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia water) = 10:0.15:0.05) to obtain C28 yellow powder (0.061 g, yield 76%). m.p. 200.4-202.2 °C. 1H NMR (400 MHz, CD3OD) δ 8.99 (s, 1H), 8.40 (d, J = 2.3 Hz, 1H), 8.15 (d, J = 2.1 Hz, 1H), 7.89 (d, J = 8.9 Hz, 1H), 7.65 (dd, J = 8.9, 2.1 Hz, 1H), 7.26 (d, J = 1.7 Hz, 1H), 7.24 (dd, J = 8.0, 1.9 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.02 (s, 2H), 4.01 - 3.94 (m, 2H), 3.47 - 3.38 (m, 2H), 3.16 (d, J = 6.7 Hz, 2H), 1.87 - 1.73 (m, 1H), 1.72 - 1.66 (m, 2H), 1.41 - 1.31 (m, 2H). 13 C NMR (100 MHz, CD3OD) δ 156.5, 148.7, 148.6, 147.9, 146.6, 141.7, 133.5, 132.0, 128.5, 124.2, 120.9, 120.6, 112.5, 108.5, 106.9, 101.4, 67.4, 45.1, 35.6, 30.3. HRMS-ESI: calcd for C 23 H 24 N3O4[M+H] + 406.1767, found: 406.1750.

[0274] The synthetic route of compound C29 is as follows:

[0275]

[0276] Compound C29 was prepared by the method described in example 28, using compound 9 (0.073 g, 0.2 mmol) and 4-trifluoromethoxybenzeneboronic acid (0.049 g, 0.24 mmol, 1.2 eq) as starting materials. The product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia)=10:0.15:0.05) to give compound C29 as a white powder (0.073 g, yield 82%). m.p. 214.8-219.4 °C. 1H NMR (400 MHz, CD3OD) δ 9.02 (d, J = 2.3 Hz, 1H), 8.45 (d, J = 2.3 Hz, 1H), 8.14 (d, J = 2.1 Hz, 1H), 7.90 (d, J = 8.9 Hz, 1H), 7.86 (d, J = 8.7 Hz, 2H), 7.69 (dd, J = 8.9, 2.2 Hz, 1H), 7.42 (d, J = 7.9 Hz, 2H), 3.99 - 3.92 (m, 2H), 3.46 - 3.38 (m, 2H), 3.16 (d, J = 6.7 Hz, 2H), 1.90 - 1.75 (m, 1H), 1.73 - 1.64 (m, 2H), 1.44 - 1.22 (m, 2H). 13 C NMR (100 MHz, CD3OD) δ 157.9, 150.5, 150.3, 149.1, 143.4, 138.1, 135.2, 132.1, 130.1, 129.9, 125.4, 122.8, 122.3, 114.6, 68.8, 46.6, 37.1, 31.8. HRMS-ESI: calcd for C 23 H 23 N3O3F3[M+H] + 446.1692, found: 446.1687.

[0277] The synthetic route of compound C30 is as follows:

[0278]

[0279] With compound 9 (0.073 g, 0.2 mmol) and 3-trifluoromethoxybenzoic acid (0.049 g, 0.24 mmol, 1.2 eq) as raw materials, reaction according to the synthetic method of Example 28, the product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia)=10:0.15:0.05) to obtain compound C30 white powder (0.068 g, yield 78%). m.p. 199.9-201.2 °C. 1H NMR (400 MHz, CD3OD) δ 9.02 (d, J = 2.4 Hz, 1H), 8.48 (d, J = 2.3 Hz, 1H), 8.16 (d, J = 2.3 Hz, 1H), 7.92 (d, J = 8.9 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.69 (dd, J = 2.4, 9.0 Hz, 2H), 7.62 (t, J = 8.0 Hz, 1H), 7.34 (d, J = 8.3 Hz, 1H), 4.03 - 3.92 (m, 2H), 3.47 - 3.35 (m, 2H), 3.16 (d, J = 6.7 Hz, 2H), 1.88 - 1.76 (m, 1H), 1.72 - 1.65 (m, 2H), 1.42 - 1.25 (m, 2H). 13 C NMR (100 MHz, CD3OD) δ 157.9, 151.4, 150.2, 149.3, 143.5, 141.4, 135.4, 132.1, 131.8, 130.2, 127.0, 125.3, 123.3, 122.3, 121.4, 120.8, 114.5, 68.8, 46.6, 37.1, 31.8. HRMS-ESI: calcd for C 23 H 23 N3O3F3[M+H] + 446.1692, found: 446.1688.

[0280] The synthetic route of compound C31 is as follows:

[0281]

[0282] Compound 9 (0.073 g, 0.2 mmol) and 4-dimethylaminophenylboronic acid (0.043 g, 0.24 mmol, 1.2 eq) as raw materials, according to the synthetic method of Example 28, the product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia)=10:0.15:0.05) to obtain compound C31 yellow oil (0.063 g, yield 76%). m.p. 229.3-230.8 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.08 (d, J = 2.4 Hz, 1H), 8.78 (s, 1H), 8.33 (d, J = 2.4 Hz, 1H), 8.14 (d, J = 2.1 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 8.9 Hz, 2H), 7.53 (dd, J = 8.8, 2.2 Hz, 1H), 6.86 (d, J = 8.9 Hz, 2H), 6.36 (t, J = 5.9 Hz, 1H), 3.86 (dd, J = 11.5, 2.6 Hz, 2H), 3.27 (dd, J = 11.6, 2.1 Hz, 2H), 3.05 (t, J = 6.2 Hz, 2H), 2.96 (s, 6H), 1.66 - 1.72 (m, 1H), 1.58 - 1.61 (m, 2H), 1.21 (qd, J = 12.0, 4.4 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 155.1, 149.9, 149.1, 147.1, 140.8, 130.7, 130.0, 128.2, 127.2, 124.5, 123.1, 119.9, 113.0, 112.7, 66.7, 44.7, 35.2, 30.2. HRMS-ESI: calcd for C 24 H 29 N4O2[M+H] + 405.2291, found: 405.2290.

[0283] The synthetic route of compound C32 is as follows:

[0284]

[0285] Compound 9 (0.073 g, 0.2 mmol) and 3-dimethylaminophenylboronic acid (0.043 g, 0.24 mmol, 1.2 eq) as raw materials, according to the synthetic method of Example 28, the product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia)=10:0.15:0.05) to obtain compound C32 yellow oil (0.064 g, yield 76%). m.p. 177.5-178.9 °C. 1H NMR (400 MHz, CD3OD) δ 8.95 (d, J = 2.2 Hz, 1 H), 8.32 (d, J = 2.3 Hz, 1 H), 8.12 (d, J = 2.1 Hz, 1 H), 7.82 (d, J = 8.9 Hz, 1 H), 7.63 (dd, J = 8.9, 2.1 Hz, 1 H), 7.30 (t, J = 8.0 Hz, 1 H), 7.00 - 6.98 (m, 2 H), 6.79 (d, J = 7.1 Hz, 1 H), 3.96 - 3.92 (m, 2 H), 3.42 - 3.36 (m, 2 H), 3.14 (d, J = 6.7 Hz, 2 H), 2.98 (s, 6 H), 1.77 - 1.76 (m, 1 H), 1.68 - 1.65 (m, 2 H), 1.36 - 1.24 (m, 2 H). 13 C NMR (100 MHz, CD3OD) δ 156.5, 151.4, 149.2, 147.1, 141.5, 138.0, 133.5, 133.0, 129.5, 128.5, 124.1, 120.6, 115.2, 112.9, 112.3, 110.9, 67.4, 45.1, 39.6, 35.6, 30.3.

[0286] The synthetic route of compound C33 is as follows:

[0287]

[0288] Compound 9 (0.073 g, 0.2 mmol) and 4-(4-methyl-1-piperazinyl)benzeneboronic acid (0.053 g, 0.24 mmol, 1.2 eq) as raw material, according to the synthetic method of Example 28, the product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia)=10:0.2:0.05) to obtain compound C33 yellow powder (0.060 g, yield 76%). m.p. 217.9-219.8 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.08 (d, J = 2.4 Hz, 1H), 8.81 (s, 1H), 8.36 (d, J = 2.4 Hz, 1H), 8.15 (d, J = 2.1 Hz, 1H), 7.85 (d, J = 8.9 Hz, 1H), 7.70 (d, J = 8.8 Hz, 2H), 7.54 (dd, J = 8.9, 2.2 Hz, 1H), 7.07 (d, J = 8.7 Hz, 2H), 6.37 (t, J = 5.9 Hz, 1H), 3.86 (dd, J = 11.3, 2.8 Hz, 2H), 3.27 (dd, J = 11.7, 2.1 Hz, 2H), 3.22 (t, J = 5.0 Hz, 4H), 3.05 (t, J = 6.2 Hz, 2H), 2.48 (t, J = 4.9 Hz, 3H), 2.24 (s, 3H), 1.72 - 1.65 (m, 1H), 1.61 - 1.57 (m, 2H), 1.26 - 1.56 (m, 3H). 13 CNMR (100 MHz, DMSO-d6) δ 155.6, 151.0, 149.7, 147.9, 141.5, 131.1, 131.0, 128.8, 127.7, 123.6, 120.5, 116.1, 113.5, 67.2, 55.0, 48.2, 46.22, 5.3, 35.8, 30.8. HRMS-ESI: Calcd for C 27 H 34 N5O2[M+H] + 460.2713, Found: 460.2722.

[0289] The synthetic route of compound C34 is outlined as follows:

[0290]

[0291] Compound 9 (0.073 g, 0.2 mmol) and 4-acetylphenylboronic acid (0.039 g, 0.24 mmol, 1.2 eq) as raw materials, according to the synthetic method of Example 28, the product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia water) = 10:0.2:0.05) to obtain compound C34 yellow powder (0.065 g, yield 81 %). m.p. 224.3-224.7 °C. 1HNMR (400 MHz, DMSO-d6) δ 9.20 (d, J = 2.4 Hz, 1H), 8.94 (d, J = 4.0 Hz, 1H), 8.60 (s, 1H), 8.23 (s, 1H), 8.10 (d, J = 6.9 Hz, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.93 (d, J = 8.9 Hz, 1H), 7.59 (dd, J = 8.8, 2.2 Hz, 1H), 6.44 (t, J = 6.0 Hz, 1H), 3.88 - 3.85 (m, 2H), 3.31 - 3.25 (m, 2H), 3.06 (t, J = 6.3 Hz, 2H), 2.64 (s, 3H), 1.74 - 1.68 (m, 1H), 1.617 - 1.58 (m, 2H), 1.26 - 1.16 (m, 2H). 13 CNMR (100 MHz, DMSO-d6) δ 197.4, 154.9, 149.2, 148.3, 142.0, 141.7, 135.7, 132.9, 129.1, 128.9, 128.8, 122.6, 120.2, 112.7, 66.7, 44.7, 35.2, 30.2, 26.7. HRMS-ESI: Calcd for C 24 H 26 N3O3[M+H] + 404.1974, Found: 404.1967.

[0292] The synthetic route of compound C35 is as follows:

[0293]

[0294] The 2-pyridineacetic acid (0.041 g, 0.3 mmol, 1.2 eq) was dissolved in 10 mL of dry dichloromethane, N, N-diisopropylethylamine (DIEA, 0.087 mL, 0.5 mmol, 2 eq) and HATU (0.114 g, 0.3 mmol, 1.2 eq) were added, after stirring for 1 h, compound 10 (0.1 g, 0.25 mmol, 1 eq) was added, and the reaction was carried out at room temperature for 12 h. After the reaction was completed, the reaction liquid was washed with saturated ammonium chloride, saturated sodium carbonate, saturated brine in turn, concentrated by rotary evaporation, and dried to obtain a solid, which was subjected to column chromatography (V(dichloromethane): V(methanol): V(ammonia water) = 10:0.1:0.05) to obtain compound C35 (0.080 g, yield 65%) in the form of yellow powder. m.p. 175.6-176.2 °C. 1H NMR (400 MHz, CD3OD) δ 8.99 (d, J = 2.3 Hz, 1H), 8.53 (dd, J = 5.0, 1.8 Hz, 1H), 8.39 (d, J = 2.3 Hz, 1H), 8.14 (s, 1H), 8.05 (t, J = 1.9 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.83 (dd, J = 7.7, 1.8 Hz, 1H), 7.67 (dd, J = 8.9, 2.2 Hz, 1H), 7.61 (dt, J = 7.3, 1.9 Hz, 1H), 7.54 - 7.46 (m, 3H), 7.35 (ddd, J = 7.6, 5.0, 1.2 Hz, 1H), 4.02 - 3.94 (m, 2H), 3.98 (s, 2H), 3.48 - 3.37 (m, 2H), 3.16 (d, J = 6.7 Hz, 2H), 1.89 - 1.77 (m, 1H), 1.74 - 1.66 (m, 2H), 1.43 - 1.27 (m, 2H). 13 C NMR (100 MHz, CD3OD) δ 169.3, 156.5, 155.3, 148.9, 148.5, 147.5, 141.7, 139.3, 138.1, 137.4, 133.5, 131.7, 129.4, 128.6, 124.5, 123.9, 122.5, 122.3, 120.7, 119.3, 118.3, 113.1, 67.4, 45.1, 35.6, 30.3. HRMS-ESI: calcd for C 29 H 30 N5O3 [M+H] + 496.2349, found: 496.2341.

[0295] The synthetic route of compound C36 is as follows:

[0296]

[0297] Compound 10 (0.1 g, 0.25 mmol, 1 eq) was added after stirring for 1 h, and the reaction was allowed to react at room temperature for 12 h. After the reaction was completed, the reaction liquid was washed with saturated ammonium chloride, saturated sodium carbonate, and saturated brine in sequence, concentrated by rotary evaporation, and dried to obtain a solid, which was subjected to column chromatography (V(dichloromethane):V(methanol):V(ammonia)=10:0.1:0.05) to obtain compound C36 yellow powder (0.099 g, yield 80%) in yellow powder form. m.p. > 250 °C. 1 HNMR (400 MHz, CD3OD) δ 8.92 (d, J = 2.3 Hz, 1H), 8.56 (d, J = 2.2 Hz, 1H), 8.44 (dd, J = 5.0, 1.6 Hz, 1H), 8.28 (d, J = 2.3 Hz, 1H), 8.11 (d, J = 2.1 Hz, 1H), 7.96 (d, J = 1.2 Hz, 1H), 7.87 (dt, J = 7.9, 2.0 Hz, 1H), 7.77 (d, J = 8.9 Hz, 1H), 7.60 (dd, J = 8.9, 2.2 Hz, 1H), 7.55 (td, J = 3.7, 1.6 Hz, 1H), 7.48 - 7.32 (m, 3H), 3.99 - 3.90 (m, 2H), 3.79 (s, 2H), 3.48 - 3.34 (m, 2H), 3.13 (d, J = 6.8 Hz, 2H), 1.83 - 1.71 (m, 1H), 1.69 - 1.60 (m, 2H), 1.39 - 1.20 (m, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 169.2, 155.6, 150.7, 149.8, 148.6, 148.3, 142.2, 140.3, 138.5, 137.3, 132.8, 132.0, 130.9, 130.1, 129.2, 123.9, 123.3, 122.4, 120.7, 118.9, 117.9, 113.3, 67.2, 45.3, 40.6, 35.8, 30.8. HRMS-ESI: Calcd for C 29 H 30 N5O3[M+H] + 496.2349, Found: 496.2338.

[0298] The synthetic route of compound C37 is as follows:

[0299]

[0300] Compound 2-(6-chloropyridin-3-yl)acetic acid (0.041 g, 0.3 mmol, 1.2 eq) was dissolved in 10 mL of dry dichloromethane, N,N-diisopropylethylamine (0.087 mL, 0.5 mmol, 2 eq) and HATU (0.114 g, 0.3 mmol, 1.2 eq) were added, after stirring for 1 h, compound 10 (0.1 g, 0.25 mmol, 1 eq) was added, and the reaction was allowed to proceed at room temperature for 12 h. After the reaction was completed, the reaction solution was washed with saturated ammonium chloride, saturated sodium carbonate, and saturated brine in sequence, and was concentrated by rotary evaporation to obtain a solid, which was dried and subjected to column chromatography (V(dichloromethane):V(methanol):V(ammonia water) = 10:0.15:0.05) to obtain compound C37 as a yellow powder (0.115 g, yield 87%). m.p. > 250 °C. 1 H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 9.06 (d, J = 2.3 Hz, 1H), 8.89 (s, 1H), 8.43 (d, J = 2.4 Hz, 1H), 8.39 (d, J = 2.5 Hz, 1H), 8.21 (d, J = 2.1 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.93 (d, J = 8.9 Hz, 1H), 7.85 (dd, J = 8.2, 2.5 Hz, 1H), 7.62 (dt, J = 7.9, 1.5 Hz, 1H), 7.58 (dd, J = 8.9, 2.2 Hz, 1H), 7.55 - 7.45 (m, 3H), 6.41 (t, J = 5.9 Hz, 1H), 3.93 - 3.82 (m, 2H), 3.79 (s, 2H), 3.30 - 3.23 (m, 2H), 3.06 (t, J = 6.1 Hz, 2H), 1.74 - 1.65 (m, 1H), 1.64 - 1.55 (m, 2H), 1.29 - 1.14 (m, 2H). 13 C NMR (176 MHz, DMSO-d6) δ 168.9, 155.6, 150.9, 149.1, 142.3, 141.2, 140.3, 138.4, 131.6, 130.9, 130.2, 129.2, 124.3, 123.3, 122.5, 120.7, 119.0, 117.9, 67.2, 45.3, 40.5, 35.8, 30.8. HRMS-ESI: Calcd for C 29 H 29 N5O3Cl [M+H] + 530.1959, Found: 530.1953.

[0301] The synthetic route of compound C38 is as follows:

[0302]

[0303] Compound C38 was obtained as a yellow powder (0.075 g, 82% yield) by the reaction of compound 11 (0.083 g, 0.2 mmol) with 3,4-methylenedioxybenzeneboronic acid (0.039 g, 0.24 mmol, 1.2 eq) following the synthetic procedure of Example 28, and purified by column chromatography on silica gel (V(dichloromethane):V(methanol):V(ammonia)=10:0.2:0.05). m.p. 191.3-192.7 °C. 1 H NMR (400 MHz, CDC13) δ 8.88 (d, J = 2.3 Hz, 1H), 8.50 (s, 1H), 8.00 (d, J = 2.3 Hz, 1H), 7.91 (dd, J = 8.9, 2.1 Hz, 1H), 7.72 (d, J = 2.1 Hz, 1H), 7.64 (d, J = 8.9 Hz, 1H), 6.97 - 7.05 (m, 2H), 6.83 (d, J = 8.5 Hz, 1H), 6.21 (t, J = 6.1 Hz, 1H), 4.33 - 4.62 (m, 1H), 3.81 - 3.61 (m, 1H), 3.17 - 3.12 (m, 1H), 3.12 - 2.99 (m, 1H), 2.96 - 2.78 (m, 1H), 2.54 - 2.34 (m, 1H), 2.31 - 2.20 (m, 2H), 1.78 - 1.59 (m, 3H), 1.05 (t, J = 7.5 Hz, 5H). 13 C NMR (100 MHz, CDC13) δ 172.6, 156.3, 149.7, 148.5, 147.7, 147.6, 141.3, 132.5, 131.9, 131.8, 128.6, 123.9, 121.2, 120.8, 114.4, 108.9, 107.5, 101.4, 45.6, 44.9, 41.9, 36.8, 30.3, 29.6, 26.6, 9.7. HRMS-ESI: calcd for C 26 H 29 N4O4[M+H] + 461.2189, found: 461.2177.

[0304] The synthetic route of compound C39 is outlined below:

[0305]

[0306] Compound 11 (0.083 g, 0.2 mmol) and 3,4-dimethoxyphenylboronic acid (0.044 g, 0.24 mmol, 1.2 eq) as raw materials, according to the synthetic method of Example 28, the product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia)=10:0.15:0.05) to obtain compound C39 yellow powder (0.079 g, yield 83%). m.p. 92.2-93.0 °C. 1 H NMR (400 MHz, CD3OD) δ 9.03 (d, J = 2.3 Hz, 1H), 8.42 (d, J = 1.6 Hz, 1H), 8.15 (d, J = 2.1 Hz, 1H), 7.90 (d, J = 8.9 Hz, 1H), 7.68 (dd, J = 8.9, 2.1 Hz, 1H), 7.38 - 7.29 (m, 2H), 7.12 (d, J = 8.2 Hz, 1H), 4.58 (d, J = 13.2 Hz, 1H), 4.06 - 3.95 (m, 4H), 3.91 (s, 3H), 3.24 - 3.16 (m, 2H), 3.16 - 3.06 (m, 1H), 2.73 - 2.61 (m, 1H), 2.43 (q, J = 7.5 Hz, 2H), 1.91 - 1.73 (m, 3H), 1.35 - 1.17 (m, 2H), 1.13 (t, J = 7.5 Hz, 3H). 13 C NMR (175 MHz, CD3OD) δ 173.25, 156.53, 149.75, 149.43, 149.07, 147.06, 141.33, 132.83, 132.04, 130.42, 128.41, 124.17, 120.69, 119.45, 113.15, 112.13, 110.47, 55.25, 55.11, 45.40, 44.58, 41.54, 36.76, 30.08, 29.27, 25.99, 8.65. HRMS-ESI: Calcd for C 27 H 33 N4O4[M+H] + 477.2502, Found: 477.2493.

[0307] The synthetic route of compound C40 in Example 40 is as follows:

[0308]

[0309] Compound 11 (0.083 g, 0.2 mmol) and 3-methoxybenzeneboronic acid (0.037 g, 0.24 mmol, 1.2 eq) as raw materials, according to the synthetic method of Example 28, the product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia)=10:0.2:0.05) to obtain compound C40 (0.067 g, yield 75%). m.p. 89.1-90.6 °C. 1 H NMR (400 MHz, CD3OD) δ 9.02 (d, J = 2.3 Hz, 1H), 8.45 (s, 1H), 8.16 (s, 1H), 7.91 (d, J = 8.9 Hz, 1H), 7.69 (dd, J = 8.9, 2.2 Hz, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 2.3 Hz, 1H), 7.01 (dd, J = 8.2, 1.0 Hz, 1H), 4.62 - 4.53 (m, 1H), 4.08 - 3.95 (m, 1H), 3.90 (d, J = 1.4 Hz, 3H), 3.19 (s, 2H), 3.15 - 3.06 (m, 1H), 2.71 - 2.60 (m, 1H), 2.42 (q, J = 7.5 Hz, 2H), 1.90 - 1.74 (m, 3H), 1.30 - 1.17 (m, 2H), 1.13 (t, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, CD3OD) δ 173.2, 160.5, 156.4, 149.0, 147.4, 141.6, 138.8, 133.5, 131.9, 129.9, 128.6, 124.0, 120.7, 119.0, 113.1, 113.0, 112.3, 54.4, 45.4, 44.6, 41.5, 36.7, 30.1, 29.3, 26.0, 8.7. HRMS-ESI: Calcd for C 26 H 31 N4O3[M+H] + 447.2396, Found: 447.2391.

[0310] The synthetic route of compound C41 in Example 41 is as follows:

[0311]

[0312] Compound 11 (0.083 g, 0.2 mmol) and 3-trifluoromethoxybenzeneboronic acid (0.049 g, 0.24 mmol, 1.2 eq) as starting material, the reaction was carried out according to the synthetic procedure of Example 28, the product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia)=10:0.2:0.05) to give compound C41 yellow powder (0.071 g, yield 71 %). m.p. 158.2-159.2 °C. 1 H NMR (400 MHz, CD3OD) δ 9.00 (d, J = 2.3 Hz, 1H), 8.44 (d, J = 2.2 Hz, 1H), 8.16 (d, J = 2.1 Hz, 1H), 7.89 (d, J = 8.9 Hz, 1H), 7.75 (dd, J = 7.8, 1.0 Hz, 1H), 7.67 (dd, J = 8.8, 2.0 Hz, 2H), 7.61 (t, J = 8.0 Hz, 1H), 7.33 (dd, J = 8.2, 1.2 Hz, 1H), 4.60-4.51 (m, 1H), 4.03-3.94 (m, 1H), 3.17 (t, J = 6.9 Hz, 2H), 3.13-3.02 (m, 1H), 2.67-2.59 (m, 1H), 2.40 (q, J = 7.5 Hz, 2H), 1.91-1.77 (m, 3H), 1.33-1.15 (m, 2H), 1.12 (t, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, CD3OD) δ 173.2, 156.4, 149.8, 148.7, 147.8, 142.0, 139.8, 133.9, 130.6, 130.3, 128.7, 125.5, 123.8, 121.9, 120.8, 119.9, 119.3, 113.0, 45.4, 44.6, 41.5, 36.7, 30.1, 29.3, 26.0, 8.7. HRMS-ESI: Calcd for C 26 H 28 N4O3F3[M+H] + 501.2114, Found: 501.2102.

[0313] The synthetic route of compound C42 of Example 42 is as follows:

[0314]

[0315] Compound 11 (0.083 g, 0.2 mmol) and 4-trifluoromethoxybenzeneboronic acid (0.049 g, 0.24 mmol, 1.2 eq) as starting material, the reaction was carried out according to the synthetic procedure of Example 28, the product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia)=10:0.2:0.05) to give compound C42 white powder (0.083 g, yield 83%). m.p. 178.8-180.0 °C. 1 H NMR (400 MHz, CD3OD) δ 9.03 (d, J = 2.3 Hz, 1H), 8.47 (d, J = 2.3 Hz, 1H), 8.18 (d, J = 2.1 Hz, 1H), 7.91 (d, J = 8.9 Hz, 1H), 7.87 (d, J = 8.8 Hz, 2H), 7.69 (dd, J = 8.9, 2.1 Hz, 1H), 7.43 (d, J = 7.7 Hz, 1H), 4.62 - 4.55 (m, 1H), 4.04 - 3.93 (m, 1H), 3.19 (t, J = 6.5 Hz, 2H), 3.15 - 3.03 (m, 1H), 2.71 - 2.57 (m, 1H), 2.42 (q, J = 7.5 Hz, 2H), 1.88 - 1.80 (m, 4H), 1.30 - 1.16 (m, 2H), 1.13 (t, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, CD3OD) δ 173.3, 156.5, 149.0, 148.8, 147.5, 141.9, 136.6, 133.9, 130.6, 128.6, 128.5, 123.9, 121.4, 120.9, 113.0, 45.4, 44.6, 41.5, 36.8, 30.1, 29.3, 26.0, 8.7. HRMS-ESI: calcd for C 26 H 28 N4O3F3[M+H] + 501.2114, found: 501.2114.

[0316] The synthetic route of compound C43 in Example 43 is as follows:

[0317]

[0318] Compound 11 (0.083 g, 0.2 mmol) and 4-cyanobenzenboronic acid (0.036 g, 0.24 mmol, 1.2 eq) as starting material, the reaction was carried out according to the synthetic procedure of Example 28, the product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia)=10:0.2:0.05) to give compound C43 yellow powder (0.075 g, yield 85%). m.p. 243.8-244.9 °C. 1 HNMR (400 MHz, DMSO-d6) δ 9.19 (d, J = 2.4 Hz, 1H), 8.93 (s, 1H), 8.62 (d, J = 2.4 Hz, 1H), 8.23 (s, 1H), 8.08 (d, J = 8.5 Hz, 2H), 7.99 (d, J = 8.5 Hz, 2H), 7.92 (d, J = 8.9 Hz, 1H), 7.59 (dd, J = 8.9, 2.2 Hz, 1H), 6.43 (t, J = 5.9 Hz, 1H), 4.42-4.39 (m, 1H), 3.88-3.85 (m, 1H), 3.10-3.03 (m, 2H), 3.00-2.84 (m, 1H), 2.58-2.52 (m, 1H), 2.30 (q, J = 7.4 Hz, 2H), 1.73-1.70 (m, 3H), 1.10-1.09 (m, 1H), 0.98 (t, J = 7.4 Hz, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 170.9, 154.9, 149.1, 148.5, 142.2, 141.9, 133.4, 132.9, 128.9, 128.5, 127.5, 122.5, 120.3, 118.7, 112.7, 110.1, 44.6, 44.3, 40.8, 36.3, 29.9, 29.2, 25.5, 9.4. HRMS-ESI: Calcd for C 26 H 28 N5O2[M+H] + 442.2243, Found: 442.2232.

[0319] The synthetic route of compound C44 in Example 44 is as follows:

[0320]

[0321] Compound 11 (0.083 g, 0.2 mmol) and 4-[(dimethylamino)methyl]benzeneboronic acid (0.043 g, 0.24 mmol, 1.2 eq) as starting material, the synthetic method of Example 28 was followed to give Compound C44 yellow powder (0.064 g, yield 68 %). m.p. 118.9-119.3 °C. 1 H NMR (400 MHz, CD3OD) δ 9.06 (d, J = 2.3 Hz, 1H), 8.49 (dd, J = 2.4, 0.8 Hz, 1H), 8.17 (d, J = 2.1 Hz, 1H), 7.93 (d, J = 8.9 Hz, 1H), 7.79 (d, J = 8.2 Hz, 2H), 7.70 (dd, J = 8.9, 2.1 Hz, 1H), 7.52 (d, J = 8.3 Hz, 2H), 4.54 - 4.63 (m, 1H), 3.95 - 4.05 (m, 1H), 3.64 (s, 2H), 3.20 (t, J = 6.4 Hz, 2H), 3.17 - 3.04 (m, 1H), 2.71 - 2.61 (m, 1H), 2.44 (q, J = 7.5 Hz, 2H), 2.36 (s, 6H), 1.92 - 1.79 (m, 3H), 1.30 - 1.17 (m, 2H), 1.13 (t, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, CD3OD) δ 173.3, 156.5, 149.0, 147.4, 141.7, 136.9, 133.4, 131.7, 130.3, 128.6, 126.8, 124.1, 120.8, 113.1, 62.9, 45.4, 44.6, 43.7, 41.6, 36.8, 30.1, 29.3, 26.0, 8.6. HRMS-ESI: calcd for C 28 H 36 N5O2[M+H] + 474.2869, found: 474.2862.

[0322] The synthetic route of compound C45 is outlined below:

[0323]

[0324] The compound 11 (0.083 g, 0.2 mmol) and 4-(4-methyl-1-piperazinyl)benzeneboronic acid (0.053 g, 0.24 mmol, 1.2 eq) as raw material, according to the synthetic method of example 28, the product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia water)=10:0.2:0.05) to obtain compound C45 orange yellow powder (0.081 g, yield 79%). m.p. 221.0-222.3 °C. 1 H NMR (400 MHz, CD3OD) δ 8.98 (d, J = 2.3 Hz, 1H), 8.33 (d, 1H), 8.10 (d, J = 2.1 Hz, 1H), 7.84 (d, J = 8.9 Hz, 1H), 7.63 (d, J = 8.6 Hz, 3H), 7.07 (d, J = 8.4 Hz, 2H), 4.56-4.53 (m, 2H), 3.98-3.95 (m, 1H), 3.28-3.25 (m, 4H), 3.19-3.01 (m, 3H), 2.65-2.59 (m, 5H), 2.42-2.37 (m, 5H), 1.78-1.91 (m, 3H), 1.25-1.22 (m, 2H), 1.10 (t, J = 7.5 Hz, 3H). 13 C NMR (176 MHz, CD3OD) δ 173.3, 156.6, 151.0, 148.9, 146.8, 141.1, 132.2, 131.9, 128.3, 127.3, 124.3, 120.7, 116.2, 113.2, 54.5, 45.4, 44.7, 44.6, 41.6, 36.8, 30.1, 29.3, 26.0, 8.7. HRMS-ESI: Calcd for C 30 H 39 N6O2[M+H] + 515.3134, Found: 515.3130.

[0325] The synthetic route of compound C46 is as follows:

[0326]

[0327] The compound 11 (0.083 g, 0.2 mmol) and 4-acetylbenzeneboronic acid (0.039 g, 0.24 mmol, 1.2 eq) as raw material, according to the synthetic method of example 28, the product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia water)=10:0.2:0.05) to obtain compound C46 yellow powder (0.059 g, yield 65%). m.p. 229.7-230.4 °C. 1HNMR (400 MHz, DMSO-d6) δ 9.20 (d, J = 2.4 Hz, 1H), 8.91 (s, 1H), 8.60 (d, J = 2.4 Hz, 1H), 8.23 (d, J = 2.1 Hz, 1H), 8.10 (d, J = 8.5 Hz, 2H), 8.02 (d, J = 8.5 Hz, 2H), 7.93 (d, J = 8.9 Hz, 1H), 7.59 (dd, J = 8.9, 2.2 Hz, 1H), 6.43 (t, J = 5.9 Hz, 1H), 4.46 - 4.33 (m, 1H), 3.93 - 3.80 (m, 1H), 3.13 - 3.01 (m, 2H), 3.00 - 2.93 (m, 1H), 2.64 (s, 3H), 2.58 - 2.52 (m, 1H), 2.30 (q, J = 7.4 Hz, 2H), 1.78 - 1.63 (m, 3H), 1.18 - 1.01 (m, 2H), 0.98 (t, J = 7.4 Hz, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 197.4, 170.9, 154.9, 149.3, 148.3, 142.0, 141.7, 135.7, 133.0, 129.1, 128.9, 128.8, 126.8, 122.6, 120.2, 112.8, 44.6, 44.3, 40.8, 36.3, 29.9, 29.2, 26.7, 25.5, 9.4. HRMS-ESI: Calcd for C 27 H 31 N4O3[M+H] + 459.2396, Found: 459.2389.

[0328] The synthetic route of compound C47 is outlined as follows:

[0329]

[0330] Compound 11 (0.083 g, 0.2 mmol) and 4-(aminosulfonyl)benzeneboronic acid (0.048 g, 0.24 mmol, 1.2 eq) as raw materials, according to the synthetic method of Example 28, the product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia)=10:0.2:0.05) to obtain compound C47 white powder (0.058 g, yield 68%). m.p. 204.2-204.8 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.19 (d, J = 2.4 Hz, 1H), 8.92 (s, 1H), 8.61 (d, J = 2.4 Hz, 1H), 8.24 (d, J = 2.1 Hz, 1H), 8.06 (d, J = 8.5 Hz, 2H), 7.96 (d, J = 8.8 Hz, 2H), 7.92 (d, J = 8.9 Hz, 1H), 7.59 (dd, J = 8.8, 2.2 Hz, 1H), 7.44 (s, 2H), 6.44 (t, J = 5.9 Hz, 1H), 4.49 - 4.32 (m, 1H), 3.94 - 3.74 (m, 1H), 3.12 - 3.04 (m, 2H), 3.02 - 2.90 (m, 1H), 2.59 - 2.54 (m, 1H), 2.31 (q, J = 7.4 Hz, 2H), 1.81 - 1.60 (m, 3H), 1.18 - 1.04 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 171.5, 155.6, 149.8, 148.9, 143.6, 142.6, 141.1, 133.6, 129.5, 129.4, 127.7, 126.9, 123.2, 120.8, 113.3, 45.1, 44.9, 41.4, 36.8, 30.5, 29.8, 26.1. HRMS-ESI: Calcd for C 25 H 30 N4O4S [M+H] + 496.2019, found: 496.2013.

[0331] The synthetic route of compound C48 is outlined as follows:

[0332]

[0333] Compound 11 (0.083 g, 0.2 mmol) and 4-(methylsulfonyl)benzeneboronic acid (0.048 g, 0.24 mmol, 1.2 eq) as raw materials, according to the synthetic method of Example 28, the product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia)=10:0.2:0.05) to obtain compound C48 white powder (0.060 g, yield 61%). m.p. 253.0-254.1 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.20 (d, J = 2.4 Hz, 1H), 8.93 (s, 1H), 8.63 (d, J = 2.4 Hz, 1H), 8.24 (d, J = 2.1 Hz, 1H), 8.14 (d, J = 8.6 Hz, 2H), 8.06 (d, J = 8.6 Hz, 2H), 7.94 (d, J = 8.9 Hz, 1H), 7.60 (dd, J = 8.9, 2.2 Hz, 1H), 6.44 (t, J = 5.8 Hz, 1H), 4.47 - 4.38 (m, 1H), 3.93 - 3.81 (m, 1H), 3.29 (s, 3H), 3.07 (td, J = 6.1, 2.1 Hz, 2H), 3.04 - 2.91 (m, 1H), 2.57 - 2.53 (m, 1H), 2.31 (q, J = 7.4 Hz, 2H), 1.79 - 1.62 (m, 3H), 1.19 - 1.03 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H). 13 C NMR (176 MHz, DMSO-d6) δ 171.5, 155.5, 149.8, 149.0, 142.9, 142.7, 140.2, 134.0, 129.5, 129.2, 128.2, 128.1, 123.1, 120.9, 113.2, 45.1, 44.9, 44.0, 41.4, 40.5, 36.8, 30.5, 29.7, 26.1, 10.0. HRMS-ESI: calc C 21 H 31 N4O4S [M+H] + 495.2066, found: 495.2061.

[0334] The synthetic route of compound C49 is outlined as follows:

[0335]

[0336] The product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia)=10:0.1:0.05) to give compound C49 white powder (0.066 g, yield 69%) from compound 12 (0.087 g, 0.2 mmol) and 3,4-methylenedioxybenzeneboronic acid (0.039 g, 0.24 mmol, 1.2 eq). m.p. 230.8-231.4 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.08 (d, J = 2.4 Hz, 2H), 8.43 (d, J = 2.4 Hz, 1H), 8.20 (d, J = 2.1 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.59 (dd, J = 8.9, 2.2 Hz, 1H), 7.47 (d, J = 8.7 Hz, 2H), 7.45 (d, J = 1.9 Hz, 1H), 7.39 - 7.29 (m, 3H), 7.07 (d, J = 8.1 Hz, 1H), 6.88 (t, J = 6.0 Hz, 1H), 6.10 (s, 2H), 4.40 (s, 2H). 13 C NMR (176 MHz, DMSO-d6) δ 155.6, 149.9, 148.7, 148.1, 147.6, 141.7, 140.4, 132.4, 132.0, 130.9, 129.4, 129.0, 123.5, 121.5, 121.3, 121.0, 120.7, 113.6, 109.4, 107.7, 101.7, 42.6. HRMS-ESI: calc. for C 25 H 19 N3O4F3[M+H] + 482.1328, found: 482.1323.

[0337] The synthetic route of compound C50 is outlined as follows:

[0338]

[0339] Compound 12 (0.087 g, 0.2 mmol) and 3,4-dimethoxyphenylboronic acid (0.044 g, 0.24 mmol, 1.2 eq) as raw materials, according to the synthetic method of Example 28, the product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia)=10:0.15:0.05) to obtain compound C50 yellow powder (0.079 g, yield 83%). m.p. 199.9-200.8 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.17 (d, J = 2.3 Hz, 1H), 9.12 (s, 1H), 8.53 (d, J = 2.4 Hz, 1H), 8.25 (d, J = 2.1 Hz, 1H), 7.92 (d, J = 9.0 Hz, 1H), 7.60 (dd, J = 8.9, 2.2 Hz, 1H), 7.48 (d, J = 8.7 Hz, 2H), 7.43 (d, J = 2.2 Hz, 1H), 7.39 (dd, J = 8.3, 2.2 Hz, 1H), 7.35 (d, J = 7.9 Hz, 2H), 7.11 (d, J = 8.4 Hz, 1H), 6.91 (t, J = 6.0 Hz, 1H), 4.39 (d, J = 5.7 Hz, 2H), 3.90 (s, 3H), 3.83 (s, 3H). 13 CNMR (100 MHz, DMSO-d6) δ 155.6, 149.8, 149.7, 149.3 147.6, 141.8, 140.4, 132.6, 131.1, 130.3, 129.4, 129.0, 123.6, 121.5, 120.8, 119.6, 113.3, 112.9, 111.0, 56.2, 56.1, 42.6. HRMS-ESI: Calcd for C 26 H 23 N3O4F3[M+H] + 498.1641, Found: 498.1635.

[0340] The synthetic route of compound C51 is as follows:

[0341]

[0342] Compound 12 (0.087 g, 0.2 mmol) and 2,4-dimethoxyphenylboronic acid (0.044 g, 0.24 mmol, 1.2 eq) as raw material, according to the synthetic method of Example 28, the product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia)=10:0.1:0.05) to obtain compound C51 yellow powder (0.056 g, yield 56%). m.p. 188.6-189.7 °C. 1H NMR (400 MHz, CDC13) δ 8.86 (d, J = 2.2 Hz, 1H), 8.44 (s, 1H), 8.01 (d, J = 2.2 Hz, 1H), 7.89 - 7.71 (m, 2H), 7.60 (d, J = 8.8 Hz, 1H), 7.21 (d, J = 8.6 Hz, 2H), 7.18 (d, J = 9.2 Hz, 1H), 7.04 - 6.98 (m, 2H), 6.62 - 6.53 (m, 2H), 6.20 (t, J = 5.9 Hz, 1H), 4.36 (s, 1H), 4.35 (s, 2H), 3.86 (s, 3H), 3.75 (s, 3H). 13 C NMR (100 MHz, CDC13) δ 161.0, 157.7, 156.0, 151.9, 148.2, 146.7, 140.5, 137.8, 135.2, 131.3, 130.1, 128.8, 128.6, 124.4, 121.2, 121.0, 120.0, 119.1, 115.3, 105.1, 99.0, 55.5, 43.2. HRMS-ESI: Calcd for C 26 H 23 N3O4F3[M+H] + 498.1641, Found: 498.1641.

[0343] The synthetic route of compound C52 is outlined as follows:

[0344]

[0345] Compound C52 yellow powder (0.083 g, yield 89%) was obtained by reaction of compound 12 (0.087 g, 0.2 mmol) with 4-methoxybenzeneboronic acid (0.049 g, 0.24 mmol, 1.2 eq) according to the synthetic method of Example 28, and purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia)=10:0.1:0.05). m.p. 212.8-213.8 °C. 1 H NMR (400 MHz, CDC13) δ 8.86 (d, J = 2.2 Hz, 1H), 8.44 (s, 1H), 8.01 (d, J = 2.2 Hz, 1H), 7.89 - 7.71 (m, 2H), 7.60 (d, J = 8.8 Hz, 1H), 7.21 (d, J = 8.6 Hz, 2H), 7.18 (d, J = 9.2 Hz, 1H), 7.04 - 6.98 (m, 2H), 6.62 - 6.53 (m, 2H), 6.20 (t, J = 5.9 Hz, 1H), 4.36 (s, 1H), 4.35 (s, 2H), 3.86 (s, 3H), 3.75 (s, 3H).13 CNMR (176 MHz, MeOD) δ 159.9, 156.4, 149.0, 148.3, 146.9, 141.2, 138.8, 132.7, 132.0, 129.8, 128.6, 128.4, 127.9, 124.3, 120.8, 119.8, 114.4, 113.44, 42.5. HRMS-ESI: calculated C 25 H 21 N3O3F3[M+H] + 468.1535, found: 468.1516.

[0346] The synthetic route of compound C53 is as follows:

[0347]

[0348] The compound 12 (0.087 g, 0.2 mmol) and 3-methoxyphenylboronic acid (0.049 g, 0.24 mmol, 1.2 eq) as raw material, according to the synthetic method of example 28, the product was purified by silica gel column chromatography (V(dichloromethane): V(methanol): V(ammonia water) = 10:0.15:0.05) to obtain compound C53 brown powder (0.064 g, yield 68 %). m.p. 210.3-211.4 °C. 1 HNMR (400 MHz, DMSO-d6) δ 9.16 (s, 2H), 8.56 (s, 1H), 8.25 (s, 1H), 7.94 (d, J = 8.9 Hz, 1H), 7.60 (d, J = 2.1 Hz, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.1 Hz, 1H), 7.42 (s, 1H), 7.40 (d, J = 2.7 Hz, 1H), 7.36 (d, J = 8.2 Hz, 2H), 7.01 (d, J = 7.2 Hz, 1H), 6.92 (t, J = 6.0 Hz, 1H), 4.39 (d, J = 5.6 Hz, 2H), 3.87 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 160.4, 155.6, 149.9, 148.3, 147.6, 142.1, 140.4, 139.3, 133.2, 131.0, 130.7, 129.4, 129.2, 123.4, 121.5, 120.8, 119.6, 114.0, 113.5, 112.7, 55.7, 42.6. HRMS-ESI: calculated C 25 H 21 N3O3F3[M+H] +468.1535, found: 468.1532.

[0349] The synthetic route of compound C55 is outlined below:

[0350]

[0351] Compound 12 (0.087 g, 0.2 mmol) and 3-methylphenylboronic acid (0.033 g, 0.24 mmol, 1.2 eq) as raw materials, according to the synthetic method of Example 28, the product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia)=10:0.1:0.05) to obtain compound C54 yellow powder (0.061 g, yield 67%). m.p. 206.4-207.8 °C. 1 HNMR (400 MHz, DMSO-d6) δ 9.12 (d, J = 2.3 Hz, 1H), 9.08 (s, 1H), 8.48 (d, J = 2.4 Hz, 1H), 8.22 (d, J = 2.1 Hz, 1H), 7.91 (d, J = 8.9 Hz, 1H), 7.67 (s, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.60 (dd, J = 8.8, 2.2 Hz, 1H), 7.48 (d, J = 8.7 Hz, 2H), 7.42 (t, J = 7.6 Hz, 1H), 7.35 (d, J = 7.8 Hz, 2H), 7.24 (d, J = 7.7 Hz, 1H), 6.88 (t, J = 6.0 Hz, 1H), 4.39 (d, J = 5.9 Hz, 2H), 2.42 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 155.6, 150.0, 148.4, 141.9, 140.4, 138.8, 137.8, 132.8, 131.2, 129.5, 129.4, 129.1, 128.9, 127.9, 124.4, 123.5, 121.5, 120.7, 113.7, 42.6, 21.6. HRMS-ESI: Calcd for C 25 H 21 N3O2F3[M+H] + 452.1586, found: 452.1572.

[0352] The synthetic route of compound C55 is outlined below:

[0353]

[0354] Compound 12 (0.087 g, 0.2 mmol) and 3-trifluoromethoxyphenylboronic acid (0.049 g, 0.24 mmol, 1.2 eq) were reacted according to the synthetic method of Example 28. The product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia) = 10:0.1:0.05) to give compound C55 as a brown powder (0.067 g, yield 64%). mp 170.1-171.8 °C. 1 H NMR(400MHz,DMSO-d6)δ9.17(d,J=2.4Hz,1H),9.13(s,1H),8.59(d,J=2.4H z,1H),8.24(d,J=2.1Hz,1H),7.97-7.89(m,2H),7.86(s,1H),7.67(t,J=8. 0Hz,1H),7.62(dd,J=8.9,2.2Hz,1H),7.48(d,J=8.7Hz,2H),7.43(d,J=8.3 Hz,1H),7.35(d,J=7.8Hz,2H),6.90(t,J=6.0Hz,1H),4.39(d,J=5.9Hz,2H). 13 C NMR (100MHz, DMSO-d6) δ 155.6, 149.8, 149.6, 148.8, 147.6, 142.4, 140.4, 140.3, 133.5, 131.6, 129.5, 129.4, 126.4, 123.3, 121.5, 120.9, 120.5, 119.9, 113.6, 42.6. HRMS-ESI: Calculated C 25 H 18 N3O3F6[M+H] + 522.1252, Experimental value: 522.1243.

[0355] The synthetic route of compound C56 in Example 56 is as follows:

[0356]

[0357] Compound 12 (0.087 g, 0.2 mmol) and 4-(aminosulfonyl)phenylboronic acid (0.048 g, 0.24 mmol, 1.2 eq) were reacted according to the synthetic method of Example 28. The product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia) = 10:0.2:0.05) to give compound C56 as a yellow powder (0.068 g, yield 66%). mp>270℃. 1HNMR (400MHz, DMSO-d6) δ9.19(d,J=2.4Hz,1H),9.15(s,1H),8.61(d,J=2.4Hz,1H),8.25(d,J=2.1Hz,1H),8.06(d,J=8.5Hz,2H),7.97-7.93(m ,3H),7.63(dd,J=8.9,2.2Hz,1H),7.48(d,J=8.7Hz,2H),7.44(s,2H),7.36(d,J=8.2Hz,2H),6.91(t,J=6.0Hz,1H),4.40(s,1H),4.39(s,1H). 13 C NMR (100MHz, DMSO-d6) δ 155.6, 149.9, 148.8, 147.6, 143.6, 142.4, 141.1, 140.3, 133.6, 129.6, 129.5, 129.4, 127.7, 126.9, 123.3, 121.5, 120.9, 113.6, 42.6. HRMS-ESI: Calculated C 24 H 20 N4O4F3S[M+H] + 517.1157, Experimental value: 517.1162.

[0358] The synthetic route for compound C57 in Example 57 is as follows:

[0359]

[0360] Using compound 12 (0.087 g, 0.2 mmol) and 4-methanesulfonylphenylboronic acid (0.055 g, 0.24 mmol, 1.2 eq) as starting materials, the reaction was carried out according to the synthetic method of Example 28. The product was purified by silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia) = 10:0.1:0.05) to give compound C57 as a yellow powder (0.048 g, yield 47%). mp 236.3-237.4 °C. 1HNMR(400MHz,DMSO-d6)δ9.21(d,J=2.3Hz,1H),9.17(s,1H),8.65(d,J=2.4H z,1H),8.27(d,J=2.1Hz,1H),8.15(d,J=8.6Hz,2H),8.07(d,J=8.6Hz,2H),7 .96(d,J=8.9Hz,1H),7.64(dd,J=8.9,2.2Hz,1H),7.48(d,J=8.7Hz,2H),7.3 6(d,J=7.6Hz,2H), 6.92(t,J=6.0Hz,1H), 4.40(d,J=5.9Hz,2H), 3.29(s,3H). 13 C NMR (100MHz, DMSO-d6) δ 155.53, 149.76, 148.84, 147.63, 142.85, 142.67, 140.33, 140.26, 134.14, 129.51, 129.45, 129.31, 128.24, 128.11, 123.24, 121.47, 120.97, 113.40, 44.04, 42.61. HRMS-ESI: Calculated C 25 H 21 N3O4F3S[M+H] + 516.1205, experimental value: 516.1157.

[0361] The synthetic route of compound C58 in Example 58 is as follows:

[0362]

[0363] Compound 15 (0.1 g, 0.36 mmol) was dissolved in 15 mL of dichloromethane, and carbonyl diimidazole (0.065 g, 0.43 mmol, 1.2 eq) was added. The reaction was carried out at room temperature for 12 h. Isobutylamine (0.54 mmol, 1.5 eq) was added to the reaction solution, and the reaction was continued at room temperature for another 0.5 h. After the reaction was complete, the organic phase was washed with saturated ammonium chloride, collected, concentrated by rotary evaporation, and subjected to silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia) = 10:0.15:0.05) to give compound C58 (0.079 g, yield 61%). mp>280℃. 1H NMR(400MHz,DMSO-d6)δ8.98(d,J=2.3Hz,1H),8.78(s,1H),8.36(d,J=2.3Hz,1H ),8.12(d,J=2.4Hz,1H),7.89(d,J=9.0Hz,1H),7.65(dd,J=9.1,2.4Hz,1H),7.4 8(d,J=1.8Hz,1H),7.36(dd,J=8.1,1.9Hz,1H),7.07(d,J=8.1Hz,1H),6.32(t,J =5.8Hz,1H),6.10(s,2H),2.98(t,2H),1.87-1.66(m,1H),0.90(d,J=6.7Hz,6H). 13 C NMR (100MHz, DMSO-d6) δ 155.7, 148.7, 147.9, 147.2, 143.2, 139.5, 133.2, 131.9, 131.6, 129.5, 128.9, 122.9, 121.4, 112.6, 109.4, 107.9, 101.8, 47.0, 28.9, 20.5. HRMS-ESI: Calculated C 21 H 22 N3O3[M+H] + 364.1661, Experimental value: 364.1661.

[0364] The synthetic route for compound C59 in Example 59 is as follows:

[0365]

[0366] Compound 15 (0.1 g, 0.36 mmol) was dissolved in 15 mL of dichloromethane, and carbonyl diimidazole (0.065 g, 0.43 mmol, 1.2 eq) was added. The reaction was carried out at room temperature for 12 h. 4-Aminomethyltetrahydropyran (0.54 mmol, 1.5 eq) was added to the reaction solution, and the reaction was continued at room temperature for another 0.5 h. After the reaction was complete, the organic phase was washed with saturated ammonium chloride, collected, concentrated by rotary evaporation, and subjected to silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia) = 10:0.15:0.05) to give compound C59 (0.119 g, yield 82%). mp 283.3–284.5 °C. 1H NMR (400MHz, DMSO-d6) δ8.98(d,J=2.4Hz,1H),8.78(s,1H),8.36(d,J=2.3Hz,1H),8.11(d,J=2. 4Hz,1H),7.88(d,J=9.0Hz,1H),7.64(dd,J=9.1,2.4Hz,1H),7.47(d,J=1.9Hz,1H),7.36(dd,J=8 .1,1.9Hz,1H),7.07(d,J=8.1Hz,1H),6.34(t,J=5.9Hz,1H),6.10(s,2H),3.97–3.80(m,2H),3. 30-3.22(m,2H),3.05(t,J=6.2Hz,2H),1.68-1.57(m,1H),1.64-1.52(m,2H),1.30-1.10(m,2H). 13 C NMR (100MHz, DMSO-d6) δ 155.7, 148.7, 147.9, 147.3, 143.2, 139.4, 133.2, 131.9, 131.6, 129.5, 128.9, 122.9, 121.4, 112.6, 109.4, 107.9, 101.8, 67.3, 45.3, 35.8, 30.8. HRMS-ESI: Calculated C 23 H 24 N3O4[M+H] + 406.1767, Experimental value: 406.1764.

[0367] The synthetic route of compound C60 in Example 60 is as follows:

[0368]

[0369] Compound 15 (0.1 g, 0.36 mmol) was dissolved in 15 mL of dichloromethane, and carbonyl diimidazole (0.065 g, 0.43 mmol, 1.2 eq) was added. The reaction was carried out at room temperature for 12 h. 4-Amino-1-propionylpiperidine (0.54 mmol, 1.5 eq) was added to the reaction solution, and the reaction was continued at room temperature for another 0.5 h. After the reaction was complete, the organic phase was washed with saturated ammonium chloride, collected, concentrated by rotary evaporation, and subjected to silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia) = 10:0.15:0.05) to give compound C60 (0.117 g, yield 73%). mp 241.1–242.5 °C. 1H NMR (400MHz, DMSO-d6) δ8.99(d,J=2.3Hz,1H),8.74(s,1H),8.37(d,J=2.3Hz,1H),8.11(d,J=2.4Hz,1H),7 .90(d,J=9.0Hz,1H),7.66(dd,J=9.1,2.4Hz,1H),7.48(d,J=1.8Hz,1H),7.36(dd,J=8.1,1.8Hz,1H),7.07 (d,J=8.1Hz,1H),6.33(d,J=7.6Hz,1H),6.11(s,2H),4.30-4.11(m,1H),3.86-3.70(m,2H),3.23-3.10(m, 1H),2.91-2.78(m,1H),2.33(q,J=7.4Hz,2H),1.97-1.79(m,2H),1.47-1.16(m,2H),1.00(t,J=7.4Hz,3H). 13 C NMR (100MHz, DMSO-d6) δ 171.6, 154.9, 148.7, 147.9, 147.3, 143.3, 139.3, 133.2, 129.6, 128.9, 122.9, 121.4, 112.7, 109.4, 107.9, 101.8, 46.8, 43.9, 33.0, 32.3, 26.0, 9.9. HRMS-ESI: Calculated C 25 H 27 N4O4[M+H] + 447.2032, Experimental value: 447.2035.

[0370] The synthetic route of compound C61 in Example 61 is as follows:

[0371]

[0372] Compound 15 (0.1 g, 0.36 mmol) was dissolved in 15 mL of dichloromethane, and carbonyl diimidazole (0.065 g, 0.43 mmol, 1.2 eq) was added. The reaction was carried out at room temperature for 12 h. 4-Aminomethyl-1-propionylpiperidine (0.54 mmol, 1.5 eq) was added to the reaction solution, and the reaction was continued at room temperature for another 0.5 h. After the reaction was complete, the organic phase was washed with saturated ammonium chloride, collected, concentrated by rotary evaporation, and subjected to silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia) = 10:0.15:0.05) to give compound C61 as a yellow powder (0.134 g, yield 81%). mp 160.4–161.2 °C. 1HNMR (400MHz, DMSO-d6) δ8.98(d,J=2.3Hz,1H),8.80(s,1H),8.37(d,J=2.3Hz,1H),8.12(d,J=2.4Hz,1H),7.89( d,J=9.1Hz,1H),7.65(dd,J=9.1,2.4Hz,1H),7.48(d,J=1.9Hz,1H),7.36(dd,J=8.1,1.9Hz,1H),7.07(d,J=8.1H z,1H),6.37(t,J=5.9Hz,1H),6.10(s,2H),4.44-4.36(m,1H),3.90-3.80(m,1H),3.06(t,J=6.1Hz,2H),2.96-2. 93(m,1H),2.54-2.47(m,1H),2.30(q,J=7.4Hz,2H),1.77-1.60(m,3H),1.18-1.00(m,2H),0.98(t,J=7.4Hz,3H). 13 C NMR (100MHz, DMSO-d6) δ 170.9, 155.2, 148.1, 147.3, 146.7, 142.6, 138.8, 132.6, 131.3, 131.0, 128.9, 128.4, 122.4, 120.8, 112.1, 108.8, 107.4, 101.2, 44.6, 44.3, 40.8, 36.3, 29.9, 29.2, 25.5, 9.4. HRMS-ESI: Calculated C 26 H 29 N4O4[M+H] + 461.2189, Experimental value: 461.2181.

[0373] The following is a brief description of the synthesis method of the tetrahydroquinoline compound of the present invention. In the synthesis examples listed below, the synthesis of intermediates mainly involves the Suzuki reaction, reduction reaction, and acylation reaction.

[0374] Specifically, the following provides methods for synthesizing representative compounds of the present invention.

[0375] The synthetic route of compound C62 in Example 62 is as follows:

[0376]

[0377] Compound C1 (0.1 g, 0.328 mmol) was dissolved in 10 mL of methanol, and nickel chloride (0.435 g, 3.36 mmol, 12 eq) was added. Then, sodium borohydride (0.728 g, 19.26 mmol, 70 eq) was added in portions, and the mixture was reacted at room temperature for 2 h. After the reaction was complete, water was added, and the mixture was filtered through diatomaceous earth. Dichloromethane was added to the filtrate, and the mixture was extracted three times. The organic phase was collected and concentrated by rotary evaporation. Silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia) = 10:0.08:0.05) yielded compound C62 as a yellow powder (0.080 g, yield 66%). mp 197.8–199.2 °C. 1 H NMR (400MHz, DMSO-d6) δ8.01(s,1H),6.88(d,J=1.7Hz,1H),6.83(d,J=7.9Hz,1H),6.74(dd,J=8 .1,1.7Hz,1H),6.70(d,J=8.1Hz,1H),6.65(d,J=2.1Hz,1H),6.41(dd,J=8.1,2.1Hz,1H),6.00(t ,J=5.9Hz,1H),5.96(s,2H),5.80(d,J=3.6Hz,1H),3.25-3.18(m,1H),3.16-3.06(m,1H),2.94-2 .82(m,3H),2.78(d,J=15.3Hz,1H),2.73-2.67(m,1H),1.73-1.61(m,1H),0.86(d,J=6.7Hz,6H). 13 C NMR (100MHz, DMSO-d6) δ 155.7, 147.8, 146.0, 145.2, 139.6, 138.7, 129.4, 120.6, 113.6, 108.6, 108.2, 105.9, 102.9, 101.1, 47.9, 46.9, 38.2, 34.5, 28.9, 20.5. HRMS-ESI: Calculated C 21 H 26 N3O3[M+H] + 368.1974, experimental value: 368.1960.

[0378] The synthetic route of compound C63 in Example 63 is as follows:

[0379]

[0380] Compound C62 (0.150 g, 0.328 mmol) was dissolved in 10 mL of methanol, and nickel chloride (0.435 g, 3.36 mmol, 12 eq) was added. Then, sodium borohydride (0.728 g, 19.26 mmol, 70 eq) was added in portions, and the mixture was reacted at room temperature for 2 h. After the reaction was complete, water was added, and the mixture was filtered through diatomaceous earth. Dichloromethane was added to the filtrate, and the mixture was extracted three times. The organic phase was collected and concentrated by rotary evaporation. Silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia) = 10:0.08:0.05) yielded compound C63 as an orange-yellow powder (0.085 g, yield 56%). mp 182.4–184.2 °C. 1 H NMR (400MHz, CD3OD) δ6.91 (d, J=2.4Hz, 1H), 6.88 (dd, J=8.4, 2.5Hz, 1H), 6.71-6. 80(m,3H),6.52(d,J=8.5Hz,1H),5.90(s,2H),4.57-4.48(m,1H),4.00-3.89(m,1 H),3.17(t,J=10.5Hz,1H),3.13-3.03(m,3H),2.99-2.93(m,1H),2.85(m,2H),2. 65-2.56(m,1H),2.39(q,J=7.5Hz,2H),1.82-1.69(m,3H),1.10(t,J=7.5Hz,5H). 13 C NMR (100MHz, CDCl3) δ 172.2, 157.4, 147.9, 146.3, 142.3, 137.3, 126.9, 126.5, 124.2, 122.1, 120.1, 114.6, 108.4, 107.5, 100.9, 48.5, 45.5, 41.6, 38.1, 36.9, 34.7, 30.4, 29.5, 26.6, 9.6. HRMS-ESI: Calculated C 26 H 33 N4O4[M+H] + 465.2502, Experimental value: 465.2492.

[0381] The synthetic route of compound C64 in Example 64 is as follows:

[0382]

[0383] Compound C39 (0.150 g, 0.328 mmol) was dissolved in 10 mL of methanol, and nickel chloride (0.435 g, 3.36 mmol, 12 eq) was added. Then, sodium borohydride (0.728 g, 19.26 mmol, 70 eq) was added in portions, and the mixture was reacted at room temperature for 2 h. After the reaction was complete, water was added, and the mixture was filtered with diatomaceous earth. Dichloromethane was added to the filtrate, and the mixture was extracted three times. The organic phase was collected and concentrated by rotary evaporation. The solution was then subjected to silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia) = 10:0.08:0.05) to give compound C64 as a yellow oil (0.096 g, yield 63%). 1 H NMR(400MHz,CD3OD)δ6.81(d,J=8.1Hz,1H),6.79-6.69(m,3H),6.66(d,J=2.1Hz, 1H),6.47(dd,J=8.0,2.2Hz,1H),5.89(s,2H),4.60-4.35(m,1H),4.02-3.79(m,1H ),3.16(t,J=10.8Hz,1H),3.09-2.99(m,3H),2.98-2.88(m,1H),2.84-2.74(m,2H ),2.67-2.55(m,1H),2.39(q,J=7.5Hz,2H),1.91-1.69(m,3H),1.22-1.04(m,5H). 13 C NMR (100MHz, CD3OD) δ 174.5, 158.5, 149.1, 147.4, 145.8, 139.4, 130.3, 121.1, 117.3, 109.7, 109.1, 108.5, 106.3, 46.8, 45.9, 42.9, 39.9, 38.1, 35.5, 31.4, 30.6, 27.4, 10.1. HRMS-ESI: Calculated C 26 H 33 N4O4[M+H] + 465.2502, Experimental value: 465.2493.

[0384] The following is a brief description of the synthetic methods for the isoquinoline compounds and tetrahydroisoquinoline of the present invention. Specifically, the synthetic methods for representative compounds of the present invention are given below.

[0385]

[0386] a: Ethylene glycol, p-toluenesulfonic acid, toluene, 110℃; b: Pd / C, methanol, hydrogen, room temperature reaction; c: N-bromosuccinimide, DMF, room temperature reaction; d: Acetic anhydride, DMAP, pyridine, dichloromethane, room temperature reaction; e: Palladium acetate, Xanphos, potassium phosphate, THF, 90℃; f: Ammonium chloride, ethanol / aqueous solution, 90-120℃; g: Carbonyl diimidazole, DCM, room temperature reaction; h: Amine, DCM, room temperature reaction; i: Platinum dioxide, hydrochloric acid, ethanol, hydrogen, room temperature reaction.

[0387] The synthetic route of compound C65 in Example 65 is as follows:

[0388]

[0389] Compound 20 (0.1 g, 0.36 mmol) was dissolved in 15 mL of dry dichloromethane, and carbonyl diimidazole (0.073 g, 0.43 mmol, 1.2 eq) was added. The reaction was carried out at room temperature for 5 days. 4-Trifluoromethoxybenzylamine (0.54 mmol, 1.5 eq) was added to the reaction solution, and the reaction was continued at room temperature for 12 h. After the reaction was complete, the organic phase was washed with saturated ammonium chloride, collected, concentrated by rotary evaporation, and subjected to silica gel column chromatography (V(dichloromethane):V(ethanol) = 10:0.15) to give compound C65 (0.15 g, yield 83%). mp 179.6–180.3 °C. 1 H NMR (400MHz, DMSO-d6) δ9.22(s,1H),9.08(s,1H),8.35–8.28(m,2H),7.92(d,J=8.9Hz,1H),7.68(dd,J=8.9,2.2Hz,1H) ,7.51–7.43(m,2H),7.39–7.31(m,4H),6.90(t,J=6.0Hz,1H),6.54(t,J=2.3Hz,1H),4.38(d,J=5.9Hz,2H),3.84(s,6H). 13 C NMR (100MHz, DMSO-d6) δ 161.32, 155.67, 151.49, 147.87, 147.62, 141.67, 140.42, 139.88, 132.09, 129.47, 129.01, 128.19, 124.59, 121.86, 121.46, 116.52, 112.19, 104.55, 100.88, 55.77, 42.63. HRMS-ESI: Calculated C 26 H 23 F3N3O4[M+H] + 498.1635, experimental value: 498.1649.

[0390] The synthetic route of compound C66 in Example 66 is as follows:

[0391]

[0392] Compound 20 (0.1 g, 0.36 mmol) was dissolved in 15 mL of dry dichloromethane, and carbonyl diimidazole (0.073 g, 0.43 mmol, 1.2 eq) was added. The reaction was carried out at room temperature for 5 days. 4-Aminomethyl-1-propionylpiperidine (0.54 mmol, 1.5 eq) was added to the reaction solution, and the reaction was continued at room temperature for 12 h. After the reaction was complete, the organic phase was washed with saturated ammonium chloride, collected, concentrated by rotary evaporation, and subjected to silica gel column chromatography (V(dichloromethane):V(ethanol) = 10:0.5) to give compound C66 (0.12 g, yield 72%). mp 142.1–143.3 °C. 1 H NMR (400MHz, CD3OD) δ9.11(s,1H),8.16(d,J=2.2Hz,1H),8.08(s,1H),7.88(d,J=8.8Hz, 1H),7.68(dd,J=8.9,2.2Hz,1H),7.18(d,J=2.2Hz,2H),6.53(t,J=2.3Hz,1H),4.55(d,J =13.2Hz, 1H), 3.97 (d, J = 13.6Hz, 1H), 3.86 (s, 6H), 3.16 (t, J = 6.4Hz, 2H), 3.08 (t, J = 12. 6Hz,1H),2.69–2.57(m,1H),2.40(q,J=7.5Hz,2H),1.87–1.75(m,3H),1.23–1.07(m,5H). 13 C NMR (100MHz, CD3OD) δ 173.24, 161.33, 156.61, 150.76, 149.06, 141.33, 139.10, 132.76, 128.69, 127.47, 124.70, 117.02, 112.84, 104.57, 100.13, 54.49, 45.38, 44.59, 41.53, 36.77, 30.09, 29.28, 25.99, 8.65. HRMS-ESI: Calculated C 27 H 33 N4O4[M+H] + 477.2496, experimental value: 477.2508.

[0393] The synthetic route of compound C67 in Example 67 is as follows:

[0394]

[0395] A 50 mL ethanol solution of compound C65 (0.40 mmol, 0.2 g) was added to a high-pressure reactor, followed by a few drops of 2 M hydrochloric acid aqueous solution and platinum dioxide (0.02 g). After three cycles of hydrogen purging, the reaction was carried out at a hydrogen pressure of 60 psi for 24 h. After the reaction was completed, the mixture was filtered, and the organic phase was collected and concentrated by rotary evaporation. The resulting product was then subjected to silica gel column chromatography (V(dichloromethane):V(ethanol) = 10:0.45) to give compound C67 (0.19 g, yield 95%). mp 125.9-126.5℃. 1 H NMR (400MHz, DMSO-d6) δ8.47 (s, 1H), 7.45–7.38 (m, 2H), 7.36–7.29 (m, 2H), 7.19 (d, J = 2. 2Hz,1H),7.10(dd,J=8.2,2.2Hz,1H),6.93(d,J=8.3Hz,1H),6.68–6.59(m,3H),6.38(t, J=2.3Hz,1H),4.31(d,J=6.0Hz,2H),3.97(q,J=16.0Hz,2H),3.80(dd,J=10.8,3.9Hz,1H ),3.73(s,6H),3.00(s,1H),2.81(dd,J=16.0,3.8Hz,1H),2.65(dd,J=15.9,10.7Hz,1H). 13 C NMR (100MHz, DMSO) δ 160.81, 155.76, 147.82, 147.56, 140.66, 138.43, 136.11, 129.37, 129.32, 128.19, 121.86, 121.42, 119.31, 116.37, 115.47, 104.93, 99.05, 58.18, 55.55, 48.97, 42.52, 37.04. HRMS-ESI: Calculated C 26 H 27 F3N3O4[M+H] + 502.1948, experimental value: 502.1978.

[0396] The synthetic route of compound C68 in Example 68 is as follows:

[0397]

[0398] 50 mL of an ethanol solution of C66 (0.42 mmol, 0.2 g) was added to a high-pressure reactor, followed by a few drops of 2 M hydrochloric acid aqueous solution and platinum dioxide (0.02 g). After three cycles of hydrogen purging, the reaction was carried out at a hydrogen pressure of 60 psi for 16 h. After the reaction was completed, the mixture was filtered, and the organic phase was collected and concentrated by rotary evaporation. The resulting product was then subjected to silica gel column chromatography (V(dichloromethane):V(ethanol) = 10:1.2) to give compound C68 (0.19 g, yield 96%). mp 110.7-111.9℃. 1 H NMR (400MHz, CD3OD) δ7.16 (d, J=2.2Hz, 1H), 7.10 (dd, J=8.3, 2.2Hz, 1H), 7.01 (d, J=8.3 Hz,1H),6.60(d,J=2.3Hz,2H),6.40(t,J=2.3Hz,1H),4.58–4.49(d,J=13.1Hz,1H),4.16 -4.00(q,J=15.9Hz,2H),4.00–3.85(m,2H),3.77(s,6H),3.13–3.02(m,3H),2.90(d,J=7.5Hz,2H),2.6 1(td,J=12.9,2.7Hz,1H),2.40(q,J=7.5Hz,2H),1.78(td,J=14.2,11.9,7.6Hz,3H),1.21–1.07(m,5H). 13 C NMR (100MHz, CD3OD) δ 173.25, 161.16, 157.04, 145.66, 137.55, 134.31, 128.95, 128.40, 117.44, 116.31, 104.26, 98.90, 58.68, 54.37, 45.40, 44.55, 41.54, 36.81, 35.95, 30.08, 29.27, 25.99, 8.66. HRMS-ESI: Calculated C 27 H 37 N4O4[M+H] + 481.2809, Experimental value: 481.2801.

[0399] The following is a brief description of the synthesis method of the benzimidazole compound of the present invention. In the synthesis examples listed below, the synthesis of intermediates mainly involves coupling, cyclization, reduction, and acylation reactions.

[0400] Specifically, the following provides methods for synthesizing representative compounds of the present invention.

[0401]

[0402] a: 4-Nitro-o-phenylenediamine, aldehyde, anhydrous ethanol, 80℃; b: nitrobenzene, anhydrous ethanol, 80℃; c: iron powder, ammonium chloride, water, ethanol, 90℃; d: carbonyl diimidazole, dichloromethane, reaction at room temperature; e: amine, dichloromethane, reaction at room temperature.

[0403] The synthetic route of compound C69 in Example 69 is as follows:

[0404]

[0405] Compound 22 (0.1 g, 0.40 mmol) was dissolved in 15 mL of dry dichloromethane, and carbonyl diimidazole (0.073 g, 0.48 mmol, 1.2 eq) was added. The reaction was carried out at room temperature for 12 h. Isobutylamine (0.60 mmol, 1.5 eq) was added to the reaction solution, and the reaction was continued at room temperature for another 0.5 h. After the reaction was complete, the organic phase was washed with saturated ammonium chloride, collected, concentrated by rotary evaporation, and subjected to silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia) = 10:0.15:0.05) to give compound C69 (0.099 g, yield 71%). mp 147.5-149.3℃. 1 H NMR (400MHz, Methanol-d4) δ7.77(d,J=2.0Hz,1H),7.56(dd,J=8.1,1.8Hz,1H),7.52(d,J=1.8Hz,1H),7.44(d,J=8.6Hz,1H),7 .05(dd,J=8.6,2.0Hz,1H),6.95(d,J=8.1Hz,1H),6.04(s,2H),3.04(d,J=6.8Hz,2H),1.88-1.70(m,1H),0.96(d,J=6.7Hz,6H). 13 C10 NMR (100MHz, Methanol-d4) δ 157.4, 151.8, 149.5, 148.5, 135.2, 123.7, 120.8, 115.8, 108.3, 106.3, 101.7, 28.8, 19.0. HRMS-ESI: Calculated C10 NMR values 19 H 21 N4O3[M+H] + 353.1614, experimental value: 353.1604.

[0406] The synthetic route of compound C70 in Example 70 is as follows:

[0407]

[0408] Compound 22 (0.1 g, 0.40 mmol) was dissolved in 15 mL of dry dichloromethane, and carbonyl diimidazole (0.073 g, 0.48 mmol, 1.2 eq) was added. The reaction was carried out at room temperature for 12 h. 4-Aminomethyl-1-propionylpiperidine (0.60 mmol, 1.5 eq) was added to the reaction solution, and the reaction was continued at room temperature for another 0.5 h. After the reaction was complete, the organic phase was washed with saturated ammonium chloride, collected, concentrated by rotary evaporation, and subjected to silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia) = 10:0.15:0.05) to give compound C70 as a white oil (0.149 g, yield 83%). 1 H NMR (400MHz, Methanol-d4) δ7.76 (d, J=2.1Hz, 1H), 7.52 (dd, J=8.2, 1.5Hz, 1H), 7.47 (d, J= 1.5Hz,1H),7.42(d,J=8.6Hz,1H),7.05(dd,J=8.6,2.1Hz,1H),6.87(d,J=8.2Hz,1H),5.97 (s,2H),4.55-4.41(m,1H),3.91-3.79(m,1H),3.16-3.03(m,2H),3.02-2.88(m,1H),2.54( td,J=12.7,2.7Hz,1H),2.38-2.27(m,2H),1.80-1.65(m,3H),1.06(td,J=7.5,1.3Hz,5H). 13 C NMR (100MHz, Methanol-d4) δ 173.2, 157.3, 151.9, 149.4, 148.4, 138.1, 135.7, 135.0, 123.5, 120.8, 115.9, 114.9, 108.3, 106.3, 104.6, 101.7, 45.3, 44.7, 41.5, 36.8, 30.1, 29.3, 25.9, 8.7. HRMS-ESI: Calculated C 24 H 28 N5O4[M+H] + 450.2141, Experimental value: 450.2136.

[0409] The synthetic route of compound C71 in Example 71 is as follows:

[0410]

[0411] Compound 22 (0.1 g, 0.40 mmol) was dissolved in 15 mL of dry dichloromethane, and carbonyl diimidazole (0.073 g, 0.48 mmol, 1.2 eq) was added. The reaction was carried out at room temperature for 12 h. 4-Aminomethyltetrahydropyran (0.60 mmol, 1.5 eq) was added to the reaction solution, and the reaction was continued at room temperature for 0.5 h. After the reaction was complete, the organic phase was washed with saturated ammonium chloride, collected, concentrated by rotary evaporation, and subjected to silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia) = 10:0.15:0.05) to give compound C71 as a brown oil (0.085 g, yield 54%). 1 H NMR (400MHz, Methanol-d4) δ7.79(d,J=2.0Hz,1H),7.60(dd,J=8.2,1.8Hz,1H),7.55(d,J=1.8Hz,1H),7.48(d,J=8.6Hz,1H),7.09(dd,J=8.7,2.1Hz,1H), 6.99(d,J=8.2Hz,1H),6.07(s,2H),4.05-3.93(m,2H),3.47-3.41(m,2H),3. 14(d,J=6.7Hz,2H),1.85-1.74(m,1H),1.74-1.66(m,2H),1.44-1.25(m,2H). 13 C10 NMR (100MHz, Methanol-d4) δ 157.4, 151.8, 149.5, 148.5, 135.2, 123.5, 120.8, 115.9, 114.9, 108.3, 106.3, 101.7, 67.4, 45.1, 35.7, 30.3. HRMS-ESI: Calculated C10 NMR values 21 H 23 N4O4[M+H] + 395.1719, experimental value: 395.1712.

[0412] The following is a brief description of the synthesis method of the indole compounds of the present invention. In the synthesis examples listed below, the synthesis of intermediates mainly involves coupling, cyclization, reduction, and acylation reactions.

[0413] Specifically, the following provides methods for synthesizing representative compounds of the present invention.

[0414]

[0415] a: Piperanal, 2,4-dinitrotoluene, piperidine, toluene, 110℃; b: Ferric acetate(II), phenanthroline, phenylsilane, ethylene glycol dimethyl ether, 80℃; c: Iron powder, ammonium chloride, water, ethanol, 90℃; d: carbonyl diimidazole, dichloromethane, react at room temperature; e: Amine, dichloromethane, react at room temperature.

[0416] The synthetic route of compound C72 in Example 72 is as follows:

[0417]

[0418] Compound 24 (0.1 g, 0.40 mmol) was dissolved in 15 mL of dry dichloromethane, and carbonyl diimidazole (0.073 g, 0.48 mmol, 1.2 eq) was added. The reaction was carried out at room temperature for 12 h. Isobutylamine (0.60 mmol, 1.5 eq) was added to the reaction solution, and the reaction was continued at room temperature for another 0.5 h. After the reaction was complete, the organic phase was washed with saturated ammonium chloride, collected, concentrated by rotary evaporation, and subjected to silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia) = 10:0.15:0.05) to give compound C72 (0.088 g, yield 63%). mp 233.8-234.1℃. 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),8.30(d,J=5.8Hz,1H),7.74(d,J=1.8Hz,1H),7.37(d,J=1.8Hz,1H),7.30(dd,J=8.3,2.3Hz,2H),6.98(d,J=8.1 Hz,1H),6.76(d,J=8.4Hz,1H),6.66(d,J=2.2Hz,1H),6.11-6.07(m,1H),6. 05(s,2H),2.94(t,J=6.2Hz,2H),1.75-1.65(m,1H),0.89(d,J=6.7Hz,6H). 13 C NMR (100MHz, DMSO-d6) δ 155.5, 147.7, 146.2, 137.4, 136.4, 135.1, 126.8, 123.4, 119.5, 118.0, 111.8, 108.6, 105.1, 100.9, 99.9, 97.8, 46.5, 28.4, 19.9. HRMS-ESI: Calculated C 20 H 22 N3O3[M+H] + 352.1661, Experimental value: 352.1653.

[0419] The synthetic route of compound C73 in Example 73 is as follows:

[0420]

[0421] Compound 24 (0.1 g, 0.40 mmol) was dissolved in 15 mL of dry dichloromethane, and carbonyl diimidazole (0.073 g, 0.48 mmol, 1.2 eq) was added. The reaction was carried out at room temperature for 12 h. 4-Aminomethyltetrahydropyran (0.60 mmol, 1.5 eq) was added to the reaction solution, and the reaction was continued at room temperature for another 0.5 h. After the reaction was complete, the organic phase was washed with saturated ammonium chloride, collected, concentrated by rotary evaporation, and subjected to silica gel column chromatography (V(dichloromethane):V(methanol):V(ammonia) = 10:0.15:0.05) to give compound C73 (0.099 g, yield 63%). mp 237.1-237.9 °C. 1 H NMR(400MHz,DMSO-d6)δ11.13(s,1H),8.28(s,1H),7.74(s,1H),7.37(s,1H),7.30( dd,J=8.6,3.9Hz,2H),6.98(d,J=8.1Hz,1H),6.76(d,J=8.3Hz,1H),6.62-6.70(m,1H ),6.11(t,J=5.9Hz,1H),6.05(s,2H),3.85-3.83(m,2H),3.29(dd,J=21.8,10.3Hz, 3H), 3.01 (t, J = 6.2Hz, 2H), 1.65-1.64 (m, 1H), 1.59-1.56 (m, 2H), 1.23-1.14 (m, 2H). 13 C NMR (100MHz, DMSO-d6) δ 155.4, 147.7, 146.2, 137.3, 136.4, 135.0, 126.8, 123.5, 119.5, 118.0, 111.8, 108.6, 105.1, 100.9, 99.9, 97.8, 66.7, 44.7, 35.3, 30.2. HRMS-ESI: Calculated C 22 H 24 N3O4[M+H] + 394.1767, experimental value: 394.1762.

[0422] Test Example 1

[0423] The following demonstrates the technical effects and advantages of this invention by applying the compounds of the present invention, such as quinoline, isoquinoline, tetrahydroquinoline, tetrahydroisoquinoline, indole, and benzimidazoles, to the inhibition of soluble epoxide hydrolases.

[0424] Specifically, in the embodiments of the present invention, the compound is co-incubated with a sample containing soluble epoxide hydrolase and the endogenous hydrolytic substrate 14,15-EET of the hydrolase, and the content of the hydrolysis product 14,15-DHET is detected. The relative amount of DHET produced reflects the inhibitory effect of the compound on soluble epoxide hydrolase. The specific steps are as follows:

[0425] Add 1:10 (mg / μL) pre-cooled PBS (phosphate buffer saline) (pH=7.4) to the collected brain tissue samples of adult (25-30g) male C57BL / 6J mice, homogenize for 30 seconds (4℃, 4500rpm) using a BertinPrecellys 24-Dual homogenizer, and then centrifuge at 9000g for 15 minutes at 4℃ using a small low-temperature centrifuge. Take the supernatant and dilute it 20 times. Add 160 μL of PBS, 20 μL of tissue fluid diluted 20 times, and 2 μL of compounds with concentration gradients of 10000, 5000, 1000, 500, 100, 50, 10, 1, 0.1, and 0.01 μg / mL (final concentrations of 100, 50, 10, 5, 1, 0.5, 0.1, 0.01, 0.001, and 0.0001 μg / mL) to an EP (Eppendorf) tube. Incubate at room temperature for 15 minutes. The negative control is PBS without tissue dilution but with added solvent (180 μL PBS plus 2 μL LDMSO). The positive control is the same concentration of sample dilution plus an equal volume of solvent (160 μL PBS plus 20 μL tissue fluid diluted 20 times plus 2 μL LDMSO). After incubation at room temperature, all samples were placed on ice, and the enzyme reaction substrate (10 μL of 14,15-EET (10 μg / mL)) was quickly added and mixed. The mixture was then incubated at 37°C in a shaker. After incubation, the samples were placed on ice, and 10 μL of 800 nMt-TUCB (No. 6757, Tocris Bioscience, UK, Bristol) was quickly added to terminate the reaction, resulting in a final reaction volume of 200 μL. To detect enzyme activity, the concentration of the reaction product 14,15-DHET was determined using high-performance liquid chromatography-mass spectrometry (HPLC-MS / MS). The pretreatment process was as follows: 1. An equal volume (200 μL) of a 50 / 50, v / v mixture of methanol and acetonitrile was added to the sample. The mixture contained 0.4% acetic acid and the internal standard 11,12-EET-d. 11 and 11,12-DHET-d 11(20 ng / mL); 2. Homogenize at 4500 rpm for 10 minutes and incubate at -20℃ for 2 hours to allow protein precipitation; 3. Centrifuge the sample for 10 minutes (14000 rpm) and collect the supernatant for UPLC-MS / MS analysis. Calculate the relative enzyme activity of sEH by comparing the amount of 14,15-DHET produced at a certain concentration of the tested compound with that produced without inhibitor. The inhibition rate is 100% minus the relative enzyme activity. Inhibition rate = 100 - (C t / C0)×100, where C t C0 represents the amount of 14,15-DHET produced by the tested compound, and C0 represents the amount of 14,15-DHET produced without an inhibitor.

[0426] The positive control compounds were TPPU and EC5026.

[0427] The verification results of the compounds prepared in this invention are shown in Tables 1, 2, and 3:

[0428]

[0429] Table 1. Inhibitory activity of compounds of general formulas I-1 and I-2 against sEH

[0430]

[0431]

[0432]

[0433] Table 2. Inhibitory activities of compounds of general formulas I-3 and I-4 against sEH

[0434] Number IC 50 (nM) C62 11.5±1.73 C63 33.3±0.5248 C64 3.14±0.177

[0435]

[0436] Table 3. Inhibitory activity of compounds of general formulas I-5 and I-6 against sEH

[0437]

[0438]

[0439] Table 4. Inhibitory activity of compounds of general formulas I-8 and I-10 against sEH.

[0440]

[0441]

[0442] Based on the above test results, it can be seen that the compounds prepared in this invention all have good sEH inhibition activity.

[0443] Test Example 2

[0444] The following demonstration of the technical effects and advantages of the present invention is achieved by applying the compound of the present invention to inhibit carrageenan-induced paw edema and inflammation in mice.

[0445] The specific steps are as follows: Male BALBC mice, weighing 23-25g, were selected and acclimatized for 5-7 days before the experiment began. Oral administration was given at 20mg / kg (C17 has three dosages: 1mg / kg, 10mg / kg, and 20mg / kg), using 5% DMSO + 95% soybean oil as the solvent, with an administration volume of 10mL / kg. Before the experiment, the animals were fasted for 12 hours and randomly divided into groups of 10 mice per group. One hour after oral administration, 0.05ml of 1% carrageenan (prepared with sterile physiological saline) was injected into the right hind paw. The volume of the right hind paw was measured before and 15min, 30min, 1h, 2h, 3h, 4h, 5h, and 6h after inflammation. The peak and subsidence times of swelling were observed, and the difference in paw thickness before and after inflammation was used as the degree of swelling. A t-test was performed on the data from each group to compare the significance of differences between groups. Swelling degree = Post-inflammatory foot thickness - Pre-inflammatory foot thickness; Inhibition rate = (Swelling degree of blank control group - Swelling degree of experimental group) / Swelling degree of blank control group.

[0446] The in vivo anti-inflammatory activity verification results of the compounds prepared in this invention are shown in Table 5:

[0447] Table 5. Anti-inflammatory activity of oral medications in vivo

[0448]

[0449] As shown in Table 5, the quinoline compounds prepared in this invention exhibit superior oral anti-inflammatory activity. Dose-effect experiments demonstrate that the compounds have a broad efficacy range (effective from 1-20 mg / kg), possessing good in vivo oral anti-inflammatory activity, rapid onset of action, high anti-inflammatory activity, and long duration of action.

[0450] Test Example 3

[0451] The following demonstrates the technical effects and advantages of this invention by applying compound C17 to the inhibition of taurine-induced acute pancreatitis in mice.

[0452] The specific steps are as follows: The acute pancreatitis experiment used CD-1 male mice (33-39g, 8 weeks old). After 3 days of acclimatization, the mice were randomly divided into a solvent group, a model group, and an experimental group (C17), with 8 mice in each group. The drug dosage was 10 mg / kg, administered intraperitoneally, dissolved in 5% DMSO + 95% 2-hydroxypropyl-β-cyclodextrin. The mice were fasted for 6-8 hours before the experiment. In the model and experimental groups, spirulina extract (50 μg / kg, 0.05 mL, 0-5 h) was injected intraperitoneally every hour for a total of 6 times to induce acute pancreatitis (AP); the solvent group received an equal volume of physiological saline. Subsequently, 30 minutes and 2.5 hours after the first injection of spirulina extract, the model group received an intraperitoneal injection of the solvent, and the drug administration group received an intraperitoneal injection of the test drug to treat pancreatitis (see...). Figure 1 and Figure 2 ).

[0453] Pathological changes observed in HE-stained sections of mouse pancreatic tissue showed that treatment with compound C17 significantly alleviated inflammatory infiltration in the mouse pancreas. Further analysis of plasma inflammatory markers revealed that compound C17 reduced IL-6 and TNF-α levels by 24.6% and 32.7%, respectively. In conclusion, compound C17 significantly alleviated inflammation levels in the pancreas and plasma, effectively preventing subsequent cascading systemic inflammatory responses and avoiding further deterioration of pancreatitis.

[0454] Test Example 4

[0455] The following application of compound C17 of the present invention in an analgesic test to inhibit acetic acid writhing is used to verify the technical effects and advantages of the present invention.

[0456] The specific steps are as follows:

[0457] The analgesic experiment used male BALB / c mice (6-8 weeks old, weighing approximately 23-25g). Mice were randomly divided into a model group, an experimental group, and a positive control group, with 8 mice in each group. The oral dosage was set at 20 mg / kg, with a dosage volume of 10 mL / kg, and the solvent was 5% dimethyl sulfoxide + 95% 2-hydroxypropyl-β-cyclodextrin (0.2 g / mL). Mice were fasted for 12 hours before the experiment. At the start of the experiment, mice in the experimental and control groups were given the drug orally, while mice in the model group were given the solvent only orally. One hour after administration, acetic acid solution (0.6% v / v, 0.01 mL / g) was injected intraperitoneally to induce pain. Animals were observed 5 minutes after pain induction, and the number of times the mice arched their backs, extended their bodies, and extended their hind limbs was recorded and counted for 30 minutes. The analgesic effect is shown in [the table below]. Figure 3 .

[0458] Based on the results of the paw edema anti-inflammatory experiment, compounds C5, C9, C17, and C30, which exhibit superior anti-inflammatory activity, rapid onset of action, and long duration of effect, were selected for an acetic acid-induced writhing analgesia experiment in mice. Celecoxib was used as the positive control, with an oral dose of 20 mg / kg. The results showed that oral administration of these four compounds significantly reduced the number of writhing movements induced by acetic acid in mice. C9 and C17 showed particularly outstanding analgesic effects, reducing the number of writhing movements by up to 50% (compared to the model group), comparable to the analgesic effect of celecoxib. These anti-inflammatory and analgesic experiments demonstrate that the compounds of this invention (sEH) have the potential to be developed into anti-inflammatory and analgesic drugs.

[0459] In summary, the compounds prepared by this invention exhibit good sEH inhibition activity, and the IC50 of some highly active compounds is [missing information]. 50 The values ​​even reached below 1 nM, indicating the highly efficient inhibitory effect of the compound on sEH. In vivo paw edema anti-inflammatory activity experiments showed that the compound of this invention has good in vivo and oral anti-inflammatory activity. The compound has a rapid onset of action, a long duration of action, and a broad spectrum of efficacy after oral administration, thus achieving an anti-inflammatory effect by inhibiting sEH. Furthermore, the compound of this invention also exhibited good anti-inflammatory and analgesic activity in mouse models of acute pancreatitis and acetic acid writhing, showing promising application prospects.

[0460] The embodiments of the technical solution of the present invention have been described above by way of example. It should be understood that the protection scope of the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art within the spirit and principles of the present invention should be included within the protection scope of the claims of this application.

Claims

1. The compound represented by formula (I), its tautomers, stereoisomers, isotopic labels, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs: in, Ring B is selected from 5-6 membered heterocyclic rings and 5-6 membered heteroaromatic rings; R1 is selected from unsubstituted or arbitrarily selected by one, two or more R1s. 11 The following groups are substituted: C 1-10 Alkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 quinone heteroaryl; each R 11 They may be identical or different, independently selected from H, without substitution, or optionally by one, two, or more Rs. 12 The following groups are substituted: C 1-10 Alkoxy, C 3-10 cycloalkyl, C 1-10 Alkyl-C(=O)-, 3-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 quinone heteroaryl; each R 12 They may be identical or different, and are independently selected from H, CN, halogens, unsubstituted, or optionally substituted by one, two, or more R groups. 13 The following groups are substituted: C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Alkyl-C(=O)-, C 1-10 Alkoxy-C(=O)-, C 3-10 Cycloalkyl-C(=O)-, C 1-10 Alkyl-S(=O)2-, H2N-S(=O)2-; each R 13 They are either the same or different, and are independently selected from H, halogens, and C. 1-10 Alkyl, C 1-10 Alkoxy, C 6-14 Aryl; Each R2 may be the same or different, and is independently selected from H and C. 1-10 Alkyl, C 1-10 Alkoxy; Each R3 may be the same or different, and is independently selected from H, CN, unsubstituted, or optionally by one, two, or more R3s. 31 The following groups are substituted: amino, C 1-10 Alkyl, C 1-10 Alkoxy, 3-14 membered heterocyclic group, C 1-10 Alkyl-S(=O)2-, H2N-S(=O)2-, C 1-10 Alkyl-C(O)NH-; each R 31 They are either the same or different, and are independently selected from H, halogens, oxometalates (=O), and C. 1-10 Alkyl, C 1-10 Alkoxy, -NH(C 1-10 Alkyl), N(C) 1-10 Alkyl)(C 1-10 Alkyl groups, 5-14 membered heteroaryl groups, and halogenated 5-14 membered heteroaryl groups; Alternatively, two adjacent R3 atoms and their respective attached atoms form an unsubstituted or optionally substituted arrangement with one, two or more R3 atoms. 32 Substituted 3-14 membered heterocyclic groups; each R 32 They are either the same or different, and are independently selected from H and C. 1-10 Alkyl, C 1-10 Alkoxy; Each R b Whether the two are the same or different, they are selected independently from H and C. 1-10 Alkyl, C 1-10 Alkoxy; m is selected from 0, 1, 2, or 3; n is selected from 0, 1, 2, 3, 4 or 5; p is selected from 0, 1, or 2.

2. The compound represented by formula (I) according to claim 1, its tautomers, stereoisomers, isotopic labels, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, characterized in that, Ring B is selected from 5-membered nitrogen-containing heterocycles, 5-membered nitrogen-containing heteroaromatic rings, 6-membered nitrogen-containing heterocycles, and 6-membered nitrogen-containing heteroaromatic rings; Preferably, ring B is selected from imidazole ring, pyrrole ring, pyridine ring or piperidine ring; Preferably, Selected from Preferably, Selected from 3. The compound of formula (I) according to claim 1 or 2, its tautomers, stereoisomers, isotopic markers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, characterized in that, R1 is selected from unsubstituted or arbitrarily selected by one, two or more R1s. 11 The following groups are substituted: C 1-6 Alkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl; each R 11 They may be identical or different, independently selected from H, without substitution, or optionally by one, two, or more Rs. 12 The following groups are substituted: C 1-6 Alkoxy, C 3-8 cycloalkyl, C 1-6 Alkyl-C(=O)-, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl; each R 12 They may be identical or different, and are independently selected from H, CN, halogens, unsubstituted, or optionally substituted by one, two, or more R groups. 13 The following groups are substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C(=O)-, C 1-6 Alkoxy-C(=O)-, C 3-8 Cycloalkyl-C(=O)-, C 1-6 Alkyl-S(=O)2-, H2N-S(=O)2-; each R 13 They are either the same or different, and are independently selected from H, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl; Preferably, R1 is selected from unsubstituted or optionally substituted by one, two or more R1s. 11 The following groups are substituted: C 1-6 Alkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl; each R 11 They are either the same or different, and are independently selected from H and C. 1-6 Alkyl-C(=O)-, Halogenated C 1-6 Alkoxy, unsubstituted, or optionally with one, two, or more R groups 12 The following groups are substituted: C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl; each R 12 They may be the same or different, and are independently selected from H, CN, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl-C(=O)-, Halogenated C 1-6 Alkyl-C(=O)-, C 1-6 Alkoxy-C(=O)-, C 6-10 Aryl-C 1-6 Alkoxy-C(=O)-, C 3-8 Cycloalkyl-C(=O)-, C 1-6 Alkyl-S(=O)2-, H2N-S(=O)2-; Preferably, R1 is selected from -CH2-R 11 ; Preferably, each R 11 They may be the same or different, and are independently selected from trifluoromethoxy groups. No substitution or optional use by one, two or more R 12 The following groups are substituted: tetrahydrofuranyl, tetrahydropyranyl, cyclohexyl, piperidinyl, phenyl; Preferably, each R 11 Same or different, selected independently from each other Preferably, each R 12 They may be the same or different, and are independently selected from H, CN, methoxy, -C(O)OCH3, benzyloxycarbonyl, trifluoromethoxy, difluoromethoxy, trifluoromethyl, methylsulfonyl, aminosulfonyl. Preferably, R1 is selected from C 1-6 Alkyl, 5-6 membered heterocyclic -C 1-3 Alkyl, C 1-6 Alkyl-C(=O)-piperidinyl, halogenated C 1-3 Alkoxyphenyl, C 1-3 Alkoxy-C(=O)-cyclohexyl-C 1-3 Alkyl, C 1-3 alkyl-C(=O)-piperidinyl-C 1-3 Alkyl, Halogenated C 1-3 alkyl-C(=O)-piperidinyl-C 1-3 Alkyl, C 3-6 Cycloalkyl-C(=O)-piperidinyl-C 1-3 Alkyl, phenyl C 1-3 alkyl-C(=O)-piperidinyl-C 1-3 Alkyl, C 1-3 Alkoxyphenyl C 1-3 Alkyl, Halogenated C 1-3 Alkoxyphenyl C 1-3 Alkyl, Halogenated C 1-3 Alkylphenyl C 1-3 Alkyl, cyanophenyl C 1-3 Alkyl, H2N-S(O)2-phenylC 1-3 Alkyl, C 1-3 Alkyl-S(O)2-phenylC 1-3 Alkyl, pyridyl C 1-3 alkyl; Preferably, R1 is selected from 4. The compound represented by formula (I) according to any one of claims 1-3, its tautomers, stereoisomers, isotopic labels, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, characterized in that, Each R2 is either identical or different, and is independently selected from H and C. 1-6 Alkyl, C 1-6 Alkyl group.

5. The compound of formula (I) according to any one of claims 1-4, its tautomers, stereoisomers, isotopic labels, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, characterized in that, Each R3 may be the same or different, and is independently selected from H, CN, unsubstituted, or optionally by one, two, or more R3s. 31 The following groups are substituted: amino, C 1-6 Alkyl, C 1-6 Alkoxy, 3-8 membered heterocyclic group, C 1-6 Alkyl-S(=O)2-, H2N-S(=O)2-, C 1-6 Alkyl-C(O)NH-; each R 31 They are either the same or different, and are independently selected from H, halogens, oxometalates (=O), and C. 1-6 Alkyl, C 1-6 Alkoxy, -NH(C 1-6 Alkyl), N(C) 1-6 Alkyl)(C 1-6 Alkyl groups, 5-10 membered heteroaryl groups, and halogenated 5-10 membered heteroaryl groups; Alternatively, two adjacent R3 atoms and their respective attached atoms form an unsubstituted or optionally substituted arrangement with one, two or more R3 atoms. 32 Substituted 3-8 membered heterocyclic groups; each R 32 Whether the two are the same or different, they are selected independently from H and C. 1-6 Alkyl, C 1-6 Alkoxy; Preferably, each R 31 They are either the same or different, and are independently selected from H, halogens, oxometalates (=O), and C. 1-3 Alkyl, C 1-3 Alkoxy, -NH(C 1-3 Alkyl), N(C) 1-3 Alkyl)(C 1-3 alkyl), pyridinyl, halopyridinyl; Preferably, each R3 may be the same or different, and is independently selected from H, CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 1-6 Alkyl-C(O)-, -NH(C)- 1-6 alkyl), -N(C) 1-6 Alkyl)(C 1-6 Alkyl), -C 1-6 Alkyl-NH(C) 1-6 Alkyl), -C 1-6 Alkyl-N(C) 1-6 Alkyl)(C 1-6 Alkyl), C 1-6 Alkyl-3-8-membered heterocyclic group, C 1-6 Alkyl-S(=O)2-, H2N-S(=O)2-, 5-10 heteroaryl-C 1-6 Alkyl-C(O)NH-, halogenated 5-10-membered heteroaryl-C 1-6 Alkyl-C(O)NH-; Alternatively, two adjacent R3 atoms and their respective connected atoms form 3-8 membered heterocyclic groups; Preferably, R3 is selected from H, CN, amino, methyl, methoxy, trifluoromethoxy, acetyl, dimethylamino, ... Alternatively, two adjacent R3 atoms and their respective connected atoms form Preferably, Selected from Preferably, each R b Whether they are the same or different, they are selected independently from H and C. 1-6 Alkyl, C 1-6 Alkyl group.

6. The compound of formula (I) according to any one of claims 1-5, its tautomers, stereoisomers, isotopic labels, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, characterized in that, The compound shown in formula (I) has the following structure: Among them, R1, R2, R3, R b m, n, and p each have the definition as described in any one of claims 1-5; Preferably, the compound represented by formula (I) has the following structure: Among them, rings B, R1, R2, and R 31 R b m and p independently have the definitions described in any one of claims 1-5; Preferably, the compound represented by formula (I) has the following structure: Among them, rings B, R2, R3, and R 12 R b m and p independently have the definitions described in any one of claims 1-5; Preferably, the compound represented by formula (I) has the following structure: Among them, rings B, R2, R3, and R 11 R b m, n, and p each have the definition as described in any one of claims 1-5; Preferably, the compound represented by formula (I) has the following structure: Among them, R3, R 12 They each possess the definitions described above independently.

7. The compound of formula (I) according to any one of claims 1-6, its tautomers, stereoisomers, isotopic labels, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, characterized in that, The compound represented by formula (I) is selected from one of the following structures:

8. A method for preparing the compound represented by formula (I) according to any one of claims 1-7, its tautomers, stereoisomers, isotope-labeled derivatives, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, said preparation method comprising the following steps: Compound a was reacted with compound b in the presence of carbonyl diimidazole to give the compound shown in formula (I); Among them, rings B, R1, R2, R3, and R b m, n, and p each have the definition as described in any one of claims 1-7 independently.

9. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1-7, a tautomer, a stereoisomer, an isotope label, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug.

10. The use of the compound of formula (I) according to any one of claims 1-7, its tautomers, stereoisomers, isotope labels, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the use of the pharmaceutical composition of claim 9 in the preparation of a medicament; Preferably, the drug is used to treat diseases associated with sEH inhibition, such as inflammation (e.g., foot edema, pancreatitis, neuroinflammation), analgesia, myocardial ischemia, fibrosis, renal failure, diabetes, hypertension, and cardiovascular diseases.

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