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 double bond, Y is selected from CR 7b , X is selected from N;

[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 7b Selected from hydrogen, deuterium, halogen, -NH2, -CN, -OR 9a 、-COR 9a 、-COOR 9a 、-CONHR 9a 、-CON(R 9b R 9c )、-N(R 9b R 9c ),-NR 9a COR 9b 、-SO2R 9a or the following group 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 7b wherein the substituent is selected from hydrogen, deuterium, halogen, -OH, -NH2 or -CN; R 7b 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 9a 、R 9b and R 9c 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; R 9a 、R 9b and R 9c wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 or CN; R 9a 、R 9b and R 9c wherein the 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl in the substituent contains 1 to 3 heteroatoms selected from at least one of N, S, and O;

[0022] R 10a 、R 10b 、R 11a and R 11b are independently selected from hydrogen or C 1-4 alkyl;

[0023] The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled substances, metabolites, or prodrugs.

[0024] 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.

[0025] 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.

[0026] 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.

[0027] 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.

[0028] 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.

[0029] 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.

[0030] 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.

[0031] 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, 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 and 5-6 membered heteroaryl contain 1 to 2 heteroatoms selected from at least one of N, S and O.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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 1-4 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.

[0037] 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.

[0038] 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 1-4Deuterated 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.

[0039] 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

[0040] In some embodiments of the present invention, the structural unit Selected from:

[0041] In some embodiments of the present invention, R 7b Selected from hydrogen, deuterium, halogen, -NH2, -CN, -OR 9a 、-COR 9a 、-COOR 9a 、-CONHR 9a 、-CON(R 9b R 9c )、-N(R 9b R 9c ),-SO2R 9a or the following group optionally substituted by 0-3 substituents: C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; R 9a 、R 9b and R 9c independently selected from hydrogen, deuterium or the following groups substituted with 0-3 substituents: C 1-4 Alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; R 9a 、R 9b and R 9c wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 or CN.

[0042] In some preferred embodiments of the present invention, R 7b Selected from hydrogen, deuterium, halogen, -NH2, -CN, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4Deuterated 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, -CONHR 9a ; R 9a Selected from hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Deuterated alkyl, 3-6 membered cycloalkyl, 3-6 membered fluorocycloalkyl; X1 and X2 are independently selected from CH, N; X3 is selected from NC 1-4 Alkyl, NH, S, O.

[0043] In some more preferred embodiments of the present invention, R 7b is selected from hydrogen, deuterium, F, Cl, cyano, amino, methyl, deuterated methyl, fluoromethyl, ethyl, fluoroethyl, isopropyl, fluoroisopropyl, methoxy, deuterated methoxy, fluoromethoxy, carboxyl, methoxycarbonyl, fluoromethoxycarbonyl, deuterated methoxycarbonyl, ethoxycarbonyl, fluoroethoxycarbonyl, cyclopropyl, fluorocyclopropyl, cyclohexyl, fluorocyclohexyl, phenyl, 2-pyridyl, -CONHR 9a ; R 9a is selected from hydrogen, deuterium, methyl, fluoromethyl, deuterated methyl, cyclopropyl, fluorocyclopropyl; X1 is selected from N; X2 is selected from CH, N; X3 is selected from N-methyl, S, O.

[0044] In some embodiments of the present invention, the structural unit Selected from:

[0045] In some embodiments of the present invention, L is selected from O, -NH-, -NH-CH2-, -NH-CH(CH 3) -.

[0046] 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,

[0047] In some embodiments of the present invention, R6 is selected from the following structures:

[0048] 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.

[0049] 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.

[0050] 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 1-4Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy, C 1-4 deuterated alkoxy, 3-6 membered cycloalkyl, 3-6 membered fluorocycloalkyl, amino, dimethylamino,

[0051] In some embodiments of the present invention, R6 is selected from the following structures:

[0052] The present invention also provides some specific compounds, which are selected from:

[0053] The present invention also provides another similar compound. In some embodiments of the present invention, the structural unit Selected from:

[0054] In some embodiments of the present invention, the structural unit Selected from:

[0055] In some embodiments of the present invention, L is selected from O, -NH-, -NH-CH2-, -NH-CH(CH 3) -.

[0056] In some embodiments of the present invention, R6 is selected from the following structures:

[0057] The present invention also provides some specific compounds, which are selected from:

[0058] In some embodiments of the present invention, the structural unit Selected from:

[0059] The present invention also provides some specific compounds, which are selected from:

[0060] In some embodiments of this aspect, the structural unit Selected from:

[0061] In some embodiments of this aspect, the structural unit Selected from:

[0062] In some embodiments of this aspect, L is selected from O, -NH-, -NH-CH2-, -NH-CH(CH 3) -.

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

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

[0065] The present invention also provides some specific compounds, which are selected from:

[0066] In some embodiments of this aspect, R6 is selected from the following structures:

[0067] The present invention also provides some specific compounds, which are selected from:

[0068] 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.

[0069] 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.

[0070] 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).

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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).

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] Beneficial effects of the present invention:

[0085] 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.

[0086] Definition of terms:

[0087] 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."

[0088] 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.

[0089] 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.

[0090] In the present invention, unless otherwise specified, halogen means fluorine, chlorine, bromine or iodine.

[0091] 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.

[0092] 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.

[0093] 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 include -CH2F, -CHF2, -CF3, -C2F5, -CH2CF3, etc. The fluoroalkyl groups of the present invention are optionally substituted with one or more substituents described herein.

[0094] 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).

[0095] 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.

[0096] 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%).

[0097] 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.

[0098] 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.

[0099] 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.

[0100] 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).

[0101] 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.

[0102] 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)).

[0103] 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.

[0104] 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.

[0105] 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.

[0106] 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.

[0107] 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.

[0108] 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

[0109] 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.

[0110] The reagents and raw materials used in the examples of the present invention are all commercially available.

[0111] Table 1 Abbreviations and their meanings in the present invention

[0112] 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 NMR 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 -6The units are given in ppm.

[0113] MS was measured using an Agilent SQD (ESI) mass spectrometer (manufacturer: Agilent, signal: 6110).

[0114] 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).

[0115] 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.

[0116] Column chromatography generally uses Qingdao Ocean 100-200, 200-300 mesh silica gel as the carrier.

[0117] 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.

[0118] Intermediate INT1: 2-(4-methoxybenzo[b]thiophene-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0119] Step 1: Add CuBr2 (146.5 g, 656 mmol) to EtOAc (250 mL) and stir at 80°C for 10 minutes. Then, compound INT1a (25.0 g, 164 mmol) was dissolved in chloroform (250 mL) and added to the suspension. The mixture was refluxed at 80°C overnight. After the reaction was complete, 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 obtain the target compound INT1b (46.0 g, 148 mmol, light brown solid, 90% yield). MS: [M+H] + =309.0,311.0,313.0.

[0120] 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.

[0121] 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).

[0122] 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).

[0123] Intermediate INT2: 2-(2-(difluoromethoxy)-4-(trifluoromethyl)phenyl)-4,4,5-5-tetramethyl-1,3,2-dioxaborane

[0124] 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).

[0125] 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).

[0126] Intermediate INT3: 2-(1-(difluoromethylene)-4-methoxy-2,3-dihydro-1H-inden-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0127] 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 afford the target compound INT3a (yellow oily liquid, 22.5 g, yield: 84%). No further purification was required. MS / ESI [M+H] + :215.1.

[0128] 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.

[0129] 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.

[0130] 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).

[0131] 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).

[0132] Intermediate INT4: 2-(4-methoxybenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0133] 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).

[0134] 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).

[0135] 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).

[0136] 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).

[0137] Intermediate INT5: 2-(4-cyclopropyl-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0138] Step 1: Compound INT5a (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 thorough 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 afford the crude compound INT5b, which was used directly in the next step.

[0139] Step 2: Compound INT5b (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 mixture 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 INT5 (0.82 g) was obtained by column chromatography (PE:EtOAc = 10:1).

[0140] Intermediate INT6: 2-(4-(methoxymethoxy)benzo[b]thiophene-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0141] 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 hour. After the reaction was complete, saturated aqueous ammonium chloride (300 mL x 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) was used to obtain the target compound INT6a (183 g, 670 mmol, light yellow oil, 70% yield). 1 H NMR (400MHz, CDCl3) δ7.55-7.45 (m, 3H), 7.43 (d, J = 5.5Hz, 1H), 5.27 (s, 2H), 3.70 (s, 3H).

[0142] Step 2: Compound INT6a (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, concentrated under reduced pressure, and dried by spin-drying. Column chromatography (PE:EtOAc = 30:1) was used to obtain the target compound INT6 (14.5 g, 45.3 mmol, colorless solid, 62% yield). 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).

[0143] Example 1: (R)-5-(5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)benzothiophene-4-ol

[0144] Step 1: Under nitrogen protection, 1a (163 mg, 1 mmol), 1b (115 mg, 1 mmol), and DIPEA (5 mL) were refluxed at 150°C overnight. The mixture was returned to room temperature, and the solvent was removed from the filtrate under reduced pressure. The residue was separated by column chromatography (DCM:MeOH = 10:1) to obtain the target compound 1c (green solid, 93.2 mg). MS / ESI [M+H] + :242.1.

[0145] Step 2: Under nitrogen protection, compound INT1 (87 mg, 0.3 mmol), Pd(PPh3)4 (17.33 mg, 0.015 mmol) , NaHCO3 (50.4 mg, 0.6 mmol) and 1c (58.56 mg, 0.2 mmol) were dissolved in 1,4-dioxane (2 mL) and aqueous solution (0.5 mL), reacted at 105°C overnight, returned to room temperature, added with water, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:MeOH=10:1) to give the title compound 1d (yellow solid, 46.2 mg). MS / ESI [M+H] + :370.5.

[0146] Step 3: Compound 1d (37 mg, 0.1 mmol) was dissolved in DCM (1 mL). BBr3 (1 M, 0.2 mL) was added under nitrogen protection and the reaction was carried out at -10°C for one hour. The mixture was quenched with MeOH and the solvent was removed under reduced pressure. The residue was separated by column chromatography (DCM:MeOH = 10:1) to obtain the target compound 1 (yellow solid, 21.1 mg). 1 H NMR (400MHz, MeOD) δ8.51(s,1H),7.61(dd,J=5.6,0.6Hz,1H),7.57-7.47(m,2H),7.25(d,J=8.2Hz,1H),4.33(dt,J=13.2,4.8Hz,1H),3.57(d,J= 10.5Hz,1H),3.27(s,1H),3.06-2.82(m,2H),2.79(s,3H),2.42-2.28(m, 2H), 2.17-2.01 (m, 2H), 1.96-1.82 (m, 1H), 1.71 (dd, J = 20.1, 9.5Hz, 1H). MS / ESI[M+H] + :356.5.

[0147] Example 2: (R)-5-(3-((1-ethylpiperidin-3-yl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophene-4-ol

[0148] The preparation method of (R)-5-(3-((1-ethylpiperidin-3-yl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophene-4-ol is as described in Example 1. MS / ESI[M+H] + =370.2. 1 H NMR (400MHz, CDCl3) δ8.45(s,1H),7.66(dd,J=5.5,0.5Hz,1H),7.45(dd,J=8 .5,0.5Hz,1H),7.36(dd,J=10.7,7.0Hz,2H),4.53(s,1H),4.42-4.25(m,2H) ,3.21-2.95(m,2H),2.89(q,J=7.3Hz,2H),2.84-2.61(m,1H),2.57(s,3H),2 .16(ddd,J=21.0,15.5,7.0Hz,1H),1.99-1.77(m,3H),1.26(d,J=7.2Hz,3H).

[0149] Example 3: (R)-5-(3-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophene-4-ol

[0150] The preparation method of (R)-5-(3-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophene-4-ol is as described in Example 1. MS / ESI[M+H] + =386.2. 1 H NMR (400MHz, CDCl3) δ7.66(d,J=5.1Hz,1H),7.44(d,J=8.6Hz,1H),7.36(t,J=6.5Hz,2H),5.69(s,1H),4.30(s,1 H),3.65(s,2H),2.81(s,1H),2.63(s,3H),2.59-2.56(m,2H),1.83(s,2H),1.69(s,2H),1.28(d,J=22.8Hz,4H).

[0151] Example 4: (R)-5-(5-methyl-3-((1-(oxetan-3-yl)piperidin-3-yl)amino)-1,2,4-triazin-6-yl)benzothiophene-4-ol

[0152] The preparation method of (R)-5-(5-methyl-3-((1-(oxetane-3-yl)piperidin-3-yl)amino)-1,2,4-triazin-6-yl)benzothiophene-4-ol is as shown in Example 1. MS / ESI[M+H] + =398.2.

[0153] Example 5: 5-(3-(((1R,2R)-2-hydroxycyclohexyl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophene-4-ol

[0154] The preparation method of 5-(3-(((1R,2R)-2-hydroxycyclohexyl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophene-4-ol is shown in Example 1. MS / ESI[M+H] + =357.5. 1H NMR (400MHz, CDCl3) δ7.66(d,J=5.5Hz,1H),7.44(d,J=8.5Hz,1H),7.38(d,J=5.5Hz,1H),7.34(d,J=8.5Hz,1H),5.30(s,1 H),3.97-3.83(m,1H),3.53(td,J=10.1,4.5Hz,1H),2.63(s,3H),2.21-2.12(m,2H),1.82-1.78(m,2H),1.43-1.29(m,5H).

[0155] Example 6: (R)-6-(2-(difluoromethoxy)-4-(trifluoromethyl)phenyl)-5-methyl-N-(1-methylpiperidin-3-yl)-1,2,4-triazin-3-amine

[0156] Under nitrogen protection, compound INT2 (101.4 mg, 0.3 mmol), Pd(PPh3)4 (17.33 mg, 0.015 mmol), NaHCO3 (50.4 mg, 0.6 mmol), 1c (58.56 mg, 0.2 mmol) were dissolved in 1,4-dioxane (2 mL) and aqueous solution (0.5 mL), reacted at 105 ° C overnight, returned to room temperature, added water, 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 (DCM:MeOH=10:1) to give the target compound 6 (white solid, 32.2 mg), MS / ESI [M+H] + :418.5. 1 HNMR(400MHz, Methanol-d4)δ7.74-7.64(m,2H),7.60(s,1H),7.02(td,J=72.4,6.2Hz,1H),3.18(s,3H),2.93-2.85 (m,1H),2.83(s,3H),2.80-2.72(m,2H),2.15-1.97(m,2H),1.94-1.74(m,2H),1.69-1.54(m,1H),1.27-1.17(m,1H).

[0157] Example 7: (R)-6-(2-(difluoromethoxy)-4-(trifluoromethyl)phenyl)-N-(1-ethylpiperidin-3-yl)-5-methyl-1,2,4-triazin-3-amine

[0158] The preparation method of (R)-6-(2-(difluoromethoxy)-4-(trifluoromethyl)phenyl)-N-(1-ethylpiperidin-3-yl)-5-methyl-1,2,4-triazin-3-amine is shown in Example 6. MS / ESI[M+H] + =432.2.

[0159] Example 8: (R)-2-(3-((6-(2-(difluoromethoxy)-4-(trifluoromethyl)phenyl)-5-methyl-1,2,4-triazin-3-yl)amino)piperidin-1-yl)ethan-1-ol

[0160] The preparation method of (R)-2-(3-((6-(2-(difluoromethoxy)-4-(trifluoromethyl)phenyl)-5-methyl-1,2,4-triazin-3-yl)amino)piperidin-1-yl)ethan-1-ol is shown in Example 6. MS / ESI[M+H] + =448.2.

[0161] Example 9: (R)-6-(2-(difluoromethoxy)-4-(trifluoromethyl)phenyl)-5-methyl-N-(1-(oxetan-3-yl)piperidin-3-yl)-1,2,4-triazin-3-amine

[0162] The preparation method of (R)-6-(2-(difluoromethoxy)-4-(trifluoromethyl)phenyl)-5-methyl-N-(1-(oxetan-3-yl)piperidin-3-yl)-1,2,4-triazin-3-amine is shown in Example 6. MS / ESI[M+H] + =460.2.

[0163] Example 10: (1R,2R)-2-((6-(2-(difluoromethoxy)-4-(trifluoromethyl)phenyl)-5-methyl-1,2,4-triazin-3-yl)amino)cyclohexane-1-ol

[0164] The preparation method of (1R,2R)-2-((6-(2-(difluoromethoxy)-4-(trifluoromethyl)phenyl)-5-methyl-1,2,4-triazin-3-yl)amino)cyclohexane-1-ol is shown in Example 6. MS / ESI [M+H] + =419.2.

[0165] Example 11: 5-(3-(((1R,2R)-2-hydroxycyclohexyl)amino)-5-methyl-1,2,4-triazin-6-yl)benzofuran-4-ol

[0166] Step 1: To a reaction flask were added compound 5c (300 mg, 1.24 mmol), compound INT4 (500 mg, 1.9 mmol), Pd(dppf)Cl2 (90 mg, 0.124 mmol), cesium carbonate (1.2 g, 3.72 mmol), dioxane (10 ml), and deoxygenated water (1 ml). The system was replaced with a nitrogen atmosphere and the reaction was carried out at 100°C overnight. The reaction solution was passed through a pad of celite, and the filtrate was concentrated under reduced pressure. Silica gel was added to the sample, and column chromatography was performed to obtain the desired product 11a (900 mg). MS / ESI [M+H] + =355.4.

[0167] Step 2: Compound 11a (120 mg, 0.3 mmol) and DCM (8 ml) were added to the reaction flask and cooled to -10°C. A 1 M solution of BBr in DCM (1.2 ml) was added dropwise and the mixture was allowed to react at -10°C for 6 h. After the reaction was complete, methanol was added to quench the reaction. Most of the solvent was removed by swirl, and the title compound 11 (10 mg) was obtained by preparative liquid chromatography (MS / ESI) [M+H] + =341.3. 1 H NMR(400MHz,Chloroform-d)δ7.57(d,J=2.2Hz,1H),7.28(d,J=8.7Hz,1H),7.12(dd,J=8.7,0.9Hz,1H),7.01(dd,J=2.2,0.9Hz,1 H),5.56-5.15(m,1H),3.85(m,1H),3.61-3.41(m,1H),2.61(s,3H),2.15(t,J=12.0Hz,3H),2.04-1.50(m,3H),1.59-1.32(m,4H).

[0168] Example 12: (R)-5-(3-((1-(3,3-difluorocyclobutyl)piperidin-3-yl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophene-4-ol

[0169] Step 1: Weigh 12a (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 12b (light yellow).

[0170] Step 2: Compound 12c (50.9 g, 254 mmol) and triethylamine (70.1 g, 693 mmol) were dissolved in dichloromethane (250 mL). The dichloromethane solution of compound 12b was added dropwise at room temperature and stirred overnight. After the reaction was complete, silica gel was added, concentrated under reduced pressure, and dried. The mixture was separated by column chromatography (PE:EtOAc = 3:1, iodine developer) to give the target compound 12d (20.0 g, 68.9 mmol, light yellow solid, 30% yield for two steps). MS / ESI [M+H] + =291.1.

[0171] Step 3: Compound 12d (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 12e (15.6 g, 59.3 mmol, white solid, 86% yield). MS / ESI [M+H] + =191.2.

[0172] Step 4: 1a (300 mg, 1.83 mmol), 12e (579 mg, 2.20 mmol), DIPEA (946 mg, 7.32 mmol), and DMF (3 mL) were weighed and added to a flask and stirred at room temperature overnight. After the reaction was complete, the mixture was evaporated to dryness under reduced pressure, then dissolved in acetonitrile, added to silica gel, and evaporated to dryness under reduced pressure. The product was purified by column chromatography (DCM:MeOH = 10:1) to obtain the target compound 12f (290 mg, 0.91 mmol, light yellow oil, 50% yield). MS / ESI [M+H] + =318.2.

[0173] Step 5: Compound 12f (290 mg, 0.91 mmol), INT1 (316 mg, 1.09 mmol), Cs2CO3 (594 mg, 1.82 mmol), and Pd(dppf)Cl2 (65.9 mg, 0.09 mmol) were dissolved in dioxane (5 mL) and water (1 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, concentrated under reduced pressure to dryness, and separated by column chromatography (DCM:MeOH = 10:1) to afford the title compound 12g (400 mg, 0.90 mmol, light yellow oil, yield 98%). MS / ESI [M+H] + =446.3.

[0174] Step 6: Dissolve compound 12g (400 mg, 0.90 mmol) in DCM (4 mL), cool to 0°C, then add BBr3 (2.7 mL, 2.7 mmol, 1.0 M) dropwise and stir at room temperature for 2 h. After the reaction is complete, methanol (2 mL) is added at 0°C to quench the reaction. The crude product is then evaporated to dryness under reduced pressure, dissolved in methanol (5 mL), and purified by preparative organic fractionation to afford the target compound 12 (195 mg, 0.45 mmol, light yellow powder, 50% yield). 1 H NMR(400MHz,MeOD)δ7.60(d,J=5.3Hz,1H),7.53(dd,J=6.9,5.0Hz,2H),7.26 (d,J=8.3Hz,1H),4.23-4.14(m,1H),3.31(s,3H),3.03(s,1H),2.84-2.65(m, 4H),2.55-2.39(m,2H),2.37-2.28(m,1H),2.18(dd,J=21.5,13.9Hz,2H),2. 00(d,J=8.6Hz,1H),1.92-1.82(m,1H),1.76-1.65(m,1H),1.61-1.51(m,1H). MS / ESI[M+H] + =432.2.

[0175] Example 13: 5-(3-(((1R,3S)-3-hydroxycyclohexyl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophene-4-ol

[0176] Preparation of 5-(3-(((1R,3S)-3-hydroxycyclohexyl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophene-4-ol Refer to Example 1. 1 H NMR (400MHz, MeOD) δ7.60(d,J=5.6Hz,1H),7.52(dd,J=6.7,5.0Hz,2H),7.26(d,J=8.3Hz,1H),4.59(s,1H),3.98(ddt,J=10.9 ,7.6,3.7Hz,1H),3.77-3.61(m,1H),3.31(s,3H),2.37-2.29(m,1H),2.08-1.91(m,2H),1.90-1.80(m,1H),1.45-1.25(m,4H). MS / ESI[M+H] + =357.4.

[0177] Example 14: (R)-5-(5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)benzofuran-4-ol

[0178] Preparation of (R)-5-(5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)benzofuran-4-ol Reference Example 1. MS / ESI [M+H] + =340.3, 1 H NMR (400MHz, DMSO-d6) δ10.06 (s, 1H), 7.95 (s, 1H), 7.91 (d, J = 2.2Hz, 1H), 7.19-7.15 (m, 3H), 2.89 (s,3H),2.73(s,3H),2.66-2.54(m,4H),2.01-1.83(m,3H),1.79-1.64(m,1H),1.59-1.38(m,2H).

[0179] Example 15: 5-(3-(((1R,2R)-2-hydroxycyclopentyl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophene-4-ol

[0180] Preparation of 5-(3-(((1R,2R)-2-hydroxycyclopentyl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophene-4-ol Refer to Example 1. 1 H NMR (400MHz, DMSO) δ9.91(s,1H),7.71-7.65(m,2H),7.57(d,J=8.2Hz,1H),7.53(s,1H),7.25(d,J=8.2Hz,1H),4.87(s,1H),4.04(ddd,J =14.3,10.5,4.8Hz,2H),2.21(s,3H),2.10(td,J=14.1,7.4Hz,1H),1.96-1.85(m,1H),1.75-1.65(m,2H),1.52(qd,J=13.9,7.5Hz,2H). MS / ESI[M+H] + =343.2.

[0181] Example 16: 5-(3-((3-hydroxycyclopentyl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophene-4-ol

[0182] Preparation of 5-(3-((3-hydroxycyclopentyl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophene-4-ol Reference Example 1. MS / ESI[M+H] + =343.2.16-cis: 1H NMR (400MHz, DMSO) δ8.27(s,1H),7.73-7.64(m,2H),7.56(d,J=8.2Hz,1H),7.25(d,J=8.2Hz,1H),4.57-4.45(m,1H),4.28- 4.22(m,1H),2.19(d,J=10.0Hz,3H),2.17-2.07(m,1H),2.01-1.89(m,2H),1.78-1.67(m,1H),1.51(tt,J=13.3,6.7Hz,2H). 16-trans: 1 H NMR (400MHz, DMSO) δ9.88 (s, 1H), 7.74-7.62 (m, 2H), 7.56 (d, J = 8.2Hz, 1H) ,7.47(s,1H),7.24(d,J=8.2Hz,1H),4.78-4.60(m,1H),4.34-4.20(m,1H), 4.19-4.10(m,1H),2.25(dd,J=13.2,6.7Hz,1H),2.20(s,3H),1.95(dd,J= 11.8,7.3Hz,1H),1.82-1.68(m,2H),1.67-1.59(m,1H),1.58-1.48(m,1H).

[0183] Example 17: 1-(Difluoromethylene)-5-(3-(((1R,2R)-2-hydroxycyclohexyl)amino)-5-methyl-1,2,4-triazin-6-yl)-2,3-dihydro-1H-inden-4-ol

[0184] Preparation of 1-(difluoromethylene)-5-(3-(((1R,2R)-2-hydroxycyclohexyl)amino)-5-methyl-1,2,4-triazin-6-yl)-2,3-dihydro-1H-inden-4-ol Reference Example 1. MS / ESI [M+H] + =389.2. 1 H NMR(400MHz, CD3OD)7.10(d,J=7.9Hz,1H),6.93(d,J=7.9Hz,1H),4.07-4.03(m,1H),3.21-3.13( m,2H),2.94-2.83(m,2H),2.75(s,3H),2.27-2.05(m,3H),1.85-1.69(m,3H),1.43-1.26(m,4H).

[0185] Example 18: (R)-1-(difluoromethylene)-5-(5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)-2,3-dihydro-1H-inden-4-ol

[0186] Step 1: Compound 1c (67 mg, 0.28 mmol), INT3 (109.5 mg, 0.34 mmol), Pd(PPh3)4 (34.7 mg, 0.03 mmol), NaHCO3 (50.4 mg, 0.6 mmol), and 1,4-dioxane / H2O (3 mL / 0.5 mL) were added to a dry flask and reacted at 100°C overnight. After TLC plate detection, the reaction was returned to room temperature, filtered, and concentrated under reduced pressure to remove excess solvent. The residue was purified by column chromatography to obtain compound 18a (yellow oil, 45 mg). MS / ESI [M+H] + =402.2.

[0187] Step 2: Under nitrogen, compound 18a (45 mg, 0.11 mmol) and DCM (1 mL) were added to a dry flask. BBr (1 M) (0.4 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 18 (light brown solid, 10.2 mg). MS / ESI [M+H] + =388.2. 1 H NMR (400MHz, CD3OD)7.08(d,J=7.9Hz,1H),6.86(d,J=7.8Hz,1H),3.99(S,1H),3.13-2.98(m,2H),2. 92-2.78(m,2H),2.75(s,3H),2.21(s,3H),2.27-2.05(m,3H),1.85-1.69(m,2H),1.43-1.26(m,4H).

[0188] Example 19: (R)-1-(difluoromethylene)-5-(5-methyl-3-(piperidin-3-ylamino)-1,2,4-triazin-6-yl)-2,3-dihydro-1H-inden-4-ol

[0189] Step 1: Compound 1a (326 mg, 2.00 mmol), 19a (400 mg, 2.00 mmol), DIPEA (1.03 g, 8 mmol), and 1,4-dioxane (15 mL) were added to a dry flask and reacted at 80°C overnight. After the reaction was complete, the excess solvent was removed by concentration under reduced pressure. The residue was purified by column chromatography to yield compound 19b (yellow solid, 206 mg). MS / ESI [M+H] + =328.1.

[0190] Step 2: Compound 19b (206 mg, 0.63 mmol), INT3 (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 allowed to proceed at 100°C overnight. After TLC plate analysis, the reaction was completed, filtered, and concentrated under reduced pressure to remove excess solvent. The residue was purified by column chromatography to yield compound 19c (a light brown oil, 103 mg). MS / ESI [M+H] + =488.2.

[0191] Step 3: Compound 19c (103 mg, 0.21 mmol), 1,4-dioxane (4 mL), and HCl (4M in dioxane) (1 mL) were added to a dry flask and reacted at room temperature for 3 h. A yellow solid formed. The residue was concentrated under reduced pressure to remove excess solvent, and purified by column chromatography to yield compound 19d (yellow solid, 67 mg). MS / ESI [M+H] + =388.2.

[0192] Step 4: Under nitrogen, compound 19d (67 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 19 (light brown solid, 25.2 mg). MS / ESI [M+H] + =373.2. 1H NMR(400MHz, CD3OD)7.11(d,J=7.82Hz,1H),6.96(d,J=8.0Hz,1H),4.06-4.02(m,1H),3.11-2.96 (m,2H),2.94-2.84(m,2H),2.80(s,3H),2.30-2.11(m,3H),1.67-1.52(m,2H),1.48-1.33(m,4H).

[0193] Example 20: (R)-1-(difluoromethylene)-5-(3-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-5-methyl-1,2,4-triazin-6-yl)-2,3-dihydro-1H-inden-4-ol

[0194] Compound 19 (15 mg, 0.04 mmol), 2-bromoethanol (5 mg, 0.04 mmol), NaOH (3.2 mg, 0.8 mmol), and acetonitrile (1 mL) were added to a dry flask and allowed to react at room temperature for 4 h. After the reaction was complete as determined by TLC, the excess solvent was removed by concentration under reduced pressure. The residue was purified by thin-layer chromatography to yield compound 20 (light brown solid, 10.3 mg). MS / ESI [M+H] + =418.2. 1 H NMR(400MHz, CD3OD)7.09(d,J=7.89Hz,1H),6.88(d,J=7.79Hz,1H),4.13-4.09(m,1H),3.51-3.41(m,2H),3.13-2.98 (m,2H),2.95-2.84(m,2H),2.82(s,3H),2.60-2.48(m,2H),2.27-2.05(m,3H),1.85-1.71(m,2H),1.44-1.28(m,4H).

[0195] Example 21: (R)-5-(3-((1-(3,3-difluorocyclobutyl)piperidin-3-yl)amino)-5-methyl-1,2,4-triazin-6-yl)-1-(difluoromethylene)-2,3-dihydro-1H-inden-4-ol

[0196] Preparation of (R)-5-(3-((1-(3,3-difluorocyclobutyl)piperidin-3-yl)amino)-5-methyl-1,2,4-triazin-6-yl)-1-(difluoromethylene)-2,3-dihydro-1H-inden-4-ol: Reference Example 12. MS / ESI [M+H] + =464.2. 1H NMR (400MHz, CD3OD)7.11(d,J=7.86Hz,1H),6.96(d,J=7.83Hz,1H),4.33-4.28(m,1H),3.10-3.04(m,2H),2.94-2.91 (m,2H),2.75(s,3H),2.62-2.51(m,2H),2.25-2.09(m,3H),2.04-1.94(m,3H),1.82-1.72(m,2H),1.34-1.31(m,4H).

[0197] Example 22: (S)-1-(Difluoromethylene)-5-(5-methyl-3-((tetrahydrofuran-3-yl)amino)-1,2,4-triazin-6-yl)-2,3-dihydro-1H-inden-4-ol

[0198] Preparation of (S)-1-(difluoromethylene)-5-(5-methyl-3-((tetrahydrofuran-3-yl)amino)-1,2,4-triazin-6-yl)-2,3-dihydro-1H-inden-4-ol Reference Example 1. MS / ESI [M+H] + =361.2.

[0199] Example 23: (R)-1-(difluoromethylene)-5-(5-methyl-3-((tetrahydrofuran-3-yl)amino)-1,2,4-triazin-6-yl)-2,3-dihydro-1H-inden-4-ol

[0200] Preparation of (R)-1-(difluoromethylene)-5-(5-methyl-3-((tetrahydrofuran-3-yl)amino)-1,2,4-triazin-6-yl)-2,3-dihydro-1H-inden-4-ol Reference Example 1. MS / ESI [M+H] + =361.2.

[0201] Example 24: (S)-5-(5-methyl-3-((tetrahydrofuran-3-yl)amino)-1,2,4-triazin-6-yl)benzothiophene-4-ol

[0202] Preparation of (S)-5-(5-methyl-3-((tetrahydrofuran-3-yl)amino)-1,2,4-triazin-6-yl)benzothiophen-4-ol Reference Example 1. MS / ESI [M+H] + =329.2. 1H NMR (400MHz, MeOD) δ7.62(t,J=5.2Hz,1H),7.49-7.42(m,1H),7.40-7.29(m,1H),7.17(dd,J=11.6,5.2Hz,1H),4.46-4.28(m,2H),3.78(ddd,J =11.3,6.3,2.5Hz,1H),3.62(dd,J=11.1,4.5Hz,1H),3.52-3.46(m,1H) ,3.32(s,3H),3.10-2.87(m,1H),2.18-2.05(m,1H),1.98-1.79(m,1H).

[0203] Example 25: (3S,4R)-4-((6-(4-hydroxybenzo[b]thiophen-5-yl)-5-methyl-1,2,4-triazin-3-yl)amino)tetrahydrofuran-3-ol

[0204] Preparation of (3S,4R)-4-((6-(4-hydroxybenzo[b]thiophen-5-yl)-5-methyl-1,2,4-triazin-3-yl)amino)tetrahydrofuran-3-ol Reference Example 1. MS / ESI [M+H] + =345.1.

[0205] Example 26: (R)-5-(5-methyl-3-((1-(methyl-d3)piperidin-3-yl)amino)-1,2,4-triazin-6-yl)benzothiophen-4-ol

[0206] Preparation of (R)-5-(5-methyl-3-((1-(methyl-d3)piperidin-3-yl)amino)-1,2,4-triazin-6-yl)benzothiophen-4-ol Reference Example 1. MS / ESI [M+H] + =359.2.

[0207] Example 27: 2-(3-(((1R,2R)-2-hydroxycyclohexyl)amino)-5-methyl-1,2,4-triazin-6-yl)naphthalen-1-ol

[0208] Preparation of 2-(3-(((1R,2R)-2-hydroxycyclohexyl)amino)-5-methyl-1,2,4-triazin-6-yl)naphthalen-1-ol Reference Example 1. MS / ESI [M+H] + =351.1.

[0209] Example 28: (R)-2-(5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)naphthalen-1-ol

[0210] Preparation of (R)-2-(5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)naphthalen-1-ol Reference Example 1. MS / ESI [M+H] + =351.1.

[0211] Example 29: (R)-2-(3-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-5-methyl-1,2,4-triazin-6-yl)naphthalen-1-ol

[0212] Preparation of (R)-2-(3-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-5-methyl-1,2,4-triazin-6-yl)naphthalen-1-ol Reference Example 1. MS / ESI [M+H] + =380.1.

[0213] Example 30: (R)-6-(4-hydroxybenzo[b]thiophen-5-yl)-N-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazine-5-carboxamide

[0214] Step 1: Compound 1a (4.5 g, 27.6 mmol) and acetonitrile (90 ml) were added to a round-bottom flask. After stirring, 2 M potassium hydroxide solution (4.65 g, 82.8 mmol) was added. Potassium permanganate (8.73 g, 55.2 mmol) was then added portionwise to the mixture over 30 minutes. Stirring was continued at room temperature for 6 hours. Volatile substances were removed under vacuum, the mixture was diluted with water, and acidified to pH = 1 with 3 M HCl. The aqueous phase was extracted with EtOAc (3 x 50 mL). The collected organic phase was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to remove the solvent to give compound 30a (white solid, 4.12 g, 79%). MS / ESI [M+H] + =195.0.

[0215] Step 2: To a solution of compound 30a (3.0 g, 15.5 mmol) in dichloromethane (40 ml) was added oxalyl chloride (1.5 ml, 17.7 mmol) and two drops of DMF. The mixture was stirred at room temperature for 1 hour. After concentration, the residue was dissolved in dichloromethane (40 mL). Methylamine hydrochloride (2.4 g, 37.3 mmol) and triethylamine (4 mL) were added to the above solution. The resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated and purified by column chromatography to give compound 30b (brown solid, 1.87 g, 59% yield). MS / ESI[M+H]+ =208.1.

[0216] Step 3: Compound 30b (416 mg, 2.00 mmol), 1b (228 mg, 2.00 mmol), DIPEA (1.03 g, 8 mmol), and 1,4-dioxane (15 mL) were added to a dry flask and reacted overnight at 80°C. After the reaction was complete, the excess solvent was removed by concentration under reduced pressure. The residue was purified by column chromatography to obtain compound 30c (yellow solid, 206 mg). MS / ESI [M+H] + =285.2.

[0217] Step 4: Compound 30c (179 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 allowed to proceed at 100°C overnight. After TLC plate analysis, the reaction was completed, filtered, and concentrated under reduced pressure to remove excess solvent. The residue was purified by column chromatography to yield compound 30d (a light brown oil, 112 mg). MS / ESI [M+H] + =413.2.

[0218] Step 5: Under nitrogen, compound 30d (70 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 (light brown solid, 25.2 mg). MS / ESI [M+H] + =399.2.

[0219] Example 31: (R)-3-((1-ethylpiperidin-3-yl)amino)-6-(4-hydroxybenzo[b]thiophen-5-yl)-N-methyl-1,2,4-triazine-5-carboxamide

[0220] Preparation of (R)-3-((1-ethylpiperidin-3-yl)amino)-6-(4-hydroxybenzo[b]thiophen-5-yl)-N-methyl-1,2,4-triazine-5-carboxamide Reference Example 30. MS / ESI[M+H] + =413.2.

[0221] Example 32: (R)-5-(3-((1-(ethyl-d5)piperidin-3-yl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophene-4-ol

[0222] Preparation of (R)-5-(3-((1-(ethyl-d5)piperidin-3-yl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophene-4-ol Reference Example 1. MS / ESI [M+H] + =375.2.

[0223] Example 33: (R)-5-(5-methyl-3-(((4-methylmorpholin-2-yl)methyl)amino)-1,2,4-triazin-6-yl)benzothiophen-4-ol

[0224] Preparation of (R)-5-(5-methyl-3-(((4-methylmorpholin-2-yl)methyl)amino)-1,2,4-triazin-6-yl)benzothiophen-4-ol Reference Example 1. MS / ESI [M+H] + =372.1. 1 H NMR (400MHz, CDCl3) δ7.68(d,J=5.5Hz,1H),7.41(d,J=8.5Hz,1H),7.34(t,J=5. 9Hz, 2H), 5.78 (s, 1H), 3.92 (d, J = 11.3Hz, 1H), 3.86-3.74 (m, 2H), 3.71 (td, J = 11. 4,2.0Hz,1H),3.57-3.46(m,1H),2.80(d,J=11.2Hz,1H),2.67(d,J=11.4Hz,1H) ,2.61(s,3H),2.30(s,3H),2.16(td,J=11.5,3.2Hz,1H),1.97(t,J=10.6Hz,1H).

[0225] Example 34: (S)-5-(5-methyl-3-(((4-methylmorpholin-2-yl)methyl)amino)-1,2,4-triazin-6-yl)benzothiophen-4-ol

[0226] Preparation of (S)-5-(5-methyl-3-(((4-methylmorpholin-2-yl)methyl)amino)-1,2,4-triazin-6-yl)benzothiophen-4-ol Reference Example 1. MS / ESI [M+H] + =372.1. 1H NMR (400MHz, CDCl3) δ7.68(d,J=5.5Hz,1H),7.41(d,J=8.5Hz,1H),7.34(t,J=5. 9Hz, 2H), 5.78 (s, 1H), 3.92 (d, J = 11.3Hz, 1H), 3.86-3.74 (m, 2H), 3.71 (td, J = 11. 4,2.0Hz,1H),3.57-3.46(m,1H),2.80(d,J=11.2Hz,1H),2.67(d,J=11.4Hz,1H) ,2.61(s,3H),2.30(s,3H),2.16(td,J=11.5,3.2Hz,1H),1.97(t,J=10.6Hz,1H).

[0227] Example 35: (R)-5-(3-((5,5-difluoro-1-methylpiperidin-3-yl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophene-4-ol

[0228] Preparation of (R)-5-(3-((5,5-difluoro-1-methylpiperidin-3-yl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophen-4-ol Reference Example 1. MS / ESI [M+H] + =392.2.

[0229] Example 36: 5-(3-(((1R,2R)-2-hydroxy-2-methylcyclohexyl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophene-4-ol and 5-(3-(((1R,2S)-2-hydroxy-2-methylcyclohexyl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophene-4-ol

[0230] Step 1: Compound 36a (1.06 g, 5 mmol) was dissolved in anhydrous THF (10 ml) under a nitrogen balloon. The temperature was lowered to -10°C, and a THF solution of methylmagnesium chloride (15 ml, 15 mmol) was added dropwise. The mixture was then allowed to react at room temperature overnight. TLC confirmed the complete reaction of the starting material. The reaction was quenched by adding saturated aqueous ammonium chloride. The aqueous phase was extracted three times with EA. The combined organic phases were dried over saturated brine and anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to afford the desired product 36b (634 mg). MS / ESI [M+H] + =230.3.

[0231] Step 2: Compound 36b (634 mg, 2.8 mmol) was dissolved in 10 ml of DCM, and a 4 M dioxane hydrochloride solution (10 ml) was added. The mixture was reacted at room temperature overnight. The mixture was concentrated under reduced pressure to obtain the target product 36c (550 mg). MS / ESI [M+H] + =130.2.

[0232] Step 3: Compound 36c (200 mg, 1.2 mmol), compound 1a (212 mg, 1.3 mmol), and DIEA (619 mg, 4.8 mmol) were dissolved in 5 ml of ACN. The mixture was allowed to react overnight at room temperature. Silica gel was added and the sample was stirred. Column chromatography was performed to obtain the desired product 36d (130 mg). MS / ESI [M+H] + =257.7.

[0233] Step 4: Compound 36d (130 mg, 0.5 mmol), compound INT6 (192 mg, 0.6 mmol), Pd(dppf)Cl2 (37 mg), and cesium carbonate (489 mg, 1.5 mmol) were dissolved in dioxane (5 ml) and water (1 ml). The system was replaced with a nitrogen atmosphere and the reaction was carried out at 100°C overnight. The reaction solution was added with silica gel and mixed. Column chromatography was performed to obtain the desired product 36e (246 mg). MS / ESI [M+H] + =415.5.

[0234] Step 5: Compound 36e (246 mg, 0.6 mmol) was dissolved in 5 ml of methanol, and a methanolic hydrochloric acid solution (4 M, 5 ml) was added. The mixture was reacted at room temperature overnight. The mixture was concentrated under reduced pressure to remove most of the methanol, and 36-1 or 36-2 (54 mg) was obtained by preparative liquid phase separation. MS / ESI [M+H] + =371.4, 1 H NMR(400MHz,Chloroform-d)δ7.65(dd,J=5.5,0.8Hz,1H),7.44(dd,J=8.5,0.8Hz,1H),7.38(d,J=5.5Hz,1H),7.32(d,J=8.5Hz,1H),5.43(br,1H),4.06(s, 1H),2.62(s,3H),2.06-1.96(m,1H),1.95-1.87(m,1H),1.84-1.76(m,1H),1. 76-1.68(m,1H),1.61(td,J=12.8,4.0Hz,1H),1.52-1.35(m,3H),1.26(s,3H).

[0235] 36-2 or 36-1 (11 mg), MS / ESI [M+H] +=371.4,1H NMR (400MHz, DMSO-d6) δ7.69(s,2H),7.55(d,J=8.2Hz,1H),7.25(d,J=8.3Hz,1H),4.39(s,1H),2.22(s,3H), 2.05-1.96(m,1H),1.70-1.67(m,3H),1.61-1.55(m,1H),1.45-1.34(m,2H),1.32-1.24(m,2H),1.17(s,3H).

[0236] Example 37: 5-(3-((2-(methoxy-d3)-2-methylpropyl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophene-4-ol

[0237] Step 1: Compound 37a (2 g, 22.43 mmol), PMBCl (17.57 g, 112 mmol), TEA (11.4 g, 112 mmol), and DMF (20 ml) were added to a reaction flask. The reaction was allowed to react at room temperature for 2 h. The reaction was monitored for completion by LC-MS. Water and ethyl acetate were added, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the target compound 37b (6.1 g). MS / ESI [M+H] + =330.4.

[0238] Step 2: Compound 37b (6.1 g, 18.5 mmol) was dissolved in 20 ml of THF and cooled to 0°C. NaH (2.2 g, 93 mmol) was added and the reaction was continued at 0°C for 30 min. Deuterated iodomethane (8.1 g, 56 mmol) was dissolved in 15 ml of THF and slowly added to the reaction system. The reaction was continued at room temperature for 1 h. 50 ml of saturated aqueous ammonium chloride was added and the THF was evaporated off. The aqueous phase 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. Silica gel was added and the sample was mixed. The target product 37c (6.2 g) was obtained by column chromatography. MS / ESI [M+H] + =347.4.

[0239] Step 3: Compound 37c (6.2 g) and Pd / C (620 mg) were dissolved in 100 ml of methanol, and the system was replaced with a hydrogen atmosphere. The reaction was allowed to proceed overnight at room temperature. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain the target product 37d (3.1 g). MS / ESI [M+H] + =107.2.

[0240] Preparation of 5-(3-((2-(methoxy-d3)-2-methylpropyl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophen-4-ol Reference Example 36, yield 37 (20 mg), MS / ESI [M+H] + =348.4, 1 H NMR(400MHz,Chloroform-d)δ7.66(dd,J=5.6,0.8Hz,1H),7.44(dd,J=8.5,0.8Hz,1 H),7.40-7.34(m,2H),5.64(s,1H),3.60(d,J=5.6Hz,2H),2.63(s,3H),1.27(s,6H).

[0241] Example 38: 5-(3-(((1R,3R)-3-hydroxy-3-methylcyclohexyl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophene-4-ol and 5-(3-(((1R,3S)-3-hydroxy-3-methylcyclohexyl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophene-4-ol

[0242] Preparation of 5-(3-(((1R,3R)-3-hydroxy-3-methylcyclohexyl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophene-4-ol and 5-(3-(((1R,3S)-3-hydroxy-3-methylcyclohexyl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophene-4-ol Reference Example 36 to obtain 38-1 or 38-2 (7 mg), MS / ESI [M+H] + =371.4, 1 H NMR(400MHz,Chloroform-d)δ7.66(d,J=5.5Hz,1H),7.44(d,J=8.5Hz,1H),7.40-7.32(m,2H),4.33(d,J=7.4Hz,1H),2.62(s,3H),2 .28-2.10(m,2H),1.76-1.61(m,3H),1.41-1.34(m,1H),1.33(s,1H),1.31(s,3H),1.28-1.24(m,2H),1.18(td,J=12.3,3.5Hz,1H).

[0243] 38-1 or 38-2 (12 mg), MS / ESI [M+H] + =371.4, 1H NMR(400MHz,Chloroform-d)δ7.66(d,J=5.5Hz,1H),7.43(d,J=8.5Hz,1H),7.40-7.32(m,2H),6.82(s,1H),4 .40(s,1H),2.61(s,3H),2.03-1.76(m,3H),1.75-1.62(m,1H),1.61-1.49(m,2H),1.32(s,3H),1.25(s,1H).

[0244] Example 39: (3S,4R)-4-((6-(4-hydroxybenzo[b]thiophen-5-yl)-5-methyl-1,2,4-triazin-3-yl)amino)tetrahydro-2H-pyran-3-ol

[0245] Preparation of (3S,4R)-4-((6-(4-hydroxybenzo[b]thiophen-5-yl)-5-methyl-1,2,4-triazin-3-yl)amino)tetrahydro-2H-pyran-3-ol Reference Example 36 to obtain Compound 39 (45 mg), MS / ESI [M+H] + =359.4, 1 H NMR(400MHz,Chloroform-d)δ11.07(s,1H),7.65(d,J=5.5Hz,1H),7.45(d,J=8.5Hz,1H),7 .39(d,J=5.5Hz,1H),7.31(d,J=8.5Hz,1H),5.55(s,1H),4.10(dd,J=11.3,4.8Hz,1H),4.0 0(dt,J=10.2,3.0Hz,2H),3.68(td,J=9.5,4.9Hz,1H),3.50(td,J=11.8,2.2Hz,1H),3.25( dd,J=11.4,9.8Hz,1H),2.61(s,3H),2.13(ddt,J=13.1,4.6,2.2Hz,1H),1.79-1.69(m,1H).

[0246] Example 40: (R)-2-(3-((6-(4-hydroxybenzo[b]thiophen-5-yl)-5-methyl-1,2,4-triazin-3-yl)amino)piperidin-1-yl)acetonitrile

[0247] Preparation of (R)-2-(3-((6-(4-hydroxybenzo[b]thiophen-5-yl)-5-methyl-1,2,4-triazin-3-yl)amino)piperidin-1-yl)acetonitrile Reference Example 36 to obtain Compound 40 (20 mg), MS / ESI [M+H] +=381.4, 1 HNMR (400MHz, DMSO-d6) δ8.05(s,1H),7.73(d,J=5.7Hz,1H),7.70(d,J=5.5Hz,1H),7.59(d,J=8.2Hz,1H),7.25(d,J=8.2Hz,1H),4.21(s,2H ), 4.11(s,2H),3.24(s,1H),2.99(s,1H),2.61-2.51(m,2H),2.27(s,3H),2.04-1.83(m,2H),1.73(t,J=14.1Hz,1H),1.49(q,J=11.5Hz,1H).

[0248] Example 41: (R)-5-(5-amino-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)benzothiophene-4-ol

[0249] Step 1: Compound 41a (1.84 g, 10 mmol) was dissolved in 30 ml of THF, cooled to -78°C, and ammonia methanol solution (1.6 ml, 11 mmol) was added dropwise. The temperature was gradually raised to room temperature and the reaction was allowed to proceed overnight. Silica gel was added and the sample was stirred. Column chromatography was performed to obtain the target product 41b (270 mg). MS / ESI [M+H] + =165.9.

[0250] Step 2: Compound 41b (160 mg, 1 mmol), compound 1b (168 mg, 0.9 mmol), Pd(OAc)2 (22.4 mg, 0.1 mmol), BINAP (125 mg, 0.2 mmol), and cesium carbonate (1.3 g, 4 mmol) were dissolved in 10 ml of dioxane, replaced with a nitrogen atmosphere, and reacted at 100°C overnight. Filtered, silica gel was added to the sample, and column chromatography was performed to obtain the desired product 41c (210 mg). MS / ESI [M+H] + =243.7.

[0251] Preparation of (R)-5-(5-amino-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)benzothiophen-4-ol Reference Example 36. MS / ESI [M+H] + =357.4; 1H NMR (400MHz, DMSO-d6) δ7.61(d,J=5.6Hz,1H),7.57(d,J=5.5Hz,1H),7.44(d,J=8.2Hz,1H),7.16(d,J=8.2Hz,1H),6.57(br,2H),3.86(s, 1H),2.84-2.72(m,1H),2.53(d,J=11.0Hz,1H),2.10(s,3H),1.99-1.68(m,4H),1.66-1.57(m,1H),1.52-1.36(m,1H),1.31-1.17(m,1H).

[0252] Example 42: 5-(3-(((3R,5R)-5-(difluoromethyl)-1-methylpiperidin-3-yl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophen-4-ol

[0253] Step 1: Compound 42a (250 mg, 1 mmol), paraformaldehyde (36 mg, 1.2 mmol), and a catalytic amount of acetic acid were dissolved in methanol and stirred for 0.5 h. NaBH3CN (189 mg, 3 mmol) was then added and allowed to react overnight. The reaction was quenched by adding saturated sodium bicarbonate and extracted three times with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. Filtration, concentration under reduced pressure, and column chromatography afforded the desired product 42b (240 mg). MS / ESI [M+H] + =292.7.

[0254] Step 2: Compound 42b (240 mg) was dissolved in 5 ml of 4 M hydrochloric acid and dioxane solution, reacted at room temperature overnight, and concentrated under reduced pressure to obtain the target product 42c (410 mg). MS / ESI [M+H] + =165.1.

[0255] Preparation of 5-(3-(((3R,5R)-5-(difluoromethyl)-1-methylpiperidin-3-yl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophen-4-ol Reference Example 36. MS / ESI [M+H] + =406.4, 1H NMR(400MHz,Chloroform-d)δ7.66(d,J=5.5Hz,1H),7.44(d,J=8.5Hz,1H),7.40 -7.32(m,2H),6.07(s,1H),5.66(td,J=56.4,4.4Hz,1H),4.45(s,1H),2.93(dd,J =11.3,3.7Hz,1H),2.83(d,J=11.6Hz,1H),2.63(s,3H),2.49-2.37(m,1H),2.33 (s, 4H), 2.23-2.07 (m, 1H), 1.98 (t, J = 11.0Hz, 1H), 1.46 (td, J = 12.9, 3.3Hz, 1H).

[0256] Example 43: 5-(3-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophen-4-ol

[0257] Step 1: Compound 43a (165 mg, 1.0 mmol), compound 1c (163 mg, 1.0 mmol), dioxane (8 mL), and DIEA (516 mg, 4 mmol) were added to a dry flask and stirred at room temperature overnight. After completion of the reaction, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to yield compound 43b (112 mg, 44%). MS / ESI [M+H] + =257.1.

[0258] Step 2: Compound 43b (112 mg, 0.44 mmol), compound INT6 (169.6 mg, 0.53 mmol), Pd(dppf)Cl2 (36.6 mg, 0.05 mmol), Cs2CO3 (286.9 mg, 0.88 mmol), and 1,4-dioxane / H2O (5 mL / 1 mL) were added to a dry flask under nitrogen protection and stirred overnight at 100°C. After the reaction was complete, the mixed 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 43c (89 mg, 49%). MS / ESI [M+H] + =415.2.

[0259] Step 3: Compound 43c (89 mg, 0.21 mmol), 1,4-dioxane (3 mL), and HCl (4 M, 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 43 (30.7 mg, 40%); MS / ESI [M+H] + =371.2. 1 H NMR (400MHz, CD3OD) δ7.60(d,J=5.6Hz,1H,1H),7.55-7.50(m,2H),7.25(d,J=8.3Hz,1H),4.30-4.17(m,1H),4.09-3.97(m ,1H),3.61-3.50(m,2H),3.30(s,3H),2.37-2.28(m,1H),1.92-1.70(m,2H),1.41-1.25(m,1H),1.10(s,3H),0.92(s,3H).

[0260] Example 44: 5-(3-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophen-4-ol

[0261] Preparation of 5-(3-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophen-4-ol Reference Example 36 to obtain Compound 44 (36.7 mg, 26%); MS / ESI [M+H] + =371.2. 1 H NMR (400MHz, CD3OD) δ7.59(d,J=6.1Hz,1H),7.55-7.49(m,2H),7.25(d,J=8.3Hz,1H),4.40-4.29(m,1H),3.88 -3.74(m,2H),3.32(s,3H),2.33-2.29(m,1H),2.11-1.95(m,2H),1.59-1.41(m,2H),1.33(s,3H),1.26(s,3H).

[0262] Example 45: 5-(3-(((1S,3S)-3-hydroxy-3-methylcyclobutyl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophen-4-ol

[0263] Preparation of 5-(3-(((1S,3S)-3-hydroxy-3-methylcyclobutyl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophen-4-ol Reference Example 36 to obtain compound 45 (8.3 mg, 32%), MS / ESI [M+H] + =343.2. 1 HNMR NMR (400MHz, CD3OD)7.79-7.70(m,2H),7.63(d,J=8.0Hz,1H),7.28(d,J=8.4Hz,1H),5.13( s,1H),4.41-4.29(m,1H),2.82(s,3H),2.06-1.94(m,2H),1.86-1.68(m,2H),1.12(s,3H).

[0264] Example 46: 5-(5-cyclopropyl-3-(((1R,2R)-2-hydroxycyclohexyl)amino)-1,2,4-triazin-6-yl)benzothiophen-4-ol

[0265] Step 1: Compound 46a (18.5 g, 166.43 mmol, 1.4 eq), acetic acid (5 g, 83.22 mmol, 0.7 eq), and water (3.3 g, 184.26 mmol, 1.55 eq) were added to 1,4-dioxane (75 mL) and heated to reflux for 2 h. 1-Cyclopropylethanone (10 g, 118.88 mmol, 1.0 eq) was added and heated to reflux for 22 h. The mixture was cooled to room temperature and filtered. The filter cake was rinsed with 1,4-dioxane and the filtrate was used in the next step according to the theoretical amount.

[0266] Step 2: To a dioxane solution of compound 46b (118.88 mmol, 1.0 eq), water (150 mL) was added, and sodium bicarbonate (20 g, 237.76 mmol, 2.0 eq) was slowly added. The temperature was cooled to -5-0°C, and an aqueous solution (100 mL) of S-methylisothiosemicarbazide hydroiodide (30.5 g, 130.77 mmol, 1.1 eq) was added dropwise. The temperature was naturally warmed to room temperature and the reaction was carried out for 48 h. TLC monitoring showed that there was no starting material. The mixture was extracted with ethyl acetate (200 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 to obtain product 46d (12.6 g, two-step yield: 65%).

[0267] Step 3: Compound 46d (2 g, 11.96 mmol, 1.0 eq) was dissolved in DCM (40 mL). 85% m-chloroperbenzoic acid (6 g, 29.9 mmol, 2.5 eq) was added portionwise and allowed to react at room temperature for 1 h. TLC confirmed the absence of residual starting material. Saturated aqueous sodium carbonate (50 mL) was added and stirred for 2 min. The mixture was extracted with DCM (50 mL x 3). The organic phases were combined and washed with 10% aqueous sodium thiosulfate (50 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford compound 46e (2.1 g, 88.2% yield). MS / ESI [M+H] + =199.9.

[0268] Step 4: Compound 46e (2.1 g, 10.54 mmol, 1.0 eq) was added to 1.4-dioxane (30 mL), followed by compound 5b (4.8 g, 21.08 mmol, 2.0 eq) and DIPEA (4.1 g, 31.62 mmol, 3.0 eq). The mixture was heated to 80°C for 20 h. TLC confirmed the absence of residual starting material. The mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 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 to afford compound 46f (2.47 g, 73.5% yield). MS / ESI [M+H] + =235.9.

[0269] Step 5: Compound 46f (2.47 g, 10.54 mmol, 1.0 eq) was added to ACN / H2O (20 / 2 mL), followed by Br2 (3.4 g, 21.08 mmol, 2.0 eq) and allowed to react at room temperature for 3 h. TLC confirmed the absence of residual starting material. Water (50 mL) was added and the mixture was extracted with ethyl acetate (50 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 to afford compound 46g (1.76 g, 53% yield). MS / ESI [M+H] + =312.9.

[0270] Step 6: Under nitrogen protection, compound 46g (150 mg, 0.48 mmol), compound INT6 (192 mg, 0.6 mmol), Pd(dppf)Cl2 (36.6 mg, 0.05 mmol), Cs2CO3 (313.0 mg, 0.96 mmol), and 1,4-dioxane / H2O (5.0 mL / 1.0 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 46h (67 mg of bright yellow oily liquid). MS / ESI [M+H] + =426.9.

[0271] Step 7: Compound 46h (67 mg, 0.16 mmol) and dioxane (2 mL) were added to a dry flask. HCl in dioxane (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, and the residue was purified by column chromatography to yield compound 46 (pale yellow solid, 17.2 mg); MS / ESI [M+H] + =383.2. 1 H NMR (400MHz, CD3OD) δ7.59(d,J=5.4Hz,1H),7.52(d,J=8.4Hz,1H),7.37(d,J=8.4Hz,1H),7.30 (d,J=5.4Hz,1H),5.18(s,1H),3.74(s,1H),3.50-3.40(m,1H),3.12(s,1H),2.32-2.16(m,1H), 2.14-2.04(m,2H),1.76-1.66(m,2H),1.64-1.45(m,3H),1.32-1.25(m,4H),1.17-1.02(m,2H).

[0272] Example 47: 5-(3-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophen-4-ol

[0273] Step 1: Compound 47a (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 47b (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.

[0274] Step 2: Compound 47b (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 47c (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.

[0275] Preparation of 5-(3-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophen-4-ol Reference Example 36 to obtain compound 47 (8.02 mg, 34%), MS / ESI [M+H] + =374.2. 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),4.18-4.10(m,1H) ,3.10-3.04(m,2H),2.94-2.91(m,2H),2.83(s,3H),2.62-2.51(m,2H),2.18(s,3H),2.15-2.09(m,2H).

[0276] Example 48: (R)-5-(5-(dimethylamino)-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)benzothiophen-4-ol

[0277] Step 1: Compound INT1 (3.4 g, 0.012 mol), compound 48a (3.2 g, 0.016 mol), Pd(dppf)Cl2 (857 mg, 0.001 mmol), potassium carbonate (4.8 g, 0.035 mol), dioxane (40 mL), and water (10 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 the solid was collected by filtration. The filter cake was washed with water and ethyl acetate to obtain compound 48b (1.9 g, 59.4%); MS / ESI [M+H] + =276.0.

[0278] Step 2: Compound 48b (1.7 g, 6.18 mmol) was dissolved in POCl3 (20 mL), and PCl5 (3.2 g, 15.45 mmol) and N,N-diethylaniline (2.7 g, 18.54 mmol) were added. The mixture was stirred at 110°C for 3 h. The solvent was evaporated, and the residue was dispersed in DCM (30 mL). DIEA was added to adjust the pH to 6-7. The mixture was directly added to silica gel and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0-19:1) to obtain compound 48c (100 mg, 5.3%); MS / ESI [M+H] + =311.8.

[0279] Step 3: Compound 48c (160 mg, 0.51 mmol) was placed in a reaction flask, and DIEA (99 mg, 0.77 mmol) and dimethylamine (0.26 mL, 0.51 mmol, 2 M in THF) were added. The reaction was allowed to proceed at room temperature for 1 h. The solvent was evaporated to give compound 48d (160 mg), which was used directly in the next step without further purification; MS / ESI [M+H] + =321.0.

[0280] Step 4: Compound 48d (160 mg, 0.50 mmol) was placed in a reaction flask, DIEA (97 mg, 0.75 mmol) and (3R)-1-methylhexahydropyridin-3-amine 1b (74 mg, 0.65 mmol) were added, and the mixture was reacted at 100°C for 15 h. After the reaction was complete, the solvent was directly evaporated, and the residue was purified by Pre-HPLC (formic acid system) to obtain compound 48e (200 mg, crude product); MS / ESI [M+H] + =399.0.

[0281] Step 5: Compound 48e (200 mg, crude) and dichloromethane (10 mL) were placed in a reaction flask under nitrogen atmosphere. The temperature was lowered to -5°C, and a 1 M solution of boron tribromide in dichloromethane (1.5 mL, 1.5 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 directly evaporated. The residue was purified by Pre-HPLC (ammonia system) to afford compound 48 (20 mg, 16.2% yield over three steps); MS / ESI [M+H] + =385.2. 1 H NMR (400MHz, DMSO-d6) δ9.91(br s,1H),7.70-7.59(m,2H),7.53(d,J=8.4Hz,1H),7.25(d,J=8.4Hz,1H),6.70(br s,0H),4.02-3.87(m,1H),2.97-2.86(m,1H),2.80(s,6H),2.68-2.58(m,0 H),2.21(s,3H),2.01-1.79(m,3H),1.75-1.64(m,1H),1.61-1.47(m,2H).

[0282] Example 49: (R)-5-(5-isopropyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)benzothiophen-4-ol

[0283] Step 1: Place tin dioxide (9.0 g, 0.081 mol), acetic acid (2.4 g, 0.041 mol), and water (1.6 g, 0.090 mol) in a sealed tube. Add dioxane (40 mL) and stir at 105°C for 2 h until most of the tin dioxide dissolves. Add 3-methylbutan-2-one 49a (5.0 g, 0.058 mol), seal the tube, and stir at 105°C for 12 h. Filter and collect the filtrate. Cool to -5-0°C, add water (70 mL) and sodium bicarbonate (9.8 g, 0.116 mol), and then add an aqueous solution of compound 46c (50 mL) dropwise. After completion of the addition, react at room temperature for 48 h. After the reaction was complete, ethyl acetate (100 mL) was added for extraction. The aqueous phase was further extracted with ethyl acetate (50 mL). The ethyl acetate layers were combined, 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 = 1:0-49:1) to obtain compound 49b (2.4 g, 24.5%); MS / ESI [M+H] + =170.0.

[0284] Step 2: Dissolve 49b (2.4 g, 0.014 mol) in dichloromethane (50 mL), cool to 0-5°C, and add m-CPBA (7.2 g, 0.036 mol, 85% purity) in batches. After addition, react at room temperature for 1 h. After the reaction is complete, add saturated aqueous sodium carbonate solution (100 mL) and stir for 5 minutes. Separate the layers, and extract the aqueous phase twice with dichloromethane (30 mL). The organic phases are combined, washed with saturated aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and dried to obtain compound 49c, which is used directly in the next step without further purification. MS / ESI [M+H] + =186.0.

[0285] Step 3: Compound 49c (1000 mg, 5.41 mmol) was placed in a reaction flask, and DIEA (2789 mg, 21.62 mmol) and (3R)-1-methylhexahydropyridin-3-amine 1b (1232 mg, 10.81 mmol) were added. The mixture was reacted at 85°C for 12 h. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 1:0-12:1) to obtain compound 49d (729 mg, 53.0% yield over two steps); MS / ESI [M+H] + =236.0.

[0286] Step 4: Compound 49d (460 mg, 1.96 mmol) was placed in a reaction flask, acetonitrile (15 mL) and water (10 mL) were added, and bromine (0.5 mL) was added dropwise. The mixture was stirred at room temperature overnight. After the reaction was complete, the solvent was directly dried, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 1:0-10:1) to obtain compound 49e (660 mg, 85.6%); MS / ESI [M+H] + =314.0.

[0287] Step 5: Compound 49e (225 mg, 0.703 mmol), compound INT6 (200 mg, 0.639 mol), Pd(dppf)Cl2 (47 mg, 0.064 mmol), cesium carbonate (1454 mg, 4.47 mmol), dioxane (15 mL), and water (3 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 = 1:0-12:1) afforded compound 49f (104 mg, 38.2%); MS / ESI [M+H] + =428.0.

[0288] Step 6: Compound 49f (100 mg, 0.234 mmol) was dissolved in dioxane hydrochloride (4 M) and reacted at 40°C for 3 h. After the reaction was complete, the solvent was directly evaporated and the residue was purified by Pre-HPLC (ammonia system) to obtain compound 49 (17 mg, 19.1%); MS / ESI [M+H] + =384.2. 1 H NMR (400MHz, DMSO-d6) δ9.68(br s,1H),7.67-7.56(m,2H),7.49(d,J=8.4Hz,1H),7.14(d,J=8.4Hz,1H),3.94(br s,1H),2.91-2.81(m,1H),2.78-2.69(m,1H),2.61-2.51(m,1H),2.12(s,3H),1.88-1.76(m,3 H),1.71-1.58(m,1H),1.55-1.43(m,1H),1.35-1.23(m,1H),1.03-0.96(m,6H); MS / ESI[M+H] + =384.0.

[0289] Example 50: 5-(3-(((1R,2R)-2-aminocyclohexyl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophen-4-ol

[0290] Preparation of 5-(3-(((1R,2R)-2-aminocyclohexyl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophen-4-ol Reference Example 36. MS / ESI [M+H] + =356.1, 1 H NMR (400MHz, Methanol-d4) δ8.55(s,1H),7.64(d,J=5.6Hz,1H),7.59-7.52(m,2H),7.28(d,J=8.2Hz,1H),4.15(td,J=10 .8,4.2Hz,1H),3.17(td,J=11.2,4.1Hz,1H),2.44-2.34(m,1H),2.24-2.12(m,2H),1.96-1.83(m,2H),1.67-1.39(m,4H).

[0291] Example 51: (3R,4R)-3-((6-(4-hydroxybenzo[b]thiophen-5-yl)-5-methyl-1,2,4-triazin-3-yl)amino)-1-methylpiperidin-4-ol

[0292] Preparation of (3R,4R)-3-((6-(4-hydroxybenzo[b]thiophen-5-yl)-5-methyl-1,2,4-triazin-3-yl)amino)-1-methylpiperidin-4-ol Reference Example 47. MS / ESI[M+H] + =372.1, 1 H NMR(400MHz, Methanol-d4)δ7.64(d,J=5.6Hz,1H),7.61-7.49(m,2H),7.28(d,J=8.2Hz,1H),4.30(d, J=14.5Hz,1H),3.98-3.69(m,1H),3.68-3.52(m,1H),3.28-3.12(m,1H),3.09-2.85(m,4H) ,2.42(s,3H),2.37-2.28(m,1H),2.09-1.82(m,1H),1.43-1.36(m,2H),1.36-1.29(m,1H).

[0293] Example 52: 5-(3-(((3S,4S)-4-Fluoro-1-methylpiperidin-3-yl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophen-4-ol

[0294] Preparation of 5-(3-(((3S,4S)-4-fluoro-1-methylpiperidin-3-yl)amino)-5-methyl-1,2,4-triazin-6-yl)benzothiophen-4-ol Referring to Example 47, compound 52 (yellow solid, 13.2 mg) was obtained; 1 H NMR(400MHz,CD3OD)δ7.51(d,J=5.6Hz,1H),7.44-7.39(m,2H),7.15(d,J=8.2Hz,1H),4.53-4.42(m,2H), 4.31(m,1H),2.95(m,1H),2.86(s,3H),2.66(m,1H),2.26(s,2H),2.24(s,3H),2.09(m,1H),1.80(m,1H).

[0295] Example 53: (R)-6-(4-Hydroxybenzo[b]thiophen-5-yl)-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazine-5-carboxylic acid

[0296] Step 1: Place compound INT1d (4.80 g, 19.75 mmol), tributyl(1-ethoxyvinyl)stannane (8.55 g, 23.70 mmol), Pd(PPh3)Cl2 (0.84 g, 1.19 mmol) and dioxane (50 mL) in a reaction flask, protect with nitrogen, and stir at 100°C for 15 h. After the reaction was complete, the temperature was lowered to room temperature, 2 M hydrochloric acid (40 mL) was added, and the mixture was stirred for 1 h. Saturated sodium chloride (40 mL) and ethyl acetate (50 mL) were added for extraction. The organic phase was directly added to silica gel and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0-9:1) to obtain the title compound 53a (3.6 g, 88.2%); 1H NMR (400 MHz, Chloroform-d) δ 7.71 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 5.6 Hz, 1H), 7.47 (d, J = 5.6 Hz, 1H), 4.04 (s, 3H), 2.72 (s, 3H).

[0297] Step 2: Disperse NaH (2.8 g, 0.069 mol) in tetrahydrofuran (80 mL) and stir at room temperature. Add dimethyl carbonate (2.8 g, 0.069 mol) to the reaction system, followed by a solution of compound 53a (3.6 g, 0.017 mol) in tetrahydrofuran (10 mL). After addition, react at 60°C for 3 h. After the reaction is complete, cool to room temperature and pour the reaction solution into ice water. Extract with saturated sodium chloride (40 mL) and ethyl acetate (50 mL). The organic phase is directly added to silica gel and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0-4:1) to obtain compound 53b (4.2 g, 91.3%); LC-MS: ESI [M+H] + =265.0.

[0298] Step 3: Dissolve compound 53b (3.1 g, 0.012 mol) in dioxane (60 mL) and add SeO2 (3.9 g, 0.036 mol). Incubate at 100°C for 15 h. After the reaction is complete, filter the mixture and use the filtrate in the next step without further processing.

[0299] Step 4: Add amino(ethylamino)methylthiophene hydroiodide (2.85 g, 0.012 mol) to acetonitrile (80 mL) and stir at 60°C for 20 min until the solid dissolves. Add DIEA (4.3 g, 0.033 mol) to a dioxane solution of compound 53b. Stir at room temperature for 20 min, then add the remaining DIEA to the reaction mixture all at once. Stir at 60°C for 15 h. After the reaction is complete, cool to room temperature and extract with saturated ammonium chloride (40 mL) and ethyl acetate (50 mL). The organic phase is directly added to silica gel and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0-3:1) to afford compound 53c (840 mg, 21.8%); LC-MS: ESI [M+H] + =348.0.

[0300] Step 5: Compound 53c (300 mg, 0.865 mmol) was dissolved in dichloromethane (20 mL), cooled to 0-5°C, and m-CPBA (437 mg, 2.161 mol, 85% purity) was added in batches. After addition, the mixture was allowed to react at room temperature for 1 h. After completion of the reaction, dichloromethane (20 mL) was added, and the mixture was washed sequentially with saturated aqueous sodium bicarbonate (20 mL), saturated sodium thiosulfate (20 mL), and saturated sodium chloride (20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and dried to obtain crude compound 53d, which was used directly in the next step without further purification. LC-MS: ESI [M+H] + =364.0.

[0301] Step 6: Compound 53d (300 mg, 0.824 mmol) was placed in a reaction flask, and dioxane (10 mL), DMF (5 mL), DIEA (531 mg, 4.12 mmol), and (3R)-1-methylhexahydropyridin-3-amine dihydrochloride (231 mg, 1.236 mmol) were added. The reaction was incubated at 100°C for 12 h. The mixture was cooled to room temperature, and extracted with saturated ammonium chloride (10 mL) and ethyl acetate (10 mL). The organic phase was directly added to silica gel and purified by silica gel column chromatography (dichloromethane:methanol = 1:0-15:1) to obtain compound 53e (280 mg, 81.4%); LC-MS: ESI [M+H] + =414.0.

[0302] Step 7: Compound 53e (140 mg, 0.339 mmol) was placed in a sealed tube, and ammonia methanol solution (20 mL) was added. The reaction was allowed to react at 100°C for 12 h. The mixture was cooled to room temperature and concentrated directly to obtain the crude product, which was then purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to afford compound 53f (100 mg, 74.6%); LC-MS:ESI [M+H] + =399.0.

[0303] Step 8: Compound 53f (110 mg, 0.276 mmol) and dichloromethane (12 mL) were placed in a reaction flask, protected with nitrogen, cooled to -5°C, and 2M boron tribromide dichloromethane solution (0.4 mL, 0.828 mmol) was added, and the reaction was kept warm for 2 h. After the reaction was complete, methanol (4 mL) was added to quench the reaction, the solvent was directly dried, and the residue was purified by Pre-HPLC (ammonia system) to give compound 53 (26 mg, 24.5%); 1H NMR (400 MHz, DMSO-d6) δ 12.92 (br s, 1H), 9.82 (br s, 1H), 7.97 (br s, 1H), 7.61 (d, J = 5.2 Hz, 1H), 7.55-7.50 (m, 2H), 7.38 (d, J = 8.4 Hz, 1H), 4.36-4.18 (m, 1H), 3.69-3.42 (m, 2H), 2.93-2.66 (m, 5H), 2.09-1.89 (m, 2H), 1.82-1.43 (m, 2H); LC-MS: ESI [M+H] + =386.0.

[0304] Example 54: (3R,4R)-4-((6-(4-hydroxybenzo[b]thiophen-5-yl)-5-methyl-1,2,4-triazin-3-yl)amino)-1-methylpiperidin-3-ol

[0305] Preparation of (3R,4R)-4-((6-(4-hydroxybenzo[b]thiophen-5-yl)-5-methyl-1,2,4-triazin-3-yl)amino)-1-methylpiperidin-3-ol Reference Example 47; 1 H NMR (400MHz, CD3OD-d4) δ7.68–7.64(m,1H),7.60(q,J=4.2,3.5Hz,2H),7.30(d,J=8.1Hz,1H),4.06(s,1H),3.74–3.55(m,2H),3.46(d,J=8.4Hz,1 H),3.25(d,J=12.8Hz,1H),3.09(t,J=11.4Hz,1H),2.98(s,3H),2.61(d,J=6.4Hz,3H),2.37(d,J=14.4Hz,1H),2.21–2.09(m,1H); LC-MS:ESI[M+H] + =372.0.

[0306] Biological activity test:

[0307] 1. Assay of NLRP3 inflammasome inhibitory activity in human monocytes

[0308] 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).

[0309] Experimental method: THP-1 cells were cultured in RPMI medium containing PMA (10 μM) at a rate of 2×10 5 The cells were seeded in 48-well plates at a cell density of 1 μg / mL and placed in a 37°C, 5% CO2 incubator for overnight induction. The next day, the culture medium was replaced with Opti-MEM medium containing 1 μg / mL LPS; 3 hours later, the drug was added for 40 minutes; Nigericin (10 μM) was added for 40 minutes; and 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, and Ref-2 was synthesized according to the synthesis method of Example 1 in patent WO2022230912.

[0310] The experimental results are shown in Table 2 below.

[0311] Table 2 NLRP3 inflammasome inhibitory activity

[0312] 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 and Ref-2.

[0313] 2. Determination of the inhibitory activity of compounds on IL-1β production in human PBMC cells

[0314] 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.

[0315] The experimental results are shown in Table 3 below:

[0316] Table 3 Inhibition results of compounds on IL-1β in PBMC cells

[0317] Conclusion: The compounds of the present invention have good inhibitory activity on the production of IL-1β in human PBMC cells, and compound 5 is preferred. 50 Better than MCC950.

[0318] 3. Inhibition experiment of compounds on hERG potassium channels

[0319] 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.

[0320] 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.

[0321] 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).

[0322] 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))

[0323] 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.

[0324] The experimental results are shown in Table 4 below:

[0325] Table 4 Inhibition results of compounds on hERG potassium channels

[0326] Conclusion: The inhibitory effects of compounds 5, 13, 36-1 and 39 of the present invention on hERG potassium channels are weaker than that of the reference compound Ref-1.

[0327] 4. Pharmacokinetic evaluation of the compound in Balb / c mice

[0328] Experimental purpose: To understand the pharmacokinetics of the compound.

[0329] Experimental basis: Technical Guidelines for Nonclinical Pharmacokinetic Studies of Chemical Drugs, 2014.

[0330] Experimental plan: The pharmacokinetics of the compound were investigated by intravenous and oral administration to Balb / c mice.

[0331] Sample preparation: Weigh the compound and dissolve it in DMSO, then add sodium chloride solution for injection to prepare the compound solution for administration.

[0332] 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.

[0333] The results of the pharmacokinetic evaluation are shown in Table 5 below:

[0334] Table 5 Pharmacokinetic test results of the compounds in Balb / c mice

[0335] 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 5, 17, 18, 39 and 52 have good C max , AUC (0-t) 、T 1 / 2 The PK parameters were better than those of the reference compound Ref-2.

[0336] 5. Evaluation of LPS-induced mouse model

[0337] 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.

[0338] The experimental results are shown in Table 6:

[0339] Table 6 Effects of compounds on the survival rate of LPS-induced mice

[0340] Conclusion: The compounds of the present invention can increase the survival rate of LPS-induced mice, especially compound 5 and the like have better survival rate on LPS-induced mice than reference compounds MCC950 and Ref-2 at the same dose.

[0341] 6. Evaluation of compound brain-blood ratio in vivo

[0342] Experimental purpose: To obtain the brain-to-blood ratio of the compound.

[0343] 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.

[0344] 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 -1Oral 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.

[0345] Standard curve range: 10~10000ng·ml -1 .

[0346] Drug content in brain = measured value × 0.03 × (M3-M1) / [(M2-M1) × (M3-M4)].

[0347] The results of the compound brain-to-blood ratio are shown in Table 7 below:

[0348] Table 7 Results of brain-to-blood ratio test in mice after compound administration

[0349] Conclusion: Some compounds of the present invention have good brain penetration potential, especially compounds 5, 36-1 and 44, whose brain-blood ratio is significantly better than that of reference compounds Ref-1 and Ref-2.

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 double bond, Y is selected from CR 7b , X is selected from N; 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 7b Selected from hydrogen, deuterium, halogen, -NH2, -CN, -OR 9a 、-COR 9a 、-COOR 9a ,-CONHR 9a 、-CON(R 9b R 9c )、-N(R 9b R 9c ),-NR 9a COR 9b 、-SO2R 9a 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 7b wherein the substituent is selected from hydrogen, deuterium, halogen, -OH, -NH2 or -CN; R 7b 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 9a , R 9b and R 9c 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; R 9a , R 9b and R 9c wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 or CN; R 9a , R 9b and R 9c In the substituent, the 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl contains 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 fluorinated cycloalkyl, 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 heterocyclic ring or 5-6 membered heteroaromatic ring contains 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 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.

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 7b Selected from hydrogen, deuterium, halogen, -NH2, -CN, -OR 9a 、-COR 9a 、-COOR 9a ,-CONHR 9a 、-CON(R 9b R 9c )、-N(R 9b R 9c ),-SO2R 9a or the following groups optionally substituted by 0-3 substituents: C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; R 9a , R 9b and R 9c independently selected from hydrogen, deuterium or the following groups substituted by 0-3 substituents: C 1-4 Alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; R 9a , R 9b and R 9c wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 or CN; Preferably, R 7b Selected from hydrogen, deuterium, halogen, -NH2, -CN, 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, -CONHR 9a ; R 9a Selected from hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 deuterated alkyl, 3-6 membered cycloalkyl, 3-6 membered fluorinated cycloalkyl; X1 and X2 are independently selected from CH, N; X3 Selected from NC 1-4 Alkyl, NH, S, O; More preferably, R 7b is selected from hydrogen, deuterium, F, Cl, cyano, amino, methyl, deuterated methyl, fluoromethyl, ethyl, fluoroethyl, isopropyl, fluoroisopropyl, methoxy, deuterated methoxy, fluoromethoxy, carboxyl, methoxycarbonyl, fluoromethoxycarbonyl, deuterated methoxycarbonyl, ethoxycarbonyl, fluoroethoxycarbonyl, cyclopropyl, fluorocyclopropyl, cyclohexyl, fluorocyclohexyl, phenyl, 2-pyridyl, -CONHR 9a ; R 9a is selected from hydrogen, deuterium, methyl, fluoromethyl, deuterated methyl, cyclopropyl, fluorocyclopropyl; 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 any one of claims 17 to 19, characterized in that: Structural unit Selected from:

22. The compound according to claim 1, characterized in that: The compound is selected from:

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

24. The compound according to claim 23, characterized in that: Structural unit Selected from:

25. The compound according to claim 23 or 24, characterized in that: L is selected from O, -NH-, -NH-CH2-, -NH-CH(CH 3) -.

26. The compound according to any one of claims 23 to 25, characterized in that: R6 is selected from the following structures:

27. The compound according to any one of claims 23 to 26, characterized in that: The compound is selected from:

28. The compound according to any one of claims 23 to 26, characterized in that: The compound is selected from:

29. The compound according to any one of claims 1 to 13, characterized in that: R6 is selected from the following structures:

30. The compound according to claim 29, characterized in that: The compound is selected from:

31. A pharmaceutical composition, characterized in that: The active ingredient is a compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite or prodrug thereof, supplemented with a pharmaceutically acceptable carrier.

32. Use of the compound according to any one of claims 1 to 30 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite or prodrug, and the pharmaceutical composition according to claim 31 in the preparation of a medicament for preventing and / or treating NLRP3-related diseases.

33. The use according to claim 32, characterized in that: The NLRP3-related diseases include: inflammatory diseases, autoimmune diseases, cardiovascular diseases, cancer, renal diseases, gastrointestinal diseases, respiratory diseases, endocrine diseases or central nervous system diseases.

34. The use according to claim 33, 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 steatohepatitis, 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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