Triazine compound and application thereof

Abstract

The invention discloses a triazine compound and application thereof, and belongs to the technical field of chemical medicines. The triazine compound as shown in the formula I provided by the invention can be used as an NLRP3 inhibitor, has high activity and excellent pharmacokinetic properties, and provides a new way for treating NLRP3 related diseases.

Description

Triazine compounds and uses thereof Technical Field

[0001] The present invention belongs to the field of chemical medicine and relates to a class of triazine compounds and uses thereof. Background Art

[0002] Inflammasomes are protein complexes that recognize intracellular pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). Inflammasome assembly triggers proteolysis, cleaving dormant procaspase-1 into active caspase-1 and converting the cytokine precursors pro-IL-1β and pro-IL-18 into mature, biologically active IL-1β and IL-18, respectively. These complexes regulate the expression of inflammation-related genes and produce various biological effects. As receptors of innate immunity, inflammasome activation protects against pathogen infection and stress injury, but uncontrolled activation can also amplify inflammatory effects and cause organ damage. Currently, research on the nucleotide-binding oligomerization domain (NOD)-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasomes is the most active.

[0003] The NLRP3 inflammasome is composed of a sensor (NLRP3), an adaptor (ASC, also known as PYCARD), and an effector (caspase 1). Classic NLRP3 inflammasome activation is activated by two signals co-stimulating the body. The first signal activates the TLR4 (Toll-like receptor 4) signaling pathway, promoting the nuclear translocation of NF-κB, inducing the production of precursors such as IL-1β and IL-18, and inducing post-translational modification of NLRP3. The second signal promotes the formation of the NLRP3 / ASC / pro-caspase-1 complex. Upon activation, it aggregates with the apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC). ASC then interacts with the cysteine ​​protease caspase-1 to form a complex called the inflammasome. The pro-caspase (pro-caspase-1) self-cleaves into its active form. Activated caspase-1 cleaves the pro-inflammatory cytokines IL-1β and IL-18, converting them into their active forms and releasing them into the extracellular space. This recruits inflammatory cells and amplifies the inflammatory response. ASC speck-like proteins can also recruit and activate caspase-8, cleaving the pro-caspase forms of IL-1β and IL-18 into their mature forms, triggering pyroptosis. Non-classical NLRP3 inflammasome activation does not depend on TLR4 signaling pathway activation. It is caused by caspase-11 directly recognizing intracellular LPS, initiating NLRP3 inflammasome activation, promoting the activation and release of gasdermin D, and thus mediating cell death.

[0004] Abnormal activation of NLRP3 is associated with many diseases, including inflammasome-related diseases, immunological diseases, inflammatory diseases, neurological diseases, autoimmune diseases and / or autoinflammatory diseases, cancer, chronic metabolic diseases, and neurological diseases. For example, cryptopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), non-alcoholic steatohepatitis, alcoholic liver disease, graft-versus-host disease, multiple sclerosis (MS), rheumatoid arthritis, type I / type II diabetes and related complications (e.g., nephropathy, retinopathy), psoriasis, Alzheimer's disease, atherosclerosis, gout, chronic kidney disease, sepsis, liver fibrosis, idiopathic pulmonary fibrosis, epilepsy, neuropathic pain, depression, Parkinson's disease, asthma, acute myocardial infarction, lupus erythematosus, rheumatoid arthritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, bronchial asthma, acute respiratory distress syndrome, chronic obstructive pulmonary disease or ischemic stroke. NLRP3 is upstream of cytokines and can block inflammation at the root, so the development of new NLRP3 inflammasome inhibitors has high research value.

[0005] Summary of the Invention

[0006] The present invention aims to invent a class of triazine compounds and their uses, or their stereoisomers, solvates, metabolites, deuterated products, prodrugs, pharmaceutically acceptable salts or cocrystals, including pharmaceutical compositions thereof, for the treatment of NLRP3-related diseases.

[0007] In the first aspect, the present invention provides a compound represented by Formula I or a pharmaceutically acceptable form thereof, wherein the structure of Formula I is as follows:

[0008] in:

[0009] is a single bond, Y is selected from NR 7a , X is selected from C(═O);

[0010] R1 is selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN or the following groups optionally substituted with 0-6 substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NHC(=O)-C 1-6 Alkyl, -(C=O)NH-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, 3-6 membered cycloalkyl; in R1, the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN;

[0011] R2 and R4 are independently selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN or the following groups optionally substituted with 0-6 substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NHC(=O)-C 1-6 Alkyl, -(C=O)NH-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-6 membered cycloalkyl; in R2 and R4, the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN;

[0012] R3 is selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN or the following groups optionally substituted with 0-6 substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NHC(=O)-C 1-6 Alkyl, -(C=O)NH-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; in R3, the substituent is selected from: deuterium, halogen, -OH, -NH2, -CN or 3-6 membered cycloalkyl; in R3, the 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl contain 1 to 3 heteroatoms selected from at least one of N, S and O;

[0013] R5 is selected from hydrogen, deuterium, halogen, -NH2, -CN or the following groups optionally substituted with 0-6 substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NHC(=O)-C 1-6 Alkyl, -(C=O)NH-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-6 membered cycloalkyl; in R5, the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN;

[0014] Alternatively, R2 and R3, R3 and R4, or R4 and R5 together with the atoms to which they are attached form a 5-6 membered alkane ring, a benzene ring, a 5-6 membered alkane heterocycle, or a 5-6 membered heteroaromatic ring substituted with 0-6 substituents, wherein the substituents are selected from deuterium, halogen, -OH, -NH2, -CN, oxo, C1-6 Alkyl, C 1-6 Fluorinated alkyl, C 1-6 Deuterated alkyl, -OC 1-6 Alkyl, -OC 1-6 Fluorinated alkyl, -OC 1-6 Deuterated alkyl, C 3-6 Cycloalkyl, C 3-6 A fluorinated cycloalkyl group, or two of the substituents connected to the same carbon atom form a 3-6 membered cycloalkyl group; when R2 and R3, R3 and R4, or R4 and R5 are connected to the atoms to which they are connected to form a ring, the 5-6 membered alkane heterocycle or 5-6 membered heteroaromatic ring contains 1 to 3 heteroatoms selected from at least one of N, S, and O;

[0015] Furthermore, when R1 is selected from -OH, R2 and R3 together with the atoms to which they are attached form a benzene ring, a 5-7 membered alkane heterocycle or a 5-6 membered heteroaromatic ring substituted with 0-6 substituents selected from deuterium, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Fluorinated alkyl, C 1-6 Deuterated alkyl, -OC 1-6 Alkyl, -OC 1-6 Fluorinated alkyl, -OC 1-6 Deuterated alkyl, C 3-6 Cycloalkyl, C 3-6 A fluorinated cycloalkyl group, or two of the substituents connected to the same carbon atom form a 3-6 membered cycloalkyl group; when R2 and R3 are connected to the atoms to which they are connected to form a ring, the 5-7 membered alkane heterocycle or 5-6 membered heteroaromatic ring contains 1 to 3 heteroatoms selected from at least one of N and S or contains 2 O atoms;

[0016] L is selected from -(CH2) n1 -、O、-(CH2) n1 -NH-, -NH-(CH2) n1 -、-NH-CH(CH2) n1 (CH3)-, n1 is an integer selected from 0-3;

[0017] R6 is selected from 6-10 membered aryl, 5-10 membered heteroaryl, 3-8 membered heterocycloalkyl, 3-8 membered cycloalkyl, 6-10 membered spirocycloalkyl, 6-10 membered heterospirocycloalkyl, 6-10 membered bridged cycloalkyl, 6-10 membered heterobridged cycloalkyl, C 1-6 Alkyl; in R6, the substituent is selected from R 8a , halogen, oxo, -OR 8a 、-SR 8a 、-C(=O)R 8a 、-OC(=O)R8a 、-C(=O)OR 8a 、-C(=O)NR 8a R 8b 、-NR 8a C(=O)R 8b 、-NR 8a R 8b 、-SO2R 8a 、-SO2NR 8a R 8b 、-NR 8a SO2R 8b , -CN; in R6, the 5- to 10-membered heteroaryl, 3- to 8-membered heterocycloalkyl, 6- to 10-membered heterospirocycloalkyl, and 6- to 10-membered heterobridged cycloalkyl contain 1 to 3 heteroatoms selected from at least one of N, S, and O;

[0018] R 8a and R 8b independently selected from hydrogen, deuterium or the following groups substituted with 0-6 substituents: C 1-4 alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, 3-6 membered cycloalkylmethylene or 4-6 membered heterocycloalkylmethylene; R 8a 、R 8b wherein the substituent is selected from the group consisting of: deuterium, halogen, -N(R 10a R 10b ), -OH, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 deuterated alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 3-6 membered cycloalkylmethylene or 4-6 membered heterocycloalkylmethylene; R 8a 、R 8b wherein the 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkylmethylene groups contain 1 to 3 heteroatoms selected from at least one of N, S, and O, and the 4-6 membered heterocycloalkyl and 4-6 membered heterocycloalkylmethylene groups in the substituent groups contain 1 to 3 heteroatoms selected from at least one of N, S, and O;

[0019] Or, R 8a With R 8b Together with the atoms to which they are attached, they form a 3-6 membered alkyl heterocyclic ring substituted with 0-6 substituents; R 8a With R 8b When connected to the atoms to which they are attached to form a ring, the substituents are selected from: deuterium, halogen, -N(R 11a R 11b ), -OH, -CN, C 1-4 Alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl; R 8a With R8b When connected to the atoms to which they are attached to form a ring, the 3-6 membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from at least one of N, S, and O, and the 4-6 membered heterocycloalkyl group in the substituent group contains 1 to 3 heteroatoms selected from at least one of N, S, and O;

[0020] R 7a is selected from hydrogen or the following groups optionally substituted by 0-6 substituents: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; R 7a wherein the substituent is selected from hydrogen, deuterium, halogen, -OH, -NH2 or -CN; R 7a wherein the 4-6 membered heterocycloalkyl group and the 5-6 membered heteroaryl group contain 1 to 3 heteroatoms selected from at least one of N, S and O;

[0021] R 10a 、R 10b 、R 11a and R 11b are independently selected from hydrogen or C 1-4 alkyl;

[0022] The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled substances, metabolites, or prodrugs.

[0023] In some embodiments of the present invention, R1 is selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN, or the following groups optionally substituted with 0-6 substituents: C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-6 membered cycloalkyl, wherein the substituent is selected from deuterium, halogen, -OH, -NH2 or -CN.

[0024] In some preferred embodiments of the present invention, R1 is selected from hydrogen, deuterium, F, Cl, -OH, -NH2, -CN or the following groups optionally substituted with 0-3 substituents: C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, 3-6 membered cycloalkyl, the substituent is selected from: deuterium, F, Cl, -OH, -NH2 or -CN.

[0025] In some more preferred embodiments of the present invention, R1 is selected from hydrogen, deuterium, F, Cl, -OH, -CH3, fluoromethyl, deuterated methyl, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl, and fluorocyclopropyl.

[0026] In some embodiments of the present invention, R2 and R4 are independently selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN, or the following groups optionally substituted with 0-6 substituents: C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-6 membered cycloalkyl, wherein the substituent is selected from deuterium, halogen, -OH, -NH2 or -CN.

[0027] In some preferred embodiments of the present invention, R2 and R4 are independently selected from hydrogen, deuterium, F, Cl, -OH, -NH2, -CN or the following groups optionally substituted with 0-3 substituents: C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, 3-6 membered cycloalkyl, the substituent is selected from: deuterium, F, Cl, -OH, -NH2 or -CN.

[0028] In some more preferred embodiments of the present invention, R2 and R4 are independently selected from hydrogen, deuterium, F, Cl, -OH, -CH3, fluoromethyl, deuterated methyl, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl, fluorocyclopropyl.

[0029] In some embodiments of the present invention, R3 is selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN, or the following groups optionally substituted with 0-6 substituents: C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; in R3, the substituent is selected from: deuterium, halogen, -OH, -NH2, -CN, -CF3 or cyclopropyl; in R3, the 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl contain 1 to 3 heteroatoms selected from at least one of N, S and O.

[0030] In some preferred embodiments of the present invention, R3 is selected from hydrogen, deuterium, F, Cl, -CN, or the following groups optionally substituted with 0-3 substituents: C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C2-4 Alkenyl, C 2-4 Alkynyl, 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; in R3, the substituent is selected from: deuterium, F, Cl, -OH, -NH2, -CF3, -CN or cyclopropyl; in R3, the 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl contain 1 to 2 heteroatoms selected from at least one of N, S and O.

[0031] In some more preferred embodiments of the present invention, R3 is selected from hydrogen, deuterium, F, Cl, methyl, fluoromethyl, deuterated methyl, methylthio, fluoromethylthio, deuterated methylthio, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl, fluorocyclopropyl, vinyl, ethynyl, phenyl, fluorophenyl, deuterated phenyl.

[0032] In some embodiments of the present invention, R5 is selected from hydrogen, deuterium, halogen, -NH2, -CN, or the following groups optionally substituted with 0-6 substituents: C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-6 membered cycloalkyl, wherein the substituent is selected from deuterium, halogen, -OH, -NH2 or -CN.

[0033] In some preferred embodiments of the present invention, R5 is selected from hydrogen, deuterium, F, Cl, -NH2, -CN or the following groups optionally substituted with 0-3 substituents: C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, 3-6 membered cycloalkyl, the substituent is selected from: deuterium, F, Cl, -OH, -NH2 or -CN.

[0034] In some more preferred embodiments of the present invention, R5 is selected from hydrogen, deuterium, F, Cl, -CH3, fluoromethyl, deuterated methyl, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl, and fluorocyclopropyl.

[0035] In some embodiments of the present invention, R2 and R3, R3 and R4, or R4 and R5 can form, together with the atoms to which they are attached, a 5-6 membered alkane ring, a benzene ring, a 5-6 membered alkane heterocycle, or a 5-6 membered heteroaromatic ring substituted with 0-6 substituents selected from the group consisting of deuterium, halogen, -OH, -NH2, -CN, oxo, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Deuterated alkyl, -OC 1-4 Alkyl, -O-fluoroC 1-4 Alkyl, -O-deuterated C 1-4Alkyl, 3-6 membered cycloalkyl or 3-6 membered fluorocycloalkyl, or two of the substituents connected to the same carbon atom form a 3-4 membered cycloalkyl; when R2 and R3, R3 and R4, or R4 and R5 are connected to the atoms to which they are connected to form a ring, the 5-6 membered alkane heterocycle and 5-6 membered heteroaromatic ring contain 1 to 2 heteroatoms selected from at least one of N, S, and O.

[0036] In some preferred embodiments of the present invention, R2 and R3 or R3 and R4 together with the atoms to which they are attached form a group substituted with 0-3 substituents. The substituents are selected from: deuterium, F, Br, Cl, -OH, -NH2, -CN, oxo, methyl, fluoromethyl, deuterated methyl, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl or fluorocyclopropyl, or two of the substituents connected to the same carbon atom form a 3-4 membered cycloalkyl.

[0037] In some embodiments of the present invention, when R1 is selected from -OH, R2 and R3 together with the atoms to which they are attached form a benzene ring, a 5-6 membered alkane heterocycle or a 5-6 membered heteroaromatic ring substituted with 0-6 substituents selected from deuterium, halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Deuterated alkyl, -OC 1-4 Alkyl, -O-fluoroC 1-4 Alkyl, -O-deuterated C 1-4 Alkyl, 3-6 membered cycloalkyl or 3-6 membered fluorocycloalkyl, or two of the substituents connected to the same carbon atom form a 3-4 membered cycloalkyl; when R2 and R3 are connected to the atoms to which they are connected to form a ring, the 5-6 membered alkane heterocycle contains 2 O atoms, and the 5-6 membered heteroaromatic ring contains 1 to 2 heteroatoms selected from at least one of N and S.

[0038] In some preferred embodiments of the present invention, when R1 is selected from -OH, R2 and R3 together with the atoms to which they are attached form

[0039] In some embodiments of the present invention, the structural unit Selected from:

[0040] In some embodiments of the present invention, R 7a is selected from hydrogen or the following groups optionally substituted by 0-3 substituents: C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; R 7a wherein the substituent is selected from hydrogen, deuterium, halogen, -OH, -NH2 or -CN.

[0041] In some preferred embodiments of the present invention, R 7a Selected from hydrogen or C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy, C 1-4 Deuterated alkoxy, carboxyl, C 1-4 Alkoxycarbonyl, C 1-4 Fluoroalkoxycarbonyl, C 1-4 Deuterated alkoxycarbonyl, 3-6 membered cycloalkyl, 3-6 membered fluorocycloalkyl, phenyl, pyridyl or X1 and X2 are independently selected from CH, N; X3 is selected from NC 1-4 Alkyl, NH, S, O.

[0042] In some more preferred embodiments of the present invention, R 7a is selected from hydrogen, methyl, deuterated methyl, fluoromethyl, ethyl, fluoroethyl, isopropyl, fluoroisopropyl, cyclopropyl, fluorocyclopropyl, cyclohexyl, fluorocyclohexyl, phenyl, 2-pyridyl, X1 is selected from N; X2 is selected from CH, N; X3 is selected from N-methyl, S, O.

[0043] In some embodiments of the present invention, the structural unit Selected from:

[0044] In some embodiments of the present invention, L is selected from O, -NH-, -NH-CH2-, -NH-CH(CH 3) -.

[0045] In some embodiments of the present invention, in R6, the substituent is selected from fluorine, chlorine, hydroxyl, cyano, oxo, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy, C 1-4 deuterated alkoxy, 3-6 membered cycloalkyl, 3-6 membered fluorocycloalkyl, amino, dimethylamino,

[0046] In some embodiments of the present invention, R6 is selected from the following structures:

[0047] R 12a and R 12b Independently selected from R 8a , halogen, oxo, -OR 8a 、-SR 8a 、-C(=O)R 8a 、-OC(=O)R 8a 、-C(=O)OR 8a 、-C(=O)NR 8a R 8b 、-NR 8a C(=O)R 8b 、-NR 8a R 8b 、-SO2R 8a 、-SO2NR 8a R 8b 、-NR 8a SO2R 8b , -CN; n2 is an integer from 0 to 6.

[0048] In some preferred embodiments of the present invention, R 12a and R 12b Independently selected from R 8a , fluorine, oxo, -OR 8a 、-SR 8a 、-C(=O)R 8a 、-OC(=O)R 8a 、-C(=O)OR 8a 、-C(=O)NR 8a R 8b 、-NR 8a C(=O)R 8b 、-NR 8a R 8b 、-SO2R 8a 、-SO2NR 8a R 8b 、-NR 8a SO2R 8b , -CN; n2 is an integer from 0 to 3.

[0049] In some more preferred embodiments of the present invention, R 12a and R 12b Independently selected from fluorine, chlorine, hydroxyl, cyano, oxo, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy, C 1-4deuterated alkoxy, 3-6 membered cycloalkyl, 3-6 membered fluorocycloalkyl, amino, dimethylamino,

[0050] In some embodiments of the present invention, R6 is selected from the following structures:

[0051] The present invention also provides some specific compounds, which are selected from:

[0052] The present invention also provides another similar compound. In some embodiments of the present invention, the structural unit Selected from:

[0053] In some embodiments of the present invention, the structural unit Selected from:

[0054] In some embodiments of the present invention, L is selected from O, -NH-, -NH-CH2-, -NH-CH(CH 3) -.

[0055] In some embodiments of the present invention, R6 is selected from the following structures:

[0056] The present invention also provides some specific compounds, which are selected from:

[0057] In some embodiments of this aspect, the structural unit Selected from:

[0058] In some embodiments of this aspect, the structural unit Selected from:

[0059] In some embodiments of this aspect, L is selected from O, -NH-, -NH-CH2-, -NH-CH(CH 3) -.

[0060] In some embodiments of this aspect, R6 is selected from the following structures:

[0061] The present invention also provides some specific compounds, which are selected from:

[0062] In some embodiments of the present invention, the structural unit Selected from:

[0063] In some embodiments of the present invention, R6 is selected from the following structures:

[0064] The present invention also provides some specific compounds, which are selected from:

[0065] In a second aspect, the present invention provides a pharmaceutical composition comprising the aforementioned compound of formula I or its pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotope-labeled substances, metabolites or prodrugs as an active ingredient, supplemented with a pharmaceutically acceptable carrier.

[0066] A further object of the present invention is to provide a method for preparing the pharmaceutical composition of the present invention, which comprises combining a compound of formula I or a pharmaceutically acceptable form thereof, or a mixture thereof, with one or more pharmaceutically acceptable carriers.

[0067] The pharmaceutically acceptable carrier that can be used in the pharmaceutical composition of the present invention is a pharmaceutically acceptable carrier. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (2005).

[0068] The pharmaceutical composition can be administered in any form, as long as it prevents, alleviates, prevents or cures the symptoms of a human or animal patient. For example, it can be prepared into various suitable dosage forms according to the route of administration.

[0069] In other embodiments, the administration of the compound or pharmaceutical composition of the present invention can be combined with another treatment method. The other treatment method can be selected from, but not limited to: radiation therapy, chemotherapy, immunotherapy, or a combination thereof.

[0070] The present invention also relates to a pharmaceutical preparation comprising the compound of formula I or a pharmaceutically acceptable form thereof, or a mixture thereof, or a pharmaceutical composition of the present invention as an active ingredient. In some embodiments, the preparation is in the form of a solid preparation, a semisolid preparation, a liquid preparation, or a gaseous preparation.

[0071] A further object of the present invention is to provide an article of manufacture, for example, in the form of a kit. As used herein, an article of manufacture is intended to include, but is not limited to, a kit and packaging. The article of manufacture of the present invention comprises: (a) a first container; (b) a pharmaceutical composition located in the first container, wherein the composition comprises: a first therapeutic agent comprising: a compound of Formula I or a pharmaceutically acceptable form thereof, or a mixture thereof; (c) an optional package insert indicating that the pharmaceutical composition can be used to treat a neoplastic condition (as defined below); and (d) a second container.

[0072] The first container is a container for holding a pharmaceutical composition. This container can be used for preparation, storage, transportation and / or individual / bulk sales. The first container is intended to encompass bottles, jars, vials, flasks, syringes, tubes (e.g., for cream products), or any other container for preparing, holding, storing, or dispensing pharmaceutical products.

[0073] The second container is a container for accommodating the first container and optional package insert. Examples of the second container include, but are not limited to, boxes (e.g., paper or plastic boxes), boxes, cartons, bags (e.g., paper or plastic bags), pouches, and sacks. The package insert can be physically adhered to the outside of the first container via a cable tie, glue, staples, or other adhesion methods, or it can be placed inside the second container without any physical tool for adhering to the first container. Alternatively, the package insert is located outside the second container. When located outside the second container, it is preferred that the package insert is physically adhered via a cable tie, glue, staples, or other adhesion methods. Alternatively, it can abut or contact the outside of the second container without physical adhesion.

[0074] The package insert is a trademark, label, or indicia that lists information about the pharmaceutical composition within the first container. The information listed is typically determined by the regulatory agency (e.g., the U.S. Food and Drug Administration) that governs the region in which the product is to be sold. Preferably, the package insert specifically lists the indications for which the pharmaceutical composition is approved. The package insert can be made of any material from which the information contained therein or thereon can be read. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive paper, or plastic, etc.) onto which the desired information can be formed (e.g., printed or applied).

[0075] In a third aspect, the present invention provides the use of the aforementioned compound of formula I, and related specific compounds or pharmaceutically acceptable forms thereof, or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating NLRP3-related diseases.

[0076] The present invention provides a method for preventing or treating NLRP3-related diseases, comprising administering the compound of formula I or a pharmaceutically acceptable form thereof, or the pharmaceutical composition of the present invention to an individual in need thereof.

[0077] The present invention provides a method for preventing or treating NLRP3-related diseases by combining the compound of Formula I or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention with another treatment method, wherein the other treatment method includes but is not limited to: radiotherapy, chemotherapy, immunotherapy, or a combination thereof.

[0078] In some embodiments, the NLRP3-related disease includes: inflammatory disease, autoimmune disease, cardiovascular disease, cancer, renal disease, gastrointestinal disease, respiratory disease, endocrine system disease or central nervous system disease.

[0079] In some embodiments, the NLRP3-associated disease comprises: cryptopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), non-alcoholic steatohepatitis, alcoholic liver disease, graft-versus-host disease, multiple sclerosis (MS), rheumatoid arthritis, type I / type II diabetes and related complications (e.g., nephropathy, retinopathy), psoriasis, Alzheimer's disease, atherosclerosis, gout, chronic kidney disease, sepsis, liver fibrosis, idiopathic pulmonary fibrosis, epilepsy, neuropathic pain, depression, Parkinson's disease, asthma, acute myocardial infarction, lupus erythematosus, rheumatoid arthritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, bronchial asthma, acute respiratory distress syndrome, chronic obstructive pulmonary disease, or ischemic stroke.

[0080] In a further preferred embodiment, the compounds of the present invention can be used in combination with radiotherapy, chemotherapy or immunotherapy to prevent or treat NLRP3-related diseases.

[0081] Beneficial effects of the present invention:

[0082] The present invention provides a class of triazine compounds and uses thereof. The compounds and compositions can be used to prepare NLRP3 inflammasome inhibitors, providing a new approach for treating NLRP3-related diseases.

[0083] Definition of terms:

[0084] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by those skilled in the art. The terms "include," "comprising," "having," "containing," or "involving," and their variations herein, are inclusive or open-ended and do not exclude other unrecited elements or method steps. It should be understood by those skilled in the art that the above terms, such as "comprising," encompass the meaning of "consisting of."

[0085] In the present invention, "a", "an", "the", "at least one" and "one or more" are used interchangeably. Thus, for example, a composition comprising "a" pharmaceutically acceptable excipient can be interpreted to mean that the composition includes "one or more" pharmaceutically acceptable excipients.

[0086] For example, the statement "C 1-4 " should be understood to include any sub-ranges therein and each point value, such as C 2-4 、C 3-4 、C 1-2 、C 1-3 、C 1-4 etc., as well as C1, C2, C3, C4, etc.

[0087] In the present invention, unless otherwise specified, halogen means fluorine, chlorine, bromine or iodine.

[0088] In the present invention, unless otherwise specified, "alkyl" includes a linear or branched monovalent saturated hydrocarbon group. For example, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, "C 1-4 C in "alkyl" 1-4 It refers to a group containing 1, 2, 3 or 4 carbon atoms in a straight or branched chain.

[0089] In the present invention, unless otherwise specified, "cycloalkyl", "carbocycle" or "cycloalkylene" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic hydrocarbon group. Common cycloalkyl groups include (but are not limited to) monocyclic cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclobutene, cyclopentene, cyclohexene, etc.; or bicyclic cycloalkyl groups, including fused rings, bridged rings or spiro rings, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, decalinyl, etc. For example, "C 3-12 cycloalkyl" refers to a cycloalkyl group having 3-12 ring carbon atoms (such as 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12). The cycloalkyl or cycloalkylene group in the present invention is optionally substituted with one or more substituents described herein.

[0090] In the present invention, unless otherwise specified, "fluoroalkyl" refers to the alkyl group described above, wherein one or more hydrogen atoms are replaced by fluorine atoms. For example, the term "C 1-4 "Fluoroalkyl" refers to a C group optionally substituted by one or more (e.g. 1-3) fluorine atoms. 1-4 Alkyl. It will be understood by those skilled in the art that when there are more than one fluorine atom substituent, the fluorine atoms may be the same or different and may be located on the same or different C atoms. Examples of haloalkyl groups include -CH2F, -CHF2, -CF3, -C2F5, -CH2CF3, etc. The fluoroalkyl groups of the present invention are optionally substituted with one or more substituents described herein.

[0091] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds, which are identical to the compounds of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2 H), tritium ( 3 H)); carbon isotopes (e.g. 13 C and 14 C); isotopes of chlorine (such as 37Cl); isotopes of iodine (such as 125 I); isotopes of nitrogen (e.g. 13 N and 15 N); oxygen isotopes (e.g. 17 O and 18 O); isotopes of phosphorus (such as 32 P); and sulfur isotopes (e.g. 34 S).

[0092] As used herein, "polymorph" refers to different solid crystalline phases of certain compounds of the present invention resulting from the presence of two or more different molecular arrangements in the solid state. Certain compounds of the present invention may exist in more than one crystalline form, and the present invention is intended to encompass various crystalline forms and mixtures thereof. Typically, crystallization produces solvates of the compounds of the present invention. The term "solvate," as used herein, refers to an aggregate comprising one or more molecules of the compound of the present invention and one or more solvent molecules. The solvent may be water, in which case the solvate is a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as corresponding solvated forms. The compounds of the present invention may form true solvates, but in some cases, they may only retain adventitious water or a mixture of water and a portion of adventitious solvent. The compounds of the present invention may react in a solvent or precipitate or crystallize from a solvent. Solvates of the compounds of the present invention are also encompassed by the present invention. The present invention also encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

[0093] In the present invention, "stereoisomer" means an isomer formed due to at least one asymmetric center. In compounds with one or more (e.g., one, two, three, or four) asymmetric centers, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, and imine-enamine tautomers. It is to be understood that the scope of the present invention encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0094] In the present invention, pharmaceutically acceptable salts include acid addition salts and base addition salts thereof. Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. For a review of suitable salts, see, for example, "Remington's Pharmaceutical Sciences," Mack Publishing Company, Easton, Pa., (2005); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use," Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art. "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate, trifluoroacetate, propionate, caproate, octanoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, and naphthalene disulfonate. These salts can be prepared by methods known in the art. "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Preferred inorganic salts are ammonium salts, sodium salts, calcium salts, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like.Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline hexyl caffeine. These salts can be prepared by methods known in the art.

[0095] In the present invention, unless otherwise indicated, "ester" refers to an ester derived from a compound described herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compound of the present invention in the form of a free acid or alcohol). The compound of the present invention itself may also be an ester.

[0096] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0097] Those skilled in the art will appreciate that, since nitrogen requires an available lone pair of electrons to be oxidized to oxides, not all nitrogen-containing heterocycles are capable of forming nitrogen oxides. Those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming nitrogen oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming nitrogen oxides. Synthetic methods for preparing nitrogen oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidizing heterocycles and tertiary amines with peroxyacids such as Peracetic Acid and Metachloroperbenzoic Acid (mCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethyldioxirane. These methods for preparing nitrogen oxides have been extensively described and reviewed in the literature, see for example: TL Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750 (AR Katritzky and AJ Boulton, Eds., Academic Press); and GWH Cheeseman and ESGWerstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392 (AR Katritzky and AJ Boulton, Eds., Academic Press).

[0098] As used herein, "metabolite" refers to a substance formed in vivo upon administration of a compound of the present invention. Metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized using assays. Such products can be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, and the like of the administered compound. Therefore, the present invention includes metabolites of the compounds of the present invention, including compounds produced by contacting a compound of the present invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0099] In the present invention, "prodrug" refers to certain derivatives of the compounds of the present invention that can be converted into compounds of the present invention having the desired activity by, for example, hydrolytic cleavage when administered to the body or thereon. Typically, such prodrugs will be functional group derivatives of the compound that are easily converted into the desired therapeutically active compound in vivo. Further information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella). Prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g., as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985)).

[0100] As used herein, a "pharmaceutical composition" refers to a formulation of a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient, and thereby exert its biological activity.

[0101] In this application, "pharmaceutically acceptable carrier" includes but is not limited to any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved or accepted by relevant governmental regulatory authorities for use in humans or livestock.

[0102] As used herein, the terms "drug combination," "drug combination," "combination therapy," "administration of an additional therapy," "administration of an additional therapeutic agent," and the like refer to a drug therapy obtained by mixing or combining more than one active ingredient, and include both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient as a single entity or single dosage form. The term "non-fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient as separate entities, either in combination or sequentially at variable intervals. This also applies to cocktail therapies, e.g., administration of three or more active ingredients.

[0103] In the present invention, unless otherwise specified, "tumor" includes but is not limited to leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, squamous cell lung cancer, lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, intestinal cancer, rhinitis cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer and other diseases.

[0104] As used herein, unless otherwise indicated, "treating" or "treating" means reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

[0105] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention. DETAILED DESCRIPTION

[0106] The scheme of the present invention will be explained below with reference to the examples. Those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be construed as limiting the scope of the present invention. Where specific techniques or conditions are not specified in the examples, the techniques or conditions described in the literature in this area or the product specifications shall be followed.

[0107] The reagents and raw materials used in the examples of the present invention are all commercially available.

[0108] Table 1 Abbreviations and their meanings in the present invention

[0109] The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetic spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS). Chemical shifts were measured at 10-6 The units are given in ppm.

[0110] MS was measured using an Agilent SQD (ESI) mass spectrometer (manufacturer: Agilent, signal: 6110).

[0111] HPLC analysis was performed using an Agilent 1200DAD high pressure liquid chromatograph (Sunfirc C18, 150×4.6 mm, 5 μm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18, 150×4.5 mm, 5 μm column).

[0112] The thin layer chromatography silica gel plate used was Qingdao Ocean GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) had a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products was 0.4mm-0.5mm silica gel plate.

[0113] Column chromatography generally uses Qingdao Ocean 100-200, 200-300 mesh silica gel as the carrier.

[0114] Unless otherwise specified, all reactions in the following examples were conducted under an argon or nitrogen atmosphere. Argon or nitrogen atmosphere refers to the reaction flask being connected to an approximately 1 L argon or nitrogen balloon. Hydrogen atmosphere refers to the reaction flask being connected to an approximately 1 L hydrogen balloon. The hydrogenation reaction was typically performed by evacuating the flask and then filling it with hydrogen, repeating this process three times.

[0115] Intermediate INT1: 2-(4-methoxybenzo[b]thiophene-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0116] Step 1: CuBr2 (146.5 g, 656 mmol) was added to EtOAc (250 mL) and stirred at 80°C for 10 minutes. Compound INT1a (25.0 g, 164 mmol) was then dissolved in chloroform (250 mL) and added to the suspension. The mixture was refluxed at 80°C overnight. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was slurried with EtOAc (500 mL) for 0.5 h, filtered, and the filtrate was concentrated to dryness to afford the target compound INT1b (46.0 g, 148 mmol, light brown solid, 90% yield). MS: [M+H] + =309.0,311.0,313.0.

[0117] Step 2: Compound INT1b (45.0 g, 145 mmol) and Li2CO3 (26.8 g, 363 mmol) were added to DMF (450 mL) and stirred at 100°C for 6 h. After the reaction was complete, the mixture was filtered and the filtrate was treated with aqueous hydrochloric acid (900 mL, 0.5 N) and extracted with EtOAc (400 mL × 2). The organic phase was washed with water (300 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to afford the target compound INT1c (31.0 g, 135 mmol, light brown solid, 93% yield). MS: [MH] - =227.0,229.0.

[0118] Step 3: Compound INT1c (15.0 g, 65.5 mmol) and K2CO3 (18.1 g, 131 mmol) were added to MeCN (150 mL), followed by Me2SO4 (9.9 g, 78.6 mmol). The mixture was stirred at 60°C overnight under nitrogen. The reaction mixture was cooled to room temperature and filtered. Silica gel (30 g) was added to the filtrate, which was then concentrated to dryness under reduced pressure. The target compound INT1d (13.7 g, 56.4 mmol, white solid, 86% yield) was obtained by column chromatography (PE:EtOAc = 10:1). 1 H NMR (400MHz, CDCl3) δ7.51-7.46(m,2H),7.45-7.42(m,2H),4.00(s,3H).

[0119] Step 4: Compound INT1d (13.7 g, 56.4 mmol), bis-pinacol boronate (17.2 g, 67.7 mmol), KOAc (11.1 g, 113 mmol), and Pd(PPh3)Cl2 (2.00 g, 2.82 mmol) were added to dioxane (137 mL) and reacted at 90°C under nitrogen for 12 h. After the reaction, the mixture was filtered, and 30 g of silica gel was added to the filtrate. The mixture was concentrated under reduced pressure and dried by spin-drying. Column chromatography (PE:EtOAc = 30:1) was used to obtain the target compound INT1 (7.6 g, 26.2 mmol, colorless solid, 46% yield). 1 H NMR (400MHz, CDCl3) δ7.67 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 5.6 Hz, 1H), 7.35 (d, J = 5.2 Hz, 1H), 4.00 (s, 3H), 1.39 (s, 12H).

[0120] Intermediate INT2: 2-(2-(difluoromethoxy)-4-(trifluoromethyl)phenyl)-4,4,5-5-tetramethyl-1,3,2-dioxaborane

[0121] Step 1: Compound INT2a (5 g, 20.7 mmol), INT2b (7.1 g, 52 mmol), and cesium carbonate (11.5 g, 41.5 mmol) were added to a 250 mL three-necked flask. Water (20 mL) and DMF (80 mL) were then added, and the mixture was heated to 120°C and stirred for 12 hours. After the reaction mixture cooled to room temperature, ethyl acetate was added for extraction. The layers were separated, and the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was then dried and purified by column chromatography to obtain compound INT2c (2.8 g, yellow solid).

[0122] Step 2: Under nitrogen, compound INT2c (2.8 g, 9.6 mmol), pinacol diboronate (3.7 g, 14.4 mmol), potassium acetate (2.8 g, 29 mmol), Pd(dppf)Cl2 (0.7 g, 0.96 mmol), and dioxane (30 mL) were added to a 100 mL three-necked flask. The reaction mixture was heated to 100°C and stirred for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through a pad of celite, and the filtrate was extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was spin-dried and purified by column chromatography to yield compound INT2 (1.7 g, white solid). 1 H NMR (400MHz, Chloroform-d) δ7.86 (d, J = 7.7 Hz, 1H), 7.49 (d, J = 7.8, 1H), 7.39 (s, 1H), 6.54 (t, J = 72.5 Hz, 1H), 1.35 (s, 12H).

[0123] Intermediate INT3: 2-(1-(difluoromethylene)-4-methoxy-2,3-dihydro-1H-inden-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0124] Step 1: Dissolve 3-bromo-2-hydroxybenzaldehyde (25.0 g, 104.65 mmol), CH3I (60.63 g, 373.14 mmol), and K2CO3 (34.38 g, 248.76 mmol) in DMF (200 mL) and heat to 50°C for 3 hours. Water was added to the reaction mixture, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent removed from the filtrate under reduced pressure to obtain the target compound INT3a (yellow oily liquid, 22.5 g, yield: 84%). No further purification was required. MS / ESI [M+H] + :215.1.

[0125] Step 2: Et3N (12.71 g, 125.58 mmol) was added dropwise to HCOOH (14.45 g, 313.95 mmol) at 0°C. The mixture was allowed to react at room temperature for 30 minutes. A solution of INT3a (22.5 g, 104.65 mmol) and cycloisopropyl malonate (15.08 g, 104.65 mmol) in DMF (200 mL) was then added and the mixture was heated to 100°C and allowed to react overnight. Aqueous NaOH was added to the reaction mixture to adjust the pH to 9, and the mixture was extracted with ethyl acetate. Aqueous HCl (3 M) was added to the aqueous phase to adjust the pH to 5, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent removed from the filtrate under reduced pressure. The residue was separated by column chromatography (PE:EA = 5:1) to afford the target compound INT3b (white solid, 20.3 g, yield: 75%). MS / ESI [M+H] + :259.1.

[0126] Step 3: Polyphosphoric acid (200 g) was heated to 90°C, and compound INT3b (20.3 g, 78.34 mmol) was added. After reacting for one hour, heating was stopped and aqueous solution was added. The solution was cooled to room temperature and extracted with dichloromethane. The organic phase was washed with saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The residue was separated by column chromatography (PE:EA=5:1) to obtain the target compound INT3c (yellow solid, 9.7 g, yield: 51.3%). MS / ESI [M+H] + :241.1.

[0127] Step 4: Compound INT3c (4.7 g, 19.50 mmol) and 2-(difluoromethanesulfonyl)pyridine (5.65 g, 29.25 mmol) were dissolved in DMF (30 mL), cooled to -50°C, and a DMF solution of potassium tert-butoxide was added under nitrogen. The temperature was raised to -40°C. After reacting for 3 hours, saturated aqueous ammonium chloride (26 ml) was added to quench the reaction. 3N HCl (26 ml) was then added, and the temperature was raised to room temperature. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The residue was separated by column chromatography (PE:EA=20:1) to obtain the target compound INT3e (yellow oily liquid, 1.92 g, yield: 35.8%). 1 H NMR (400MHz, CDCl3) δ7.53 (d, J = 7.7Hz, 1H), 7.11 (d, J = 7.7Hz, 1H), 3.75 (s, 3H), 3.01–2.95 (m, 2H), 2.76–2.65 (m, 2H).

[0128] Step 5: Under nitrogen protection, compound INT3e (1.92 g, 6.98 mmol), pinacol diboron (2.66 g, 10.47 mmol), PdCl2(dppf) (0.57 g, 0.7 mmol), and potassium acetate (2.05 g, 20.94 mmol) were dissolved in 1,4-dioxane solution and refluxed at 100°C overnight. After the reaction was complete, the temperature was returned to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The residue was separated by column chromatography (PE:EA=10:1) to obtain the target compound INT3 (yellow solid, 1.02 g, yield: 45.4%). 1 H NMR (400MHz, CDCl3) δ7.60 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 3.81 (s, 3H), 2.97–2.82 (m, 2H), 2.62–2.51 (m, 2H), 1.30 (s, 12H).

[0129] Intermediate INT4: 2-(4-methoxybenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0130] Step 1: Add CuBr2 (66 g, 223 mmol) to EtOAc (120 mL) and stir at 80°C for 10 minutes. INT4a (10 g, 136 mmol) was then dissolved in chloroform (120 mL) and added to the suspension. The mixture was refluxed at 80°C overnight. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was slurried with EtOAc (200 mL) for 0.5 h, filtered, and the filtrate was concentrated to dryness to afford the target compound INT4b (7.3 g). 1 H NMR (400MHz, Chloroform-d) δ7.39 (d, J = 1.8 Hz, 1H), 6.76 (dt, J = 4.7, 2.1 Hz, 1H), 3.12 (m, 2H), 3.05–2.98 (m, 2H).

[0131] Step 2: Compound INT4b (7.3 g, 25 mmol) and Li2CO3 (11 g, 150 mmol) were added to DMF (70 mL) and stirred at 100°C for 6 h. After the reaction was complete, the mixture was filtered and the filtrate was adjusted to pH 1 with aqueous hydrochloric acid. The filtrate was extracted with EtOAc (150 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to yield the target compound INT4c (5.5 g). 1H NMR (400MHz, Chloroform-d) δ7.55 (d, J = 2.2 Hz, 1H), 7.34 (d, J = 8.7 Hz, 1H), 7.02 (dd, J = 8.7, 0.9 Hz, 1H), 6.89 (dd, J = 2.2, 1.0 Hz, 1H), 5.94 (s, 1H).

[0132] Step 3: Compound INT4c (5.5 g, 26 mmol) and K2CO3 (7.17 g, 52 mmol) were added to MeCN (60 mL), followed by Me2SO4 (4.1 g, 33 mmol). The mixture was stirred at 60°C overnight under nitrogen. The reaction mixture was cooled to room temperature, filtered, and the filtrate was added with silica gel. The mixture was then concentrated to dryness under reduced pressure and separated by column chromatography (PE:EtOAc = 10:1) to afford the target compound INT4d (5 g). 1 H NMR (400MHz, Chloroform-d) δ7.56 (d, J = 2.3 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.12 (dd, J = 8.7, 1.0 Hz, 1H), 6.91 (dd, J = 2.4, 1.0 Hz, 1H), 4.08 (s, 3H).

[0133] Step 4: Compound INT4d (1 g, 4.4 mmol), bis-pinacol boronate (2.2 g, 8.8 mmol), KOAc (1.7 g, 17.6 mmol), and Pd(dppf)Cl2 (322 mg, 0.44 mmol) were added to dioxane (15 mL) and reacted at 90°C under nitrogen for 12 h. After the reaction, the mixture was filtered, and silica gel was added to the filtrate. The mixture was concentrated under reduced pressure and dried. Column chromatography (PE:EtOAc = 10:1) was used to obtain the target compound INT4 (410 mg). 1 H NMR(400MHz,Chloroform-d)δ7.63(d,J=8.3Hz,1H),7.54(d,J=2.2Hz,1H),7.22 (dd, J = 8.3, 1.0 Hz, 1H), 6.90 (dd, J = 2.2, 1.0 Hz, 1H), 4.05 (s, 3H), 1.37 (s, 12H).

[0134] Intermediate INT5: 6-bromo-2-(4-methoxybenzyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione

[0135] Step 1: Dissolve compound int5a (50 g, 260 mmol) and iodomethane (37 g, 260 mmol) in ultra-dry DMF (250.0 mL). Add DIEA (36 g, 281 mmol) to the reaction flask and allow to react at room temperature for 3 hours. After the reaction is mostly complete, extract the mixture four times with EA and saturated brine. The organic phase is concentrated and purified by column chromatography on silica gel (PE / EA ratio 8:1 to 6:1) to yield 39 g of compound int5b as a white solid.

[0136] Step 2: Dissolve int5b (39 g, 189.3 mmol) and 4-methoxybenzyl chloride (40 g, 265 mmol) in ultra-dry DMF (500.0 mL). Add KCO (52 g, 378.6 mmol) to the reaction flask and allow to react at room temperature for 8 hours. After TLC monitoring of the reaction, extract the mixture three times with 200 mL of ethyl acetate and water. The organic phase is washed twice with 200 mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent is evaporated to yield compound INT5. 1 H NMR (400MHz, DMSO-d6) δ7.36–7.20 (m, 2H), 7.00–6.82 (m, 2H), 5.01 (s, 2H), 3.74 (s, 3H), 3.20 (s, 3H).

[0137] Intermediate INT6: 2-(4-cyclopropyl-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0138] Step 1: Compound INT6a (500 mg, 1.6 mmol), cyclopropylboronic acid (505 mg, 5.87 mmol) and potassium carbonate (883 mg, 6.39 mmol) were mixed in dioxane (10 mL) and water (5 mL). Pd(dppf)Cl2 (65.9 mg, 0.080 mmol) was added under nitrogen and the mixture was stirred at 120°C under nitrogen for sufficient reaction. After cooling to room temperature, ethyl acetate (20 mL) was added to dilute the mixture. The organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to obtain the crude compound INT6b, which was used directly in the next step.

[0139] Step 2: Compound INT6b (1.2 g, 4.4 mmol), bis-pinacol boronate (2.2 g, 8.8 mmol), KOAc (1.7 g, 17.6 mmol), and Pd(dppf)Cl2 (322 mg, 0.44 mmol) were added to dioxane (15 mL) and reacted at 90°C under nitrogen for 12 h. After the reaction, the reaction was filtered, and the filtrate was added with silica gel. The mixture was concentrated under reduced pressure and dried by spin-drying. The target compound INT6 (0.82 g) was obtained by column chromatography (PE:EtOAc = 10:1).

[0140] Intermediate INT7: 6-bromo-3-chloro-4-methyl-1,2,4-triazine-5(4H)-one

[0141] Step 1: Compound INT7a (10 g, 57.15 mmol) and cuprous chloride (11 g, 111.11 mmol) were placed in a sealed tube. Tert-butyl nitrite (12 g, 116.50 mmol) and acetonitrile (35 mL) were then added. The tube was quickly sealed and heated to 80°C for 4 h. After completion of the reaction, the reaction solution was concentrated and the residue was purified by column chromatography using 10% EA:PE as the eluting agent. The product was concentrated to afford INT7b (5.31 g) as a pale yellow solid. LC-MS: ESI [M+H] + =193.0.

[0142] Step 2: Compound INT7b (5.31 g, 25.24 mmol) was placed in a reaction flask, acetic acid (25 mL) was added, and the mixture was placed in an ice bath. Hydrogen peroxide (5 mL) was slowly added dropwise. After the addition was complete, the mixture was slowly returned to room temperature and allowed to react overnight. After the reaction was complete, sodium thiosulfate was added to quench the reaction. EA and 5% TEA were then added for extraction. The organic phase was concentrated and the residue was purified by column chromatography to obtain the product INT7c (5.12 g) as a pale yellow solid. LC-MS: ESI [M+H] + =209.1.

[0143] Step 3: Compound INT7c (3 g, 14.26 mmol) was placed in a three-necked flask under nitrogen protection. Anhydrous DMF (30 mL) was added and the reaction was placed in an ice bath. NaH (1.15 g, 28.79 mmol) was slowly added. After addition, the mixture was returned to room temperature and reacted for 1 hour. Iodomethane (2.02 g, 14.26 mmol) was then slowly added dropwise. After addition, the mixture was allowed to react overnight at room temperature. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with EA. The mixture was washed with saturated brine, dried, and concentrated. The residue was purified by column chromatography to obtain the white solid product INT7 (0.8 g). LC-MS: ESI [M+H] + =224.0. 1H NMR (400MHz, DMSO-d6) δ3.45 (s, 3H).

[0144] Intermediate INT8: 2-(4-(methoxymethoxy)benzo[b]thiophene-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0145] Step 1: Compound INT1c (220 g, 960 mmol) and diisopropylethylamine (186 g, 1440 mmol) were added to dichloromethane (1.1 L). Bromomethyl methyl ether (132 g, 1056 mmol) was slowly added dropwise at 0°C. After completion, the mixture was stirred at room temperature for 1 h. After completion of the reaction, saturated aqueous ammonium chloride solution (300 mL × 3) was added for washing. The organic phase was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. Column chromatography (PE:EtOAc = 30:1) afforded the target compound INT8a (183 g, 670 mmol, light yellow oil, 70% yield). 1H NMR (400 MHz, CDCl3) δ 7.55-7.45 (m, 3H), 7.43 (d, J = 5.5 Hz, 1H), 5.27 (s, 2H), 3.70 (s, 3H).

[0146] Step 2: Compound INT8a (20.0 g, 73.2 mmol), bis-pinacol boronate (22.3 g, 87.8 mmol), KOAc (14.3 g, 146 mmol), and Pd(PPh3)Cl2 (2.57 g, 3.66 mmol) were added to anhydrous dioxane (200 mL) and reacted at 100°C under nitrogen for 12 h. After the reaction, the mixture was filtered, the filtrate was concentrated under reduced pressure and dried, and then separated by column chromatography (PE:EtOAc = 30:1) to obtain the target compound INT8 (14.5 g, 45.3 mmol, colorless solid, yield 62%). 1 H NMR (400MHz, CDCl3) δ7.71(d,J=8.1Hz,1H),7.63(d,J=8.1Hz,1H),7.55(d,J=5.5Hz,1H),7.35(d,J=5.6Hz,1H),5.25(s,2H),3.62(s,3H),1.37(s,12H).

[0147] Example 1: (R)-3-(1-(difluoromethylene)-4-hydroxy-2,3-dihydro-1H-inden-5-yl)-6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-4-methyl-1,2,4-triazine-5(4H)-one

[0148] Step 1: Compound INT5 (8.00 g, 24.54 mmol), compound 1a (12.71 g, 49.08 mmol), Pd(OAc)2 (0.56 g, 2.45 mmol), BINAP (1.53 g, 2.45 mmol), cesium carbonate (23.93 g, 73.62 mmol), and dioxane (180 mL) were placed in a reaction flask under nitrogen and stirred at 100°C for 15 h. After the reaction was complete, the mixture was cooled to room temperature and directly mixed with silica gel. The mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0-2:1) to obtain compound 1b (7.00 g, 66.7%); MS / ESI [M+H] + =432.0.

[0149] Step 2: Compound 1b (7.00 g, 16.24 mmol) was placed in a reaction flask, dichloromethane (60 mL) was added, the temperature was lowered to 0°C, and trifluoromethanesulfonic acid (6 mL) was slowly added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 15 h. After the reaction was complete, acetonitrile (60 mL) was added, the temperature was lowered to 0-5°C, solid sodium bicarbonate was added until no bubbles were generated, and then ammonia was added to adjust the pH to 7-8. The mixture was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0-1:2) to obtain compound 1c (4.05 g, 80.5%); MS / ESI [M+H] + =312.0.

[0150] Step 3: Disperse compound 1c (4.00 g, 12.86 mmol) in phosphorus oxychloride (25 mL) under nitrogen atmosphere and stir at 110°C for 12 h. After the reaction is complete, the solvent is concentrated to dryness, and the residue is dispersed in acetonitrile (60 mL) and dichloromethane (100 mL). The temperature is lowered to 0-5°C, and solid sodium bicarbonate is added until no bubbles form. Ammonia is then added to adjust the pH to 7-8. Dry with anhydrous sodium sulfate, filter, and spin dry. The crude product is purified by silica gel column chromatography (dichloromethane:methanol = 1:0-10:1) to obtain compound 1d (3.00 g, 71.4%); MS / ESI [M+H] + =330.0.

[0151] Step 4: Compound 1d (2.12 g, 6.43 mmol), compound INT3 (1.80 g, 5.59 mmol), Pd(dppf)Cl2 (409 mg, 0.06 mmol), cesium carbonate (5.45 g, 16.77 mmol), dioxane (60 mL), and water (6 mL) were placed in a reaction flask under nitrogen and stirred at 100°C for 15 h. After the reaction was complete, the mixture was cooled to room temperature and directly mixed with silica gel. Purification by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0-0:1) afforded compound 1e (1.10 g, 40.3%); MS / ESI [M+H] + =490.1.

[0152] Step 5: Compound 1e (1.10 g, 2.25 mmol) and dichloromethane (50 mL) were placed in a reaction flask under nitrogen atmosphere. The temperature was lowered to -10°C, and a 1 M solution of boron tribromide in dichloromethane (6.71 mL, 6.71 mmol) was added. The reaction was incubated for 2 h. Upon completion, methanol (10 mL) was added to quench the reaction. The solvent was then evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 1:0-9:1) to obtain compound 1f (498 mg, 46.6%). MS / ESI [M+H] + =476.0.

[0153] Step 6: Compound 1f (479 mg, 1.01 mmol) and ethanol (25 mL) were placed in a reaction flask under nitrogen protection. Solid lithium borohydride (177 mg, 8.07 mmol) was added in batches. After addition, the mixture was reacted at 55°C for 12 h. After the reaction was complete, saturated ammonium chloride (20 mL) was added to quench the reaction. 50 mL of ethyl acetate was added, and the aqueous phase was extracted three times with ethyl acetate (30). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue was purified by Pre-HPLC (FA system) to obtain compound 1 (14 mg, 3.2%). 1 H NMR(400MHz,Methanol-d4)δ8.39(br s,2H),7.13(d,J=8.0Hz,1H),6.98(dd,J=8.0,1.6Hz,1H),4.26-4.14(m,1H),3.72(t,J=5.2Hz,2H),3.45-3.35(m,1H),3 .23(s,3H),3.17-3.07(m,1H),2.98-2.87(m,4H),2.82-2.64(m,4H),2.01-1.86(m,2H),1.81-1.58(m,2H); MS / ESI[M+H] + =434.0.

[0154] Example 2: (R)-3-(1-(difluoromethylene)-4-hydroxy-2,3-dihydro-1H-inden-5-yl)-6-((1-ethylpiperidin-3-yl)amino)-4-methyl-1,2,4-triazine-5(4H)-one

[0155] Step 1: Compound INT5 (1.50 g, 4.60 mmol), compound 2a (1.13 g, 6.90 mmol), BINAP Pd G3 (0.46 g, 0.46 mmol), cesium carbonate (4.48 g, 13.8 mmol), and dioxane (30 mL) were placed in a reaction flask under nitrogen and stirred at 100°C for 15 h. After the reaction was complete, the mixture was cooled to room temperature and directly mixed with silica gel. Purification by silica gel column chromatography (dichloromethane:methanol = 1:0-35:1) afforded compound 2b (1.41 g, 82.4%); MS / ESI [M+H] + =374.0.

[0156] Step 2: Compound 2b (1.41 g, 3.79 mmol) was placed in a reaction flask, dichloromethane (10 mL) was added, the temperature was lowered to 0°C, and trifluoromethanesulfonic acid (3 mL) was slowly added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 15 h. After the reaction was complete, acetonitrile (10 mL) was added, the temperature was lowered to 0-5°C, and solid sodium bicarbonate was added until no bubbles were generated. Ammonia was then added to adjust the pH to 7-8. The mixture was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 1:0-4:1) to obtain compound 2c (850 mg, 89.5%); MS / ESI [M+H] + =254.0.

[0157] Step 3: Disperse compound 2c (850 mg, 3.36 mmol) in phosphorus oxychloride (10 mL) under nitrogen atmosphere and stir at 110°C for 12 h. After the reaction is complete, the solvent is concentrated to dryness, and the residue is dispersed in acetonitrile (10 mL) and dichloromethane (10 mL). The temperature is lowered to 0-5°C, and solid sodium bicarbonate is added until no bubbles form. Ammonia is then added to adjust the pH to 7-8. The mixture is dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product is purified by silica gel column chromatography (dichloromethane:methanol = 1:0-10:1) to afford compound 2d (605 mg, 65.9%); MS / ESI [M+H] + =272.0.

[0158] Step 4: Compound 2d (200 mg, 0.74 mmol), INT3 (261 mg, 0.81 mmol), Pd(dppf)Cl2 (54 mg, 0.07 mmol), cesium carbonate (720 mg, 2.21 mmol), dioxane (12 mL), and water (2 mL) were placed in a reaction flask under nitrogen and stirred at 100°C for 15 h. After the reaction was complete, the mixture was cooled to room temperature and directly mixed with silica gel. Purification by silica gel column chromatography (dichloromethane:methanol = 1:0-10:1) afforded compound 2e (99 mg, 31.1%); MS / ESI [M+H] + =432.1.

[0159] Step 5: Compound 2e (99 mg, 0.23 mmol) and dichloromethane (6 mL) were placed in a reaction flask under nitrogen atmosphere. The temperature was lowered to -10°C, and a 1 M solution of boron tribromide in dichloromethane (0.69 mL, 0.69 mmol) was added. The reaction was incubated for 2 h. Upon completion, methanol (4 mL) was added to quench the reaction. The solvent was then evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 1:0-9:1) to obtain compound 2 (70 mg, 73.2%). 1 H NMR(400MHz,DMSO-d6)δ9.78(br s,1H),9.58(br s,1H),7.24(d,J=8.0Hz,1H),7.07-6.97(m,1H),4.36-4.23(m,1H),3.57-3.48(m,3H),3.26-3.18(m,5H),3 .08-2.98(m,2H),2.87-2.80(m,3H),2.05-1.93(m,2H),1.88-1.65(m,2H),1.28-1.20(m,3H); MS / ESI[M+H] + [M+H] + =418.0.

[0160] Example 3: (R)-6-((1-ethylpiperidin-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazine-5(4H)-one

[0161] Preparation of (R)-6-((1-ethylpiperidin-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazin-5(4H)-one Referring to Example 2, the compound (R)-6-((1-ethylpiperidin-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazin-5(4H)-one (70 mg, 80.6%) was obtained; 1H NMR(400MHz,DMSO-d6)δ10.46(br s,1H),9.60(br s,1H),7.80-7.73(m,2H),7.65(d,J=8.0Hz,1H),7.30(d,J=8.0Hz,1H),4.37-4.27(m,1H),3.58-3.48(m,3H) ,3.29-3.18(m,5H),2.92-2.82(m,1H),2.05-1.96(m,2H),1.88-1.68(m,2H),1.28-1.24(m,3H); MS / ESI[M+H] + [M+H] + =386.0.

[0162] Example 4: (R)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-6-((1-methylpiperidin-3-yl)amino)-1,2,4-triazine-5(4H)-one

[0163] Step 1: Compound INT5 (3.00 g, 9.20 mmol), 4a (1.15 g, 10.1 mmol), Cs2CO3 (6.01 g, 18.4 mmol), BINAP (573 mg, 0.92 mmol), and Pd(OA)2 (208 mg, 0.92 mmol) were weighed and added to dioxane (60 mL). The mixture was then replaced with N2 three times and heated to 110°C with stirring overnight. After the reaction was complete, silica gel was added and dried under reduced pressure. The mixture was then purified by column chromatography (DCM:MeOH = 10:1) to obtain the target compound 4b (3.30 g, 9.18 mmol, light yellow viscous product, yield 99%). MS / ESI [M+H] + =360.2.

[0164] Step 2: Compound 4b (3.30 g, 9.18 mmol) was dissolved in dichloromethane (30 mL). TfOH (4.13 g, 27.5 mmol) was slowly added at room temperature and stirred overnight. After the reaction was complete, the pH was adjusted to approximately 8 with aqueous ammonia, dried over anhydrous Na2SO4, filtered, and the filtrate was added to silica gel and dried under reduced pressure. The resulting mixture was separated by column chromatography (DCM:MeOH = 5:1) to afford the target compound 4c (770 mg, 3.22 mmol, light yellow solid, yield 35%). MS / ESI [M+H] + =240.1.

[0165] Step 3: Add POCl3 (4 mL) to compound 4c (770 mg, 3.22 mmol), heat to 110°C, and stir overnight. After the reaction is complete, remove the excess POCl3 and dry it to obtain the target compound 4d (1.5 g, 3.30 mmol, light brown solid, 100% yield). MS / ESI [M+H] + =258.2.

[0166] Step 4: Compound 4d (1.1 g, 2.42 mmol), INT1 (772 mg, 2.66 mmol), Cs2CO3 (3.94 g, 12.1 mmol), and Pd(dppf)Cl2 (176 mg, 0.24 mmol) were weighed and added to dioxane (20 mL) and water (4 mL). The mixture was then replaced with N2 three times and heated to 100°C with stirring overnight. After the reaction was complete, silica gel was added and dried under reduced pressure. The mixture was then purified by column chromatography (DCM:MeOH = 10:1) to obtain the target compound 4e (550 mg, 1.43 mmol, light yellow viscous product, yield 59%). MS / ESI [M+H] + =386.2.

[0167] Step 5: Compound 4e (550 mg, 1.43 mmol) was dissolved in DCM (5.5 mL), cooled to 0°C, and BBr (4.29 mL, 4.29 mmol, 1.0 M) was added dropwise. Stir at room temperature for 1 h. After the reaction was complete, an appropriate amount of methanol was added to quench the reaction. The crude product was evaporated to dryness under reduced pressure and then dissolved in methanol (5 mL). Purification and preparative purification yielded the target compound 4 (295 mg, 0.79 mmol, light yellow powder, 55% yield). 1 H NMR(400MHz,MeOD)δ8.46(s,1H),7.63(d,J=5.6Hz,1H),7.58(dd,J=6.9,4.3Hz,2H),7.29(d,J=8.3Hz,1H),4.30(dt,J=13.0,4.7Hz,1H), 3.52(d,J=11.5Hz,1H),3.36(s,3H),3.25–3.15(m,1H),3.02–2.80(m,2H),2.75(s,3H),2.07(dd,J=21.0,10.1Hz,2H),1.94–1.69(m,2H). MS / ESI[M+H] + =372.2.

[0168] Example 5: (R)-6-((1-(3,3-difluorocyclobutyl)piperidin-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazine-5(4H)-one

[0169] Step 1: Weigh 5a (25.0 g, 231 mmol), pyridine (21.6 g, 277 mmol), and dichloromethane (125 mL) into a flask. Cool to 0°C, then slowly add Tf2O (71.7 g, 254 mmol) dropwise. Stir at room temperature for 1 hour. Filter, wash the filter cake with dichloromethane (20 mL), and collect the filtrate to obtain a dichloromethane solution of the target compound 5b (light yellow).

[0170] Step 2: Dissolve compound 5c (50.9 g, 254 mmol) and triethylamine (70.1 g, 693 mmol) in dichloromethane (250 mL). Add the dichloromethane solution of compound 5b dropwise at room temperature and stir overnight. After the reaction is complete, add silica gel, concentrate under reduced pressure, and spin dry. Separate by column chromatography (PE:EtOAc = 3:1, iodine developer) to obtain the target compound 5d (20.0 g, 68.9 mmol, light yellow solid, 30% yield for two steps). MS / ESI [M+H] + =291.1.

[0171] Step 3: Compound 5d (20.0 g, 68.9 mmol) was dissolved in ethyl acetate (100 mL), and then HCl / EtOAc (86 mL, 345 mmol, 4.0 M) was added and stirred at room temperature for 1 h. After the reaction was complete, the mixture was concentrated under reduced pressure and dried to give the target compound 5e (15.6 g, 59.3 mmol, white solid, 86% yield). MS / ESI [M+H] + =191.2.

[0172] Preparation of (R)-6-((1-(3,3-difluorocyclobutyl)piperidin-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazin-5(4H)-one Reference Example 2. 1 H NMR (400MHz, CDCl3) δ7.62(d,J=5.5Hz,1H),7.47–7.31(m,2H),7.21(d,J=8.5Hz,1H),6.31(s,1H),4.24(s,1H),3.60(s, 3H), 2.67 (dd, J=11.5, 7.9Hz, 3H), 2.52–2.33 (m, 4H), 2.23 (dd, J=16.5, 9.0Hz, 1H), 1.83–1.70 (m, 4H), 1.66–1.61 (m, 1H). MS / ESI[M+H] + =448.3.

[0173] Example 6: (R)-6-((1-(ethyl-d5)piperidin-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazine-5(4H)-one

[0174] Step 1: Compound 5c (10.0 g, 49.9 mmol) and K2CO3 (13.8 g, 99.8 mmol) were added to MeCN (100 mL), followed by deuterated bromoethane (6.83 g, 59.9 mmol). The mixture was stirred at room temperature overnight. After completion, the reaction was filtered and the filtrate was dried by rotary evaporation. The filter cake was dissolved in EtOAc (100 mL) and washed with water (30 mL x 3). The organic phase was collected, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to dryness to afford the target compound 6a (10.1 g, 43.3 mmol, as a light brown solid, in 87% yield). 1 H NMR (400MHz, CDCl3) δ4.99(s,1H),3.73(s,1H),2.54–2.21(m,4H),1.74–1.52(m,4H),1.45(s,9H).

[0175] Step 2: Dissolve compound 6a (10.1 g, 43.3 mmol) in dioxane (50 mL), then slowly add HCl / dioxane (65 mL, 4.0 M) and stir at room temperature for 1 h. The mixture was then concentrated under reduced pressure and dried to afford the target compound 6b (9.20 g, 44.6 mmol, as a white solid, 100% yield).

[0176] The preparation of (R)-6-((1-(ethyl-d5)piperidin-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazin-5(4H)-one was carried out in Reference Example 2. 1 H NMR (400MHz, MeOD) δ8.51(s,1H),7.64(d,J=5.6Hz,1H),7.58(dd,J=6.9,4.5Hz,2H),7.30(d,J=8.2Hz,1H),4.35(t,J=8.8Hz,1H ), 3.65 (d, J = 9.4Hz, 1H), 3.36 (s, 3H), 3.30 (d, J = 4.5Hz, 1H), 3.09–2.80 (m, 2H), 2.09 (dd, J = 26.7, 9.0Hz, 2H), 1.96–1.71 (m, 2H). MS / ESI[M+H] + =391.5.

[0177] Example 7: (R)-6-((1-(ethyl-d5)piperidin-3-yl)amino)-3-(1-hydroxynaphthalen-2-yl)-4-methyl-1,2,4-triazin-5(4H)-one

[0178] Preparation of (R)-6-((1-(ethyl-d5)piperidin-3-yl)amino)-3-(1-hydroxynaphthalen-2-yl)-4-methyl-1,2,4-triazin-5(4H)-one Reference Example 2 (60 mg, 19.5%); 1 H NMR (400MHz, DMSO-d6) δ10.14(br s,1H),8.29(d,J=8.0Hz,1H),7.92(d,J=7.6Hz,1H),7.68-7.45(m,3H),7.38(d,J=8.4Hz,1H),6.83(br s,1H),4.16-4.01(m,1H),3.19(s,3H),2.95-2.74(m,1H),2.65-2.54(m,1H),2.29-2.09(m,2H),1.84-1.45(m,4H); MS / ESI[M+H] + =385.0.

[0179] Example 8: (R)-6-((1-(cyclopropylmethyl)piperidin-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazine-5(4H)-one

[0180] Step 1: Dissolve compound 5c (1.0 g, 5 mmol) and bromomethylcyclopropane (675 mg, 5 mmol) in 10 mL of anhydrous acetonitrile, add potassium carbonate (759 mg, 5.5 mmol), and stir the reaction mixture at room temperature overnight. LC-MS monitoring of the target product was performed. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate, and the organic phase was washed three times with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified using methanol / dichloromethane to obtain the target product 8a (300 mg, 24% yield). MS / ESI [M+H] + =255.6.

[0181] Step 2: Compound 8a (300 mg, 1.18 mmol) was completely dissolved in anhydrous DCM (5 ml) and a dioxane hydrochloride solution (4 M, 5 ml) was added. The reaction was allowed to proceed at room temperature for 2 h. LC-MS monitoring indicated that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain compound 8b (267 mg, 100% yield). MS / ESI [M+H] + =155.1

[0182] Synthesis of (R)-6-((1-(cyclopropylmethyl)piperidin-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazin-5(4H)-one Reference Example 2 (128 mg, 39.1%); 1 H NMR(400MHz,DMSO-d6)δ10.41(br s,1H),9.54(br s,1H),7.79-7.70(m,2H),7.63(d,J=8.0Hz,1H),7.28(d,J=8.4Hz,1H),4.41-4.29(m,1H),3.72-3.54(m,2H),3.23(s,3H),3.15 -3.02(m,2H),2.97-2.80(m,2H),2.06-1.94(m,2H),1.86-1.68(m,2H),1.14-1.01(m,1H),0.72-0.58(m,2H),0.46-0.33(m,2H). MS / ESI[M+H] + =412.0.

[0183] Example 9: (R)-3-(4-hydroxybenzo[b]thiophen-5-yl)-6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-4-methyl-1,2,4-triazine-5(4H)-one

[0184] Preparation of (R)-3-(4-hydroxybenzo[b]thiophen-5-yl)-6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-4-methyl-1,2,4-triazin-5(4H)-one Reference Example 1. MS / ESI[M+H] + =402.2. 1 H NMR (400MHz, Methanol-d4) δ7.52(d,J=5.6Hz,1H),7.47-7.40(m,2H),7.18(d,J=8.0Hz,1H),4.12-4.02(m,1H),3.64-3.57(m,2H ),3.24(s,3H),3.01-2.91(m,1H),2.66-2.57(m,1H),2.55-2.47(m,2H),2.44-2.26(m,2H),1.87-1.67(m,2H),1.65-1.47(m,2H).

[0185] Example 10: (R)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-6-((1-(methyl-d3)piperidin-3-yl)amino)-1,2,4-triazine-5(4H)-one

[0186] Step 1: Compound 5c (2 g, 10 mmol), CD3I (1.5 g, 10 mmol), K2CO3 (2.76 g, 20 mmol), and acetonitrile (30 mL) were added to a dry flask and allowed to react overnight at room temperature. After adding water, the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to yield compound 10a (white solid, 2.03 g). MS / ESI [M+H] + =218.2.

[0187] Step 2: Compound 10a (2.03 g, 9.35 mmol), 1,4-dioxane (10 mL) and HCl (4 M, in dioxane) (9.35 mL) were added to a dry flask and reacted at room temperature for 3 h. The excess solvent was removed by concentration under reduced pressure to obtain compound 10b (white solid, 1.32 g), which was directly used in the next reaction.

[0188] Step 3: Compound 10b (1.32 g, 7 mmol), INT5 (2.28 g, 7 mmol), Pd(OAc)2 (157.2 mg, 0.7 mmol), BINAP (435.9 mg, 0.7 mmol), and Cs2CO3 (6.6 g, 35 mmol) were added to a dry flask under nitrogen protection and dioxane (35 mL) as the solvent. The reaction was allowed to proceed overnight at 100°C. After completion of the reaction as determined by TLC, the mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 10c (0.95 g of a brown oily liquid). MS / ESI [M+H] + =363.2.

[0189] Step 4: Compound 10c (0.95 g, 2.6 mmol), DCM (10 mL), and TfOH (1.17 g, 7.8 mmol) were added to a dry flask and allowed to react overnight at room temperature. After completion of the reaction, a TLC plate was used to adjust the pH to 8-9 with dry NaHCO₃ and a small amount of aqueous ammonia. The product was then dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to yield compound 10d (brown oil, 600 mg). MS / ESI [M+H] + =243.2.

[0190] Step 5: Compound 10d (600 mg, 2.5 mmol) and POCl3 (6 mL) were added to a dry flask and reacted at 100°C overnight. After the reaction was complete, the excess POCl3 was removed by concentration under reduced pressure. The pH was adjusted to 8-9 with dry NaHCO3 and a small amount of aqueous ammonia. The product was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography to obtain compound 10e (light brown solid, 487 mg). MS / ESI [M+H] + =261.1.

[0191] Step 6: Compound 10e (200 mg, 0.77 mmol), INT1 (268 mg, 0.93 mmol), Pd(dppf)Cl2 (58.6 mg, 0.08 mmol), Cs2CO3 (1.17 g, 3.6 mmol), and 1,4-dioxane / H2O (6 mL / 1 mL) were added to a dry flask and reacted overnight at 100°C. After TLC, the reaction mixture was returned to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 10f (yellow oil, 108 mg). MS / ESI [M+H] + =389.2.

[0192] Step 7: Under nitrogen, compound 10f (108 mg, 0.28 mmol) and DCM (2 mL) were added to a dry flask. BBr (1 M) (1 mL) was added dropwise at -10°C and allowed to react for 3 h. The reaction was quenched with MeOH, returned to room temperature, and concentrated under reduced pressure. The residue was purified by column chromatography to yield compound 10 (pale yellow solid, 15.6 mg). 1 HNMR(400MHz, CDCl3)δ7.55(d,J=5.5Hz,1H),7.35-7.28(m,2H),7.14(d,J=8.5Hz,1H ),4.15(s,1H),3.51(s,3H),2.64-2.38(m,4H),2.28-2.09(m,4H),1.59-1.48(m,1H).

[0193] Example 11: (R)-3-(4-cyclopropyl-2-hydroxyphenyl)-6-((1-ethylpiperidin-3-yl)amino)-4-methyl-1,2,4-triazine-5(4H)-one

[0194] Step 1: Compound 2d (150 mg, 0.32 mmol), INT6 (104.2 mg, 0.38 mmol), Pd(dppf)Cl2 (22 mg, 0.03 mmol), and Cs2CO3 (417.3 mg, 1.28 mmol) were added to a dry flask under nitrogen protection. Using dioxane as the solvent, the mixture was reacted at 100°C overnight. After TLC plate analysis, the reaction was complete, filtered, and concentrated under reduced pressure to remove excess solvent. The residue was purified by column chromatography to yield compound 11a (a light brown oil, 79 mg). MS / ESI [M+H] + =384.2.

[0195] Step 2: Under nitrogen, compound 11a (79 mg, 0.21 mmol) and DCM (1 mL) were added to a dry flask. BBr (1 M) (0.84 mL) was added dropwise at -10°C and allowed to react for 3 h. The reaction was quenched with MeOH, returned to room temperature, and concentrated under reduced pressure. The residue was purified by column chromatography to yield compound 11 (off-white solid, 4.5 mg). 1 HNMR (400MHz, CD3OD) δ7.61 (d, J=4.1Hz, 1H), 7.16-7.08 (m, 2H), 4.25–4.19 (m, 1H), 3.34 (s, 3H), 2.95–2. 75(m,4H),2.15-2.02(m,4H),1.97-1.78(m,3H),1.79-1.62(m,2H),1.33-1.24(m,5H),1.23-1.12(m,1H).

[0196] Example 12: (R)-4-ethyl-6-((1-ethylpiperidin-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-1,2,4-triazine-5(4H)-one

[0197] Step 1: Compound INT5a (200 mg, 1.04 mmol) was placed in a reaction flask, and DMF (10 mL) was added, followed by DIEA (269 mg, 2.08 mmol), followed by the slow dropwise addition of ethyl iodide (163 mg, 1.04 mmol) at room temperature for 3 h. LC-MS monitoring indicated that the reaction was complete. Water was added, and the mixture was extracted with EA. The aqueous phase was re-extracted, and the combined organic phases were concentrated. The residue was purified by column chromatography to afford product 12a (200 mg). LC-MS: ESI [M+H] + =221.0.

[0198] Step 2: Compound 12a (200 mg, 0.91 mmol), potassium carbonate (251 mg, 1.82 mmol), and PMBCl (213 mg, 1.36 mmol) were placed in a reaction flask, DMF (10 mL) was added, and the temperature was raised to 60°C for 3 h. LC-MS monitoring indicated that the reaction was complete. Water was added, and the mixture was extracted with EA. The aqueous phase was re-extracted, and the organic phases were combined and concentrated. The residue was purified by column chromatography to obtain product 12b (110 mg). LC-MS: ESI [M+H] + =341.1.

[0199] Step 3: Compound 12b (110 mg, 0.32 mmol), compound 2a (83 mg, 0.65 mmol), palladium acetate (6 mg, 0.03 mmol), BINAP (35 mg, 0.06 mmol), cesium carbonate (185 g, 0.57 mmol), and dioxane (10 mL) were placed in a reaction flask under nitrogen and stirred at 100°C for 15 h. After the reaction was complete, the temperature was cooled to room temperature, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography to obtain product 12c (69 mg); LC-MS: ESI [M+H] + =387.0.

[0200] Step 4: Compound 12c (69 mg, 0.18 mmol) was placed in a reaction flask, dichloromethane (5 mL) was added, the temperature was lowered to 0°C, and trifluoromethanesulfonic acid (1 mL) was slowly added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 15 h. After the reaction was complete, acetonitrile (10 mL) was added and the temperature was lowered to 0-5°C. Solid sodium bicarbonate was added until no bubbles were generated. Ammonia water was then added to adjust the pH to 7-8. The mixture was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by silica gel column chromatography to obtain product 12d (43 mg); LC-MS: ESI [M+H] + =268.1.

[0201] Step 5: Compound 12d (43 mg, 0.16 mmol) was dispersed in phosphorus oxychloride (10 mL) under nitrogen protection and stirred at 110°C for 12 h. After the reaction was complete, the solvent was directly concentrated to dryness, and the residue was dispersed in acetonitrile (10 mL) and dichloromethane (10 mL). The temperature was lowered to 0-5°C, and solid sodium bicarbonate was added until no bubbles were generated. Ammonia was then added to adjust the pH to 7-8. The mixture was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by silica gel column chromatography to obtain product 12e (30 mg); LC-MS: ESI [M+H] + =286.1.

[0202] Step 6: Compound 12e (30 mg, 0.10 mmol), INT1 (46 mg, 0.16 mmol), Pd(dppf)2Cl2 (7 mg, 0.01 mmol), cesium carbonate (68 mg, 0.21 mmol), and dioxane (8 mL) / water (2 mL) were placed in a reaction flask under nitrogen atmosphere and stirred at 100°C for 15 h. After the reaction was complete, the temperature was cooled to room temperature, and the residue was purified by silica gel column chromatography to obtain compound 12f (22 mg); LC-MS: ESI [M+H] + =414.0.

[0203] Step 7: Compound 12f (22 mg, 0.05 mmol) was placed in a reaction flask, DCM (10 mL) was added, and the temperature was cooled to -10°C. BBr3 (67 mg, 0.27 mmol) was then slowly added dropwise. After the addition was complete, the reaction was maintained at -10°C for 3 h. After MS monitoring, the reaction was completed and methanol was added to quench the reaction. The reaction solution was concentrated and the residue was purified by column chromatography to obtain compound 12 (5 mg); LC-MS: ESI [M+H] + =400.1. 1 H NMR (400MHz, DMSO-d6) δ10.26(s,1H),7.73(d,J=8.0Hz,1H),7.71(d,J=8.0Hz,1H),7.59(d,J=8.0Hz,1H),7.30(d, J=8.0Hz,1H),3.83(q,J=8.0,4.0Hz,2H),2.38-2.34(m,4H),1.67-1.55(m,4H),1.49-1.45(m,2H),1.14(t,J=8.0Hz 3H), 1.02 (t, J=8.0Hz 3H).

[0204] Example 13: (R)-3-(1-(difluoromethylene)-4-hydroxy-2,3-dihydro-1H-inden-5-yl)-4-methyl-6-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one

[0205] Preparation of (R)-3-(1-(difluoromethylene)-4-hydroxy-2,3-dihydro-1H-inden-5-yl)-4-methyl-6-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one Reference Example 2. MS / ESI[M+H] + =404.2. 1HNMR(400MHz,CD3OD)δ7.28(d,J=7.7Hz,1H),7.13(d,J=7.5Hz,1H),4.33-4.28(m,1H),3.36(s,3H),3.12–3.03(m,2H),2.9 5-2.91(m,2H),2.84-2.81(m,1H),2.27(s,3H),2.25-2.09(m,3H),2.04-1.94(m,2H),1.82-1.74(m,1H),1.42-1.34(m,2H).

[0206] Example 14: (R)-6-((1-(3,3-difluorocyclobutyl)piperidin-3-yl)amino)-3-(1-(difluoromethylene)-4-hydroxy-2,3-dihydro-1H-inden-5-yl)-4-methyl-1,2,4-triazin-5(4H)-one

[0207] Preparation of (R)-6-((1-(3,3-difluorocyclobutyl)piperidin-3-yl)amino)-3-(1-(difluoromethylene)-4-hydroxy-2,3-dihydro-1H-inden-5-yl)-4-methyl-1,2,4-triazin-5(4H)-one: Reference Example 2. MS / ESI [M+H] + =480.2. 1 H NMR (400MHz, CD3OD) δ7.08(d,J=7.9Hz,1H),6.86(d,J=7.8Hz,1H),4.02(s,1H),3.25(S,3H),2.96-2.90(m,2H),2.76-2.72(m,2H),2 .65-2.52(m,2H),2.47-2.24(m,3H),2.12-2.07(m,1H),1.98-1.92(m,1H),1.59-1.46(m,3H),1.25-1.23(m,2H),1.20-1.18(m,4H).

[0208] Example 15: (R)-3-(1-(difluoromethylene)-4-hydroxy-2,3-dihydro-1H-inden-5-yl)-6-((1-(ethyl-d5)piperidin-3-yl)amino)-4-methyl-1,2,4-triazin-5(4H)-one

[0209] Step 1: Under nitrogen, compound 6e (132 mg, 0.5 mmol), INT3 (193.2 mg, 0.6 mmol), Pd(dppf)Cl2 (36.6 mg, 0.05 mmol), Cs2CO3 (652 mg, 2 mmol), and dioxane / H2O (5 mL / 1 mL) were added to a dry flask and reacted overnight at 100°C. After TLC, the reaction mixture was returned to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 15a (brown oil, 108 mg). MS / ESI [M+H] + =437.2.

[0210] Step 2: Under nitrogen, compound 15a (108 mg, 0.25 mmol) and DCM (2 mL) were added to a dry flask. BBr (1 M) (1 mL) was added dropwise at -10°C for 3 h. The reaction was quenched with MeOH, returned to room temperature, and concentrated under reduced pressure. The residue was purified by preparative isolation to afford compound 15 (pale yellow solid, 42.5 mg). 1 H NMR(400MHz,CD3OD)δ7.28(d,J=7.7Hz,1H),7.13(d,J=7.5Hz,1H),4.33-4.28(m,1H) ,3.38(s,3H),3.10–3.04(m,2H),2.94-2.91(m,2H),2.84-2.80(m,1H),2.25–2.09(m, 3H),2.04-1.94(m,2H),1.82-1.72(m,1H),1.34-1.31(m,2H).

[0211] Example 16: (R)-6-((1-cyclopropylpiperidin-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazin-5(4H)-one

[0212] Step 1: Dissolve compound 5c (400 mg, 2 mmol) and compound 16a (522 mg, 3 mmol) in 9 mL of tetrahydrofuran and 1 mL of methanol. Then, under nitrogen protection at room temperature, sodium cyanoborohydride (378 mg, 6 mmol) and glacial acetic acid (1.44 g, 24 mmol) were added sequentially. The reaction solution was stirred at 65°C for 16 h. TLC monitored the reaction completion, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with saturated sodium bicarbonate solution and extracted three times with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography using a methanol / dichloromethane system to obtain compound 16b (300 mg, 62.5% yield). MS / ESI [M+H] + =241.3.

[0213] Step 2: Compound 16b (300 mg, 1.25 mmol) was completely dissolved in anhydrous DCM (5 ml) and dioxane hydrochloride solution (4 M, 10 ml) was added. The reaction was allowed to proceed at room temperature for 2 hours. LC-MS monitoring indicated that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain compound 16c (270 mg). MS / ESI [M+H] + =141.1.

[0214] Step 3: Add compound INT5 (300 mg, 0.92 mmol), compound 16c (193.2 mg, 1.38 mmol), Pd(OAc)2 (20.2 mg, 0.09 mmol), BINAP (56.1 mg, 0.09 mmol), Cs2CO3 (1.47 g, 4.5 mmol), and dioxane (10 mL) as solvent to a dry flask. Under nitrogen protection, react at 100°C overnight. After completion of the reaction by TLC, filter and concentrate under reduced pressure. The residue is purified by column chromatography to obtain compound 16d (yellow oily liquid, 385 mg). MS / ESI [M+H] + =386.2.

[0215] Step 4: Compound 16d (325 mg, 0.84 mmol), DCM (4 mL), and TfOH (378.2 mg, 2.52 mmol) were added to a dry flask and allowed to react overnight at room temperature. After completion of the reaction, a TLC plate was used to determine the pH of the reaction. The mixture was adjusted to 8-9 using dry NaHCO₃ and a small amount of aqueous ammonia. The mixture was then dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to yield compound 16e (brown solid, 201 mg). MS / ESI [M+H] + =266.2.

[0216] Step 5: Compound 16e (201 mg, 0.81 mmol) and POCl₃ (5 mL) were added to a dry flask and reacted overnight at 100°C. After the reaction was complete, excess POCl₃ was removed by concentration under reduced pressure. The pH was adjusted to 8-9 with dry NaHCO₃ and a small amount of aqueous ammonia. The product was dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 16f (light brown solid, 102 mg). MS / ESI [M+H] + =284.1.

[0217] Step 6: Under nitrogen protection, compound 16f (102 mg, 0.36 mmol), INT1 (125.3 mg, 0.43 mmol), Pd(dppf)Cl2 (29.3 mg, 0.04 mmol), Cs2CO3 (469.4 mg, 1.44 mmol), and 1,4-dioxane / H2O (4 mL / 0.8 mL) were added to a dry flask and reacted overnight at 100°C. After TLC detection, the reaction solution was returned to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 16g (87 mg of bright yellow oily liquid). MS / ESI [M+H] + =412.2.

[0218] Step 7: Under nitrogen, compound 16g (87 mg, 0.21 mmol) and DCM (2 mL) were added to a dry flask. BBr (1 M) (0.84 mL) was added dropwise at -10°C and allowed to react for 3 h. The reaction was quenched with MeOH, returned to room temperature, and concentrated under reduced pressure. The residue was purified by column chromatography to yield compound 16 (off-white solid, 22.1 mg). 1 HNMR(400MHz,CD3OD)δ7.52(d,J=5.5Hz,1H),7.48-7.44(m,2H),7.19(d,J=8.3Hz,1H),4.01(s,1H),3.23(s,3H),3.15-3.0 2(m,2H),2.97-2.80(m,2H),2.06-1.94(m,2H),1.86-1.68(m,2H),1.14-1.01(m,1H),0.72-0.58(m,2H),0.46-0.33(m,2H). MS / ESI[M+H] + =398.2.

[0219] Example 17: (R)-4-ethyl-3-(4-hydroxybenzo[b]thiophen-5-yl)-6-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one

[0220] Reference Example 12 was used to prepare (R)-4-ethyl-3-(4-hydroxybenzo[b]thiophen-5-yl)-6-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one. 1 H NMR (400MHz, DMSO) δ10.22(s,1H),7.73(d,J=4.0Hz,2H),7.59(d,J=8.0Hz,1H),7.29(d,J=8.0Hz,1H),4.14(s,1H),3.72(q,J=8 .0,4.0Hz,2H),3.05-2.95(m,1H),2.74-2.68(m,1H),2.41(s,3H),1.85-1.73(m,2H),1.68-1.55(m,2H),1.00(t,J=8.0Hz,3H). MS / ESI[M+H] + =386.1.

[0221] Example 18: (R)-3-(1-hydroxynaphthalen-2-yl)-4-methyl-6-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one

[0222] Preparation of (R)-3-(1-hydroxynaphthalen-2-yl)-4-methyl-6-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one Reference Example 2. MS / ESI [M+H] + =366.2.

[0223] Example 19: (R)-6-((1-ethylpiperidin-3-yl)amino)-3-(1-hydroxynaphthalen-2-yl)-4-methyl-1,2,4-triazin-5(4H)-one

[0224] Preparation of (R)-6-((1-ethylpiperidin-3-yl)amino)-3-(1-hydroxynaphthalen-2-yl)-4-methyl-1,2,4-triazin-5(4H)-one Reference Example 2. MS / ESI [M+H] + =380.2.

[0225] Example 20: (R)-6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-3-(1-hydroxynaphthalen-2-yl)-4-methyl-1,2,4-triazin-5(4H)-one

[0226] Preparation of (R)-6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-3-(1-hydroxynaphthalen-2-yl)-4-methyl-1,2,4-triazin-5(4H)-one Reference Example 1. MS / ESI [M+H] + =396.2.

[0227] Example 21: (R)-4-cyclopropyl-3-(4-hydroxybenzo[b]thiophen-5-yl)-6-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one

[0228] Preparation of (R)-4-cyclopropyl-3-(4-hydroxybenzo[b]thiophen-5-yl)-6-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one: Reference Example 12. MS / ESI[M+H] + =398.2.

[0229] Example 22: (R)-4-Cyclopropyl-6-((1-ethylpiperidin-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-1,2,4-triazine-5(4H)-one

[0230] Preparation of (R)-4-cyclopropyl-6-((1-ethylpiperidin-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-1,2,4-triazin-5(4H)-one Reference Example 12. MS / ESI[M+H] + =412.2.

[0231] Example 23: (R)-4-cyclopropyl-3-(4-hydroxybenzo[b]thiophen-5-yl)-6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one

[0232] Preparation of (R)-4-cyclopropyl-3-(4-hydroxybenzo[b]thiophen-5-yl)-6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one Reference Example 11. MS / ESI[M+H] + =428.2.

[0233] Example 24: (R)-3-(4-ethynyl-2-hydroxyphenyl)-4-methyl-6-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one

[0234] Step 1: Compound 24a (2.0 g, 9.35 mmol) and HBr (48%) (18 mL) were added to a dry flask and the resulting mixed solution was stirred at 100°C overnight. After the reaction was complete, the mixed solution was returned to room temperature, quenched with water, and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to yield compound 24b (1.13 g, 60%). LC-MS: ESI [M+H] + =200.9.

[0235] Step 2: Compound 24b (1.13 g, 5.65 mmol) was added to a dry flask and dissolved in THF (20 mL). The temperature was lowered to 0°C, and NaH (60%) (339.2 mg, 8.48 mmol) was added. The mixture was stirred for 20 min, and MOMCl (797.1 mg, 8.48 mmol) was added. The reaction was allowed to proceed for 4 h. The mixture was quenched by addition of saturated aqueous NH4Cl solution. The mixture was separated and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to afford compound 24c (1.24 g, 90%). LC-MS: ESI [M+H] + =245.1.

[0236] Step 3: Compound 24c (1.24 g, 5.08 mmol), (Bpin)2 (1.55 g, 6.1 mmol), Pd(dppf)Cl2 (36.6 mg, 0.05 mmol), KOAc (1.0 g, 10.2 mmol), and 1,4-dioxane (20 mL) were added to a dry flask and stirred at 100°C overnight. After the reaction was complete, the mixture was returned to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 24d (684 mg, 46%). LC-MS: ESI [M+H] + =293.1.

[0237] Step 4: To a solution of compound 24d (684 mg, 2.34 mmol) in MeOH (8 mL) was added KCO (646.8 mg, 4.68 mmol) and compound 24e (539.2 mg, 2.81 mmol) at room temperature. The mixture was reacted for 3 h at room temperature. The excess solvent was removed by concentration under reduced pressure, the mixture was dissolved in water, extracted with DCM, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to yield compound 24f (366 mg, 54%). LC-MS: ESI [M+H] + =289.2.

[0238] Step 5: Compound 24f (182 mg, 0.63 mmol), compound 16c (206.0 mg, 0.76 mmol), Pd(dppf)Cl2 (43.9 mg, 0.06 mmol), CS2CO3 (616.1 mg, 1.89 mmol), and 1,4-dioxane (20 mL) were added to a dry flask and reacted overnight at 100°C. After completion of the reaction, the mixture was returned to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to yield compound 24g (87 mg, 35%). LC-MS: ESI [M+H] + =384.2.

[0239] Step 6: Compound 24g (87 mg, 0.22 mmol), 1,4-dioxane (3 mL), and HCl (4M, in dioxane) (0.3 mL) were added to a dry flask and reacted at room temperature for 3 h. The excess solvent was removed by concentration under reduced pressure to obtain compound 24 (9.8 mg, 13%). LC-MS: ESI [M+H] + =340.2.1H NMR (400MHz, CD3OD) δ7.30(d,J=7.8Hz,1H),7.05(d,J=7.8Hz,1H),7.01(s,1H),4.20-4.13(m,1H),3.32(s,3H),3.04-2.88(m,1H) ),2.72-2.54(m,1H),2.32(s,3H),2.30-2.19(m,2H),1.98-1.86(m,1H),1.84-1.75(m,1H),1.70-1.55(m,2H),1.34-1.32(m,1H).

[0240] Example 25: (R)-6-((1-ethylpiperidin-3-yl)amino)-3-(4-ethynyl-2-hydroxyphenyl)-4-methyl-1,2,4-triazin-5(4H)-one

[0241] Preparation of (R)-6-((1-ethylpiperidin-3-yl)amino)-3-(4-ethynyl-2-hydroxyphenyl)-4-methyl-1,2,4-triazin-5(4H)-one Reference Example 24. MS / ESI [M+H] + =354.2. 1H NMR(400MHz,CD3OD)δ7.33(d,J=7.8Hz,1H),7.11–7.00(m,2H),4.20–4.13(m, 1H),3.60(s,1H),3.35(s,1H),3.10-3.02(m,1H),2.77-2.68(m,1H),2.52(dd, J=14.2,7.0Hz,2H),2.34–2.21(m,1H),2.02-1.92(m,1H),1.86–1.78(m,1H),1 .75-1.67(m,1H),1.64-1.54(m,1H),1.36-1.31(m,1H),1.14(t,J=7.2Hz,3H).

[0242] Example 26: (R)-3-(4-ethynyl-2-hydroxyphenyl)-6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-4-methyl-1,2,4-triazin-5(4H)-one

[0243] Preparation of (R)-3-(4-ethynyl-2-hydroxyphenyl)-6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-4-methyl-1,2,4-triazin-5(4H)-one Reference Example 1. MS / ESI[M+H] + =370.2.

[0244] Example 27: (R)-3-(2-hydroxy-4-(prop-1-yn-1-yl)phenyl)-4-methyl-6-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one

[0245] Step 1: Compound 24c (8 g, 30.88 mmol, 1.0 eq), compound 24e (8.9 g, 46.32 mmol, 1.5 eq), and anhydrous potassium carbonate (8.5 g, 61.76 mmol, 2.0 eq) were added to methanol (150 mL) and reacted at room temperature for 3 h. TLC confirmed the absence of starting material. The mixture was concentrated under reduced pressure, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE = 1:150) to afford product 27a (3 g, 38.5% yield).

[0246] Step 2: Compound 27a (500 mg, 1.96 mmol, 1.0 eq) was dissolved in anhydrous THF (10 mL), cooled to -70°C, and a 1.6 mol / L n-butyllithium solution in THF (1.35 mL, 1.1 eq) was added dropwise. The reaction was allowed to proceed at -75°C to -70°C for 1 h. Methyl iodide (834.6 mg, 5.88 mmol, 3.0 eq) was then added dropwise. The mixture was allowed to warm to room temperature and react for 16 h. LC-MS confirmed the reaction was complete. Saturated aqueous ammonium chloride (50 mL) was added and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE = 1:100) to afford product 27b (485 mg, 91.9% yield).

[0247] Step 3: Compound 27b (1.28 g, 5.0 mmol), (Bpin)2 (1.55 g, 6.0 mmol), Pd(dppf)Cl2 (36.6 mg, 0.05 mmol), KOAc (1.0 g, 10.2 mmol), and 1,4-dioxane (20 mL) were added to a dry flask and stirred at 100°C overnight. After the reaction was complete, the mixture was returned to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 27c (684 mg, 46%). LC-MS: ESI [M+H] + =303.1.

[0248] Preparation of (R)-3-(2-hydroxy-4-(prop-1-yn-1-yl)phenyl)-4-methyl-6-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one Reference Example 24. LC-MS: ESI [M+H] + =354.2. 1 H NMR(400MHz,DMSO-d6)δ10.36(br s,1H),7.31(d,J=8.0Hz,1H),7.06-6.93(m,2H),6.82(d,J=8.0Hz,1H),4.18-3.91(m,1H),3.23( s,3H),2.79-2.70(m,1H),2.54-2.45(m,1H),2.24(s,3H),2.21-2.08(m,5H),1.79-1.52(m,4H).

[0249] Example 28: (R)-6-((1-ethylpiperidin-3-yl)amino)-3-(2-hydroxy-4-(prop-1-yn-1-yl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one

[0250] Preparation of (R)-6-((1-ethylpiperidin-3-yl)amino)-3-(2-hydroxy-4-(prop-1-yn-1-yl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one: Reference Example 27. MS / ESI [M+H] + =368.2. 1 H NMR (400MHz, Methanol-d4) δ7.25(d,J=8.0Hz,1H),6.95(dd,J=8.0,1.2Hz,1H),6.91(d,J=1.2Hz,1H),4.60(br s,1H),4.23-4.06(m,1H),3.32(s,3H),3.09-2.98(m,1H),2.75-2.63(m,1H),2.56-2.41(m,2H),2.35-2 .19(m,2H),2.03(s,3H),1.99-1.91(m,1H),1.86-1.77(m,1H),1.74-1.52(m,2H),1.12(d,J=7.2Hz,3H).

[0251] Example 29: (R)-3-(2-hydroxy-4-(prop-1-yn-1-yl)phenyl)-6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-4-methyl-1,2,4-triazin-5(4H)-one

[0252] Preparation of (R)-3-(2-hydroxy-4-(prop-1-yn-1-yl)phenyl)-6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-4-methyl-1,2,4-triazin-5(4H)-one Reference Example 1. MS / ESI [M+H] + =384.2.

[0253] Example 30: 3-(4-Hydroxybenzo[b]thiophen-5-yl)-6-(((1R,2R)-2-hydroxycyclohexyl)amino)-4-methyl-1,2,4-triazin-5(4H)-one

[0254] Step 1: Add compound INT7 (444 mg, 2.00 mmol), 30a (230 mg, 2.00 mmol), DIPEA (1.03 g, 8 mmol), and 1,4-dioxane (15 mL) as solvent to a dry flask and react at 80°C overnight. After the reaction is complete, the excess solvent is removed by concentration under reduced pressure. The residue is purified by column chromatography to obtain compound 30b (526 mg). MS / ESI [M+H] +=259.1.

[0255] Step 2: Compound 30b (163 mg, 0.63 mmol), INT1 (250.9 mg, 0.76 mmol), Pd(dppf)Cl2 (43.9 mg, 0.06 mmol), and Cs2CO3 (782.4 mg, 2.4 mmol) were added to a dry flask under nitrogen protection. 1,4-dioxane / H2O (6 mL / 0.5 mL) was used as the solvent and the reaction was carried out at 100°C overnight. After TLC plate detection, the reaction was completed, filtered, and the excess solvent was removed by concentration under reduced pressure. The residue was purified by column chromatography to obtain compound 30c (202 mg). MS / ESI [M+H] + =387.1.

[0256] Step 3: Under nitrogen, compound 30c (66 mg, 0.17 mmol) and DCM (1.5 mL) were added to a dry flask. BBr (1 M) (0.7 mL) was added dropwise at -10°C and allowed to react for 3 h. The reaction was quenched with MeOH, returned to room temperature, and concentrated under reduced pressure. The residue was purified by column chromatography to yield compound 30 (33.5 mg). MS / ESI [M+H] + =373.2. 1 H NMR (400MHz, DMSO-d6) δ7.66-7.60(m,2H),7.49(d,J=8.4Hz,1H),7.19(d,J=8.4Hz,1H),6.65(d,J=7.2Hz,1H),4.75-4.64(m,1H) ,3.63-3.52(m,1H),3.49-3.40(m,1H),3.13(s,3H),2.09-1.99(m,1H),1.91-1.79(m,1H),1.66-1.51(m,2H),1.28-1.10(m,4H).

[0257] Example 31: 3-(4-ethynyl-2-hydroxyphenyl)-6-(((1R,2R)-2-hydroxycyclohexyl)amino)-4-methyl-1,2,4-triazin-5(4H)-one

[0258] Preparation of 3-(4-ethynyl-2-hydroxyphenyl)-6-(((1R,2R)-2-hydroxycyclohexyl)amino)-4-methyl-1,2,4-triazin-5(4H)-one Reference Example 24. MS / ESI [M+H] + =341.2.

[0259] Example 32: 3-(2-Hydroxy-4-(prop-1-yn-1-yl)phenyl)-6-(((1R,2R)-2-hydroxycyclohexyl)amino)-4-methyl-1,2,4-triazin-5(4H)-one

[0260] Preparation of 3-(2-hydroxy-4-(prop-1-yn-1-yl)phenyl)-6-(((1R,2R)-2-hydroxycyclohexyl)amino)-4-methyl-1,2,4-triazin-5(4H)-one Reference Example 24. MS / ESI [M+H] + =355.2.

[0261] Example 33: 6-(((1R,2R)-2-hydroxycyclohexyl)amino)-3-(1-hydroxynaphthalen-2-yl)-4-methyl-1,2,4-triazin-5(4H)-one

[0262] Preparation of 6-(((1R,2R)-2-hydroxycyclohexyl)amino)-3-(1-hydroxynaphthalen-2-yl)-4-methyl-1,2,4-triazin-5(4H)-one Reference Example 30. MS / ESI [M+H] + =367.2.

[0263] Example 34: (R)-3-(4-Hydroxybenzo[b]thiophen-5-yl)-4-methyl-6-(((4-methylmorpholin-2-yl)methyl)amino)-1,2,4-triazin-5(4H)-one

[0264] Preparation of (R)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-6-(((4-methylmorpholin-2-yl)methyl)amino)-1,2,4-triazin-5(4H)-one: Reference Example 4. MS / ESI[M+H] + =388.2. 1 H NMR (400MHz, CD3OD) δ7.53(d,J=5.7Hz,1H),7.43-7.37(m,2H),7.21(d,J=8.3Hz,1H),4.03(s,1H),3.62-3.57(m,2H) ,3.52-3.47(m,2H),3.35(s,1H),3.25(s,3H),2.68-2.62(m,2H),2.63-2.54(m,2H),2.48-2.42(m,2H),2.18(s,3H).

[0265] Example 35: (S)-3-(4-Hydroxybenzo[b]thiophen-5-yl)-4-methyl-6-(((4-methylmorpholin-2-yl)methyl)amino)-1,2,4-triazin-5(4H)-one

[0266] Preparation of (S)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-6-(((4-methylmorpholin-2-yl)methyl)amino)-1,2,4-triazin-5(4H)-one: Reference Example 4. MS / ESI[M+H] + =388.2. 1 H NMR (400MHz, CD3OD) δ7.53(d,J=5.7Hz,1H),7.43-7.37(m,2H),7.21(d,J=8.3Hz,1H),4.03(s,1H),3.62-3.57(m,2H) ,3.52-3.47(m,2H),3.35(s,1H),3.25(s,3H),2.68-2.62(m,2H),2.63-2.54(m,2H),2.48-2.42(m,2H),2.18(s,3H).

[0267] Example 36: (R)-3-(4-hydroxybenzo[b]thiophen-5-yl)-6-((1-isopropylpiperidin-3-yl)amino)-4-methyl-1,2,4-triazin-5(4H)-one

[0268] Preparation of (R)-3-(4-hydroxybenzo[b]thiophen-5-yl)-6-((1-isopropylpiperidin-3-yl)amino)-4-methyl-1,2,4-triazin-5(4H)-one Reference Example 4. MS / ESI[M+H] + =400.2. 1 H NMR (400MHz, DMSO-d6) δ8.16(s,1H),7.76-7.64(m,2H),7.58(d,J=8.2Hz,1H),7.27(d,J=8.2Hz,1H),6.84(d,J=8.4Hz,1H),4.11- 4.03(m,1H),3.19(s,3H),2.91-2.83(m,2H),2.69-2.61(m,1H),2.45-2.36(m,2H),1.79-1.51(m,4H),1.02(dd,J=6.5,1.8Hz,6H).

[0269] Example 37: (R)-6-((5,5-difluoro-1-methylpiperidin-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazin-5(4H)-one

[0270] Preparation of (R)-6-((5,5-difluoro-1-methylpiperidin-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazin-5(4H)-one Reference Example 4. MS / ESI[M+H] + =408.2. 1 H NMR (400MHz, CD3OD) δ7.52(d,J=5.5Hz,1H),7.48-7.44(m,2H),7.19(d,J=8.3Hz,1H),4.01(s,1H) ,3.23(s,3H),2.87(s,1H),2.68-2.62(m,2H),2.63-2.54(m,2H),2.18(s,3H).2.15-2.12(m,2H).

[0271] Example 38: (R)-3-(4-(difluoromethoxy)benzothiophen-5-yl)-4-methyl-6-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one

[0272] Step 1: 5-Bromobenzo[b]thiophene-4-ol INT1c (1.00 g, 4.37 mmol), 2-(difluoromethyl)sulfonyl)pyridine (1.69 g, 8.74 mmol), KOH (1.23 g, 21.85 mmol), dioxane (10 mL), and water (2.5 mL) were placed in a reaction flask and stirred at 50°C for 4 h. After completion of the reaction, the system was separated and the upper organic phase was collected and directly mixed with silica gel. The sample was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 30:1) to obtain compound 38a (1.10 g, 3.94 mmol, 90%). 1 H NMR (400MHz, CDCl3) δ7.65(d,J=8.6Hz,1H),7.54(d,J=8.6Hz,1H),7.50(t,J=6.4Hz,2H),6.61(t,J=74.3Hz,1H); 19 F NMR (377MHz, CDCl3) δ-80.02.

[0273] Step 2: Compound 38a (1.10 g, 3.94 mmol), pinacol diboronate (1.20 g, 4.73 mmol), potassium acetate (773 mg, 7.88 mmol), and bistriphenylphosphine palladium dichloride (274 mg, 0.39 mmol) were placed in a reaction flask. Dioxane (10 mL) was added and stirred at 100°C under a nitrogen atmosphere for 12 h. After completion of the reaction, the sample was directly added to silica gel and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain compound 38b (760 mg, 2.33 mmol, 59%). 1 H NMR (400MHz, CDCl3) δ7.78 (dd, J=8.1, 0.5Hz, 1H), 7.71 (d, J=8.1Hz, 1H), 7.56 (d,J=5.3Hz,1H),7.43(d,J=5.5Hz,1H),6.68(t,J=76.2Hz,1H),1.38(s,12H); 19 FNMR (377MHz,CDCl3)δ-80.86.

[0274] Step 3: Compound 4d (100 mg, 0.39 mmol), 2-(4-(difluoromethoxy)benzo[b]thiophen-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 38b (153 mg, 0.47 mmol), cesium carbonate (254 mg, 0.78 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (29.3 mg, 0.04 mmol) were added to dioxane (1 mL) and water (0.2 mL) under nitrogen atmosphere and stirred at 100°C for 12 h. After completion of the reaction, the sample was directly added to silica gel and purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain the crude product. This was then separated by reverse phase preparative separation to afford compound 38 (40.0 mg, 0.095 mmol, 24%); MS / ESI [M+H] + =422.2; 1 H NMR (400MHz, MeOD) δ8.50(s,1H),8.07(d,J=8.3Hz,1H),7.84(d,J=5.6Hz,1H),7.57(d,J=5.6Hz,1H),7.51(d,J=8.3Hz,1H),6.81(t,J=73.2Hz,1H), 4.31-4.20(m,1H),3.37(d,J=9.0Hz,1H),3.29(s,3H),3.16-3.01(m,1H), 2.74(d,J=8.2Hz,2H),2.66(s,3H),2.12-1.93(m,2H),1.86-1.66(m,2H).

[0275] Example 39: (R)-3-(4-cyclopropyl-2-hydroxyphenyl)-4-methyl-6-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one

[0276] Preparation of (R)-3-(4-cyclopropyl-2-hydroxyphenyl)-4-methyl-6-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one Reference Example 11. MS / ESI [M+H] + =356.2; 1 H NMR (400MHz, CD3OD) δ7.55 (d, J = 4.1Hz, 1H), 7.17-7.10 (m, 2H), 4.25-4.19 (m, 1H), 3.34 (s, 3H), 2.95- 2.75(m,3H),2.18(s,3H),1.97-1.78(m,3H),1.77-1.61(m,2H),1.32-1.25(m,5H),1.23-1.12(m,1H).

[0277] Example 40: 6-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazin-5(4H)-one

[0278] Step 1: Compound 40a (4.75 g, 21.8 mmol), paraformaldehyde (1.31 g, 43.6 mmol), and acetic acid (0.26 g, 4.36 mmol) were added to methanol (50 mL), followed by sodium cyanoborohydride (2.74 g, 43.6 mmol). The mixture was stirred at 50°C for 1 h. After the reaction was complete, silica gel was added, the sample was spin-dried, and purified by column chromatography (DCM:MeOH = 10:1, iodine developer) to afford compound 40b (4.67 g, 20.1 mmol, 92% yield). 1 H NMR (400MHz, CDCl3-d) δ4.92-4.64(m,2H),3.99(s,1H),2.77-2.39(m,3H),2.30(s,3H),1.94-1.80(m,1H),1.45(s,9H); MS / ESI[M+H] + =233.0.

[0279] Step 2: Compound 40b (4.67 g, 20.1 mmol) was dissolved in dioxane (25 mL), and then HCl / dioxane (25 mL, 101 mmol, 4.0 M) was added. The mixture was stirred at 25°C for 1 h. After completion of the reaction, the mixture was evaporated to dryness under reduced pressure to obtain the desired product 40c (4.60 g, 22.4 mmol, yield 111%). 1 H NMR (400MHz, CD3OD-d4) δ5.37-5.24(m,1H),4.98-4.89(m,1H),3.92-3.77(m,3H),3.51( dd,J=39.2,13.9Hz,1H),3.06(s,3H),2.63-2.55(m,1H),2.15-1.98(m,1H); MS / ESI[M+H] + =133.0.

[0280] Preparation of 6-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazin-5(4H)-one Reference Example 4. MS / ESI[M+H] + =390.0; 1 H NMR(400MHz, CDCl3-d)δ7.60(d,J=5.4Hz,1H),7.43-7.31(m,2H),7.19(d,J=8.5Hz,1H),6.17(d,J=8.1Hz,1H),4.90-4.72(m,1H),4.45(s,1H) ,3.57(s,3H),2.91-2.78(m,1H),2.68-2.60(m,1H),2.56-2.48(m,1H) ,2.46-2.38(m,1H),2.37(s,3H),2.28-2.17(m,1H),1.91-1.81(m,1H).

[0281] Example 41: 6-(((3R,5R)-1-ethyl-5-fluoropiperidin-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazin-5(4H)-one

[0282] Preparation of 6-(((3R,5R)-1-ethyl-5-fluoropiperidin-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazin-5(4H)-one Reference Example 40. MS / ESI[M+H] + =404.0; 1H NMR(400MHz, CD3OD-d)δ7.61(d,J=5.6Hz,1H),7.58-7.49(m,2H),7.28(d,J=8.3Hz,1H),4.98-4.93(m,1H),4.85-4.80(m,2H),4.51 -4.43(m,1H),3.34(s,3H),3.12-3.01(m,1H),2.98-2.83(m,1H),2.55(t,J=7.2Hz,2H),2.52-2.41(m,1H),2.31-2.13(m,2H),2.03- 1.86(m,1H),1.12(t,J=7.2Hz,3H).

[0283] Example 42: 4-Ethyl-6-(((3R,5R)-1-ethyl-5-fluoropiperidin-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-1,2,4-triazin-5(4H)-one

[0284] Step 1: Compound 12b (300 mg, 0.88 mmol), compound 41b (192 mg, 0.88 mmol), Pd(OAc)2 (20.4 mg, 0.09 mmol), BINAP (56.04 mg, 0.09 mmol), Cs2CO3 (1.15 g, 3.52 mmol), and dioxane (8 mL) were added to a dry flask. Under nitrogen, the mixture was reacted at 100°C overnight. After completion of the reaction as determined by TLC, the mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography to yield compound 42a (yellow oil, 217 mg). MS / ESI [M+H] + =406.2.

[0285] Step 2: Compound 42a (217 mg, 0.54 mmol), DCM (5 mL), and TfOH (243.2 mg, 1.62 mmol) were added to a dry flask and allowed to react overnight at room temperature. After completion of the reaction, a TLC plate was used to adjust the pH to 8-9 using dry NaHCO₃ and a small amount of aqueous ammonia. The mixture was then dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to yield compound 42b (pale yellow solid, 114 mg). MS / ESI [M+H] + =286.2.

[0286] Step 3: Compound 42b (114 mg, 0.4 mmol) and POCl3 (8 mL) were added to a dry flask and reacted at 100°C overnight. After the reaction was complete, the excess POCl3 was removed by concentration under reduced pressure. The residue was purified by column chromatography to obtain compound 42c (light brown solid, 106 mg). MS / ESI [M+H] + =304.1.

[0287] Step 4: Compound 42c (106 mg, 0.35 mmol), INT8 (112 mg, 0.35 mmol), Pd(dppf)Cl2 (29.3 mg, 0.04 mmol), Cs2CO3 (456.4 mg, 1.4 mmol), and 1,4-dioxane / H2O (5 mL / 1 mL) were added to a dry flask and reacted overnight at 100°C. After TLC, the reaction mixture was returned to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 42d (yellow oil, 86 mg). MS / ESI [M+H] + =462.2.

[0288] Step 5: Compound 42d (86 mg, 0.19 mmol) and dioxane (2 mL) were added to a dry flask. HCl in MeOH (4 M) (0.2 mL) was added dropwise at room temperature and allowed to react for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography to yield compound 42 (pale yellow solid, 7.8 mg); MS / ESI [M+H] + =418.2. 1 H NMR (400MHz, CD3OD) δ7.51(d,J=5.5Hz,1H),7.22(d,J=5.5Hz,1H),7.12-7.05(m,2H),4.41-4.30(m,1H),3.94 -3.84(m,2H),3.02-2.94(m,1H),2.89-2.75(m,1H),2.48-2.38(m,3H),2.19- 2.02(m,3H),1.99-1.76(m,2H),1.02(t,J=7.2Hz,3H),0.96(t,J=7.2Hz,3H).

[0289] Example 43: 4-Ethyl-6-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-1,2,4-triazin-5(4H)-one

[0290] Preparation of 4-ethyl-6-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-1,2,4-triazin-5(4H)-one Reference Example 42. MS / ESI[M+H] + =404.2. 1 H NMR (400MHz, CD3OD) δ7.51(d,J=5.5Hz,1H),7.26(d,J=5.5Hz,1H),7.15(d,J=8.1Hz,1H),7.08(d,J=8.2Hz,1H),4.43-4.31(m,1H),3.89-3.8 5(m,2H),2.99-2.93(m,1H),2.83-2.75(m,1H),2.41-2.28(m,1H),2.2 4(s,3H),2.16-2.03(m,3H),1.96-1.78(m,2H),0.97(t,J=7.1Hz,3H).

[0291] Example 43: (R)-3-(4-(cyclopropylethynyl)-2-hydroxyphenyl)-4-methyl-6-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one

[0292] Step 1: 2-Bromo-5-iodophenol 44a (5.0 g, 16.72 mmol) was placed in a reaction flask, tetrahydrofuran (50 mL) was added, and the temperature was cooled to 0°C. NaH (1.0 g, 25.08 mmol, 60%) was added portionwise. The reaction was allowed to proceed for 0.5 h. Chloro(methoxy)methane (2.02 g, 25.08 mmol) was added and allowed to proceed for 1 h at room temperature. Upon completion, the reaction was quenched with saturated aqueous ammonium chloride (50 mL). The mixture was extracted with ethyl acetate (50 mL), and the aqueous phase was further extracted with ethyl acetate (20 mL). The ethyl acetate layers were combined and directly added to silica gel. Compound 44b (5.7 g, 99.5%) was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0-19:1) to obtain compound 44b (MS / ESI [M+H]). + =342.8.

[0293] Step 2: Compound 44b (2000 mg, 5.85 mmol), Pd(PPh3)Cl2 (410 mg, 0.59 mmol), CuI (222 mg, 1.17 mmol), DIEA (2.3 g, 17.54 mmol), and tetrahydrofuran (50 mL) were placed in a reaction flask under nitrogen and stirred at room temperature for 0.5 h. Then, ethynylcyclopropane (385 mg, 5.85 mmol) was added. After addition, the mixture was allowed to react at room temperature for 15 h. After completion of the reaction, the sample was directly added to silica gel and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 24:1) to obtain compound 44c (1.7 g, crude product).

[0294] Step 3: Compound 44c (1.4 g, 5.00 mmol) was placed in a reaction flask under nitrogen atmosphere. Tetrahydrofuran (50 mL) was added and the temperature was lowered to -78°C. n-Butyllithium (2.6 mL, 6.50 mmol, 0.5 M) was added dropwise. After completion, the reaction was incubated for 1 h. A solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.4 g, 7.50 mmol) in tetrahydrofuran (10 mL) was added. The reaction was incubated for 1 h, then warmed to room temperature for 1 h. Upon completion, the reaction was quenched by the addition of saturated aqueous ammonium chloride (50 mL). The reaction was extracted with ethyl acetate (50 mL). The aqueous phase was further extracted with ethyl acetate (50 mL). The ethyl acetate layers were combined and directly added to silica gel. Purification was performed by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0-10:1) to obtain compound 44d (1.2 g, 73.1%). 1 H NMR(400MHz,Chloroform-d)δ7.58(d,J=8.0Hz,1H),7.26(s,1H),7.02(d,J=8.0Hz, 1H),5.17(s,2H),3.50(s,3H),1.47-1.41(m,1H),1.34(s,12H),0.90-0.79(m,4H).

[0295] Preparation of (R)-3-(4-(cyclopropylethynyl)-2-hydroxyphenyl)-4-methyl-6-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one Reference Example 24. MS / ESI [M+H] + =380.2; 1H NMR NMR (400MHz, CD3OD) δ7.25(d,J=7.8Hz,1H),6.96(d,J=7.8Hz,1H),6.90(s,1H),4.25(s,1H),3.56-3.43(m,1H),3.32(s,3H),3.01-2.81(m,2H),2 .77(s,3H),2.12-1.99(m,3H),1.89-1.80(m,1H),1.78-1.67(m,1H),1.5 4-1.44(m,1H),1.37-1.27(m,1H),0.97-0.88(m,2H),0.79-0.70(m,2H).

[0296] Example 45: (R)-3-(4-(cyclopropylethynyl)-2-hydroxyphenyl)-6-((1-ethylpiperidin-3-yl)amino)-4-methyl-1,2,4-triazin-5(4H)-one

[0297] Preparation of (R)-3-(4-(cyclopropylethynyl)-2-hydroxyphenyl)-6-((1-ethylpiperidin-3-yl)amino)-4-methyl-1,2,4-triazin-5(4H)-one Reference Example 44. MS / ESI[M+H] + =394.2; 1 H NMR NMR (400MHz, CD3OD) δ7.25(d,J=7.8Hz,1H),6.95(d,J=7.9Hz,1H),6.90(s,1H),4.25(d,J =9.6Hz,1H),3.55-3.42(m,1H),3.33(s,3H),3.05(dd,J=14.1,6.9Hz,2H),2.93-2.76(m, 2H),2.10-2.01(m,3H),1.93-1.70(m,2H),1.53-1.43(m,1H),1.32-1.26(m,4H),0.95-0.86(m,2H),0.80-0.69(m,2H).

[0298] Example 46: (R)-3-(4'-Fluoro-3-hydroxy-[1,1'-biphenyl]-4-yl)-4-methyl-6-((1-methylpiperidin-3-yl)amino)-1,2,4-triazine-5(4H)-one

[0299] Step 1: To a dry flask were added compound 44b (400 mg, 1.17 mmol), 46a (259.7 mg, 1.17 mmol), Pd(dppf)Cl2 (87.8 mg, 0.12 mmol), Cs2CO3 (750.0 mg, 2.3 mmol), and 1,4-dioxane / H2O (10 / 2 mL) under nitrogen atmosphere. The mixture was stirred at 100°C overnight. After completion of the reaction, the mixture was returned to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to yield compound 46b (312 mg, 86%). 1 H NMR (400MHz, CDCl3) δ7.51 (d, J = 8.2 Hz, 2H), 7.47-7.40 (m, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.09-6.96 (m, 3H), 5.23 (s, 2H), 3.48 (s, 3H).

[0300] Step 2: Compound 46b (312 mg, 1.01 mmol), (Bpin)2 (304.8 mg, 1.2 mmol), Pd(dppf)Cl2 (73.2 mg, 0.1 mmol), KOAc (198.2 mg, 2.02 mmol), and 1,4-dioxane (10 mL) were added to a dry flask and stirred at 100°C overnight. After the reaction was complete, the mixture was returned to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to yield compound 46c (201 mg, 56%). MS / ESI [M+H] + =359.2.

[0301] Step 3: Compound 46c (201 mg, 0.56 mmol), 4d (143.9 mg, 0.56 mmol), Pd(dppf)Cl2 (43.9 mg, 0.06 mmol), Cs2CO3 (730.2 mg, 2.24 mmol), and 1,4-dioxane / H2O (6 mL / 1 mL) were added to a dry flask under nitrogen and stirred overnight at 100°C. After completion of the reaction, the mixture was returned to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to yield compound 46d (154 mg, 60%). MS / ESI [M+H] + =454.2.

[0302] Step 4: Compound 46d (154 mg, 0.34 mmol), 1,4-dioxane (3 mL) and HCl (4 M, in dioxane) (0.4 mL) were added to a dry flask and reacted at room temperature for 3 h. The excess solvent was removed by concentration under reduced pressure to obtain compound 46 (16.5 mg, 12%); MS / ESI [M+H] + =410.2. 1 H NMR (400MHz, CD3OD) δ7.65 (dd, J=8.8, 5.3Hz, 2H), 7.40 (d, J=7.9Hz, 1H), 7.25-7.12 (m, 4H), 4.18-4. 10(m,1H),3.37(s,3H),3.05-2.89(m,1H),2.70-2.54(m,1H),2.31(s,3H),2.30-2.14(m,2H),1.98- 1.87(m,1H),1.85-1.76(m,1H),1.74-1.62(m,1H),1.61-1.50(m,1H),1.36-1.28(m,1H).

[0303] Example 47: (R)-3-(2-hydroxy-4-(pyrimidin-2-yl)phenyl)-4-methyl-6-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one

[0304] Step 1: Compound 47a (460 mg, 2 mmol), compound 47b (480 mg, 3 mmol), Pd(PPh3)4 (230 mg, 0.2 mmol), sodium carbonate (640 mg, 6 mmol), dioxane (10 ml), and water (2 ml) were added to a reaction flask. The replacement reaction system was placed under a nitrogen atmosphere at 100°C overnight. The filtrate was filtered, concentrated under reduced pressure, and the sample was added with silica gel. Column chromatography was performed to obtain the target compound 47c (310 mg). MS / ESI [M+H] + =266.1.

[0305] Step 2: Compound 47c (160 mg, 0.6 mmol), Pd(dppf)Cl2 (44 mg, 0.06 mmol), potassium acetate (176 mg, 108 mmol), B2pin2 (305 mg, 1.2 mmol), and dioxane (6 ml) were added to a reaction flask. The replacement reaction system was placed under a nitrogen atmosphere at 100°C overnight. The filtrate was filtered, concentrated under reduced pressure, and the sample was added with silica gel. The sample was purified by column chromatography to obtain the target compound 47d (220 mg). MS / ESI [M+H] +=313.1. Preparation of (R)-3-(2-hydroxy-4-(pyrimidin-2-yl)phenyl)-4-methyl-6-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one: Reference Example 4. MS / ESI [M+H] + =394.4. 1 H NMR (400MHz, Chloroform-d) δ8.82(d,J=4.8Hz,2H),8.13(d,J=1.7Hz,1H),8.01(dd,J=8.2,1.7Hz,1H),7.42(d,J=8.3Hz,1H),7.23(t,J=4 .8Hz,1H),6.42(s,1H),4.34-4.12(m,1H),3.58(s,3H),2.59(s,2H),2.50(s,2H),2.28(s,3H),1.76(d,J=21.9Hz,4H),1.67-1.55(m,1H).

[0306] Example 48: 3-(4-Hydroxybenzo[b]thiophen-5-yl)-4-methyl-6-(7-methyloctahydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-1,2,4-triazine-5(4H)-one

[0307] Preparation of 3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-6-(7-methyloctahydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-1,2,4-triazin-5(4H)-one Reference Example 4. MS / ESI[M+H] + =398.4. 1 H NMR (400MHz, CD3OD) δ7.53(d,J=5.7Hz,1H),7.43-7.37(m,2H),7.21(d,J=8.3Hz,1H),4.21-4.13(m,1H),3.31(s, 3H),2.95-2.87(m,2H),2.67-2.42(m,2H),2.55-2.39(m,3H),2.18(s,3H),1.97-1.78(m,3H),1.53-1.34(m,2H).

[0308] Example 49: 6-(((2R,3R)-1,2-dimethylpiperidin-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazin-5(4H)-one

[0309] The preparation of 6-(((2R,3R)-1,2-dimethylpiperidin-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazin-5(4H)-one was carried out by referring to Example 40 to obtain Compound 49 (115 mg, 33.8%); 1 H NMR(400MHz,DMSO-d6)δ10.22(br s,1H),7.72(d,J=5.6Hz,1H),7.69(d,J=5.6Hz,1H),7.59(d,J=8.0Hz,1H),7. 29(d,J=8.0Hz,1H),6.39-6.31(m,1H),4.07-3.97(m,1H),3.20(s,3H),2.87-2 .74(m,1H),2.44-2.31(m,1H),2.21(s,3H),2.16-2.02(m,1H),1.99-1.90(m, 1H),1.74-1.58(m,1H),1.55-1.39(m,2H),1.04(d,J=6.4Hz,3H); MS / ESI[M+H] + =386.0.

[0310] Example 50: 6-(((3R,6S)-1,6-dimethylpiperidin-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazin-5(4H)-one

[0311] Preparation of 6-(((3R,6S)-1,6-dimethylpiperidin-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazin-5(4H)-one Reference Example 40. MS / ESI[M+H] + =386.2. 1 H NMR(400 MHz, CD3OD) δ7.53(d,J=5.7Hz,1H),7.43-7.37(m,2H),7.21(d,J=8.3Hz,1H),4.03(m,1H),3.27(s,3H) ,2.86-2.74(m,2H),2.46-2.41(m,2H),2.18(s,3H),1.84-1.79(m,2H),1.77-1.61(m,2H),1.16(s,3H).

[0312] Example 51: 3-(4-Hydroxybenzo[b]thiophen-5-yl)-6-{[(3R)-1-methylhexahydropyridin-3-yl]amino}-4-(2-methoxyethyl)-4H,5H-1,2,4-triazine-5-one

[0313] Preparation of 3-(4-hydroxybenzo[b]thiophen-5-yl)-6-{[(3R)-1-methylhexahydropyridin-3-yl]amino}-4-(2-methoxyethyl)-4H,5H-1,2,4-triazin-5-one Referring to Example 12, compound 51 (24 mg, 44.4%) was obtained; 1 H NMR(400MHz, Methanol-d4)δ7.61(d,J=5.6Hz,1H),7.56-7.51(m,2H),7.29(d,J=8.4Hz,1H),4.23-4.14(m,1H),4.08(t,J=5.6Hz,2H), 3.44(t,J=5.6Hz,2H),3.11-3.01(m,4H),2.76-2.66(m,1H),2.45-2.34(m,5H),2.02-1.81(m,2H),1.77-1.56(m,2H); LC-MS:ESI[M+H] + =416.0.

[0314] Example 52: 3-(2-Fluoro-4-hydroxybenzo[b]thiophen-5-yl)-6-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}-4-methyl-5H,4H-1,2,4-triazine-5-one

[0315] Step 1: Dissolve compound INT1d (5.00 g, 20.6 mmol) in tetrahydrofuran (25 mL) and cool to -70°C under nitrogen. Then slowly add LDA (12.4 mL, 2.0 M, 24.7 mmol) dropwise. Stir for 1 hour. Then, add a solution of N-fluorobisbenzenesulfonamide (7.16 g, 22.7 mmol) in tetrahydrofuran (25 mL) dropwise. Stir for 1 hour, then warm to room temperature and stir overnight. After the reaction is complete, quench with saturated aqueous ammonium chloride (100 mL). Extract with ethyl acetate (30 mL x 3), dry over anhydrous sodium sulfate, filter, and pour the filtrate onto silica gel, concentrate, and purify by column chromatography (PE:EtOAc = 1:0) to afford compound 52a (2.80 g, 10.7 mmol, 52% yield). 1 H NMR (400MHz, CDCl3-d) δ7.41 (d, J = 8.4Hz, 1H), 7.23 (d, J = 6.4Hz, 1H), 6.80 (d, J = 2.4Hz, 1H), 3.91 (s, 3H).

[0316] Step 2: Compound 52a (2.80 g, 10.7 mmol), pinacol borate (3.25 g, 12.8 mmol), KOAc (2.10 g, 21.4 mmol), and Pd(PPh3)Cl2 (751 mg, 1.07 mmol) were added to anhydrous dioxane (30 mL) and reacted at 100°C under nitrogen for 12 h. After the reaction, the mixture was filtered, concentrated under reduced pressure, and separated by column chromatography (PE:EtOAc = 30:1) to afford the target compound 52b (2.10 g, 6.81 mmol, colorless solid, 64% yield). 1 HNMR (400MHz, CDCl3) δ7.63 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 2.4 Hz, 1H), 3.94 (s, 3H), 1.38 (s, 12H).

[0317] The preparation of the compound 3-(2-fluoro-4-hydroxybenzo[b]thiophen-5-yl)-6-{[(3R,5R)-5-fluoro-1-methylhexahydropyridin-3-yl]amino}-4-methyl-5H,4H-1,2,4-triazine-5-one was performed in Example 4. 1 H NMR (400MHz, CDCl3-d) δ7.20–7.13(m,2H),6.94(d,J=2.4Hz,1H),6.17(d,J=8.0Hz,1H),4.90–4.71(m,1H),4.42(s,1H),3.54(s,3H),2.86 –2.77(m,1H),2.67–2.61(m,1H),2.55–2.48(m,1H),2.45–2.39(m,1H),2.37(s,3H),2.25–2.17(m,1H),1.89–1.81(m,1H); LC-MS:ESI[M+H] + =408.0.

[0318] Example 53: 3-(4-cyclopropyl-2-hydroxyphenyl)-6-(((3R,5R)-1-ethyl-5-fluoropiperidin-3-yl)amino)-4-methyl-1,2,4-triazin-5(4H)-one

[0319] Preparation of 3-(4-cyclopropyl-2-hydroxyphenyl)-6-(((3R,5R)-1-ethyl-5-fluoropiperidin-3-yl)amino)-4-methyl-1,2,4-triazin-5(4H)-one Referring to Example 11, compound 53 (pale yellow solid, 42.3 mg) was obtained; 1H NMR (400MHz, CD3OD) δ7.41(d,J=8.0Hz,1H),6.85(d,J=8.1Hz,1H),6.79(s,1H),4.65(t,J=12.0Hz,1H),3.91–3.72(m ,3H),3.49(s,3H),3.37(m,4H),3.19–3.03(m,1H),2.57(m,1H),1.99(m,1H),1.41(m,4H),1.11(m,2H),0.80(m,2H).

[0320] Example 54: (R)-3-(4-Hydroxybenzo[b]thiophen-5-yl)-4-isopropyl-6-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one

[0321] Preparation of (R)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-isopropyl-6-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one: Reference Example 12 to obtain yellow compound 54 (11 mg, yield: 19.30%). LC-MS: ESI [M+H] + =400.0. NMR (400MHz, MeOD) δ7.53(d,J=5.6Hz),7.47(dd,J=8.2,7.2Hz),7.14(d,J=8.3Hz),4.32(dt,J=12.8,6.4Hz),3.96–3 .86(m),2.25(s),2.14–2.05(m),1.91(s),1.76(dd,J=9.2,4.4Hz),1.64–1.55(m),1.54–1.40(m),1.29(d,J=6.4Hz).

[0322] Example 55: (R)-6-((1-ethylpiperidin-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-(methyl-d3)-1,2,4-triazin-5(4H)-one

[0323] Preparation of (R)-6-((1-ethylpiperidin-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-(methyl-d3)-1,2,4-triazin-5(4H)-one: Reference Example 12 to obtain the target compound 55 as a yellow solid (37 mg, yield: 14.34%). LC-MS: ESI [M+H] + =389.0. 1H NMR (400MHz, DMSO) δ7.76(q,J=5.6Hz,2H),7.65(d,J=8.3Hz,1H),7.30(d,J=8.3Hz,1H),3.54(dd,J=25.8,10.7Hz ,2H),3.20(d,J=7.0Hz,2H),2.91–2.75(m,2H),1.99(d,J=10.6Hz,2H),1.84–1.67(m,2H),1.24(t,J=7.2Hz,3H).

[0324] Biological activity test:

[0325] 1. Assay of NLRP3 inflammasome inhibitory activity in human monocytes

[0326] Reagents: THP-1 cells: Wuhan Punosai Life Science Technology Co., Ltd., PMA: Sigma-Aldrich, RPMI medium: Hyclone, LPS: Sigma-Aldrich, Opti-MEM medium: Gibco, Nigericin: Invivogen, Human IL-1β ELISA detection kit: 4A Biotech, reference compound MCC950: MedChemExpress (MCE).

[0327] Experimental method: THP-1 cells were cultured in RPMI medium containing PMA (10 μM) at a rate of 2×10 5 / mL cell density, the cells were seeded in 48-well plates and placed in a 37°C, 5% CO2 incubator for induction overnight. The next day, the culture medium was replaced with Opti-MEM medium containing 1μg / mL LPS; 3h later, the drug was added for 40min; Nigericin (10μM) was added for 40min; the cell supernatant was collected for ELISA analysis. Compound MCC950 was purchased from MCE. Ref-1 was synthesized according to the synthesis method of Example 63 in patent WO2021193897, Ref-2 was synthesized according to the synthesis method of Example 1 in patent WO2022230912, and Ref-3 was synthesized according to the synthesis method of Example 26 in patent WO2022238347.

[0328] The experimental results are shown in Table 2 below.

[0329] Table 2 NLRP3 inflammasome inhibitory activity

[0330] Conclusion: The compounds of the present invention have good inhibitory activity against NLRP3 inflammasome, and the preferred compounds have better inhibitory effects on NLRP3 inflammasome than MCC950, Ref-1, Ref-2 and Ref-3.

[0331] 2. Determination of the inhibitory activity of compounds on IL-1β production in human PBMC cells

[0332] Human peripheral blood mononuclear cells (PBMCs) were cultured overnight in RPMI 1640 medium supplemented with 10% FBS and antibiotics before stimulation. The next day, the medium was changed to reduced-serum medium and stimulated with 1 μg / ml LPS for 3 hours, followed by drug stimulation for 40 minutes and nigericin at 10 μM for 40 minutes. Cell supernatants were collected and IL-1β production was measured by ELISA.

[0333] The experimental results are shown in Table 3 below:

[0334] Table 3 Inhibitory effects of compounds on IL-1β in PBMC cells

[0335] Conclusion: The compounds of the present invention have good inhibitory activity on the production of IL-1β in human PBMC cells, and the preferred compounds 3 and 4 have an inhibitory activity IC of IL-1β in human PBMC cells. 50 Better than MCC950.

[0336] 3. Inhibition experiment of compounds on hERG potassium channels

[0337] Cell culture and treatment: CHO cells stably expressing hERG were cultured in a cell culture flask at 37°C in a 5% CO2 incubator. When the cell density reached 60-80%, the cell culture medium was removed, the cells were washed once with PBS, and then digested with Detachin. After digestion was complete, the cells were neutralized with culture medium, centrifuged, and the supernatant was removed. The cells were then resuspended in culture medium to adjust the cell density to 2-5×10 6 / mL for future use.

[0338] Compound preparation: Dilute the compound stock solution with 100% DMSO. Add 10 μL of the compound stock solution to 20 μL of DMSO and serially dilute 3-fold to six concentrations. Add 4 μL of each of the six concentrations to 396 μL of extracellular fluid, creating a 100-fold dilution to obtain six intermediate concentrations. Then, add 80 μL of each of the six intermediate concentrations to 320 μL of extracellular fluid, creating a 5-fold dilution to the desired final concentration. The highest concentration tested was 40 μM, followed by concentrations of 40, 13.33, 4.44, 1.48, 0.49, and 0.16 μM. The DMSO content in the final test concentration did not exceed 0.2%, as this concentration has no effect on hERG potassium channels. Compound preparation was performed entirely on the Bravo instrument.

[0339] Electrophysiological recordings: Single-cell high-impedance sealing and whole-cell pattern formation were automated by the Qpatch instrument. After acquiring whole-cell recording mode, cells were clamped at -80 mV. A 50-millisecond pre-depolarization of -50 mV was applied before a 5-second depolarization of +40 mV. The cells then repolarized to -50 mV for 5 seconds before returning to -80 mV. This voltage was applied every 15 seconds. After recording for 2 minutes, extracellular solution was added for 5 minutes. Drug administration then began. Compound concentrations were administered for 2.5 minutes at each test concentration, starting with the lowest tested concentration. After all concentrations were administered, the positive control compound, 3 μM Cisapride, was administered. At least three cells were tested for each concentration (n ≥ 3).

[0340] Data processing: GraphPad Prism 5.0 and Excel software were used for data analysis. 50 Calculated using GraphPad Prism 5 software by fitting the following equation: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC50-X)*HillSlope))

[0341] Where X is the Log value of the test sample concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0342] The experimental results are shown in Table 4 below:

[0343] Table 4 Inhibition results of compounds on hERG potassium channels

[0344] Conclusion: The inhibitory effect of compounds 3, 4, 5, 9, 16, 17, 24, 30, 40, 41, 42, 43 and 54 of the present invention on hERG potassium ion channels is weaker than that of the reference compound Ref-1.

[0345] 4. Pharmacokinetic evaluation of the compound in Balb / c mice

[0346] Experimental purpose: To understand the pharmacokinetics of the compound.

[0347] Experimental basis: Technical Guidelines for Nonclinical Pharmacokinetic Studies of Chemical Drugs, 2014.

[0348] Experimental plan: The pharmacokinetics of the compound were investigated by intravenous and oral administration to Balb / c mice.

[0349] Sample preparation: Weigh the compound and dissolve it in DMSO, then add sodium chloride solution for injection to prepare the compound solution for administration.

[0350] Sample collection: 6 male Balb / c mice (Chengdu Dashuo Experimental Animal Co., Ltd., license number: SCXK (Chuan) 2020-030), 3 were intravenously administered (IV) and 3 were gavage administered (PO). About 0.05 mL of blood was collected at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 24 h and 48 h after administration. The collected blood was centrifuged at 3500 rpm for 15 min, the supernatant plasma was collected, and frozen at -40 ° C for testing. The blood concentration was quantitatively analyzed by LC-MS / MS analysis method, and pharmacokinetic parameters such as peak time (Cmax), area under the concentration-time curve (AUC(0-t)), half-life (T 1 / 2 ), clearance (CL), tissue distribution (Vdss), bioavailability (F), etc.

[0351] The results of the pharmacokinetic evaluation are shown in Table 5 below:

[0352] Table 5 Pharmacokinetic test results of the compounds in Balb / c mice

[0353] Conclusion: The compounds of the present invention have good pharmacokinetic properties in Balb / c mice, including good oral bioavailability, exposure, half-life and clearance. Compounds 2, 3, 4, 6, 9, 12, 13, 17, 30, 36, 40, 41, 43, 51, 52, 53, 54 and 55 have good C max , AUC (0-t) 、T 1 / 2The PK parameters were better than those of reference compounds Ref-2 and Ref-3.

[0354] 5. Evaluation of LPS-induced mouse model

[0355] Experimental Methods: 7-8 week old Balb / c mice were orally administered 25 mg / kg or 50 mg / kg of the compound or vehicle control (sterile 0.9% NaCl solution). One hour later, 10 mg / kg of LPS (Sigma, L2880) was intraperitoneally injected. The mice were observed every 12 hours for 72 hours, and the 72-hour survival rate was calculated.

[0356] The experimental results are shown in Table 6:

[0357] Table 6 Effects of compounds on the survival rate of LPS-induced mice

[0358] Conclusion: The compounds of the present invention can increase the survival rate of LPS-induced mice, especially compounds 3, 4, 9, 40 and 41 at the same dose have better survival rates on LPS-induced mice than reference compounds MCC950 and Ref-2.

[0359] 6. Evaluation of compound brain-blood ratio in vivo

[0360] Experimental purpose: To obtain the brain-to-blood ratio of the compound.

[0361] Experimental plan: The brain-to-blood ratio of the compound was investigated by monitoring the content of the compound in the mouse brain and plasma.

[0362] Experimental steps: Weigh the compound, add a small amount of DMSO, and then add sodium chloride solution for injection to make 10 mg mL -1 The compound solution is ready for administration. Mice, male, 10 mg kg -1 Oral administration was performed, and whole blood and whole brain were collected 1 hour and 6 hours after administration (n=3). Whole blood was centrifuged at 3500rpm for 15 minutes, and the supernatant plasma was collected. The weight of the centrifuge tube was weighed as M1, the weight of the centrifuge tube containing the whole brain was weighed as M2, the weight of the centrifuge tube after adding water homogenate was weighed as M3, and the weight of the centrifuge tube after taking out 30μL of homogenate was weighed as M4. 30μL of plasma and 30μL of brain homogenate were taken into the centrifuge tube, and 120μL of 20ng·ml -1 The internal standard SAHA was precipitated with acetonitrile, vortexed for 30 seconds, centrifuged at 13,000 rpm for 15 minutes, and the supernatant was collected and placed in a sample vial for testing.

[0363] Standard curve range: 10~10000ng·ml -1 .

[0364] Drug content in brain = measured value × 0.03 × (M3-M1) / [(M2-M1) × (M3-M4)].

[0365] The results of the compound brain-to-blood ratio are shown in Table 7 below:

[0366] Table 7 Results of brain-to-blood ratio test in mice after compound administration

[0367] Conclusion: Some compounds of the present invention have good brain penetration potential, especially compounds 3, 4, 12, 17, 40, etc., whose brain-blood ratios are significantly better than those of reference compounds Ref-1 and Ref-2.

[0368] 7. Evaluation of compound distribution in cerebrospinal fluid and plasma

[0369] Experimental steps: Weigh the compound and add a small amount of DMSO, then add sodium chloride solution for injection to make 5 mg mL -1 The compound solution is ready for administration. Rats, male rats, 5 mg kg -1 After intravenous administration, cerebrospinal fluid and whole blood were collected 0.25 h and 2 h after administration (n=1). Whole blood was centrifuged at 3500 rpm for 15 min, and the supernatant plasma was collected. 10 μL of plasma and 10 μL of cerebrospinal fluid were placed in a centrifuge tube and 40 μL of 20 ng·ml -1 The internal standard SAHA was precipitated with acetonitrile, vortexed for 30 seconds, centrifuged at 13000 rpm for 15 minutes, and the supernatant was transferred to a sample vial for testing. Standard curve range: 1-1000 ng ml -1 .

[0370] Table 8 Test results of distribution of compounds in rat cerebrospinal fluid and plasma after administration

[0371] Conclusion: Some compounds of the present invention have good brain penetration potential, especially compounds 40 and 43, which have higher distribution concentrations in cerebrospinal fluid.

[0372] 8. Evaluation of compound affinity for human NLRP3 protein

[0373] Experimental purpose: The protein is immobilized on a CM5 chip as a solid phase. Small molecules are diluted in a concentration gradient and injected to interact with the protein to obtain the fitted affinity value.

[0374] Instrument model and specific consumables: Biacore T200 Cytiva (Sweden); consumables: Series S Sensor Chip CM5 Cytiva (Sweden) BR100012 LOT 10344853, Amine Coupling Kit Cytiva (Sweden) BR100050 LOT 35063.

[0375] Reagents: Buffer: PBS10X (1.37M Nacl; 26.8mM KCL; 81mM Na2HPO4; 17.6mM KH2PO4; pH7.2-7.4) (Sangon Biotech, Lot#J806FC0551), Tween20(Sigma)(Cat.No.P9416), DMSO(Sigma))(Cat.No.67-68-5; Lot#WXBF-1310V).

[0376] Experimental steps:

[0377] Protein Fixation: Chip Selection: CM5 Experimental Procedure: Run → Manual Run for manual saturation fixation. Protein fixation requires a specific acidic environment (pH 4.0, 4.5, and 5.0 were tested). Dilute the ligand protein to 10 μg / mL with 10 mM sodium acetate at different pH values. Run manual mode and inject samples sequentially, selecting the pH environment with the highest signal. Protein fixation parameters: concentration 30-50 μg / mL, pH 4.0, flow rate 10 μl / min, temperature 25°C. Fixation Solution: 100 μL NHS, 100 μL EDC, 150 μL Ethamolamine (NHS; EDC is a chip activation reagent to activate the dextran groups on the chip surface; ethamolamine is a blocking reagent to block groups not bound to the protein). The instrument automatically mixes EDC and NHS to activate the chip surface. After protein fixation, block the reference channel (using EDC, NHS, and ethamolamine).

[0378] Small molecule injection: Set the experimental procedure: Method-LMW Kinetics, injection time setting: 120s binding (Contact) 300s dissociation (Dissociation Time); all samples and buffers were filtered using a 0.22μm filter membrane before the experiment began.

[0379] NLRP3 protein sequence SEQ ID NO: 1:

[0380] The experimental results showed that the Kd value of compound 40 for human NLRP3 protein was 62.13 nM.

Claims

1. A compound of formula I or a pharmaceutically acceptable form thereof, characterized in that: The structure of Formula I is as follows: in: is a single bond, Y is selected from NR 7a , X is selected from C(═O); R1 is selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN or the following groups optionally substituted by 0-6 substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NHC(=O)-C 1-6 Alkyl, -(C=O)NH-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-6 membered cycloalkyl; in R1, the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN; R2 and R4 are independently selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN or the following groups optionally substituted with 0-6 substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NHC(=O)-C 1-6 Alkyl, -(C=O)NH-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-6 membered cycloalkyl; in R2 and R4, the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN; R3 is selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN or the following groups optionally substituted by 0-6 substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NHC(=O)-C 1-6 Alkyl, -(C=O)NH-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; in R3, the substituent is selected from: deuterium, halogen, -OH, -NH2, -CN or 3-6 membered cycloalkyl; in R3, the 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from at least one of N, S and O; R5 is selected from hydrogen, deuterium, halogen, -NH2, -CN or the following groups optionally substituted by 0-6 substituents: C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NHC(=O)-C 1-6 Alkyl, -(C=O)NH-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-6 membered cycloalkyl; in R5, the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN; Alternatively, R2 and R3, R3 and R4, or R4 and R5 together with the atoms to which they are attached form a 5-6 membered alkane ring, a benzene ring, a 5-6 membered alkane heterocycle, or a 5-6 membered heteroaromatic ring substituted with 0-6 substituents, wherein the substituents are selected from: deuterium, halogen, -OH, -NH2, -CN, oxo, C 1-6 Alkyl, C 1-6 Fluorinated alkyl, C 1-6 Deuterated alkyl, -OC 1-6 Alkyl, -OC 1-6 Fluorinated alkyl, -OC 1-6 Deuterated alkyl, C 3-6 Cycloalkyl, C 3-6 Fluorinated cycloalkyl, or two of the substituents connected to the same carbon atom form a 3-6 membered cycloalkyl; R2 When connected to form a ring with R3, R3 and R4, or R4 and R5 and the atoms to which they are connected, the 5-6 membered alkane heterocyclic ring or 5-6 membered heteroaromatic ring contains 1 to 3 heteroatoms selected from at least one of N, S, and O; Furthermore, when R1 is selected from -OH, R2 and R3 together with the atoms to which they are attached form a benzene ring, a 5-7-membered alkane heterocycle or a 5-6-membered heteroaromatic ring substituted with 0-6 substituents selected from: deuterium, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Fluorinated alkyl, C 1-6 Deuterated alkyl, -OC 1-6 Alkyl, -OC 1-6 Fluorinated alkyl, -OC 1-6 Deuterated alkyl, C 3-6 Cycloalkyl, C 3-6 A fluorinated cycloalkyl group, or two of the substituents connected to the same carbon atom form a 3-6-membered cycloalkyl group; when R2 and R3 are connected to the atoms to which they are connected to form a ring, the 5-7-membered alkane heterocyclic ring or the 5-6-membered heteroaromatic ring contains 1 to 3 heteroatoms selected from at least one of N and S or contains 2 O atoms; L is selected from -(CH2) n1 -、O、-(CH2) n1 -NH-, -NH-(CH2) n1 -、-NH-CH(CH2) n1 (CH3)-, n1 is an integer selected from 0-3; R6 is selected from 6-10 membered aryl, 5-10 membered heteroaryl, 3-8 membered heterocycloalkyl, 3-8 membered cycloalkyl, 6-10 membered spirocycloalkyl, 6-10 membered heterospirocycloalkyl, 6-10 membered bridged cycloalkyl, 6-10 membered heterobridged cycloalkyl, C 1-6 Alkyl; in R6, the substituent is selected from R 8a , halogen, oxo, -OR 8a 、-SR 8a 、-C(=O)R 8a 、-OC(=O)R 8a 、-C(=O)OR 8a 、-C(=O)NR 8a R 8b 、-NR 8a C(=O)R 8b 、-NR 8a R 8b 、-SO2R 8a 、-SO2NR 8a R 8b 、-NR 8a S02R 8b , -CN; in R6, the 5- to 10-membered heteroaryl, 3- to 8-membered heterocycloalkyl, 6- to 10-membered heterospirocycloalkyl, and 6- to 10-membered heterobridged cycloalkyl contain 1 to 3 heteroatoms selected from at least one of N, S, and O; R 8a and R 8b independently selected from hydrogen, deuterium or the following groups substituted by 0-6 substituents: C 1-4 Alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, 3-6 membered cycloalkylmethylene or 4-6 membered heterocycloalkylmethylene; R 8a , R 8b In the above, the substituent is selected from the group consisting of: deuterium, halogen, -N(R 10a R 10b )、-OH、-CN、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 deuterated alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 3-6 membered cycloalkylmethylene or 4-6 membered heterocycloalkylmethylene; R 8a , R 8b In the above, the 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkylmethylene contains 1 to 3 heteroatoms selected from at least one of N, S, and O, and the 4-6 membered heterocycloalkyl, 4-6 membered heterocycloalkylmethylene in the above substituent contains 1 to 3 heteroatoms selected from at least one of N, S, and O; Or, R 8a With R 8b Together with the atoms to which they are attached, they form a 3-6 membered alkyl heterocyclic ring substituted with 0-6 substituents; R 8a With R 8b When connected to the atoms to which they are attached to form a ring, the substituents are selected from: deuterium, halogen, -N(R 11a R 11b )、-OH、-CN、C 1-4 Alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl; R 8a With R 8b When connected to the atoms to which they are attached to form a ring, the 3-6 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from at least one of N, S, and O, and the 4-6 membered heterocycloalkyl in the substituent contains 1 to 3 heteroatoms selected from N, S, and O. at least one heteroatom; R 7a is selected from hydrogen or the following groups optionally substituted by 0-6 substituents: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; R 7a wherein the substituent is selected from hydrogen, deuterium, halogen, -OH, -NH2 or -CN; R 7a wherein the 4-6 membered heterocycloalkyl group and the 5-6 membered heteroaryl group contain 1 to 3 heteroatoms selected from at least one of N, S and O; R 10a , R 10b , R 11a and R 11b are independently selected from hydrogen or C 1-4 alkyl; The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, nitrogen oxides, isotopically labeled substances, metabolites or prodrugs.

2. The compound according to claim 1, characterized in that: R1 is selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN or the following groups optionally substituted by 0-6 substituents: C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-6 membered cycloalkyl, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN; Preferably, R1 is selected from hydrogen, deuterium, F, Cl, -OH, -NH2, -CN or the following groups optionally substituted by 0-3 substituents: C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, 3-6 membered cycloalkyl, the substituent is selected from: deuterium, F, Cl, -OH, -NH2 or -CN; More preferably, R1 is selected from hydrogen, deuterium, F, Cl, -OH, -CH3, fluoromethyl, deuterated methyl, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl, fluorocyclopropyl.

3. The compound according to claim 1 or 2, characterized in that: R2 and R4 are independently selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN or the following groups optionally substituted by 0-6 substituents: C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-6 membered cycloalkyl, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN; Preferably, R2 and R4 are independently selected from hydrogen, deuterium, F, Cl, -OH, -NH2, -CN or the following groups optionally substituted by 0-3 substituents: C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, 3-6 membered cycloalkyl, the substituent is selected from: deuterium, F, Cl, -OH, -NH2 or -CN; More preferably, R2 and R4 are independently selected from hydrogen, deuterium, F, Cl, -OH, -CH3, fluoromethyl, deuterated methyl, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl, fluorocyclopropyl.

4. The compound according to any one of claims 1 to 3, characterized in that: R3 is selected from hydrogen, deuterium, halogen, -OH, -NH2, -CN or the following groups optionally substituted by 0-6 substituents: C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; in R3, the substituent is selected from: deuterium, halogen, -OH, -NH2, -CN, -CF3 or cyclopropyl; in R3, the 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from at least one of N, S, and O; Preferably, R3 is selected from hydrogen, deuterium, F, Cl, -CN or the following groups optionally substituted by 0-3 substituents: C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; in R3, the substituent is selected from: deuterium, F, Cl, -OH, -NH2, -CF3, -CN or cyclopropyl; in R3, the 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl contains 1 to 2 heteroatoms selected from at least one of N, S and O; More preferably, R3 is selected from hydrogen, deuterium, F, Cl, methyl, fluoromethyl, deuterated methyl, methylthio, fluoromethylthio, deuterated methylthio, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl, fluorocyclopropyl, vinyl, ethynyl, phenyl, fluorophenyl, deuterated phenyl.

5. The compound according to any one of claims 1 to 4, characterized in that: R5 is selected from hydrogen, deuterium, halogen, -NH2, -CN or the following groups optionally substituted by 0-6 substituents: C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-6 membered cycloalkyl, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 or -CN; Preferably, R5 is selected from hydrogen, deuterium, F, Cl, -NH2, -CN or the following groups optionally substituted by 0-3 substituents: C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, 3-6 membered cycloalkyl, the substituent is selected from: deuterium, F, Cl, -OH, -NH2 or -CN; More preferably, R5 is selected from hydrogen, deuterium, F, Cl, -CH3, fluoromethyl, deuterated methyl, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl, fluorocyclopropyl.

6. The compound according to any one of claims 1 to 5, characterized in that: R2 and R3, R3 and R4, or R4 and R5, together with the atoms to which they are attached, may form a 5-6 membered alkane ring, a benzene ring, a 5-6 membered alkane heterocycle, or a 5-6 membered heteroaromatic ring substituted with 0-6 substituents, wherein the substituents are selected from: deuterium, halogen, -OH, -NH2, -CN, oxo, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Deuterated alkyl, -OC 1-4 Alkyl, -O-fluoroC 1-4 Alkyl, -O-deuterated C 1-4 Alkyl, 3-6 membered cycloalkyl or 3-6 membered fluorocycloalkyl, or two of the substituents connected to the same carbon atom form a 3-4 membered cycloalkyl; when R2 and R3, R3 and R4, or R4 and R5 are connected to the atoms to which they are connected to form a ring, the 5-6 membered alkane heterocycle and 5-6 membered heteroaromatic ring contain 1 to 2 heteroatoms selected from at least one of N, S and O; Preferably, R2 and R3 or R3 and R4 together with the atoms to which they are attached form a group substituted with 0-3 substituents. The substituent is selected from the group consisting of deuterium, F, Br, Cl, -OH, -NH2, -CN, oxo, methyl, fluoromethyl, deuterated methyl, methoxy The substituents may be cyclopropyl, fluoromethoxy, deuterated methoxy, cyclopropyl or fluorocyclopropyl, or two of the substituents attached to the same carbon atom may form a 3-4 membered cycloalkyl group.

7. The compound according to any one of claims 1 to 5, characterized in that: When R1 is selected from -OH, R2 and R3 together with the atoms to which they are attached form a benzene ring, a 5-6 membered alkane heterocycle or a 5-6 membered heteroaromatic ring substituted with 0-6 substituents selected from: deuterium, halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Deuterated alkyl, -OC 1-4 Alkyl, -O-fluoroC 1-4 Alkyl, -O-deuterated C 1-4 Alkyl, 3-6 membered cycloalkyl or 3-6 membered fluorocycloalkyl, or two of the substituents connected to the same carbon atom form a 3-4 membered cycloalkyl; when R2 and R3 are connected to the atoms to which they are connected to form a ring, the 5-6 membered alkane heterocyclic ring contains 2 O atoms, and the 5-6 membered heteroaromatic ring contains 1 to 2 heteroatoms selected from at least one of N and S; Preferably, when R1 is selected from -OH, R2 and R3 together with the atoms to which they are attached form 8. The compound according to any one of claims 1 to 7, characterized in that: Structural unit Selected from:

9. The compound according to any one of claims 1 to 8, characterized in that: R 7a is selected from hydrogen or the following groups optionally substituted by 0-3 substituents: C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; R 7a wherein the substituent is selected from: hydrogen, deuterium, halogen, -OH, -NH2 or -CN; Preferably, R 7a Selected from hydrogen or C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy, C 1-4 Deuterated alkoxy, carboxyl, C 1-4 Alkoxycarbonyl, C 1-4 Fluoroalkoxycarbonyl, C 1-4 deuterated alkoxycarbonyl, 3-6 membered cycloalkyl, 3-6 membered fluorinated cycloalkyl, phenyl, pyridyl or X1 and X2 are independently selected from CH, N; X3 is selected from NC 1-4 Alkyl, NH, S, O; More preferably, R 7a is selected from hydrogen, methyl, deuterated methyl, fluoromethyl, ethyl, fluoroethyl, isopropyl, fluoroisopropyl, cyclopropyl, fluorocyclopropyl, cyclohexyl, fluorocyclohexyl, phenyl, 2-pyridyl, X1 is selected from N; X2 is selected from CH, N; X3 is selected from N-methyl, S, O.

10. The compound according to any one of claims 1 to 9, characterized in that: Structural unit Selected from:

11. The compound according to any one of claims 1 to 10, characterized in that: L is selected from O, -NH-, -NH-CH2-, -NH-CH(CH 3) -.

12. The compound according to any one of claims 1 to 11, characterized in that: In R6, the substituent is selected from fluorine, chlorine, hydroxyl, cyano, oxo, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy, C 1-4 deuterated alkoxy, 3- to 6-membered cycloalkyl, 3- to 6-membered fluorinated cycloalkyl, amino, dimethylamino, 13. The compound according to any one of claims 1 to 12, characterized in that: R6 is selected from the following structures: R 12a and R 12b Independently selected from R 8a , halogen, oxo, -OR 8a 、-SR 8a 、-C(=O)R 8a 、-OC(=O)R 8a 、-C(=O)OR 8a 、-C(=O)NR 8a R 8b 、-NR 8a C(=O)R 8b 、-NR 8a R 8b 、-SO2R 8a 、-SO2NR 8a R 8b 、-NR 8a S02R 8b , -CN; n2 is an integer from 0 to 6; Preferably, R 12a and R 12b Independently selected from R 8a , fluorine, oxo, -OR 8a 、-SR 8a 、-C(=O)R 8a 、-OC(=O)R 8a 、-C(=O)OR 8a 、-C(=O)NR 8a R 8b 、-NR 8a C(=O)R 8b 、-NR 8a R 8b 、-SO2R 8a 、-SO2NR 8a R 8b 、-NR 8a S02R 8b , -CN; n2 is an integer from 0 to 3; More preferably, R 12a and R 12b independently selected from fluorine, chlorine, hydroxyl, cyano, oxo, C 1-4 alkyl, C 1-4 Fluorinated alkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy, C 1-4 deuterated alkoxy, 3- to 6-membered cycloalkyl, 3- to 6-membered fluorinated cycloalkyl, amino, dimethylamino, 14. The compound according to any one of claims 1 to 13, characterized in that: R6 is selected from the following structures:

15. The compound according to any one of claims 1 to 14, characterized in that: The compound is selected from:

16. The compound according to claim 1, characterized in that: Structural unit Selected from:

17. The compound according to claim 16, characterized in that: Structural unit Selected from:

18. The compound according to claim 16 or 17, characterized in that: L is selected from O, -NH-, -NH-CH2-, -NH-CH(CH 3) -.

19. The compound according to any one of claims 1 to 18, characterized in that: R6 is selected from the following structures:

20. The compound according to any one of claims 16 to 19, characterized in that: The compound is selected from:

21. The compound according to claim 1, characterized in that: Structural unit Selected from:

22. The compound according to claim 21, characterized in that: Structural unit Selected from:

23. The compound according to claim 21 or 22, characterized in that: L is selected from O, -NH-, -NH-CH2-, -NH-CH(CH 3) -.

24. The compound according to any one of claims 21 to 23, characterized in that: R6 is selected from the following structures:

25. The compound according to any one of claims 21 to 24, characterized in that: The compound is selected from:

26. The compound according to any one of claims 1 to 14, characterized in that: Structural unit Selected from:

27. The compound according to claim 26, characterized in that: R6 is selected from the following structures:

28. The compound according to claim 26 or 27, characterized in that: The compound is selected from:

29. A pharmaceutical composition, characterized in that: The active ingredient is a compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite or prodrug thereof, supplemented with a pharmaceutically acceptable carrier.

30. Use of the compound according to any one of claims 1 to 28 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite or prodrug, and the pharmaceutical composition according to claim 29 in the preparation of a medicament for preventing and / or treating NLRP3-related diseases.

31. The use according to claim 30, characterized in that: The NLRP3-related diseases include: inflammatory diseases, autoimmune diseases, cardiovascular system diseases, cancer, renal system diseases, gastrointestinal diseases, respiratory system diseases, endocrine system diseases or central nervous system diseases.

32. The use according to claim 31, characterized in that: The NLRP3-related diseases include: cryptopyrin-associated periodic syndrome, Muckle-Wells syndrome, familial cold autoinflammatory syndrome, neonatal multisystem inflammatory disease, familial Mediterranean fever, non-alcoholic fatty hepatitis, alcoholic liver disease, graft-versus-host disease, multiple sclerosis, rheumatoid arthritis, type I / type II diabetes and related complications, psoriasis, Alzheimer's disease, atherosclerosis, gout, chronic kidney disease, sepsis, liver fibrosis, idiopathic pulmonary fibrosis, epilepsy, neuropathic pain, depression, Parkinson's disease, asthma, acute myocardial infarction, lupus erythematosus, rheumatoid arthritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, rheumatoid arthritis, ankylosing myelitis, bronchial asthma, acute respiratory distress syndrome, chronic obstructive pulmonary disease or ischemic stroke.

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