Triazine compounds and their uses

Abstract

This invention discloses a triazine compound and its use, which belongs to the field of chemical pharmaceuticals. The triazine compound represented by formula (I) provided in this invention can be used as an NLRP3 inhibitor, possesses high activity and good pharmacokinetic properties, and provides a novel approach for treating NLRP3-related diseases. [Formula 1] TIFF2026509587000138.tif29114

Description

[Technical Field]

[0001] This invention belongs to the field of chemical pharmaceuticals and relates to triazine compounds and their use. [Background technology]

[0002] Inflammasomes are protein complexes capable of recognizing intracellular pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). Inflammasome assembly triggers protein hydrolysis. Dormant procaspase-1 is degraded into active caspase-1, and cytokine precursors pro-IL-1β and pro-IL-18 are converted to mature and bioactive IL-1β and IL-18, respectively, leading to various biological effects by regulating the expression of inflammation-related genes. As receptors in the body's innate immunity, inflammasome activation can protect against pathogen infection and stress-induced injury; however, dysregulated activation can exacerbate inflammatory responses and organ damage. Currently, research on the NLRP3 (nucleotide-binding oligomeric domain (NOD)-like receptor family, pyrine domain-containing protein 3) inflammasome is one of the most popular topics.

[0003] The NLRP3 inflammasome consists of a sensor (NLRP3), an adapter (ASC, also known as PYCARD), and an effector (caspase-1). Typical activation of the NLRP3 inflammasome requires two signals. The first signal activates the TLR4 (Toll-like receptor 4) signaling pathway, promoting NF-κB nuclear translocation, which induces the production of precursors such as IL-1β and IL-18, leading to post-translational modification of NLRP3. The second signal promotes the assembly of the NLRP3 / ASC / procaspase-1 complex. Upon activation, the NLRP3 / ASC / procaspase-1 complex polymerizes with ASC (an apoptosis-associated speck-like protein containing CARD), and then ASC interacts with the cysteine ​​protease caspase-1 to form the inflammasome complex. Subsequently, the precursor form of procaspase-1 undergoes autocleavage to become the activated form. Activated caspase-1 cleaves the precursor inflammatory cytokines IL-1β and IL-18, converting them to their active forms. The cytokines IL-1β and IL-18 are then released extracellularly. This process recruits inflammatory cells and amplifies the inflammatory response. Apoptosis-associated speck-like proteins containing CARD can also be activated by recruiting caspase-8, cleaving precursor IL-1β and IL-18 and converting them to their active forms, thereby inducing pyroptosis. Atypical activation of the NLRP3 inflammasome is initiated by direct recognition of intracellular LPS by caspase-11, independent of activation of the TLR4 signaling pathway, leading to NLRP3 inflammasome activation and promoting the activation and release of gasdermin D, which mediates cell death.

[0004] Abnormal activation of NLRP3 is primarily associated with a number of diseases, including inflammasome-related disorders, immune disorders, inflammatory diseases, neurological disorders, autoimmune and / or autoinflammatory diseases, cancer, chronic metabolic diseases, and neurodegenerative diseases. For example, cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multiorgan inflammatory disease (NOMID), familial Mediterranean fever (FMF), non-alcoholic steatohepatitis, alcoholic liver disease, graft-versus-host disease, multiple sclerosis (MS), rheumatoid arthritis, type 1 / II diabetes mellitus and related complications (e.g., nephropathy and retinal inflammatory disease). NLRP3, upstream of cytokines, can ultimately block inflammation at its source. Therefore, the development of new NLRP3 inflammasome inhibitors is of high research value. [Overview of the project] The problem to be solved

[0005] The object of the present invention is to invent triazine compounds and their use or pharmaceutically acceptable salts or eutectic compounds, including stereoisomers, solvates, metabolites, deuterated variants, prodrugs, pharmaceutically acceptable salts or eutectic compounds, for the treatment of NLRP3-related diseases. [Means for solving the problem]

[0006] In a first aspect, the present invention provides a compound represented by formula I or a pharmaceutically acceptable form thereof, the structure of which is as follows: [ka] During the ceremony, [ka] represents a single bond, and Y is NR 7a selected from; X is selected from C(=O); R1 is hydrogen, deuterium, halogen, -OH, -NH2, -CN, or a C group optionally substituted with 0 to 6 substituents 1-6 alkyl, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -NHC(=O)-C 1-6 alkyl, -(C=O)NH-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and selected from 3- to 6-membered cycloalkyl; in R1, the substituents are selected from deuterium, halogen, -OH, -NH2, or -CN; R2 and R4 are each independently hydrogen, deuterium, halogen, -OH, -NH2, -CN, or a C group optionally substituted with 0 to 6 substituents 1-6 alkyl, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -NHC(=O)-C 1-6 alkyl, -(C=O)NH-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and selected from 3- to 6-membered cycloalkyl; in R2 and R4, the substituents are selected from deuterium, halogen, -OH, -NH2, or -CN; R3 is hydrogen, deuterium, halogen, -OH, -NH2, -CN, or a C group optionally substituted with 0 to 6 substituents 1-6 alkyl, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -NHC(=O)-C 1-6 alkyl, -(C=O)NH-C 1-6 alkyl, C 2-6 alkenyl, C 2-6The substituents are selected from alkynyl, 3-6 membered cycloalkyl, 5- and 6 membered heterocycloalkyl, phenyl, and 5- and 6 membered heteroaryl; in R3, the substituents are selected from deuterium, halogen, -OH, -NH2, -CN, or 3- and 6 membered cycloalkyl; in R3, the 5- and 6 membered heterocycloalkyl and 5- and 6 membered heteroaryl contain 1-3 heteroatoms selected from at least one of N, S, and O; R5 is a group that is optionally substituted with hydrogen, deuterium, halogen, -NH2, -CN, or 0 to 6 substituents. 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 Alkenil, C 2-6 Selected from alkynyls and 3- to 6-membered cycloalkyls; at 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 these groups are bonded, form a 5- and 6-membered alkane ring, a benzene ring, a 5- and 6-membered alkane heterocyclic ring, or a 5- and 6-membered aromatic heterocyclic ring substituted with 0 to 6 substituents, where the substituents are deuterium, halogen, -OH, -NH2, -CN, oxo group, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Alkyl deuterated, -OC 1-6 Alkyl, -OC 1-6 Fluoroalkyl, -OC 1-6 Alkyl deuterated, C 3-6 Cycloalkyl, C 3-6Selected from fluorocycloalkyls or 3- to 6-membered cycloalkyls formed by two substituents bonded to the same carbon atom; if R2 and R3, R3 and R4, or R4 and R5 form a ring together with the atom to which these groups are bonded, then 5- and 6-membered alkane heterocyclic rings and 5- and 6-membered aromatic heterocyclic rings contain 1 to 3 heteroatoms selected from at least one of N, S, and O; When R1 is selected from -OH, R2, and R3, these groups, together with the atom to which they are bonded, form a benzene ring, a 5- to 7-membered alkane heterocyclic ring, or a 5- and 6-membered aromatic heterocyclic ring substituted with 0- to 6 substituents, where the substituents are deuterium, halogen, -OH, -NH2, -CN, and C. 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Alkyl deuterated, -OC 1-6 Alkyl, -OC 1-6 Fluoroalkyl, -OC 1-6 Alkyl deuterated, C 3-6 Cycloalkyl, C 3-6 Selected from fluorocycloalkyls or 3- to 6-membered cycloalkyls formed by two substituents bonded to the same carbon atom; if R2 and R3 together with the atom to which these groups are bonded form a ring, the 5- to 7-membered alkane heterocyclic rings and 5- and 6-membered aromatic heterocyclic rings contain 1 to 3 heteroatoms selected from at least one of N and S, or 2 atoms of O; L is -(CH2) n1 -, O, -(CH2) n1 -NH-, -NH-(CH2) n1 -, and -NH-CH(CH2) n1 (CH3) is selected from, where n1 is an integer selected from 0 to 3; R6 is a C substituted with 6-10 member aryl, 5-10 member heteroaryl, 3-8 member heterocycloalkyl, 3-8 member cycloalkyl, 6-10 member spirocycloalkyl, 6-10 member heterospirocycloalkyl, 6-10 member crosslinked cycloalkyl, 6-10 member heterocrosslinked cycloalkyl, and 0-6 substituents.1-6 Selected from alkyl groups; in R6, the substituent is R 8a , halogen, oxo group, -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 Selected from , and -CN; in R6, 5-10 membered heteroaryls, 3-8 membered heterocycloalkyls, 6-10 membered heterospirocycloalkyls, and 6-10 membered cross-linked cycloalkyls contain 1-3 heteroatoms selected from at least one of N, S, and O; R 8a and R 8b These are C groups, each independently substituted with hydrogen, deuterium, or 0 to 6 substituents. 1-4 Selected from alkyl, 3-6 member cycloalkyl, 4-6 member heterocycloalkyl, phenyl, 5 and 6 member heteroaryl, (3-6 member cycloalkyl)-methylene, and (4-6 member heterocycloalkyl)-methylene; R 8a and R 8b In this, the substituents are deuterium, halogen, -N(R 10a R 10b ), -OH, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Selected from deuterated alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, (3-6 membered cycloalkyl)-methylene, or (4-6 membered heterocycloalkyl)-methylene; R 8a and R 8bIn this case, 4- to 6-membered heterocycloalkyl, 5- and 6-membered heteroaryl, and (4- to 6-membered heterocycloalkyl)-methylene contain 1 to 3 heteroatoms selected from at least one of N, S, and O; 4- to 6-membered heterocycloalkyl and (4- to 6-membered heterocycloalkyl)-methylene in the substituent contain 1 to 3 heteroatoms selected from at least one of N, S, and O; or, R 8a and R 8b together with the atom to which these groups are attached form a 3- to 6-membered alkyl heterocyclic ring substituted with 0 to 6 substituents; when R 8a and R 8b together with the atom to which these groups are attached form a ring, the substituents are selected from deuterium, halogen, -N(R 11a R 11b ), -OH, -CN, C 1-4 alkyl, 3- to 6-membered cycloalkyl, and 4- to 6-membered heterocycloalkyl; when R 8a and R 8b together with the atom to which these groups are attached form a ring, 3- to 6-membered heterocycloalkyl contains 1 to 3 heteroatoms selected from at least one of N, S, and O, and 4- to 6-membered heterocycloalkyl in the substituent contains 1 to 3 heteroatoms selected from at least one of N, S, and O; R 7a is hydrogen or a group substituted with 0 to 6 substituents selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- and 6-membered heteroaryl; in R 7a , the substituents are selected from hydrogen, deuterium, halogen, -OH, -NH2, or -CN; in R 7a , 4- to 6-membered heterocycloalkyl and 5- and 6-membered heteroaryl contain 1 to 3 heteroatoms selected from at least one of N, S, and O; R 10a , R 10b , R 11a, and R 11b Each of them is independently of hydrogen or C 1-4 Selected from alkyl groups; A pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, nitrogen oxides, isotopic markers, metabolites, or prodrugs.

[0007] In some embodiments of the present invention, R1 is a group optionally substituted with hydrogen, deuterium, halogen, -OH, -NH2, -CN, or 0 to 6 substituents. 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 Alkenil, C 2-4 The substituents are selected from alkynyls and 3- to 6-membered cycloalkyls, and the substituents are selected from deuterium, halogens, -OH, -NH2, or -CN.

[0008] In some preferred embodiments of the present invention, R1 is a group C which is optionally substituted with hydrogen, deuterium, halogen, F, Cl, -OH, -NH2, and -CN, or 0 to 3 substituents. 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 The substituents are selected from alkyl and 3- to 6-membered cycloalkyl groups, and the substituents are selected from deuterium, F, Cl, -OH, -NH2, or -CN.

[0009] 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.

[0010] In some embodiments of the present invention, R2 and R4 are, independently, hydrogen, deuterium, halogen, -OH, -NH2, -CN, or a group optionally substituted with 0 to 6 substituents. 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4Alkyl, C 2-4 Alkenil, C 2-4 The substituents are selected from alkynyls and 3- to 6-membered cycloalkyls, and the substituents are selected from deuterium, halogens, -OH, -NH2, or -CN.

[0011] In some preferred embodiments of the present invention, R2 and R4 are, independently, hydrogen, deuterium, halogen, F, Cl, -OH, -NH2, -CN, or a group optionally substituted with 0 to 3 substituents. 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 The substituents are selected from alkyl and 3- to 6-membered cycloalkyl groups, and the substituents are selected from deuterium, F, Cl, -OH, -NH2, or -CN.

[0012] 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, and fluorocyclopropyl.

[0013] In some embodiments of the present invention, R3 is a group optionally substituted with hydrogen, deuterium, halogen, -OH, -NH2, -CN, or 0 to 6 substituents. 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 Alkenil, C 2-4 The substituents are selected from alkynyl, 3-6 membered cycloalkyl, 5- and 6 membered heterocycloalkyl, phenyl, and 5- and 6 membered heteroaryl; in R3, the substituents are selected from deuterium, halogen, -OH, -NH2, -CN, -CF3, or cyclopropyl; in R3, the 5- and 6 membered heterocycloalkyl and 5- and 6 membered heteroaryl contain 1-3 heteroatoms selected from at least one of N, S, and O.

[0014] In some preferred embodiments of the present invention, R3 is a group optionally substituted with hydrogen, deuterium, F, Cl, -CN, or C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 Alkenil, C 2-4 The substituents are selected from alkynyl, 3-6 membered cycloalkyl, 5- and 6 membered heterocycloalkyl, phenyl, and 5- and 6 membered heteroaryl; in R3, the substituents are selected from deuterium, F, Cl, -OH, -NH2, -CF3, -CN, or cyclopropyl; in R3, the 5- and 6 membered heterocycloalkyl and 5- and 6 membered heteroaryl contain 1-2 heteroatoms selected from at least one of N, S, and O.

[0015] 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, and deuterated phenyl.

[0016] In some embodiments of the present invention, R5 is a group optionally substituted with hydrogen, deuterium, halogen, -NH2, -CN, or 0 to 6 substituents. 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 Alkenil, C 2-4 The substituents are selected from alkynyls and 3- to 6-membered cycloalkyls, and the substituents are selected from deuterium, halogens, -OH, -NH2, or -CN.

[0017] In some preferred embodiments of the present invention, R5 is a group optionally substituted with hydrogen, deuterium, F, Cl, -NH2, -CN, or C 1-4 Alkyl, -OC 1-4 Alkyl, -SC1-4 The substituents are selected from alkyl and 3- to 6-membered cycloalkyl groups, and the substituents are selected from deuterium, F, Cl, -OH, -NH2, or -CN.

[0018] In some more preferred embodiments of the present invention, R5 is selected from hydrogen, deuterium, F, Cl, -CH, -CH3, fluoromethyl, deuterated methyl, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl, and fluorocyclopropyl.

[0019] In some embodiments of the present invention, R2 and R3, R3 and R4, or R4 and R5, together with the atoms to which these groups are bonded, form a 5- and 6-membered alkane ring, a benzene ring, a 5- and 6-membered alkane heterocyclic ring, or a 5- and 6-membered aromatic heterocyclic ring substituted with 0 to 6 substituents, where the substituents are deuterium, halogen, -OH, -NH2, -CN, oxo group, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Alkyl deuterated, -OC 1-4 Alkyl, -OC 1-4 Fluoroalkyl, -OC 1-4 Selected from deuterated alkyl groups, 3- to 6-membered cycloalkyl groups, 3- to 6-membered fluorocycloalkyl groups, or 3 and 4-membered cycloalkyl groups formed by two substituents bonded to the same carbon atom; if R2 and R3, R3 and R4, or R4 and R5 together with the atoms to which these groups are bonded form a ring and a 5 and 6-membered alkane heterocyclic ring, the 5 and 6-membered aromatic heterocycles contain 1 to 2 heteroatoms selected from at least one of N, S, and O.

[0020] In some preferred embodiments of the present invention, R2 and R3, or R3 and R4, together with the atom to which these groups are bonded, are substituted with 0 to 3 substituents. [ka] The substituents are selected from deuterium, F, Br, Cl, -OH, -NH2, -CN, oxo group, methyl, fluoromethyl, deuterated methyl, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl, fluorocyclopropyl, or 3- and 4-membered cycloalkyl groups formed by two substituents bonded to the same carbon atom.

[0021] In some embodiments of the present invention, when R1 is selected from -OH, R2, and R3, these groups, together with the atom to which they are bonded, form a benzene ring, a 5- and 6-membered alkane heterocyclic ring, or a 5- and 6-membered aromatic heterocyclic ring substituted with 0 to 6 substituents, where the substituents are deuterium, halogen, -OH, -NH2, -CN, and C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Alkyl deuterated, -OC 1-4 Alkyl, -OC 1-4 Fluoroalkyl, -OC 1-4 Selected from deuterated alkyl groups, 3- to 6-membered cycloalkyl groups, 3- to 6-membered fluorocycloalkyl groups, or 3- and 4-membered cycloalkyl groups formed by two substituents bonded to the same carbon atom; if R2 and R3 together with the atom to which these groups are bonded form a ring, 5- and 6-membered alkane heterocyclic rings contain two atoms of O, and 5- and 6-membered aromatic heterocyclic rings contain one or two heteroatoms selected from at least one of N, S, and O.

[0022] In some preferred embodiments of the present invention, when R1 is selected from -OH, R2 and R3, these groups together with the atom to which they are bonded [ka] It forms.

[0023] In some embodiments of the present invention, structural units [ka] teeth, [ka] Selected from.

[0024] In some embodiments of the present invention, R 7a C is a group that is optionally substituted with hydrogen or 0 to 6 substituents. 1-4 Alkyl, C 2-6 Alkenil, C 2-6 Selected from alkynyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5- and 6 membered heteroaryl; R 7a In this, the substituent is selected from hydrogen, deuterium, halogen, -OH, -NH2, or -CN.

[0025] In some preferred embodiments of the present invention, R 7a is hydrogen, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Alkyl deuterated, 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, pyridinyl, or [ka] X1 and X2 are selected from CH and N respectively; X3 is selected from NC 1-4 Selected from alkyl, NH, S, and O.

[0026] In some more preferred embodiments of the present invention, R 7aThese include hydrogen, methyl, deuterated methyl, fluoromethyl, ethyl, fluoroethyl, isopropyl, fluoroisopropyl, cyclopropyl, fluorocyclopropyl, cyclohexyl, fluorocyclohexyl, phenyl, 2-pyridinyl, and [ka] X1 is selected from CH and N; X3 is selected from N-methyl, S and O.

[0027] In some embodiments of the present invention, structural units [ka] teeth, [ka] Selected from.

[0028] In some embodiments of the present invention, L is selected from O, -NH-, -NH-CH2-, and -NH-CH(CH3)-.

[0029] In some embodiments of the present invention, in R6, the substituent is fluorine, chlorine, hydroxyl group, cyano group, oxo group, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Alkyl deuterated, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy, C 1-4 Deuterated alkoxy, 3-6 membered cycloalkyl, 3-6 membered fluorocycloalkyl, amino group, dimethylamino group, [ka] Selected from.

[0030] In some embodiments of the present invention, R6 is selected from the following structures: [ka]

[0031] R 12a and R 12b Each of them is independent of R 8a , halogen, oxo group, -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 , and -CN are selected, and n2 is an integer selected from 0 to 6.

[0032] In some preferred embodiments of the present invention, R 12a and R 12b Each of them is independent of R 8a fluorine, oxo group, -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 , and -CN are selected, and n2 is an integer selected from 0 to 3.

[0033] In some more preferred embodiments of the present invention, R 12a and R 12bThese are, independently, fluorine, chlorine, hydroxyl group, cyano group, oxo group, and C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Alkyl deuterated, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy, C 1-4 Deuterated alkoxy, 3-6 membered cycloalkyl, 3-6 membered fluorocycloalkyl, amino group, dimethylamino group, [ka] Selected from.

[0034] In some embodiments of the present invention, R6 is selected from the following structures: [ka]

[0035] The present invention further provides several specific compounds, and these specific compounds are [ka] Selected from.

[0036] The present invention further provides another similar compound. In some embodiments of the present invention, structural units [ka] teeth, [ka] Selected from.

[0037] In some embodiments of the present invention, structural units [ka] teeth, [ka] Selected from.

[0038] In some embodiments of the present invention, L is selected from O, -NH-, -NH-CH2-, and -NH-CH(CH3)-.

[0039] In some embodiments of the present invention, R6 is selected from the following structures: [ka]

[0040] The present invention further provides several specific compounds, and these specific compounds are [ka] Selected from.

[0041] In some embodiments of the present invention, structural units [ka] teeth, [ka] Selected from.

[0042] In some embodiments of the present invention, structural units [ka] teeth, [ka] Selected from.

[0043] In some embodiments of the present invention, L is selected from O, -NH-, -NH-CH2-, and -NH-CH(CH3)-.

[0044] In some embodiments of the present invention, R6 is selected from the following structures: [ka] TIFF2026509587000028.tif41170

[0045] The present invention further provides several specific compounds, and these specific compounds are [ka] Selected from.

[0046] In some embodiments of the present invention, structural units [ka] teeth, [ka] Selected from.

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

[0048] The present invention further provides several specific compounds, and these specific compounds are [ka] Selected from.

[0049] In a second aspect, the present invention provides a pharmaceutical composition in which, together with a pharmaceutically acceptable carrier, the compound represented by formula I, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope marker, metabolite, or prodrug thereof, is used as an active ingredient.

[0050] A further object of the present invention is to provide a method for preparing a pharmaceutical composition of the present invention, the method comprising combining a compound containing formula I or a pharmaceutically acceptable form thereof, or a mixture thereof, with one or more pharmaceutically acceptable carriers.

[0051] A pharmaceutically acceptable carrier that can be used in the pharmaceutical composition of the present invention is a pharmaceutically acceptable carrier, and examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (2005).

[0052] A pharmaceutical composition can be administered in any form, as long as it can prevent, alleviate, or cure the symptoms of a human or animal patient. For example, a pharmaceutical composition can be made into various suitable dosage forms depending on the route of administration.

[0053] In some other embodiments, the administration of the compounds or pharmaceutical compositions of the present invention can be combined with other therapeutic methods. These other therapeutic methods may include, but are not limited to, radiotherapy, chemotherapy, immunotherapy, or a combination thereof.

[0054] The present invention further relates to pharmaceutical formulations, which use a 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 pharmaceutical formulation is a solid formulation, a semi-solid formulation, a liquid formulation, or a gaseous formulation.

[0055] A further object of the present invention is to provide products such as kits. Products as used herein include, but are not limited to, medicine boxes and packaging. A product of the present invention comprises (a) a first container; (b) a pharmaceutical composition in the first container, the composition comprising a first therapeutic agent, the first therapeutic agent comprising a compound containing formula I, a pharmaceutically acceptable form thereof, or a mixture thereof; (c) an optional accompanying statement indicating that the pharmaceutical composition can be used to treat a tumor disease (as defined below); and (d) a second container.

[0056] The first container is a container for containing a pharmaceutical composition. The container can be used for preparation, storage, transport and / or individual / bulk sales. The first container is intended to include bottles, cans, vials, flasks, syringes, tubes (for example, in the case of cream products), or any other container for preparing, containing, storing or dispensing pharmaceuticals.

[0057] The second container is for housing the first container and an optional instruction manual. Examples of the second container include, but are not limited to, boxes (e.g., cartons or plastic boxes), cases, cartons, bags (e.g., paper bags or plastic bags), pouches, and burlap sacks. The instruction manual can be physically attached to the outside of the first container by cable ties, adhesive, staples or other attachment methods, or it can be placed inside the second container without using any physical tools to attach it to the first container. Alternatively, the instruction manual is located outside the second container. Preferably, the instruction manual located outside the second container is physically attached by cable ties, adhesive, staples or other attachment methods. Alternatively, the instruction manual may be located in the immediate vicinity of or in contact with the outside of the second container without being physically attached.

[0058] The accompanying instructions, such as trademarks, labels, and signs, describe information about the pharmaceutical composition located in the first container. The information described is usually determined by the regulatory body that controls the region in which the product is sold (e.g., the U.S. Food and Drug Administration). Preferably, the accompanying instructions specifically describe the indications for which the pharmaceutical composition is approved. The accompanying instructions can be made of any material on which the information contained therein or on it can be read. Preferably, the accompanying instructions are made of a printable material (e.g., paper, plastic, cardboard, foil, adhesive paper, or plastic) on which the necessary information can be imprinted (e.g., printed or coated).

[0059] In a third aspect, the present invention provides the use of the compound of formula I described above, a specific compound or pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention in the preparation of a drug for the prevention and / or treatment of NLRP3-related diseases.

[0060] The present invention provides a method for preventing or treating NLRP3-related diseases, the method comprising administering the compound of formula I described above, a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention to an individual in need.

[0061] The present invention provides a method for preventing or treating NLRP3-related diseases by using a compound of formula I or a pharmaceutically acceptable form thereof, or by combining a pharmaceutical composition of the present invention with another therapeutic method, which includes, but is not limited to, radiotherapy, chemotherapy, immunotherapy, or a combination thereof.

[0062] In some embodiments, NLRP3-related diseases include inflammatory diseases, autoimmune diseases, cardiovascular diseases, cancer, kidney diseases, gastrointestinal diseases, respiratory diseases, endocrine diseases, or central nervous system diseases.

[0063] In some embodiments, NLRP3-related diseases include cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multiorgan inflammatory disease (NOMID), familial Mediterranean fever (FMF), non-alcoholic steatohepatitis, alcoholic liver disease, graft-versus-host disease, multiple sclerosis (MS), rheumatoid arthritis, type 1 / II diabetes and related complications (e.g.) This includes conditions such as nephropathy and retinopathy, psoriasis, Alzheimer's disease, atherosclerosis, gout, chronic kidney disease, sepsis, hepatic fibrosis, idiopathic pulmonary fibrosis, epilepsy, neuropathic pain, depressive disorders, Parkinson's disease, asthma, acute myocardial infarction, systemic lupus erythematosus, rheumatoid arthritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, ankylosing spondylitis, bronchial asthma, acute respiratory distress syndrome, chronic obstructive pulmonary disease, or ischemic stroke.

[0064] In a more 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.

[0065] The beneficial effects of this invention are as follows: The present invention provides triazine compounds and their uses, and the compounds and compositions can be used to prepare NLRP3 inflammasome inhibitors, thereby providing a novel method for treating NLRP3-related diseases.

[0066] Definition of Terms Unless otherwise defined herein, all technical and scientific terms used herein are intended to have meanings generally understood by those skilled in the art. The terms “including,” “comprising,” “having,” “containing,” or “relating to,” and other variations thereof, are inclusive or open-ended and do not exclude other unlisted elements or method steps. Those skilled in the art will understand that the aforementioned terms, such as “including,” encompass the meaning of “consisting of.”

[0067] In the present invention, “one,” “a,” “the,” “at least one,” and “one or more” can be used interchangeably. Therefore, for example, a composition containing “a” a pharmaceutically acceptable excipient may be interpreted as meaning that the composition contains “one or more” pharmaceutically acceptable excipients.

[0068] For example, "C 1-4 The expression " means any sub-range within it, as well as C 2-4 , C 3-4 , C 1-2 , C 1-3 , C 1-4 It should be understood that this includes the values ​​of each point, such as C1, C2, C3, C4, etc.

[0069] In this invention, unless otherwise specified, halogen refers to fluorine, chlorine, bromine, or iodine.

[0070] In the present invention, unless otherwise specified, the term "alkyl" includes linear or branched monovalent saturated hydrocarbon groups. Examples of alkyl groups include 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, and 2-methylpentyl. Similarly, "C1-4 C in "alkyl" 1-4 This refers to a group having 1, 2, 3, or 4 carbon atoms arranged in a linear or branched chain configuration.

[0071] In the present invention, unless otherwise specified, the terms “cycloalkyl,” “carbocyclic,” or “cycloalkylene” refer to saturated or partially saturated monocyclic or polycyclic (such as bicyclic) non-aromatic hydrocarbon groups. Common cycloalkyl groups include, but are not limited to, monocyclic cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, or bicyclic cycloalkyl groups including condensed, crosslinked, or spirorings such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, decahydronaphthyl. For example, “C 3-12 The term "cycloalkyl" refers to a cycloalkyl group having 3 to 12 ring carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12). The cycloalkyl or cycloalkylene group in this invention is optionally substituted with one or more substituents as described herein.

[0072] In the present invention, unless otherwise specified, the term "fluoroalkyl" refers to the aforementioned alkyl group in which one or more hydrogen atoms are substituted with fluorine atoms. For example, "C 1-4 The term "fluoroalkyl" refers to a C molecule that may be substituted with one or more (e.g., one to three) fluorine atoms. 1-4 This refers to an alkyl group. Those skilled in the art will understand that when two or more fluorine atom substituents are present, the fluorine atoms may be the same or different and may be located on the same or different carbon atoms. Examples of haloalkyl groups include, but are not limited to, -CH2F, -CHF2, -CF3, -C2F5, and -CH2CF3. The fluoroalkyl groups in this invention are optionally substituted with one or more substituents described herein.

[0073] The present invention also encompasses all pharmaceutically acceptable isotope-labeled compounds that are identical to the compounds of the present invention, except that one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from the atomic mass or mass number that is dominant in nature. Examples of isotopes suitable for incorporation into the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium) 2 H) and tritium ( 3 H)), carbon isotopes (for example, 13 C and 14 C) Isotopes of chlorine (for example, 37 Cl), isotopes of iodine (for example, 125 I) Nitrogen isotopes (for example, 13 N and 15 N), oxygen isotopes (for example, 17 O and 18 O), phosphorus isotopes (for example, 32 P), and sulfur isotopes (e.g., 34 S) is one example.

[0074] In the present invention, the term “polymorph” refers to different solid crystalline phases of a particular compound of the present invention resulting from the presence of two or more different molecular arrangements in the solid state. A particular compound of the present invention may exist in two or more crystalline forms, and the present invention is intended to encompass all such crystalline forms and mixtures thereof. Generally, crystallization results in the formation of solvates of the compounds of the present invention. As used in the present invention, the term “solvate” refers to an aggregate containing 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 monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, etc., and as corresponding solvated forms. While the compounds of the present invention may form true solvates, in some cases they may also retain simply non-stoichiometric water, or mixtures of water combined with a portion of a non-stoichiometric solvent. The compounds of the present invention may be reacted in a solvent, or precipitated or crystallized from a solvent. Solvates of the compounds of the present invention are also encompassed within the scope of the present invention. The present invention also encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of two or more polymorphs in any proportion.

[0075] In the present invention, the term "stereoisomer" refers to an isomer arising from the presence of at least one chiral center. Compounds having one or more (e.g., one, two, three, or four) chiral centers can result in racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers. Certain individual molecules can also exist as geometric isomers (cis / trans). Similarly, compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (generally referred to as tautomers). Typical examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, and imine-enamine tautomers. It should be understood that the scope of the present invention includes all such isomers, or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, and 99%).

[0076] In the present invention, pharmaceutically acceptable salts include their acid addition salts and base addition salts. Preferred acid addition salts are formed from acids that form pharmaceutically acceptable salts. Preferred base addition salts are formed from bases that form pharmaceutically acceptable salts. For an overview of preferred 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. The term “pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic or organic acid that preserves the bioavailability of the free base without other adverse effects. Examples of inorganic salts, though not limited to them, include hydrochloride, hydrobromide, sulfate, nitrate, and phosphate. Examples of organic salts, though not limited to them, include formate, acetate, 2,2-dichloroacetate, trifluoroacetate, propionate, caproate, caprylate, caprine, undecylenate, glycolate, gluconate, lactate, sebacinate, adipine, 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 naphthalenedisulfonate. These salts can be prepared by methods known in this patent. The term "pharmaceutically acceptable base addition salt" refers to a salt formed with an inorganic or organic base that retains the biological efficacy of a free acid without other adverse effects.Examples of 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, and aluminum salts. Preferred inorganic salts are ammonium salts, sodium salts, calcium salts, and magnesium salts. Examples of salts derived from organic bases include, but are not limited to, primary amines, secondary amines, and tertiary amines, substituted amines including naturally occurring 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, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and hexocaffeine. Salts of these can be prepared by methods known in this patent.

[0077] In the present invention, unless otherwise specified, the term "ester" refers to esters derived from the compounds described herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present invention in the form of free acids or alcohols). The compounds of the present invention may also be esters themselves.

[0078] The compounds of the present invention may exist in the form of solvates (preferably hydrates), and the compounds of the present invention may contain a polar solvent, particularly water, methanol, or ethanol, as a structural element of the crystal lattice of the compound. The amount of the polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric ratios.

[0079] Those skilled in the art will understand that not all nitrogen heterocyclic rings can form N-oxides, as nitrogen requires an available lone pair of electrons to be oxidized to an oxide. Those skilled in the art will recognize nitrogen heterocyclic rings that can form N-oxides. They will also recognize that tertiary amines can form N-oxides. Synthetic methods for preparing N-oxides of heterocyclic rings and tertiary amines, including oxidation of heterocyclic rings and tertiary amines using peroxy acids such as peroxyacetic acid and m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane, are well known to those skilled in the art. These methods for preparing N-oxides are widely described and outlined in the literature. For example, see TLGilchrist, Comprehensive Organic Synthesis, vol.7, pp.748-750 (ARKatritzky and AJBoulton, Eds., Academic Press), and GWHCheeseman and ESGWerstiuk, Advances in Heterocyclic Chemistry, vol.22, pp.390-392 (ARKatritzky and AJBoulton, Eds., Academic Press).

[0080] In the present invention, the term "metabolites" refers to substances formed in the body when the compounds of the present invention are administered. Metabolites of compounds can be identified using techniques well established in the art, and their activity can be characterized by experimental methods. For example, such products may arise from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic degradation, and other reactions of the administered compound. Accordingly, the present invention encompasses metabolites of the compounds of the present invention, including compounds produced by methods comprising contacting the compounds of the present invention with a mammal for a sufficient period of time to obtain their metabolites.

[0081] In the present invention, the term “prodrug” refers to a specific derivative of a compound of the present invention that, when administered in or onto the body, can be converted to a compound of the present invention having a desired activity, for example, by hydrolysis. Typically, such a prodrug is a functional group derivative of a compound that can be readily converted in vivo to a desired therapeutically active compound. Additional information regarding the use of prodrugs can be found in Pro-drugs as Novel Delivery Systems, Volume 14, ACS Symposium Series (T. Higuchi and V. Stella). For example, a prodrug of the present invention can be prepared by replacing a suitable functional group present in a compound of the present invention with a specific part known to those skilled in the art as a “pro-part” (for example, as described in Design of Prodrugs by H. Bundgaard (Elsevier, 1985)).

[0082] In this application, the term "pharmaceutical composition" refers to a formulation of the compound of the present invention and a medium commonly accepted in the art for delivering a biologically active compound to a mammal such as a human. The medium includes a pharmaceutically acceptable carrier. The objective of the pharmaceutical composition is to facilitate administration to a living organism, promote the absorption of the active ingredient, and thereby exert biological activity.

[0083] In this application, the term “pharmaceutically acceptable carrier” includes, but is not limited to, any adjuvants, carriers, excipients, flow enhancers, sweeteners, diluents, preservatives, pigments / colorants, flavorings, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that are approved by the relevant government regulatory authorities or permitted for use in humans or livestock.

[0084] As used herein, terms such as “combination of drugs,” “co-administration of drugs,” “combination therapy,” “administration of another treatment,” and “administration of another therapeutic agent” refer to therapeutic regimens obtained by mixing or combining two or more active ingredients, and include both fixed and unfixed combinations of active ingredients. The term “fixed combination” refers to the simultaneous administration to a patient of at least one compound described herein and at least one synergistic agent in the form of a single entity or dosage form. The term “unfixed combination” refers to the simultaneous administration to a patient of at least one compound described herein and at least one synergistic agent as separate entities, either co-administered, simultaneously administered, or sequentially administered at variable intervals. These principles also apply to cocktail therapies, such as the administration of three or more active ingredients.

[0085] In the present invention, unless otherwise specified, the term "tumor" includes, but is not limited to, leukemia, gastrointestinal stromal tumors, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, squamous cell carcinoma of the lung, adenocarcinoma of the lung, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, cervical cancer, ovarian cancer, colorectal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer, and other diseases.

[0086] In the present invention, unless otherwise specified, the term “treatment” means reversing, alleviating, or inhibiting the progression of a disorder or condition, or one or more symptoms thereof, to which such term applies, or preventing such disorder or condition, or one or more symptoms thereof.

[0087] Without departing from the common general knowledge in the art, the aforementioned preferred technical features can be freely combined in any way, thereby yielding various preferred embodiments of the present invention. [Modes for carrying out the invention]

[0088] The solution of the present invention will be described with reference to embodiments. It will be understood by those skilled in the art that the following embodiments are not intended to limit the scope of the present invention, but are merely for exemplifying the present invention. When no technology or conditions are specified in the embodiments, the technology or conditions described in the literature or product specifications of the relevant technical field should be followed.

[0089] All the reagents and raw materials used in the embodiments of the present invention are commercially available. [Table 1]

[0090] The structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). The NMR measurements are performed on a Bruker AVANCE-400 spectrometer using deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD) as solvents. Tetramethylsilane (TMS) is used as an internal reference standard. The chemical shifts are reported in parts per million (ppm, 10 -6 -6).

[0091] The MS measurements are performed on an Agilent SQD (ESI) mass spectrometer (manufacturer: Agilent, signal: 6110).

[0092] The HPLC measurements are performed on 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).

[0093] The Qingdao Haiyang GF254 silica gel plate is used for thin-layer chromatography. The silica gel plate used for thin-layer chromatography (TLC) is 0.15 mm~0.2 mm, and the silica gel plate used for thin-layer chromatography separation and purification of products is 0.4 mm~0.5 mm.

[0094] Generally, silica gels with 100 - 200 meshes and 200 - 300 meshes made by Qingdao Haiyang are used as carriers for column chromatography.

[0095] In the following embodiments, unless otherwise specified, all reactions are carried out under an argon atmosphere or a nitrogen atmosphere. The argon atmosphere or nitrogen atmosphere refers to a reaction flask connected to an argon balloon or nitrogen balloon with a volume of about 1 L. The hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of about 1 L. The hydrogenation reaction is usually evacuated, filled with hydrogen, and such operations are repeated 3 times.

[0096] Intermediate INT1: 2-[4-Methoxybenzo[b]thiophen-5-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Chemical formula

[0097] Step 1: CuBr2 (146.5 g, 656 mmol) was added to EtOAc (250 mL), and the resulting mixture was stirred at 80 °C for 10 minutes. Then, compound INT1a (25.0 g, 164 mmol) was dissolved in chloroform (250 mL), and the resulting solution was added to the above suspension. The resulting mixture was refluxed at 80 °C overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The obtained residue was triturated with EtOAc (500 mL) for 0.5 hour, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound INT1b (46.0 g, 148 mmol, light brown solid, yield: 90%). MS: [M+H] + = 309.0, 311.0, 313.0

[0098] Step 2: Compound INT1b (45.0 g, 145 mmol) and Li2CO3 (26.8 g, 363 mmol) were added to DMF (450 mL), and the resulting mixture was stirred at 100°C for 6 hours. After the reaction was complete, the reaction mixture was filtered, the filtrate was treated with aqueous hydrochloric acid (900 mL, 0.5 N), extracted with siRNA (400 mL x 2), the organic phase was washed with water (300 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the target compound INT1c (31.0 g, 135 mmol, light brown solid, yield: 93%). MS: [MH] - =227.0, 229.0

[0099] 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 resulting mixture was stirred overnight at 60°C under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered. Silica gel (30 g) was added to the filtrate, and the resulting mixture was concentrated under reduced pressure and purified by column chromatography (PE:siRNA = 10:1) to obtain the target compound INT1d (13.7 g, 56.4 mmol, white solid, yield: 86%). 1 ¹H NMR (400 MHz, CDCl3) δ 7.51–7.46 (m, 2H), 7.45–7.42 (m, 2H), and 4.00 (s, 3H)

[0100] Step 4: Compound INT1d (13.7 g, 56.4 mmol), bis(pinacolate)diborone (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 the resulting mixture was reacted under a nitrogen atmosphere at 90°C for 12 hours. After the reaction was complete, the reaction mixture was filtered. Silica gel (30 g) was added to the filtrate, and the resulting mixture was concentrated under reduced pressure and purified by column chromatography (PE:SiO=30:1) to obtain the target compound INT1 (7.6 g, 26.2 mmol, colorless solid, yield: 46%). 1¹H NMR (400MHz, CDCl3) δ 7.67 (d, J=8.0Hz, 1H), 7.61 (d, J=8.0Hz, 1H), 7.49 (d, J=5.6Hz, 1H), 7.35 (d, J=5.2Hz, 1H), 4.00 (s, 3H), and 1.39 (s, 12H).

[0101] Intermediate INT2: 2-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-4,4,5-5-tetramethyl-1,3,2-dioxaborolane [ka]

[0102] Step 1: Compounds INT2a (5 g, 20.7 mmol), INT2b (7.1 g, 52 mmol), cesium carbonate (11.5 g, 41.5 mmol), water (20 mL), and DMF (80 mL) were sequentially added to a 250 mL three-necked flask and heated to 120 °C, stirring for 12 hours. After cooling to room temperature, the reaction solution was extracted with ethyl acetate and layered. The organic phases were washed separately with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by column chromatography to obtain compound INT2c (2.8 g, yellow solid).

[0103] Step 2: Compound INT2c (2.8 g, 9.6 mmol), bis(pinacolate)diborone (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 under a nitrogen atmosphere. The resulting mixture was reacted, heated to 100 °C, and stirred for 16 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and then filtered through Celite. The filtrate was extracted with ethyl acetate. The organic phases were combined and then washed separately with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by column chromatography to obtain compound INT2 (1.7 g, white solid). 1¹H NMR (400MHz, chloroform-d): δ 7.86 (d, J=7.7Hz, 1H), 7.49 (d, J=7.8, 1H), 7.39 (s, 1H), 6.54 (t, J=72.5Hz, 1H), 1.35 (s, 12H).

[0104] Intermediate INT3: 2-[1-(difluoromethylene)-4-methoxy-2,3-dihydro-1H-inden-5-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka]

[0105] Step 1: Compounds 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) were dissolved in DMF (200 mL), and the resulting mixture was heated to 50°C for 3 hours. After adding water, the reaction mixture was extracted with ethyl acetate, the resulting organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to obtain the target compound INT3a (yellow oily liquid, 22.5 g, yield 84%), which did not require further purification. MS / ESI[M+H] + :215.1.

[0106] Step 2: Et3N (12.71 g, 125.58 mmol) was added dropwise to HCOOH (14.45 g, 313.95 mmol) at 0°C, and the resulting mixture was reacted at room temperature for 30 minutes. Then, a solution of compound INT3a (22.5 g, 104.65 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (15.08 g, 104.65 mmol) dissolved in DMF (200 mL) was added to the reaction mixture, and the resulting solution was heated to 100°C and reacted overnight. NaOH aqueous solution was added to the reaction solution, and the resulting mixture was adjusted to pH=9 and extracted with ethyl acetate. HCl aqueous solution (3 M) was added to the aqueous phase, and the resulting mixture was adjusted to pH=5 and extracted with ethyl acetate. After combining the organic phases, the resulting mixture was dried over anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate under reduced pressure, and the resulting residue was purified by column chromatography (PE:EA=5:1) to obtain the target compound INT3b (white solid, 20.3 g, yield: 75%). MS / ESI[M+H] + :259.1.

[0107] Step 3: Polyphosphate (200 g) was heated to 90°C, and compound INT3b (20.3 g, 78.34 mmol) was added to the polyphosphate. The resulting mixture was suspended and heated 1 hour after the reaction. An aqueous solution was added to the reaction mixture, the resulting solution was cooled to room temperature, and extracted with dichloromethane. The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate under reduced pressure, and the resulting residue was purified 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.

[0108] Step 4: Compound INT3c (4.7 g, 19.50 mmol) and 2-[(difluoromethyl)sulfonyl]pyridine (5.65 g, 29.25 mmol) were dissolved in DMF (30 mL). The DMF solution was cooled to -50°C, and potassium tert-butoxide was added to the DMF solution under a nitrogen atmosphere. The resulting mixture was heated to -40°C and reacted for 3 hours. Then, saturated aqueous ammonium chloride solution (26 mL) was added to the reaction mixture to stop the reaction. Next, 3N HCl (26 mL) was added to the solvent that had stopped the reaction, and the resulting mixture was heated to room temperature and 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 resulting residue was purified 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).

[0109] Step 5: Under a nitrogen atmosphere, compound INT3e (1.92 g, 6.98 mmol), bis(pinacolate)diborone (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. The resulting mixture was refluxed overnight at 100°C. After the reaction was complete, the reaction mixture was allowed to return to room temperature and extracted with water and ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate under reduced pressure, and the resulting residue was purified 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=8.0Hz,1H),7.12(d,J=8.0Hz,1H),3.81(s,3H),2.97-2.82(m,2H),2.62-2.51(m,2H),1.30(s,12H).

[0110] Intermediate INT4: 2-(4-Methoxybenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Chemical Structure

[0111] Step 1: CuBr2 (66 g, 223 mmol) was added to EtOAc (120 mL), and the resulting mixture was stirred at 80 °C for 10 minutes. Then, compound INT4a (10 g, 136 mmol) was dissolved in chloroform (120 mL), and the resulting solution was added to the above suspension. The resulting mixture was refluxed at 80 °C overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The obtained residue was triturated with EtOAc (200 mL) for 0.5 hour, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound INT4b (7.3 g). 1 1H NMR (400 MHz, chloroform-d) δ 7.39 (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).

[0112] Step 2: Compound INT4b (7.3 g, 25 mmol) and Li2CO3 (11 g, 150 mmol) were added to DMF (70 mL), and the resulting mixture was stirred at 100 °C for 6 hours. After the reaction was completed, the reaction mixture was filtered, and the filtrate was adjusted to pH = 1 using aqueous hydrochloric acid. It was extracted with EtOAc (150 mL × 3), the organic phase was washed with a saturated brine solution, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to obtain the target compound INT4c (5.5 g). 1 1H NMR (400 MHz, chloroform-d) δ 7.55 (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).

[0113] Step 3: Compounds INT4c (5.5 g, 26 mmol), K2CO3 (7.17 g, 52 mmol), and Me2SO4 (4.1 g, 33 mmol) were sequentially added to MeCN (60 mL), and the resulting mixture was stirred overnight at 60°C under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered. Silica gel was added to the filtrate, and the resulting mixture was concentrated under reduced pressure and purified by column chromatography (PE:siRNA = 10:1) to obtain the target compound INT4d (5 g). 1 ¹H NMR (400MHz, chloroform-d): δ 7.56 (d, J=2.3Hz, 1H), 7.42 (d, J=8.7Hz, 1H), 7.12 (dd, J=8.7, 1.0Hz, 1H), 6.91 (dd, J=2.4, 1.0Hz, 1H), 4.08 (s, 3H).

[0114] Step 4: Compound INT4d (1 g, 4.4 mmol), bis(pinacolate)diborone (2.2 g, 8.8 mmol), KOAc (1.7 g, 17.6 mmol), and Pd(PPh)Cl2 (322 mg, 0.44 mmol) were added to dioxane (15 mL), and the resulting mixture was reacted under a nitrogen atmosphere at 90°C for 12 hours. After the reaction was complete, the reaction mixture was filtered. Silica gel was added to the filtrate, and then the resulting mixture was concentrated under reduced pressure and purified by column chromatography (PE:SiO=10:1) to obtain the target compound INT4 (410 mg). 1 ¹H NMR (400MHz, chloroform-d): δ 7.63 (d, J=8.3Hz, 1H), 7.54 (d, J=2.2Hz, 1H), 7.22 (dd, J=8.3, 1.0Hz, 1H), 6.90 (dd, J=2.2, 1.0Hz, 1H), 4.05 (s, 3H), 1.37 (s, 12H).

[0115] Intermediate INT5: 6-Bromo-2-(4-methoxybenzyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione [ka]

[0116] Step 1: Compound INT5a (50 g, 260 mmol) and methyl iodide (37 g, 260 mmol) were dissolved in ultra-dried DMF (250.0 mL), and DIEA (36 g, 281 mmol) was added to the reaction flask. The resulting mixture was reacted at room temperature for 3 hours. After most of the starting materials had reacted, the reaction mixture was extracted four times with EA and saturated brine solution to concentrate the organic phase, which was then purified by column chromatography using silica gel (PE / EA 8:1~6:1) to obtain the white solid compound INT5b (39 g).

[0117] Step 2: Compound INT5b (39 g, 189.3 mmol) and 4-methoxychlorobenzyl (40 g, 265 mmol) were dissolved in ultra-dried DMF (500.0 mL), and K2CO3 (52 g, 378.6 mmol) was added to the reaction flask. The resulting mixture was reacted at room temperature for 8 hours. After confirming that the reaction of the starting materials was complete by TLC, the reaction mixture was extracted three times with 200 mL of ethyl acetate and water, the organic phase was washed twice with 200 mL of saturated brine solution, dried over anhydrous sodium sulfate, and concentrated to obtain compound INT5. 1 H NMR (400MHz, DMSO-d6) δ7.36-7.20(m,2H),7.00-6.82(m,2H),5.01(s,2H),3.74(s,3H),3.20(s,3H).

[0118] Intermediate INT6: 2-(4-cyclopropyl-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka]

[0119] Step 1: Compound INT6a (500 mg, 1.6 mmol), cyclopropylboronic acid (505 mg, 5.87 mmol), and potassium carbonate (883 mg, 6.39 mmol) were mixed in dioxane (10 mL) and water (5 mL). Subsequently, Pd(dppf)Cl2 (65.9 mg, 0.080 mmol) was added under a nitrogen atmosphere, and the resulting mixture was stirred at 120°C under a nitrogen atmosphere to allow it to react completely. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (20 mL), the organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to obtain the crude product, compound INT6b, which was used directly in the next step.

[0120] Step 2: Compound INT6b (1.2 g, 4.4 mmol), bis(pinacolate)diborone (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 the resulting mixture was reacted under a nitrogen atmosphere at 90°C for 12 hours. After the reaction was complete, the reaction mixture was filtered. Silica gel was added to the filtrate, and then the resulting mixture was concentrated under reduced pressure and purified by column chromatography (PE:SiO=10:1) to obtain the target compound INT6 (0.82 g).

[0121] Intermediate INT7: 6-Bromo-3-chloro-4-methyl-1,2,4-triazine-5(4H)-ketone [ka]

[0122] Step 1: Compound INT7a (10 g, 57.15 mmol) and cuprous chloride (11 g, 111.11 mmol) were placed in a sealed tube. Tert-butyl nitrite (12 g, 116.50 mmol) and acetonitrile (35 mL) were also added to the sealed tube, and the tube was quickly sealed. The resulting mixture was heated to 80°C and reacted for 4 hours. After the reaction was complete, the reaction mixture was concentrated. The resulting residue was purified by column chromatography, and the 10% EA:PE eluted product was concentrated to obtain the pale yellow solid product INT7b (5.31 g). LC-MS:ESI[M+H] + = 193.0.

[0123] Step 2: Compound INT7b (5.31 g, 25.24 mmol) and acetic acid (25 mL) were added to the reaction flask. The reaction flask was placed in an ice bath, and hydrogen peroxide (5 mL) was slowly added dropwise to the reaction flask. The resulting mixture was slowly allowed to return to room temperature and reacted overnight. After the reaction was complete, an aqueous solution of sodium thiosulfate was added to the reaction mixture to stop the reaction. The reaction mixture was then extracted with EA (ethyl acetate) and 5% TEA (triethylamine). The organic phase was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain the pale yellow solid product INT7c (5.12 g). LC-MS:ESI[M+H] + = 209.1.

[0124] Step 3: Compound INT7c (3 g, 14.26 mmol) and anhydrous DMF (30 mL) were placed in a three-necked bottle under a nitrogen atmosphere, and the resulting mixture was reacted. The bottle was then placed in an ice bath, and NaH (1.15 g, 28.79 mmol) was slowly added to the reaction mixture. The resulting mixture was allowed to return to room temperature and reacted for 1 hour. Methyl iodide (2.02 g, 14.26 mmol) was slowly added dropwise to the reaction mixture, and the resulting mixture was reacted overnight at room temperature. After the reaction was complete, water was added to the reaction mixture to stop the reaction. The reaction mixture was extracted with EA, washed with saturated brine solution, dried, concentrated, and the resulting residue was purified by column chromatography to obtain the white solid product INT7 (0.8 g). LC-MS:ESI[M+H]+ =224.0. 1 H NMR (400MHz, DMSO-d6) δ3.45(s,3H).

[0125] Intermediate INT8: 2-(4-(methoxymethoxy)benzo[b]thiophen-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka]

[0126] Step 1: Compound INT1c (220 g, 960 mmol) and diisopropylethylamine (186 g, 1440 mmol) were added to dichloromethane (1.1 L), followed by the slow addition of bromomethyl methyl ether (132 g, 1056 mmol) at 0°C. The resulting mixture was stirred at room temperature for 1 hour. After the reaction was complete, saturated aqueous ammonium chloride solution (300 mL x 3) was added to the reaction mixture for washing. The organic phase was dried over anhydrous sodium sulfate, then concentrated under reduced pressure, and purified by column chromatography (PE:siRNA = 30:1) to obtain the target compound INT8a (183 g, 670 mmol, pale yellow oily substance, 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).

[0127] Step 2: Compound INT8a (20.0 g, 73.2 mmol), bis(pinacolate)diborone (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 the resulting mixture was reacted under a nitrogen atmosphere at 100 °C for 12 hours. After the reaction was complete, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (PE:SiO=30:1) to obtain the target compound INT8 (14.5 g, 45.3 mmol, colorless solid, yield: 62%). 1H 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).

[0128] Embodiment 1: (R)-3-(1-(difluoromethylene)-4-hydroxy-2,3-dihydro-1H-inden-5-yl)-6-((1-(2-hydroxyethyl)piperidine-3-yl)amino)-4-methyl-1,2,4-triazine-5(4H)-ketone [ka]

[0129] Step 1: Compounds INT5 (8.00 g, 24.54 mmol), 1a (12.71 g, 49.08 mmol), Pd(OAc)2 (0.56 g, 2.45 mmol), BINAP (1.53 g, 2.45 mmol), cesium carbonate (23.93 g, 73.62 mmol), and dioxane (180 mL) were added to a reaction flask and stirred at 100°C for 15 hours under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was cooled to room temperature and stirred directly with silica gel. The resulting mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0-2:1) to obtain compound 1b (7.00 g, 66.7%). MS / ESI[M+H] + = 432.0.

[0130] Step 2: Compound 1b (7.00 g, 16.24 mmol) and dichloromethane (60 mL) were added to the reaction flask and cooled to 0°C. Subsequently, trifluoromethanesulfonic acid (6 mL) was slowly added dropwise to the reaction flask, and the resulting mixture was stirred at room temperature for 15 hours. After the reaction was complete, the reaction mixture was cooled to 0°C-5°C with acetonitrile (60 mL). Solid sodium bicarbonate was added to the cooled mixture until no more bubbles were generated. The pH of the cooled mixture was then adjusted to 7-8 with aqueous ammonia. The pH-adjusted mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0-1:2) to obtain compound 1c (4.05 g, 80.5%). MS / ESI[M+H] + =312.0.

[0131] Step 3: Compound 1c (4.00 g, 12.86 mmol) was dispersed in phosphorus oxychloride (25 mL), and the resulting mixture was stirred at 110°C for 12 hours under a nitrogen atmosphere. After the reaction was complete, the solvent was concentrated directly, and the resulting residue was dispersed in acetonitrile (60 mL) and dichloromethane (100 mL). The resulting mixture was cooled to 0°C to 5°C, and solid sodium bicarbonate was added to the cooled mixture until no more bubbles were generated. The pH of the cooled mixture was then adjusted to 7-8 with aqueous ammonia, the pH-adjusted mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting crude product was purified by silica gel column chromatography (dichloromethane:methanol = 1:0-10:1) to obtain compound 1d (3.00 g, 71.4%). MS / ESI[M+H] + =330.0.

[0132] Step 4: Compound 1d (2.12 g, 6.43 mmol), INT3 (1.80 g, 5.59 mmol), Pd(dppf)Cl2 (409 mg, 0.06 mmol), cesium carbonate (5.45 g, 16.77 mmol), dioxane (60 mL), and water (6 mL) were added to the reaction flask and stirred at 100°C for 15 hours under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was cooled to room temperature and mixed directly with silica gel. The resulting mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 0:1) to obtain compound 1e (1.10 g, 40.3%). MS / ESI[M+H] + = 490.1.

[0133] Step 5: Compound 1e (1.10 g, 2.25 mmol) and dichloromethane (50 mL) were added to a reaction flask, cooled to -10°C under a nitrogen atmosphere, and then a 1 M dichloromethane solution of boron tribromide (6.71 mL, 6.71 mmol) was added. The resulting mixture was reacted at a constant temperature for 2 hours. After the reaction was complete, methanol (10 mL) was added to the reaction mixture to stop the reaction, and the solvent was concentrated directly. The resulting residue was purified by silica gel column chromatography (dichloromethane:methanol = 1:0 to 9:1) to obtain compound 1f (498 mg, 46.6%). MS / ESI[M+H] + = 476.0.

[0134] Step 6: Compound 1f (479 mg, 1.01 mmol) and ethanol (25 mL) were added to the reaction flask. Under a nitrogen atmosphere, lithium borohydride solid (177 mg, 8.07 mmol) was added in batches to the reaction mixture, and the resulting mixture was reacted at 55°C for 12 hours. After the reaction was complete, saturated ammonium chloride (20 mL) was added to the reaction mixture to stop the reaction, followed by 50 mL of ethyl acetate. The aqueous phase was extracted three more times with ethyl acetate (30), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by Pre-HPLC (FA system) to obtain compound 1 (14 mg, 3.2%). 1H NMR(400MHz,Methanol-d4)δ8.39(brs,2H),7.13(d,J=8.0Hz,1H),6.98(dd,J=8.0,1.6Hz,1H),4.26-4.14(m,1H),3.72(t,J=5.2Hz, 2H),3.45-3.35(m,1H),3.23(s,3H),3.17-3.07(m,1H),2.98-2.87(m,4H),2.82-2.64(m,4H),2.01-1.86(m,2H),1.81-1.58(m,2H). MS / ESI[M+H] + = 434.0.

[0135] Embodiment 2: (R)-3-(1-(difluoromethylene)-4-hydroxy-2,3-dihydro-1H-inden-5-yl)-6-((1-ethylpiperidine-3-yl)amino)-4-methyl-1,2,4-triazine-5(4H)-ketone [ka]

[0136] Step 1: Compounds INT5 (1.50 g, 4.60 mmol), 2a (1.13 g, 6.90 mmol), BINAP Pd G3 (0.46 g, 0.46 mmol), cesium carbonate (4.48 g, 13.8 mmol), and dioxane (30 mL) were added to a reaction flask and stirred at 100°C for 15 hours under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was cooled to room temperature and mixed directly with silica gel. The resulting mixture was purified by silica gel column chromatography (dichloromethane:methyl alcohol = 1:0 to 35:1) to obtain compound 2b (1.41 g, 82.4%). MS / ESI[M+H] + =374.0.

[0137] Step 2: Compound 2b (1.41 g, 3.79 mmol) and dichloromethane (10 mL) were added to the reaction flask and cooled to 0°C. Subsequently, trifluoromethanesulfonic acid (3 mL) was slowly added dropwise to the reaction flask, and the resulting mixture was stirred at room temperature for 15 hours. After the reaction was complete, the reaction mixture was cooled to 0°C-5°C with acetonitrile (10 mL). Solid sodium bicarbonate was added to the cooled mixture until no more bubbles were generated. The pH of the cooled mixture was then adjusted to 7-8 with aqueous ammonia. The pH-adjusted mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting crude product was purified by silica gel column chromatography (dichloromethane:methyl alcohol = 1:0-4:1) to obtain compound 2c (850 mg, 89.5%). MS / ESI[M+H] + = 254.0.

[0138] Step 3: Compound 2c (850 mg, 3.36 mmol) was dispersed in phosphorus oxychloride (10 mL), and the resulting mixture was stirred at 110°C for 12 hours under a nitrogen atmosphere. After the reaction was complete, the solvent was concentrated directly, and the resulting residue was dispersed in acetonitrile (10 mL) and dichloromethane (10 mL). The resulting mixture was cooled to 0°C to 5°C, and solid sodium bicarbonate was added to the cooled mixture until no more bubbles were generated. The pH of the cooled mixture was then adjusted to 7-8 with aqueous ammonia, the pH-adjusted mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting crude product was purified by silica gel column chromatography (dichloromethane:methanol = 1:0-10:1) to obtain compound 2d (605 mg, 65.9%). MS / ESI[M+H] + = 272.0.

[0139] Step 4: Compound 2d (200 mg, 0.74 mmol), INT3 (261 mg, 0.81 mmol), Pd(dppf)Cl2 (54 mg, 0.07 mmol), cesium carbonate (720 mg, 2.21 mmol), dioxane (12 mL), and water (2 mL) were added to the reaction flask and stirred at 100°C for 15 hours under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was cooled to room temperature and mixed directly with silica gel. The resulting mixture was purified by silica gel column chromatography (dichloromethane:methanol = 1:0 to 10:1) to obtain compound 2e (99 mg, 31.1%). MS / ESI[M+H] + = 432.1.

[0140] Step 5: Compound 2e (99 mg, 0.23 mmol) and dichloromethane (6 mL) were added to a reaction flask, cooled to -10°C under a nitrogen atmosphere, and then a 1 M dichloromethane solution of boron tribromide (0.69 mL, 0.69 mmol) was added. The resulting mixture was reacted at a constant temperature for 2 hours. After the reaction was complete, methanol (4 mL) was added to the reaction mixture to stop the reaction, and the solvent was concentrated directly. The resulting residue was purified by silica gel column chromatography (dichloromethane:methanol = 1:0 to 9:1) to obtain compound 2 (70 mg, 73.2%). 1 H NMR(400MHz,DMSO-d6)δ9.78(brs,1H),9.58(brs,1H),7.24(d,J=8.0Hz,1H),7.07-6.97(m,1H),4.36-4.23(m,1H),3.57-3.48(m,3 H),3.26-3.18(m,5H),3.08-2.98(m,2H),2.87-2.80(m,3H),2.05-1.93(m,2H),1.88-1.65(m,2H),1.28-1.20(m,3H),MS / ESI[M+H] + [M+H] + =418.0.

[0141] Embodiment 3: (R)-6-((1-ethylpiperidine-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazine-5(4H)-ketone [ka]

[0142] Referring to Embodiment 2, (R)-6-((1-ethylpiperidine-3-yl)amino)-3-(4-hydroxybenzo[b]thiophene-5-yl)-4-methyl-1,2,4-triazine-5(4H)-ketone was prepared to obtain compound (R)-6-((1-ethylpiperidine-3-yl)amino)-3-(4-hydroxybenzo[b]thiophene-5-yl)-4-methyl-1,2,4-triazine-5(4H)-ketone (70 mg, 80.6%). 1 H NMR(400MHz,DMSO-d6)δ10.46(br s,1H),9.60(br s,1H),7.80-7.73(m,2H),7.65(d,J=8.0Hz,1H),7.30(d,J=8.0Hz,1H),4.37-4.27(m,1H),3.58-3.48(m,3H) ,3.29-3.18(m,5H),2.92-2.82(m,1H),2.05-1.96(m,2H),1.88-1.68(m,2H),1.28-1.24(m,3H),MS / ESI[M+H] + [M+H] + =386.0.

[0143] Embodiment 4: (R)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-6-((1-methylpiperidine-3-yl)amino)-1,2,4-triazine-5(4H)-ketone [ka]

[0144] Step 1: Compounds INT5 (3.00 g, 9.20 mmol), 4a (1.15 g, 10.1 mmol), Cs2CO3 (6.01 g, 18.4 mmol), BINAP (573 mg, 0.92 mmol), and Pd(OA)2 (208 mg, 0.92 mmol) were weighed and added to dioxane (60 mL). The resulting mixture was replaced three times with N2, then heated to 110°C and stirred overnight. After the reaction was complete, the reaction mixture was mixed with silica gel, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 10:1) to obtain the target compound 4b (3.30 g, 9.18 mmol, pale yellow viscous substance, yield: 99%). MS / ESI[M+H] + = 360.2.

[0145] Step 2: Compound 4b (3.30 g, 9.18 mmol) was dissolved in dichloromethane (30 mL), followed by the slow addition of TfOH (4.13 g, 27.5 mmol) at room temperature. The resulting mixture was stirred overnight. After the reaction was complete, the pH of the reaction mixture was adjusted to approximately 8 with aqueous ammonia. The pH-adjusted reaction mixture was dried over anhydrous Na2SO4, filtered, and the filtrate was mixed with silica gel. The resulting mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 5:1) to obtain target compound 4c (770 mg, 3.22 mmol, pale yellow solid, yield: 35%). MS / ESI[M+H] + = 240.1.

[0146] Step 3: Compound 4c (770 mg, 3.22 mmol) was mixed with POCl3 (4 mL), and the resulting mixture was heated to 110°C and stirred overnight. After the reaction was complete, the excess POCl3 was concentrated under pressure to obtain target compound 4d (1.5 g, 3.30 mmol, light brown solid, yield: 100%). MS / ESI[M+H] + = 258.2.

[0147] Step 4: Compound 4d (1.1 g, 2.42 mmol), INT1 (772 mg, 2.66 mmol), Cs2CO3 (3.94 g, 12.1 mmol), and Pd(dppf)Cl2 (176 mg, 0.24 mmol) were weighed and added to dioxane (20 mL) and water (4 mL). The resulting mixture was substituted with N2 three times, heated to 100°C, and stirred overnight. After the reaction was complete, the reaction mixture was mixed with silica gel, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 10:1) to obtain target compound 4e (550 mg, 1.43 mmol, pale yellow viscous substance, yield: 59%). MS / ESI[M+H] + = 386.2.

[0148] Step 5: Compound 4e (550 mg, 1.43 mmol) was dissolved in DCM (5.5 mL) and cooled to 0°C. Subsequently, BBr3 (4.29 mL, 4.29 mmol, 1.0 M) was added dropwise, and the resulting mixture was stirred at room temperature for 1 hour. After the reaction was complete, an appropriate amount of methanol was added to the reaction mixture to stop the reaction. The stopped mixture was concentrated under reduced pressure to obtain the crude product. This crude product was dissolved in methanol (5 mL), and the resulting solvent was purified to obtain target compound 4 (295 mg, 0.79 mmol, pale yellow powder, yield: 55%). 1 H NMR(400MHz,MeOD)δ8.46(s,1H),7.63(d,J=5.6Hz,1H),7.58(dd,J=6.9,4.3Hz,2H),7.29(d,J=8.3Hz,1H),4.30(dt,J=13.0,4.7Hz,1H), 3.52(d,J=11.5Hz,1H),3.36(s,3H),3.25-3.15(m,1H),3.02-2.80(m,2H),2.75(s,3H),2.07(dd,J=21.0,10.1Hz,2H),1.94-1.69(m,2H). MS / ESI[M+H] + = 372.2.

[0149] Embodiment 5: (R)-6-((1-(3,3-difluorocyclobutyl)piperidine-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazine-5(4H)-ketone [ka]

[0150] Step 1: Compound 5a (25.0 g, 231 mmol), pyridine (21.6 g, 277 mmol), and dichloromethane (125 mL) were weighed into a flask, cooled to 0°C, and then Tf2O (71.7 g, 254 mmol) was slowly added dropwise. The resulting mixture was stirred at room temperature for 1 hour to allow it to react. The reaction mixture was filtered, the filter cake was washed with dichloromethane (20 mL), and the filtrate was collected to obtain a dichloromethane solution (pale yellow) of target compound 5b.

[0151] Step 2: Compound 5c (50.9 g, 254 mmol) and triethylamine (70.1 g, 693 mmol) were dissolved in dichloromethane (250 mL). The dichloromethane solution of compound 5b was added dropwise to the solvent at room temperature, and the resulting mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was mixed with silica gel, concentrated under reduced pressure, and purified by column chromatography (PE:Â=3:1, iodine color development) to obtain target compound 5d (20.0 g, 68.9 mmol, pale yellow solid, two-step yield: 30%). MS / ESI[M+H] + =291.1.

[0152] Step 3: Compound 5d (20.0 g, 68.9 mmol) was dissolved in ethyl acetate (100 mL), followed by the addition of HCl / RINKAN (86 mL, 345 mmol, 4.0 M). The resulting mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain the target compound 5e (15.6 g, 59.3 mmol, white solid, yield: 86%). MS / ESI[M+H] + = 191.2.

[0153] Referring to Embodiment 2, (R)-6-((1-(3,3-difluorocyclobutyl)piperidine-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazine-5(4H)-ketone was prepared. 1 H NMR(400MHz,CDCl3)δ7.62(d,J=5.5Hz,1H),7.47-7.31(m,2H),7.21(d,J=8.5Hz,1H),6.31(s,1H),4.24(s,1H),3.60(s, 3H),2.67(dd,J=11.5,7.9Hz,3H),2.52-2.33(m,4H),2.23(dd,J=16.5,9.0Hz,1H),1.83-1.70(m,4H),1.66-1.61(m,1H). MS / ESI[M+H] + = 448.3.

[0154] Embodiment 6: (R)-6-((1-(ethyl-d5)piperidine-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazine-5(4H)-ketone [ka]

[0155] Step 1: Compound 5c (10.0 g, 49.9 mmol) and K2CO3 (13.8 g, 99.8 mmol) were added to MeCN (100 mL), followed by the addition of deuterated bromoethane (6.83 g, 59.9 mmol). The resulting mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, the filtrate cake was dissolved in RINKAN (100 mL), washed with water (30 mL x 3), the organic phase was recovered, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain target compound 6a (10.1 g, 43.3 mmol, light brown solid, yield: 87%). 1 H NMR (400MHz, CDCl3) δ4.99(s,1H),3.73(s,1H),2.54-2.21(m,4H),1.74-1.52(m,4H),1.45(s,9H).

[0156] Step 2: Compound 6a (10.1 g, 43.3 mmol) was dissolved in dioxane (50 mL), followed by the slow addition of HCl / dioxane (65 mL, 4.0 M). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain target compound 6b (9.20 g, 44.6 mmol, white solid, yield: 100%).

[0157] (R)-6-((1-(ethyl-d5)piperidine-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazine-5(4H)-ketone was prepared with reference to Embodiment 2. 1 H NMR(400MHz,MeOD)δ8.51(s,1H),7.64(d,J=5.6Hz,1H),7.58(dd,J=6.9,4.5Hz,2H),7.30(d,J=8.2Hz,1H),4.35(t,J=8.8Hz,1H ),3.65(d,J=9.4Hz,1H),3.36(s,3H),3.30(d,J=4.5Hz,1H),3.09-2.80(m,2H),2.09(dd,J=26.7,9.0Hz,2H),1.96-1.71(m,2H). MS / ESI[M+H] + = 391.5.

[0158] Embodiment 7: (R)-6-((1-(ethyl-d5)piperidine-3-yl)amino)-3-(1-hydroxynaphthalene-2-yl)-4-methyl-1,2,4-triazine-5(4H)-ketone [ka]

[0159] Referring to Embodiment 2, (R)-6-((1-(ethyl-d5)piperidine-3-yl)amino)-3-(1-hydroxynaphthalene-2-yl)-4-methyl-1,2,4-triazine-5(4H)-ketone (60 mg, 19.5%) was prepared. 1H NMR(400MHz,DMSO-d6)δ10.14(brs,1H),8.29(d,J=8.0Hz,1H),7.92(d,J=7.6Hz,1H),7.68-7.45(m,3H),7.38(d,J=8.4Hz,1H),6.83(br s,1H),4.16-4.01(m,1H),3.19(s,3H),2.95-2.74(m,1H),2.65-2.54(m,1H),2.29-2.09(m,2H),1.84-1.45(m,4H). MS / ESI[M+H] + =385.0.

[0160] Embodiment 8: (R)-6-((1-(cyclopropylmethyl)piperidine-3-yl)amino)-3-(4-hydroxybenzo[b]thiophene-5-yl)-4-methyl-1,2,4-triazine-5(4H)-ketone [ka]

[0161] Step 1: Compound 5c (1.0 g, 5 mmol) and bromomethylcyclopropane (675 mg, 5 mmol) were dissolved in 10 mL of anhydrous acetonitrile, followed by the addition of potassium carbonate (759 mg, 5.5 mmol). The reaction solution was stirred overnight at room temperature. The formation of the target product was confirmed by LC-MS. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate, the organic phase was washed three times with water and saturated brine solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified with methanol / dichloromethane to obtain target compound 8a (300 mg, yield: 24%). MS / ESI[M+H] + = 255.6.

[0162] Step 2: Compound 8a (300 mg, 1.18 mmol) was completely dissolved in anhydrous DCM (5 mL), followed by the addition of dioxane hydrochloride solution (4 M, 5 mL). The resulting mixture was reacted at room temperature for 2 hours, and the complete reaction of the starting materials was confirmed by LC-MS. The reaction solution was concentrated under reduced pressure to obtain compound 8b (267 mg, yield: 100%). MS / ESI[M+H] + = 155.1.

[0163] Referring to Embodiment 2, ((R)-6-((1-(cyclopropylmethyl)piperidine-3-yl)amino)-3-(4-hydroxybenzo[b]thiophene-5-yl)-4-methyl-1,2,4-triazine-5(4H)-ketone (128 mg, 39.1%) was synthesized. 1 H NMR(400MHz,DMSO-d6)δ10.41(br s,1H),9.54(br s,1H),7.79-7.70(m,2H),7.63(d,J=8.0Hz,1H),7.28(d,J=8.4Hz,1H),4.41-4.29(m,1H),3.72-3.54(m,2H),3.23(s,3H),3.15 -3.02(m,2H),2.97-2.80(m,2H),2.06-1.94(m,2H),1.86-1.68(m,2H),1.14-1.01(m,1H),0.72-0.58(m,2H),0.46-0.33(m,2H). MS / ESI[M+H] + = 412.0.

[0164] Embodiment 9: (R)-3-(4-hydroxybenzo[b]thiophen-5-yl)-6-((1-(2-hydroxyethyl)piperidine-3-yl)amino)-4-methyl-1,2,4-triazine-5(4H)-ketone [ka]

[0165] Referring to Embodiment 1, (R)-3-(4-hydroxybenzo[b]thiophen-5-yl)-6-((1-(2-hydroxyethyl)piperidine-3-yl)amino)-4-methyl-1,2,4-triazine-5(4H)-ketone was prepared. MS / ESI[M+H] + =402.2. 1H NMR(400MHz,Methanol-d4)δ7.52(d,J=5.6Hz,1H),7.47-7.40(m,2H),7.18(d,J=8.0Hz,1H),4.12-4.02(m,1H),3.64-3.57(m,2H) ),3.24(s,3H),3.01-2.91(m,1H),2.66-2.57(m,1H),2.55-2.47(m,2H),2.44-2.26(m,2H),1.87-1.67(m,2H),1.65-1.47(m,2H).

[0166] Embodiment 10: (R)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-6-((1-methyl-d3)piperidine-3-yl)amino)-1,2,4-triazine-5(4H)-ketone [ka]

[0167] Step 1: Compound 5c (2 g, 10 mmol), CD3I (1.5 g, 10 mmol), K2CO3 (2.76 g, 20 mmol), and acetonitrile (30 mL) were added to a dry flask as solvent and reacted overnight at room temperature. Water was added, and the reaction mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain compound 10a (white solid, 2.03 g). MS / ESI[M+H] + = 218.2.

[0168] Step 2: Compound 10a (2.03 g, 9.35 mmol), 1,4-dioxane (10 mL), and HCl (4 M in dioxane) (9.35 mL) were added to a dry flask and reacted at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to remove excess solvent and obtain compound 10b (white solid, 1.32 g), which can be used directly in the next reaction.

[0169] Step 3: Compound 10b (1.32 g, 7 mmol), INT5 (2.28 g, 7 mmol), Pd(OAc)2 (157.2 mg, 0.7 mmol), BINAP (435.9 mg, 0.7 mmol), and Cs2CO3 (6.6 g, 35 mmol) were added to a dry flask under a nitrogen atmosphere. The resulting mixture was reacted overnight at 100°C with dioxane (35 mL) as the solvent. After confirming the completion of the reaction by TLC, the reaction mixture was filtered, concentrated under reduced pressure, and the resulting residue was purified by column chromatography to obtain compound 10c (brown oily liquid, 0.95 g). MS / ESI[M+H] + = 363.2.

[0170] Step 4: Compound 10c (0.95 g, 2.6 mmol), DCM (10 mL), and TfOH (1.17 g, 7.8 mmol) were added to a dry flask and allowed to react overnight at room temperature. After confirming the completion of the reaction by TLC, the pH of the reaction mixture was adjusted to pH=8-9 with dry NaHCO3 and a small amount of aqueous ammonia. The reaction mixture was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain compound 10d (brown oily liquid, 600 mg). MS / ESI[M+H] + = 243.2.

[0171] Step 5: Add compound 10d (600 mg, 2.5 mmol) and POCl3 (6 mL) to a dry flask and react the resulting mixture overnight at 100°C. After the reaction is complete, concentrate the reaction mixture under reduced pressure to remove excess POCl3, adjust the pH of the reaction mixture to 8-9 with dry NaHCO3 and a small amount of aqueous ammonia, dry the reaction mixture over anhydrous Na2SO4, filter, concentrate the filtrate under reduced pressure, and purify the resulting residue by column chromatography to obtain compound 10e (light brown solid, 487 mg). MS / ESI[M+H] + = 261.1.

[0172] Step 6: Compound 10e (200 mg, 0.77 mmol), INT1 (268 mg, 0.93 mmol), Pd(dppf)Cl2 (58.6 mg, 0.08 mmol), Cs2CO3 (1.17 g, 3.6 mmol), and 1,4-dioxane / H2O (6 mL / 1 mL) were added to a dry flask and reacted overnight at 100°C. After confirming completion of the reaction by TLC, the reaction solution was allowed to return to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain compound 10f (yellow oily liquid, 108 mg). MS / ESI[M+H] + = 389.2.

[0173] Step 7: Under a nitrogen atmosphere, compound 10f (108 mg, 0.28 mmol) and DCM (2 mL) were added to a dry flask, cooled to -10°C, and then BBr3 (1 M, 1 mL) was added dropwise. The resulting mixture was reacted for 3 hours. After adding MeOH to the reaction solution to stop the reaction, the reaction solution was returned to room temperature and concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain compound 10 (pale yellow solid, 15.6 mg). 1 H NMR(400MHz,CDCl3)δ7.55(d,J=5.5Hz,1H),7.35-7.28(m,2H),7.14(d,J=8.5Hz,1H) ,4.15(s,1H),3.51(s,3H),2.64-2.38(m,4H),2.28-2.09(m,4H),1.59-1.48(m,1H).

[0174] Embodiment 11: (R)-3-(4-cyclopropyl-2-hydroxyphenyl)-6-((1-ethylpiperidine-3-yl)amino)-4-methyl-1,2,4-triazine-5(4H)-ketone [ka]

[0175] Step 1: Compound 2d (150 mg, 0.32 mmol), INT6 (104.2 mg, 0.38 mmol), Pd(dppf)Cl2 (22 mg, 0.03 mmol), and Cs2CO3 (417.3 mg, 1.28 mmol) were added to a dry flask under a nitrogen atmosphere, and the resulting mixture was reacted overnight at 100°C with dioxane as the solvent. After confirming the completion of the reaction by TLC, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure to remove excess solvent, and the resulting residue was purified by column chromatography to obtain compound 11a (brown oily liquid, 79 mg). MS / ESI[M+H] + = 384.2.

[0176] Step 2: Under a nitrogen atmosphere, compound 11a (79 mg, 0.21 mmol) and DCM (1 mL) were added to a dry flask, cooled to -10°C, and then BBr3 (1 M, 0.84 mL) was added dropwise. The resulting mixture was reacted for 3 hours. After adding MeOH to the reaction solution to stop the reaction, the reaction solution was returned to room temperature and concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain compound 11 (off-white solid, 4.5 mg). 1 H NMR(400MHz,CD3OD)δ7.61(d,J=4.1Hz,1H),7.16-7.08(m,2H),4.25-4.19(m,1H),3.34(s,3H),2.95-2.7 5(m,4H),2.15-2.02(m,4H),1.97-1.78(m,3H),1.79-1.62(m,2H),1.33-1.24(m,5H),1.23-1.12(m,1H).

[0177] Embodiment 12: (R)-4-ethyl-6-((1-ethylpiperidine-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-1,2,4-triazine-5(4H)-ketone [ka]

[0178] Step 1: Compound INT5a (200 mg, 1.04 mmol) was added to the reaction flask, then DMF (10 mL) and DIEA (269 mg, 2.08 mmol) were added to the reaction flask, followed by the slow addition of iodoethane (163 mg, 1.04 mmol). The resulting mixture was reacted at room temperature for 3 hours, and the completion of the reaction was confirmed by LC-MS. Water was then added to the reaction mixture, the reaction mixture was extracted with EA, re-extracted with the aqueous phase, the organic phases were combined and concentrated, and the resulting residue was purified by column chromatography and concentrated to obtain product 12a (200 mg). LC-MS: ESI[M+H] + = 221.0.

[0179] Step 2: Compound 12a (200 mg, 0.91 mmol), potassium carbonate (251 mg, 1.82 mmol), and PMBCl (213 mg, 1.36 mmol) were added to the reaction flask, followed by the addition of DMF (10 mL). The resulting mixture was heated to 60°C and reacted for 3 hours. After confirming the completion of the reaction by LC-MS, water was added to the reaction mixture, the reaction mixture was extracted with EA, re-extracted with the aqueous phase, the organic phases were combined and concentrated, and the resulting residue was purified by column chromatography and concentrated to obtain product 12b (110 mg). LC-MS: ESI[M+H] + =341.1.

[0180] Step 3: Compounds 12b (110 mg, 0.32 mmol), 2a (83 mg, 0.65 mmol), palladium acetate (6 mg, 0.03 mmol), BINAP (35 mg, 0.06 mmol), cesium carbonate (185 g, 0.57 mmol), and dioxane (10 mL) were added to the reaction flask and stirred at 100°C for 15 hours under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was cooled to room temperature, concentrated, and the resulting residue was purified by silica gel column chromatography to obtain product 12c (69 mg). LC-MS:ESI[M+H] + =387.0.

[0181] Step 4: Compound 12c (69 mg, 0.18 mmol) was added to the reaction flask, dichloromethane (5 mL) was added, and the mixture was cooled to 0°C. Subsequently, trifluoromethanesulfonic acid (1 mL) was slowly added dropwise to the reaction flask, and the resulting mixture was stirred at room temperature for 15 hours. After the reaction was complete, the reaction mixture was cooled to 0°C-5°C with acetonitrile (10 mL), solid sodium bicarbonate was added to the cooled mixture until no more bubbles were generated, and then the pH of the cooled mixture was adjusted to 7-8 with aqueous ammonia. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to obtain compound 12d (43 mg). LC-MS:ESI[M+H] + = 268.1.

[0182] Step 5: Compound 12d (43 mg, 0.16 mmol) was dispersed in phosphorus oxychloride (10 mL), and the resulting mixture was stirred at 110°C for 12 hours under a nitrogen atmosphere. After the reaction was complete, the solvent was concentrated directly, and the resulting residue was dispersed in acetonitrile (10 mL) and dichloromethane (10 mL). The resulting mixture was cooled to 0°C to 5°C, and solid sodium bicarbonate was added to the cooled mixture until no more bubbles were generated. The pH of the cooled mixture was then adjusted to 7-8 with aqueous ammonia, the mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to obtain compound 12e (30 mg). LC-MS: ESI[M+H] + = 286.1.

[0183] Step 6: Compound 12e (30 mg, 0.10 mmol), INT1 (46 mg, 0.16 mmol), Pd(dppf)2Cl2 (7 mg, 0.01 mmol), cesium carbonate (68 mg, 0.21 mmol), and dioxane (8 mL) / water (2 mL) were added to the reaction flask and stirred at 100°C for 15 hours under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was cooled to room temperature, and the resulting residue was purified by silica gel column chromatography to obtain compound 12f (22 mg). LC-MS: ESI[M+H]+ = 414.0.

[0184] Step 7: Compound 12f (22 mg, 0.05 mmol) was added to the reaction flask, DCM (10 mL) was added, and the mixture was cooled to -10°C. Subsequently, BBr3 (67 mg, 0.27 mmol) was slowly added dropwise, and the resulting mixture was reacted at -10°C for 3 hours. After confirming the completion of the reaction by MS, methanol was added to the reaction mixture to stop the reaction, the reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 12 (5 mg). LC-MS: ESI[M+H] + =400.1. 1 H NMR(400MHz,DMSO-d6)δ10.26(s,1H),7.73(d,J=8.0Hz,1H),7.71(d,J=8.0Hz,1H),7.59(d,J=8.0Hz,1H),7.30(d,J=8.0Hz,1H) ,3.83(q,J=8.0,4.0Hz,2H),2.38-2.34(m,4H),1.67-1.55(m,4H),1.49-1.45(m,2H),1.14(t,J=8.0Hz3H),1.02(t,J=8.0Hz3H).

[0185] Embodiment 13: (R)-3-(1-(difluoromethylene)-4-hydroxy-2,3-dihydro-1H-inden-5-yl)-4-methyl-6-((1-methylpiperidine-3-yl)amino)-1,2,4-triazine-5(4H)-ketone TIFF2026509587000055.tif19170

[0186] Referring to Embodiment 2, (R)-3-(1-(difluoromethylene)-4-hydroxy-2,3-dihydro-1H-inden-5-yl)-4-methyl-6-((1-methylpiperidine-3-yl)amino)-1,2,4-triazine-5(4H)-ketone was prepared. MS / ESI[M+H] + =404.2. 1H NMR(400MHz,CD3OD)δ7.28(d,J=7.7Hz,1H),7.13(d,J=7.5Hz,1H),4.33-4.28(m,1H),3.36(s,3H),3.12-3.03(m,2H),2.95 -2.91(m,2H),2.84-2.81(m,1H),2.27(s,3H),2.25-2.09(m,3H),2.04-1.94(m,2H),1.82-1.74(m,1H),1.42-1.34(m,2H).

[0187] Embodiment 14: (R)-6-((1-(3,3-difluorocyclobutyl)piperidine-3-yl)amino)-3-(1-(difluoromethylene)-4-hydroxy-2,3-dihydro-1H-inden-5-yl)-4-methyl-1,2,4-triazine-5(4H)-ketone [ka]

[0188] Referring to Embodiment 2, (R)-6-((1-(3,3-difluorocyclobutyl)piperidine-3-yl)amino)-3-(1-(difluoromethylene)-4-hydroxy-2,3-dihydro-1H-inden-5-yl)-4-methyl-1,2,4-triazine-5(4H)-ketone was prepared. MS / ESI[M+H] + =480.2. 1 H NMR(400MHz,CD3OD)δ7.08(d,J=7.9Hz,1H),6.86(d,J=7.8Hz,1H),4.02(s,1H),3.25(S,3H),2.96-2.90(m,2H),2.76-2.72(m,2H),2 .65-2.52(m,2H),2.47-2.24(m,3H),2.12-2.07(m,1H),1.98-1.92(m,1H),1.59-1.46(m,3H),1.25-1.23(m,2H),1.20-1.18(m,4H).

[0189] Embodiment 15: (R)-3-(1-(difluoromethylene)-4-hydroxy-2,3-dihydro-1H-inden-5-yl)-6-((1-(ethyl-d5)piperidine-3-yl)amino)-4-methyl-1,2,4-triazine-5(4H)-ketone [ka]

[0190] Step 1: Under a nitrogen atmosphere, compound 6e (132 mg, 0.5 mmol), INT3 (193.2 mg, 0.6 mmol), Pd(dppf)Cl2 (36.6 mg, 0.05 mmol), Cs2CO3 (652 mg, 2 mmol), and dioxane / H2O (5 mL / 1 mL) were added to a dry flask and reacted overnight at 100°C. After confirming the completion of the reaction by TLC, the reaction solution was allowed to return to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain compound 15a (brown oily liquid, 108 mg). MS / ESI[M+H] + = 437.2.

[0191] Step 2: Under a nitrogen atmosphere, compound 15a (108 mg, 0.25 mmol) and DCM (2 mL) were added to a dry flask and cooled to -10°C. Subsequently, BBr3 (1 M, 1 mL) was added dropwise, and the resulting mixture was reacted for 3 hours. After adding MeOH to the reaction solution to stop the reaction, the reaction solution was returned to room temperature and concentrated under reduced pressure. The resulting residue was purified to obtain compound 15 (pale yellow solid, 42.5 mg). 1 H NMR(400MHz,CD3OD)δ7.28(d,J=7.7Hz,1H),7.13(d,J=7.5Hz,1H),4.33-4.28(m,1H),3.38(s,3H),3.10-3.04(m,2H) ),2.94-2.91(m,2H),2.84-2.80(m,1H),2.25-2.09(m,3H),2.04-1.94(m,2H),1.82-1.72(m,1H),1.34-1.31(m,2H).

[0192] Embodiment 16: (R)-6-((1-(cyclopropylpiperidine-3-yl)amino)-3-(4-hydroxybenzo[b]thiophene-5-yl)-4-methyl-1,2,4-triazine-5(4H)-ketone [ka]

[0193] Step 1: Compounds 5c (400 mg, 2 mmol) and 16a (522 mg, 3 mmol) were dissolved in 9 mL of tetrahydropyran and 1 mL of methanol. Subsequently, sodium borohydride cyanohydride (378 mg, 6 mmol) and glacial acetic acid (1.44 g, 24 mmol) were added sequentially under a nitrogen atmosphere at room temperature, and the reaction solution was stirred at 65°C for 16 hours. After confirming the completion of the reaction by TLC, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with saturated sodium bicarbonate solution, the dilution was extracted three times with DCM, the organic phases were combined, washed with saturated brine solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified with methanol / dichloromethane to obtain compound 16b (300 mg, yield: 62.5%). MS / ESI[M+H] + = 241.3.

[0194] Step 2: Compound 16b (300 mg, 1.25 mmol) was completely dissolved in anhydrous DCM (5 mL), followed by the addition of dioxane hydrochloride solution (4 M, 10 mL). The resulting mixture was reacted at room temperature for 2 hours, and the complete reaction of the starting materials was confirmed by LC-MS. The reaction solution was concentrated under reduced pressure to obtain compound 16c (270 mg). MS / ESI[M+H] + = 141.1.

[0195] Step 3: Compounds INT5 (300 mg, 0.92 mmol), 16c (193.2 mg, 1.38 mmol), Pd(OAc)2 (20.2 mg, 0.09 mmol), BINAP (56.1 mg, 0.09 mmol), and Cs2CO3 (1.47 g, 4.5 mmol) were added to a dry flask under a nitrogen atmosphere. The resulting mixture was reacted overnight at 100°C with dioxane (10 mL) as the solvent. After confirming the completion of the reaction by TLC, the reaction mixture was filtered, concentrated under reduced pressure, and the resulting residue was purified by column chromatography to obtain compound 16d (yellow oily liquid, 385 mg). MS / ESI[M+H] + = 386.2.

[0196] Step 4: Compound 16d (325 mg, 0.84 mmol), DCM (4 mL), and TfOH (378.2 mg, 2.52 mmol) were placed in a dry flask and reacted overnight at room temperature. After confirming the completion of the reaction by TLC, the pH of the reaction mixture was adjusted to 8-9 with dry NaHCO3 and a small amount of aqueous ammonia. The reaction mixture was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain compound 16e (brown solid, 201 mg). MS / ESI[M+H] + = 266.2.

[0197] Step 5: Compound 16e (201 mg, 0.81 mmol) and POCl3 (5 mL) were added to a dry flask, and the resulting mixture was reacted overnight at 100°C. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to remove excess POCl3, and the pH of the reaction mixture was adjusted to 8-9 with dry NaHCO3 and a small amount of aqueous ammonia. The reaction mixture was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain compound 16f (light brown solid, 102 mg). MS / ESI[M+H] + = 284.1.

[0198] Step 6: Under a nitrogen atmosphere, compound 16f (102 mg, 0.36 mmol), compound INT1 (125.3 mg, 0.43 mmol), Pd(dppf)Cl2 (29.3 mg, 0.04 mmol), Cs2CO3 (469.4 mg, 1.44 mmol), and 1,4-dioxane / H2O (4 mL / 0.8 mL) were added to a dry flask and reacted overnight at 100°C. After confirming the completion of the reaction by TLC, the reaction solution was allowed to return to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain 16 g of compound (bright yellow oily liquid, 87 mg). MS / ESI[M+H] + = 412.2.

[0199] Step 7: Under a nitrogen atmosphere, 16 g (87 mg, 0.21 mmol) of compound and DCM (2 mL) were added to a dry flask, cooled to -10°C, and then BBr3 (1 M, 0.84 mL) was added dropwise. The resulting mixture was reacted for 3 hours. After adding MeOH to the reaction solution to stop the reaction, the reaction solution was returned to room temperature and concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain compound 16 (off-white solid, 22.1 mg). 1 H NMR(400MHz,CD3OD)δ7.52(d,J=5.5Hz,1H),7.48-7.44(m,2H),7.19(d,J=8.3Hz,1H),4.01(s,1H),3.23(s,3H),3.15-3.02 (m,2H),2.97-2.80(m,2H),2.06-1.94(m,2H),1.86-1.68(m,2H),1.14-1.01(m,1H),0.72-0.58(m,2H),0.46-0.33(m,2H). MS / ESI[M+H] + = 398.2.

[0200] Embodiment 17: (R)-4-ethyl-3-(4-hydroxybenzo[b]thiophen-5-yl)-6-[(1-methylpiperidine-3-yl)amino]-1,2,4-triazine-5(4H)-ketone [ka]

[0201] (R)-4-ethyl-3-(4-hydroxybenzo[b]thiophen-5-yl)-6-[(1-methylpiperidine-3-yl)amino]-1,2,4-triazine-5(4H)-ketone was prepared with reference to Example 12. 1 H NMR(400MHz,DMSO)δ10.22(s,1H),7.73(d,J=4.0Hz,2H),7.59(d,J=8.0Hz,1H),7.29(d,J=8.0Hz,1H),4.14(s,1H),3.72(q,J=8 .0,4.0Hz,2H),3.05-2.95(m,1H),2.74-2.68(m,1H),2.41(s,3H),1.85-1.73(m,2H),1.68-1.55(m,2H),1.00(t,J=8.0Hz,3H). MS / ESI[M+H] + = 386.1.

[0202] Embodiment 18: (R)-3-(1-hydroxy-2-naphthyl)-4-methyl-6-((1-methylpiperidine-3-yl)amino)-1,2,4-triazine-5(4H)-ketone [ka]

[0203] Referring to Embodiment 2, (R)-3-(1-hydroxy-2-naphthyl)-4-methyl-6-((1-methylpiperidine-3-yl)amino)-1,2,4-triazine-5(4H)-ketone was prepared. MS / ESI[M+H] + = 366.2.

[0204] Embodiment 19: (R)-6-((1-ethylpiperidine-3-yl)amino)-3-(1-hydroxynaphthalene-2-yl)-4-methyl-1,2,4-triazine-5(4H)-ketone [ka]

[0205] Referring to Embodiment 2, (R)-6-((1-ethylpiperidine-3-yl)amino)-3-(1-hydroxynaphthalene-2-yl)-4-methyl-1,2,4-triazine-5(4H)-ketone was prepared. MS / ESI[M+H] + = 380.2.

[0206] Embodiment 20: (R)-6-((1-(2-hydroxyethyl)piperidine-3-yl)amino)-3-(1-hydroxynaphthalene-2-yl)-4-methyl-1,2,4-triazine-5(4H)-ketone [ka]

[0207] Referring to Embodiment 1, (R)-6-((1-(2-hydroxyethyl)piperidine-3-yl)amino)-3-(1-hydroxynaphthalene-2-yl)-4-methyl-1,2,4-triazine-5(4H)-ketone was prepared. MS / ESI[M+H] + = 396.2.

[0208] Embodiment 21: (R)-4-Cyclopropyl-3-(4-Hydroxybenzo[b]thiophene-5-yl)-6-((1-Methylpiperidine-3-yl)amino)-1,2,4-Triadine-5(4H)-Ketone [ka]

[0209] Referring to Embodiment 12, (R)-4-cyclopropyl-3-(4-hydroxybenzo[b]thiophen-5-yl)-6-((1-methylpiperidine-3-yl)amino)-1,2,4-triazine-5(4H)-ketone was prepared. MS / ESI[M+H] + = 398.2.

[0210] Embodiment 22: (R)-4-Cyclopropyl-6-((1-Ethylpiperidine-3-yl)amino)-3-(4-Hydroxybenzo[b]thiophene-5-yl)-1,2,4-Triadine-5(4H)-Ketone [ka]

[0211] Referring to Embodiment 12, (R)-4-cyclopropyl-6-((1-ethylpiperidine-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-1,2,4-triazine-5(4H)-ketone was prepared. MS / ESI[M+H] + = 412.2.

[0212] Embodiment 23: (R)-4-Cyclopropyl-3-(4-Hydroxybenzo[b]thiophene-5-yl)-6-((1-(2-Hydroxyethyl)piperidine-3-yl)amino)-1,2,4-Triadine-5(4H)-Ketone [ka]

[0213] Referring to Embodiment 11, (R)-4-cyclopropyl-3-(4-hydroxybenzo[b]thiophene-5-yl)-6-((1-(2-hydroxyethyl)piperidine-3-yl)amino)-1,2,4-triazine-5(4H)-ketone was prepared. MS / ESI[M+H] + = 428.2.

[0214] Embodiment 24: (R)-3-(4-ethynyl-2-hydroxyphenyl)-4-methyl-6-((1-methylpiperidine-3-yl)amino)-1,2,4-triazine-5(4H)-ketone [ka]

[0215] Step 1: Compound 24a (2.0 g, 9.35 mmol) and HBr (48%, 18 mL) were added to a dry flask, and the resulting mixture was stirred overnight at 100°C. After the reaction was complete, the mixture was allowed to return to room temperature, the reaction was stopped with water, and the mixture was extracted three times with ethyl acetate. The resulting organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain compound 24b (1.13 g, 60%). LC-MS: ESI[M+H] + = 200.9.

[0216] Step 2: Compound 24b (1.13 g, 5.65 mmol) was added to a dry flask and dissolved in THF (20 mL). The resulting solution was cooled to 0°C, followed by the addition of NaH (60%, 339.2 mg, 8.48 mmol). The resulting mixture was stirred for 20 minutes, followed by the addition of MOMCl (797.1 mg, 8.48 mmol). The resulting solution was reacted for 4 hours, the reaction was stopped with saturated NH4Cl aqueous solution, the mixture was aliquoted, extracted three times with ethyl acetate, the resulting organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain compound 24c (1.24 g, 90%). LC-MS: ESI[M+H] + = 245.1.

[0217] Step 3: Compound 24c (1.24 g, 5.08 mmol), (Bpin)2 (1.55 g, 6.1 mmol), Pd(dppf)Cl2 (36.6 mg, 0.05 mmol), KOAc (1.0 g, 10.2 mmol), and 1,4-dioxane (20 mL) were added to a dry flask and stirred overnight at 100°C. After the reaction was complete, the mixed solution was allowed to return to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The resulting organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain compound 24d (684 mg, 46%). LC-MS:ESI[M+H] + =293.1.

[0218] Step 4: K2CO3 (646.8 mg, 4.68 mmol) and compound 24e (539.2 mg, 2.81 mmol) were added to a solution of compound 24d (684 mg, 2.34 mmol) in MeOH (8 mL) at room temperature. The resulting mixture was reacted at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to remove excess solvent, dissolved in water, extracted with DCM, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain compound 24f (366 mg, 54%). LC-MS:ESI[M+H] + = 289.2.

[0219] Step 5: Compound 24f (182 mg, 0.63 mmol), 16c (206.0 mg, 0.76 mmol), Pd(dppf)Cl2 (43.9 mg, 0.06 mmol), Cs2CO3 (616.1 mg, 1.89 mmol), and 1,4-dioxane (20 mL) were added to a dry flask and reacted overnight at 100°C. After the reaction was complete, the mixed solution was allowed to return to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain 24 g (87 mg, 35%) of compound 24 g. LC-MS: ESI[M+H] + = 384.2.

[0220] Step 6: Add 24 g (87 mg, 0.22 mmol) of compound, 1,4-dioxane (3 mL), and HCl (4 M in dioxane) (0.3 mL) to a dry flask and react at room temperature for 3 hours. The reaction mixture is concentrated under reduced pressure to remove excess solvent and obtain compound 24 (9.8 mg, 13%). LC-MS: ESI[M+H] + =340.2. 1H NMR(400MHz,CD3OD)δ7.30(d,J=7.8Hz,1H),7.05(d,J=7.8Hz,1H),7.01(s,1H),4.20-4.13(m,1H),3.32(s,3H),3.04-2.88(m,1H) ),2.72-2.54(m,1H),2.32(s,3H),2.30-2.19(m,2H),1.98-1.86(m,1H),1.84-1.75(m,1H),1.70-1.55(m,2H),1.34-1.32(m,1H).

[0221] Embodiment 25: (R)-6-((1-ethylpiperidine-3-yl)amino)-3-(4-ethynyl-2-hydroxyphenyl)-4-methyl-1,2,4-triazine-5(4H)-ketone [ka]

[0222] Referring to Embodiment 24, (R)-6-((1-ethylpiperidine-3-yl)amino)-3-(4-ethynyl-2-hydroxyphenyl)-4-methyl-1,2,4-triazine-5(4H)-ketone was prepared. MS / ESI[M+H] + =354.2. 1 H NMR(400MHz,CD3OD)δ7.33(d,J=7.8Hz,1H),7.11-7.00(m,2H),4.20-4.13(m, 1H),3.60(s,1H),3.35(s,1H),3.10-3.02(m,1H),2.77-2.68(m,1H),2.52(dd, J=14.2,7.0Hz,2H),2.34-2.21(m,1H),2.02-1.92(m,1H),1.86-1.78(m,1H),1 .75-1.67(m,1H),1.64-1.54(m,1H),1.36-1.31(m,1H),1.14(t,J=7.2Hz,3H).

[0223] Embodiment 26: (R)-3-(4-ethynyl-2-hydroxyphenyl)-6-((1-(2-hydroxyethyl)piperidine-3-yl)amino)-4-methyl-1,2,4-triazine-5(4H)-ketone [ka]

[0224] Referring to Embodiment 1, (R)-3-(4-ethynyl-2-hydroxyphenyl)-6-((1-(2-hydroxyethyl)piperidine-3-yl)amino)-4-methyl-1,2,4-triazine-5(4H)-ketone was prepared. MS / ESI[M+H] + = 370.2.

[0225] Embodiment 27: (R)-3-(2-hydroxy-4-(propa-1-in-1-yl)phenyl)-4-methyl-6-((1-methylpiperidine-3-yl)amino)-1,2,4-triazine-5(4H)-ketone [ka]

[0226] Step 1: Compounds 24c (8 g, 30.88 mmol, 1.0 equivalent), 24e (8.9 g, 46.32 mmol, 1.5 equivalent), and anhydrous potassium carbonate (8.5 g, 61.76 mmol, 2.0 equivalent) were added to methanol (150 mL), and the resulting mixture was reacted at room temperature for 3 hours. No starting materials were detected by TLC. The reaction mixture was concentrated under reduced pressure, water (30 mL) was added, and then extracted with ethyl acetate (30 mL x 3). The resulting organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (EA:PE = 1:150) to obtain compound 27a (3 g, yield: 38.5%).

[0227] Step 2: Compound 27a (500 mg, 1.96 mmol, 1.0 equivalent) was dissolved in anhydrous THF (10 mL), the resulting solvent was cooled to -70°C, and then 1.35 mL, 1.1 equivalent, of a 1.6 mol / L n-butyllithium THF solution was added dropwise. The resulting mixture was reacted at -75°C to -70°C for 1 hour, then methyl iodide (834.6 mg, 5.88 mmol, 3.0 equivalent) was added, and the resulting solvent was heated to room temperature and reacted for 16 hours. After confirming the completion of the reaction by LC-MS, saturated ammonium chloride aqueous solution (50 mL) was added to the reaction mixture, the resulting solvent was extracted with ethyl acetate (50 mL x 2), the resulting organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE = 1:100) to obtain compound 27b (485 mg, yield: 91.9%).

[0228] Step 3: Compound 27b (1.28 g, 5.0 mmol), (Bpin)2 (1.55 g, 6.0 mmol), Pd(dppf)Cl2 (36.6 mg, 0.05 mmol), KOAc (1.0 g, 10.2 mmol), and 1,4-dioxane (20 mL) were added to a dry flask and stirred overnight at 100°C. After the reaction was complete, the mixed solution was allowed to return to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The resulting organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain compound 27c (684 mg, 46%). LC-MS: ESI[M+H] + = 303.1.

[0229] Referring to Embodiment 24, (R)-3-(2-hydroxy-4-(propa-1-in-1-yl)phenyl)-4-methyl-6-((1-methylpiperidine-3-yl)amino)-1,2,4-triazine-5(4H)-ketone was prepared. LC-MS:ESI[M+H] + =354.2. 1H NMR(400MHz,DMSO-d6)δ10.36(brs,1H),7.31(d,J=8.0Hz,1H),7.06-6.93(m,2H),6.82(d,J=8.0Hz,1H),4.18-3. 91(m,1H),3.23(s,3H),2.79-2.70(m,1H),2.54-2.45(m,1H),2.24(s,3H),2.21-2.08(m,5H),1.79-1.52(m,4H).

[0230] Embodiment 28: (R)-6-((1-ethylpiperidine-3-yl)amino)-3-(2-hydroxy-4-(propa-1-in-1-yl)phenyl)-4-methyl-1,2,4-triazine-5(4H)-ketone [ka]

[0231] Referring to Embodiment 27, (R)-6-((1-ethylpiperidine-3-yl)amino)-3-(2-hydroxy-4-(propa-1-in-1-yl)phenyl)-4-methyl-1,2,4-triazine-5(4H)-ketone was prepared. MS / ESI[M+H] + =368.2. 1 H NMR(400MHz,Methanol-d4)δ7.25(d,J=8.0Hz,1H),6.95(dd,J=8.0,1.2Hz,1H), 6.91(d,J=1.2Hz,1H),4.60(brs,1H),4.23-4.06(m,1H),3.32(s,3H),3.09-2.9 8(m,1H),2.75-2.63(m,1H),2.56-2.41(m,2H),2.35-2.19(m,2H),2.03(s,3H), 1.99-1.91(m,1H),1.86-1.77(m,1H),1.74-1.52(m,2H),1.12(d,J=7.2Hz,3H).

[0232] Embodiment 29: (R)-6-((1-(2-hydroxyethyl)piperidine-3-yl)amino)-3-(2-hydroxy-4-(propa-1-in-1-yl)phenyl)-4-methyl-1,2,4-triazine-5(4H)-ketone [ka]

[0233] Referring to Embodiment 1, (R)-6-((1-(2-hydroxyethyl)piperidine-3-yl)amino)-3-(2-hydroxy-4-(propa-1-in-1-yl)phenyl)-4-methyl-1,2,4-triazine-5(4H)-ketone was prepared. MS / ESI[M+H] + = 384.2.

[0234] Embodiment 30: 3-(4-hydroxybenzo[b]thiophen-5-yl)-6-(((1R,2R)-2-hydroxycyclohexyl)amino)-4-methyl-1,2,4-triazine-5(4H)-ketone [ka]

[0235] Step 1: Compounds INT7 (444 mg, 2.00 mmol), 30a (230 mg, 2.00 mmol), and DIPEA (1.03 g, 8 mmol) were added to a dry flask, and 1,4-dioxane (15 mL) was added as the solvent. The resulting mixture was reacted overnight at 80°C. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to remove excess solvent, and the resulting residue was purified by column chromatography to obtain compound 30b (526 mg). MS / ESI [M+H] + = 259.1.

[0236] Step 2: Compound 30b (163 mg, 0.63 mmol), INT1 (250.9 mg, 0.76 mmol), Pd(dppf)Cl2 (43.9 mg, 0.06 mmol), and Cs2CO3 (782.4 mg, 2.4 mmol) were added to a dry flask under a nitrogen atmosphere. The resulting mixture was reacted overnight at 100°C with 1,4-dioxane / H2O (6 mL / 0.5 mL) as the solvent. After confirming the completion of the reaction by TLC, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure to remove excess solvent, and the resulting residue was purified by column chromatography to obtain compound 30c (202 mg). MS / ESI[M+H] + = 387.1.

[0237] Step 3: Under a nitrogen atmosphere, compound 30c (66 mg, 0.17 mmol) and DCM (1.5 mL) were added to a dry flask, cooled to -10°C, and then BBr3 (1 M, 0.7 mL) was added dropwise. The resulting mixture was reacted for 3 hours. After adding MeOH to the reaction solution to stop the reaction, the reaction solution was returned to room temperature and concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain compound 30 (33.5 mg). MS / ESI[M+H] + =373.2. 1 H NMR(400MHz,DMSO-d6)δ7.66-7.60(m,2H),7.49(d,J=8.4Hz,1H),7.19(d,J=8.4Hz,1H),6.65(d,J=7.2Hz,1H),4.75-4.64(m,1H) ,3.63-3.52(m,1H),3.49-3.40(m,1H),3.13(s,3H),2.09-1.99(m,1H),1.91-1.79(m,1H),1.66-1.51(m,2H),1.28-1.10(m,4H).

[0238] Embodiment 31: 3-(4-ethynyl-2-hydroxyphenyl)-6-(((1R,2R)-2-hydroxycyclohexyl)amino)-4-methyl-1,2,4-triazine-5(4H)-ketone [ka]

[0239] Referring to Embodiment 24, 3-(4-ethynyl-2-hydroxyphenyl)-6-(((1R,2R)-2-hydroxycyclohexyl)amino)-4-methyl-1,2,4-triazine-5(4H)-ketone was prepared. MS / ESI[M+H] + = 341.2.

[0240] Embodiment 32: 3-(2-hydroxy-4-(propa-1-in-1-yl)phenyl)-6-(((1R,2R)-2-hydroxycyclohexyl)amino)-4-methyl-1,2,4-triazine-5(4H)-ketone [ka]

[0241] Referring to Embodiment 24, 3-(2-hydroxy-4-(propa-1-in-1-yl)phenyl)-6-(((1R,2R)-2-hydroxycyclohexyl)amino)-4-methyl-1,2,4-triazine-5(4H)-ketone was prepared. MS / ESI[M+H] + = 355.2.

[0242] Embodiment 33: 6-(((1R,2R)-2-hydroxycyclohexyl)amino)-3-(1-hydroxynaphthalene-2-yl)-4-methyl-1,2,4-triazine-5(4H)-ketone [ka]

[0243] Referring to Embodiment 30, 6-(((1R,2R)-2-hydroxycyclohexyl)amino)-3-(1-hydroxynaphthalene-2-yl)-4-methyl-1,2,4-triazine-5(4H)-ketone was prepared. MS / ESI[M+H] + = 367.2.

[0244] Embodiment 34: (R)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-6-(((4-methylmorpholino-2-yl)methyl)amino)-1,2,4-triazine-5(4H)-ketone [ka]

[0245] Referring to Embodiment 4, (R)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-6-(((4-methylmorpholino-2-yl)methyl)amino)-1,2,4-triazine-5(4H)-ketone was prepared. MS / ESI[M+H] + =388.2. 1 H NMR(400MHz,CD3OD)δ7.53(d,J=5.7Hz,1H),7.43-7.37(m,2H),7.21(d,J=8.3Hz,1H),4.03(s,1H),3.62-3.57(m,2H) ,3.52-3.47(m,2H),3.35(s,1H),3.25(s,3H),2.68-2.62(m,2H),2.63-2.54(m,2H),2.48-2.42(m,2H),2.18(s,3H).

[0246] Embodiment 35: (S)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-6-(((4-methylmorpholino-2-yl)methyl)amino)-1,2,4-triazine-5(4H)-ketone [ka]

[0247] Referring to Embodiment 4, (S)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-6-(((4-methylmorpholino-2-yl)methyl)amino)-1,2,4-triazine-5(4H)-ketone was prepared. MS / ESI[M+H] + =388.2. 1H NMR(400MHz,CD3OD)δ7.53(d,J=5.7Hz,1H),7.43-7.37(m,2H),7.21(d,J=8.3Hz,1H),4.03(s,1H),3.62-3.57(m,2H) ,3.52-3.47(m,2H),3.35(s,1H),3.25(s,3H),2.68-2.62(m,2H),2.63-2.54(m,2H),2.48-2.42(m,2H),2.18(s,3H).

[0248] Embodiment 36: (R)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-6-(((1-isopropylpiperidine-3-yl)amino)-1,2,4-triazine-5(4H)-ketone [ka]

[0249] Referring to Embodiment 4, (R)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-6-(((1-isopropylpiperidine-3-yl)amino)-1,2,4-triazine-5(4H)-ketone was prepared. MS / ESI[M+H] + =400.2. 1 H NMR(400MHz,DMSO-d6)δ8.16(s,1H),7.76-7.64(m,2H),7.58(d,J=8.2Hz,1H),7.27(d,J=8.2Hz,1H),6.84(d,J=8.4Hz,1H),4.11- 4.03(m,1H),3.19(s,3H),2.91-2.83(m,2H),2.69-2.61(m,1H),2.45-2.36(m,2H),1.79-1.51(m,4H),1.02(dd,J=6.5,1.8Hz,6H).

[0250] Embodiment 37: (R)-6-((5,5-difluoro-1-methylpiperidine-3-yl)amino)-3-(4-hydroxybenzub[b]thiophene-5-yl)-4-methyl-1,2,4-triazine-5(4H)-ketone [ka]

[0251] Referring to Embodiment 4, (R)-6-((5,5-difluoro-1-methylpiperidine-3-yl)amino)-3-(4-hydroxybenzub[b]thiophen-5-yl)-4-methyl-1,2,4-triazine-5(4H)-ketone was prepared. MS / ESI[M+H] + =408.2. 1 H NMR(400MHz,CD3OD)δ7.52(d,J=5.5Hz,1H),7.48-7.44(m,2H),7.19(d,J=8.3Hz,1H),4.01(s,1H) ,3.23(s,3H),2.87(s,1H),2.68-2.62(m,2H),2.63-2.54(m,2H),2.18(s,3H),2.15-2.12(m,2H).

[0252] Embodiment 38: (R)-3-(4-(difluoromethoxy)benzo[b]thiophen-5-yl)-4-methyl-6-((1-methylpiperidine-3-yl)amino)-1,2,4-triazine-5(4H)-ketone [ka]

[0253] Step 1: 5-bromobenzo[b]thiophen-4-ol INT1c (1.00 g, 4.37 mmol), 2-(difluoromethyl)sulfonyl)pyridine (1.69 g, 8.74 mmol), KOH (1.23 g, 21.85 mmol), dioxane (10 mL), and water (2.5 mL) were added to the reaction flask and stirred at 50°C for 4 hours. After the reaction was complete, the reaction system was layered, the upper organic phase was collected, and it was directly mixed with silica gel. The mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 30:1) to obtain compound 38a (1.10 g, 3.94 mmol, 90%). 1H NMR (400MHz, CDCl3) δ7.65(d,J=8.6Hz,1H),7.54(d,J=8.6Hz,1H),7.50(t,J=6.4Hz,2H),6.61(t,J=74.3Hz,1H). 19 FNMR (377MHz, CDCl3) δ-80.02.

[0254] Step 2: Under a nitrogen atmosphere, compound 38a (1.10 g, 3.94 mmol), bis(pinacolate)diborone (1.20 g, 4.73 mmol), potassium acetate (773 mg, 7.88 mmol), and trans-dichlorobis(triphenylphosphine)palladium(II) (274 mg, 0.39 mmol) were added to the reaction flask, followed by the addition of dioxane (10 mL). The resulting mixture was stirred at 100°C for 12 hours. After the reaction was complete, the reaction mixture was directly mixed with silica gel and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain compound 38b (760 mg, 2.33 mmol, 59%). 1 H NMR(400MHz,CDCl3)δ7.78(dd,J=8.1,0.5Hz,1H),7.71(d,J=8.1Hz,1H),7.56 (d,J=5.3Hz,1H),7.43(d,J=5.5Hz,1H),6.68(t,J=76.2Hz,1H),1.38(s,12H). 19 FNMR (377MHz, CDCl3) δ-80.86.

[0255] Step 3: Compound 4d (100 mg, 0.39 mmol), 2-(4-(difluoromethoxy)benzo[b]-thiophen-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane 38b (153 mg, 0.47 mmol), cesium carbonate (254 mg, 0.78 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (29.3 mg, 0.04 mmol) were added to dioxane (1 mL) and water (0.2 mL) under a nitrogen atmosphere, and the resulting mixture was stirred at 100 °C for 12 hours. After the reaction was complete, the reaction mixture was directly mixed with silica gel and purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain the crude product. The crude product was then subjected to reverse-phase preparative fractionation to obtain compound 38 (40.0 mg, 0.095 mmol, 24%). MS / ESI[M+H] + =422.2. 1 H NMR(400MHz,MeOD)δ8.50(s,1H),8.07(d,J=8.3Hz,1H),7.84(d,J=5.6Hz,1H),7.57(d,J=5.6Hz,1H),7.51(d,J=8.3Hz,1H),6.81(t,J=73.2Hz,1H), 4.31-4.20(m,1H),3.37(d,J=9.0Hz,1H),3.29(s,3H),3.16-3.01(m,1H), 2.74(d,J=8.2Hz,2H),2.66(s,3H),2.12-1.93(m,2H),1.86-1.66(m,2H).

[0256] Embodiment 39: (R)-3-(4-cyclopropyl-2-hydroxyphenyl)-4-methyl-6-((1-methylpiperidine-3-yl)amino)-1,2,4-triazine-5(4H)-ketone [ka]

[0257] Referring to Embodiment 11, (R)-3-(4-cyclopropyl-2-hydroxyphenyl)-4-methyl-6-((1-methylpiperidine-3-yl)amino)-1,2,4-triazine-5(4H)-ketone was prepared. MS / ESI[M+H] + =356.2. 1 H NMR(400MHz,CD3OD)δ7.55(d,J=4.1Hz,1H),7.17-7.10(m,2H),4.25-4.19(m,1H),3.34(s,3H),2.95- 2.75(m,3H),2.18(s,3H),1.97-1.78(m,3H),1.77-1.61(m,2H),1.32-1.25(m,5H),1.23-1.12(m,1H).

[0258] Embodiment 40: 6-((3R,5R)-5-fluoro-1-methylpiperidine-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazine-5(4H)-ketone [ka]

[0259] Step 1: Compound 40a (4.75 g, 21.8 mmol), paraformaldehyde (1.31 g, 43.6 mmol), and acetic acid (0.26 g, 4.36 mmol) were added to methanol (50 mL), followed by sodium borohydride cyanohydride (2.74 g, 43.6 mmol), and the resulting mixture was stirred at 50°C for 1 hour. After the reaction was complete, the reaction mixture was mixed with silica gel, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 10:1, iodine color development) to obtain target compound 40b (4.67 g, 20.1 mmol, yield: 92%). 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.

[0260] Step 2: Compound 40b (4.67 g, 20.1 mmol) was dissolved in dioxane (25 mL), followed by the addition of HCl / dioxane (25 mL, 101 mmol, 4.0 M). The resulting mixture was stirred at 25°C for 1 hour until the reaction was complete. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain the target product 40c (4.60 g, 22.4 mmol, yield: 111%). 1 H NMR(400MHz,CD3OD-d4)δ5.37-5.24(m,1H),4.98-4.89(m,1H),3.92-3.77(m,3H), 3.51(dd,J=39.2,13.9Hz,1H),3.06(s,3H),2.63-2.55(m,1H),2.15-1.98(m,1H). MS / ESI[M+H] + = 133.0.

[0261] Referring to Embodiment 4, 6-(((3R,5R)-5-fluoro-1-methylpiperidine-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazine-5(4H)-ketone was prepared. MS / ESI[M+H] + =390.0. 1 H NMR(400MHz,CDCl3-d)δ7.60(d,J=5.4Hz,1H),7.43-7.31(m,2H),7.19(d,J=8.5Hz,1H),6.17(d,J=8.1Hz,1H),4.90-4.72(m,1H),4.45(s,1H) ,3.57(s,3H),2.91-2.78(m,1H),2.68-2.60(m,1H),2.56-2.48(m,1H) ,2.46-2.38(m,1H),2.37(s,3H),2.28-2.17(m,1H),1.91-1.81(m,1H).

[0262] Embodiment 41: 6-(((3R,5R)-1-ethyl-5-fluoropiperidine-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazine-5(4H)-ketone [ka]

[0263] Referring to Embodiment 40, 6-(((3R,5R)-1-ethyl-5-fluoropiperidine-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazine-5(4H)-ketone was prepared. MS / ESI[M+H] + =404.0. 1 H NMR(400MHz,CD3OD-d)δ7.61(d,J=5.6Hz,1H),7.58-7.49(m,2H),7.28(d, J=8.3Hz,1H),4.98-4.93(m,1H),4.85-4.80(m,2H),4.51-4.43(m,1H),3.3 4(s,3H),3.12-3.01(m,1H),2.98-2.83(m,1H),2.55(t,J=7.2Hz,2H),2.52 -2.41(m,1H),2.31-2.13(m,2H),2.03-1.86(m,1H),1.12(t,J=7.2Hz,3H).

[0264] Embodiment 42: 4-Ethyl-6-(((3R,5R)-1-ethyl-5-fluoropiperidine-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-1,2,4-triazine-5(4H)-ketone [ka]

[0265] Step 1: Compounds 12b (300 mg, 0.88 mmol), 41b (192 mg, 0.88 mmol), Pd(OAc)2 (20.4 mg, 0.09 mmol), BINAP (56.04 mg, 0.09 mmol), and Cs2CO3 (1.15 g, 3.52 mmol) were added to a dry flask with dioxane (8 mL) as the solvent under a nitrogen atmosphere. The resulting mixture was reacted overnight at 100°C, and the completion of the reaction was confirmed by TLC. The reaction mixture was then filtered, concentrated under reduced pressure, and the resulting residue was purified by column chromatography to obtain compound 42a (yellow oily liquid, 217 mg). MS / ESI[M+H] + = 406.2.

[0266] Step 2: Compound 42a (217 mg, 0.54 mmol), DCM (5 mL), and TfOH (243.2 mg, 1.62 mmol) were placed in a dry flask and reacted overnight at room temperature. After confirming the completion of the reaction by TLC, the reaction mixture was adjusted to approximately 8-9 with dry NaHCO3 and a small amount of aqueous ammonia, and the pH of the reaction mixture was adjusted. The reaction mixture was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain compound 42b (pale yellow solid, 114 mg). MS / ESI[M+H] + = 286.2.

[0267] Step 3: Compound 42b (114 mg, 0.4 mmol) and POCl3 (8 mL) were added to a dry flask, and the resulting mixture was reacted overnight at 100°C. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to remove excess POCl3, and the resulting residue was purified by column chromatography to obtain compound 42c (light brown solid, 106 mg). MS / ESI[M+H] + =304.1.

[0268] Step 4: Compound 42c (106 mg, 0.35 mmol), INT8 (112 mg, 0.35 mmol), Pd(dppf)Cl2 (29.3 mg, 0.04 mmol), Cs2CO3 (456.4 mg, 1.4 mmol), and 1,4-dioxane / H2O (5 mL / 1 mL) were added to a dry flask and reacted overnight at 100°C. After confirming the completion of the reaction by TLC, the reaction solution was allowed to return to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain compound 42d (yellow oily liquid, 86 mg). MS / ESI[M+H] + = 462.2.

[0269] Step 5: Compound 42d (86 mg, 0.19 mmol) and dioxane (2 mL) were added to a dry flask, followed by the dropwise addition of HCl (4 M) (0.2 mL) in MeOH. The resulting mixture was reacted at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain compound 42 (pale yellow solid, 7.8 mg). MS / ESI[M+H] + =418.2. 1 H NMR(400MHz,CD3OD)δ7.51(d,J=5.5Hz,1H),7.22(d,J=5.5Hz,1H),7.12-7.05(m,2H),4.41-4.30(m,1H),3.94-3.84(m,2H),3.02-2. 94(m,1H),2.89-2.75(m,1H),2.48-2.38(m,3H),2.19-2.02(m,3H),1.99-1.76(m,2H),1.02(t,J=7.2Hz,3H),0.96(t,J=7.2Hz,3H).

[0270] Embodiment 43: 4-Ethyl-6-(((3R,5R)-5-Fluoro-1-methylpiperidine-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-1,2,4-triazine-5(4H)-ketone [ka]

[0271] Referring to Embodiment 42, 4-ethyl-6-(((3R,5R)-5-fluoro-1-methylpiperidine-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-1,2,4-triazine-5(4H)-ketone was prepared. MS / ESI[M+H] + =404.2. 1 H NMR(400MHz,CD3OD)δ7.51(d,J=5.5Hz,1H),7.26(d,J=5.5Hz,1H),7.15(d,J=8.1Hz,1H),7.08(d,J=8.2Hz,1H),4.43-4.31(m,1H),3.89-3.8 5(m,2H),2.99-2.93(m,1H),2.83-2.75(m,1H),2.41-2.28(m,1H),2.2 4(s,3H),2.16-2.03(m,3H),1.96-1.78(m,2H),0.97(t,J=7.1Hz,3H).

[0272] Embodiment 44: (R)-3-(4-(cyclopropylethynyl)-2-hydroxyphenyl)-4-methyl-6-((1-methylpiperidine-3-yl)amino)-1,2,4-triazine-5(4H)-ketone [ka]

[0273] Step 1: 2-Bromo-5-iodophenol 44a (5.0 g, 16.72 mmol) and tetrahydrofuran (50 mL) were added to a reaction flask and cooled to 0°C. Subsequently, NaH (1.0 g, 25.08 mmol, 60%) was added in batches, and the resulting mixture was reacted for 0.5 hours. Subsequently, chloromethoxymethane (2.02 g, 25.08 mmol) was added, and the mixture was reacted at room temperature for 1 hour. After the reaction was complete, saturated aqueous ammonium chloride solution (50 mL) was added to the reaction mixture to stop the reaction. The stopped reaction mixture was then extracted with ethyl acetate (50 mL), the aqueous phase was further extracted with ethyl acetate (20 mL), the ethyl acetate layers were combined and directly mixed with silica gel, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0~19:1) to obtain compound 44b (5.7 g, 99.5%). MS / ESI[M+H] + = 342.8.

[0274] Step 2: Compound 44b (2000 mg, 5.85 mmol), Pd(PPh3)Cl2 (410 mg, 0.59 mmol), CuI (222 mg, 1.17 mmol), DIEA (2.3 g, 17.54 mmol), and tetrahydrofuran (50 mL) were added to a reaction flask under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 0.5 hours, followed by the addition of ethynylcyclopropane (385 mg, 5.85 mmol), and the mixture was reacted at room temperature for 15 hours. After the reaction was complete, the reaction mixture was directly mixed with silica gel, and the resulting mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 24:1) to obtain compound 44c (1.7 g, crude product).

[0275] Step 3: Compound 44c (1.4 g, 5.00 mmol) was added to the reaction flask, followed by the addition of tetrahydrofuran (50 mL) under a nitrogen atmosphere. The resulting mixture was cooled to -78°C, followed by the slow addition of n-butyllithium (2.6 mL, 6.50 mmol, 0.5 M) and the mixture was allowed to react at a constant temperature for 1 hour. A solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.4 g, 7.50 mmol) in tetrahydrofuran (10 mL) was added, and the reaction mixture was allowed to react at a constant temperature for 1 hour, followed by heating to room temperature and reaction for 1 hour. After the reaction was complete, saturated ammonium chloride aqueous solution (50 mL) was added to the reaction mixture to stop the reaction. The stopped reaction mixture was extracted with ethyl acetate (50 mL), the aqueous phase was further extracted with ethyl acetate (50 mL), the ethyl acetate layers were combined and directly mixed with silica gel, and the mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 10:1) to obtain compound 44d (1.2 g, 73.1%). 1 ¹H NMR (400MHz, chloroform-d): δ 7.58 (d, J=8.0Hz, 1H), 7.26 (s, 1H), 7.02 (d, J=8.0Hz, 1H), 5.17 (s, 2H), 3.50 (s, 3H), 1.47-1.41 (m, 1H), 1.34 (s, 12H), 0.90-0.79 (m, 4H).

[0276] Referring to Embodiment 24, (R)-3-(4-(cyclopropylethynyl)-2-hydroxyphenyl)-4-methyl-6-((1-methylpiperidine-3-yl)amino)-1,2,4-triazine-5(4H)-ketone was prepared. MS / ESI[M+H] + =380.2. 1H NMRNMR(400MHz,CD3OD)δ7.25(d,J=7.8Hz,1H),6.96(d,J=7.8Hz,1H),6.90(s,1H),4.25(s,1H),3.56-3.43(m,1H),3.32(s,3H),3.01-2.81(m,2H) ,2.77(s,3H),2.12-1.99(m,3H),1.89-1.80(m,1H),1.78-1.67(m,1H),1. 54-1.44(m,1H),1.37-1.27(m,1H),0.97-0.88(m,2H),0.79-0.70(m,2H).

[0277] Embodiment 45: (R)-3-(4-(cyclopropylethynyl)-2-hydroxyphenyl)-6-((1-ethylpiperidine-3-yl)amino)-4-methyl-1,2,4-triazine-5(4H)-ketone [ka]

[0278] Referring to Embodiment 44, (R)-3-(4-(cyclopropylethynyl)-2-hydroxyphenyl)-6-((1-ethylpiperidine-3-yl)amino)-4-methyl-1,2,4-triazine-5(4H)-ketone was prepared. MS / ESI[M+H] + =394.2. 1 H NMR(400MHz,CD3OD)δ7.25(d,J=7.8Hz,1H),6.95(d,J=7.9Hz,1H),6.90(s,1H),4.25(d,J=9.6Hz,1H),3.55-3.42(m,1H),3.33(s,3H),3.05(dd,J=14 .1,6.9Hz,2H),2.93-2.76(m,2H),2.10-2.01(m,3H),1.93-1.70(m,2H),1 .53-1.43(m,1H),1.32-1.26(m,4H),0.95-0.86(m,2H),0.80-0.69(m,2H).

[0279] Embodiment 46: (R)-3-(4'-fluoro-3-hydroxy-[1,1'-biphenyl]-4-yl)-4-methyl-6-((1-methylpiperidine-3'yl)amino)-1,2,4-triazine-5(4H)-ketone [ka]

[0280] Step 1: Compounds 44b (400 mg, 1.17 mmol), 46a (259.7 mg, 1.17 mmol), Pd(dppf)Cl2 (87.8 mg, 0.12 mmol), Cs2CO3 (750.0 mg, 2.3 mmol), and 1,4-dioxane / H2O (10 mL / 2 mL) were added to a dry flask and reacted overnight at 100°C under a nitrogen atmosphere. After the reaction was complete, the mixed solution was allowed to return to room temperature and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain compound 46b (312 mg, 86%). 1 H NMR (400MHz, CDCl3) δ7.51(d,J=8.2Hz,2H),7.47-7.40(m,1H),7.24(d,J=2.0Hz,1H),7.09-6.96(m,3H),5.23(s,2H),3.48(s,3H).

[0281] Step 2: Compound 46b (312 mg, 1.01 mmol), (Bpin)2 (304.8 mg, 1.2 mmol), Pd(dppf)Cl2 (73.2 mg, 0.1 mmol), KOAc (198.2 mg, 2.02 mmol), and 1,4-dioxane (10 mL) were added to a dry flask and stirred overnight at 100°C. After the reaction was complete, the mixed solution was allowed to return to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The resulting organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain compound 46c (201 mg, 56%). MS / ESI[M+H] + = 359.2.

[0282] Step 3: Compounds 46c (201 mg, 0.56 mmol), 4d (143.9 mg, 0.56 mmol), Pd(dppf)Cl2 (43.9 mg, 0.06 mmol), Cs2CO3 (730.2 mg, 2.24 mmol), and 1,4-dioxane / H2O (6 mL / 1 mL) were added to a dry flask and reacted overnight at 100°C under a nitrogen atmosphere. After the reaction was complete, the mixed solution was allowed to return to room temperature and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain compound 46b (154 mg, 60%). MS / ESI[M+H] + = 454.2.

[0283] Step 4: Compound 46d (154 mg, 0.34 mmol), 1,4-dioxane (3 mL), and HCl (4 M in dioxane) (0.4 mL) were added to a dry flask and reacted at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to remove excess solvent and obtain compound 46 (16.5 mg, 12%). MS / ESI[M+H] + =410.2. 1 H NMR(400MHz,CD3OD)δ7.65(dd,J=8.8,5.3Hz,2H),7.40(d,J=7.9Hz,1H),7.25-7.12(m,4H),4.18-4.10(m,1H),3.37(s,3H),3.05-2.89(m,1H),2 .70-2.54(m,1H),2.31(s,3H),2.30-2.14(m,2H),1.98-1.87(m,1H),1.8 5-1.76(m,1H),1.74-1.62(m,1H),1.61-1.50(m,1H),1.36-1.28(m,1H).

[0284] Embodiment 47: (R)-3-(2-hydroxy-4-(pyrimidine-2-yl)phenyl)-4-methyl-6-((1-methylpiperidine-3-yl)amino)-1,2,4-triazine-5(4H)-ketone [ka]

[0285] Step 1: Compounds 47a (460 mg, 2 mmol), 47b (480 mg, 3 mmol), Pd(PPh3)4 (230 mg, 0.2 mmol), sodium carbonate (640 mg, 6 mmol), dioxane (10 mL), and water (2 mL) were added to a reaction flask. Under a nitrogen atmosphere as a substitution reaction system, the resulting mixture was reacted overnight at 100°C. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 47c (310 mg). MS / ESI[M+H] + = 266.1.

[0286] Step 2: Compound 47c (160 mg, 0.6 mmol), Pd(dppf)Cl2 (44 mg, 0.06 mmol), potassium acetate (176 mg, 1.08 mmol), B2pin2 (305 mg, 1.2 mmol), and dioxane (6 mL) were added to the reaction flask. Under a nitrogen atmosphere as a substitution reaction system, the resulting mixture was reacted overnight at 100°C. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, mixed with silica gel, and purified by column chromatography to obtain the target compound 47d (220 mg). MS / ESI[M+H] + = 313.1.

[0287] Referring to Embodiment 4, (R)-3-(2-hydroxy-4-(pyrimidine-2-yl)phenyl)-4-methyl-6-((1-methylpiperidine-3-yl)amino)-1,2,4-triazine-5(4H)-ketone was prepared. MS / ESI[M+H] + =394.4. 1 H NMR (400MHz, chloroform-d) δ8.82(d,J=4.8Hz,2H),8.13(d,J=1.7Hz,1H),8.01(dd,J=8.2,1.7Hz,1H),7.42(d,J=8.3Hz,1H),7.23(t,J=4.8 Hz,1H),6.42(s,1H),4.34-4.12(m,1H),3.58(s,3H),2.59(s,2H),2.50(s,2H),2.28(s,3H),1.76(d,J=21.9Hz,4H),1.67-1.55(m,1H).

[0288] Embodiment 48: 3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-6-(7-methyloctahydro-1H-pyrrolo[2,3-b]pyridine-1-yl)-1,2,4-triazine-5(4H)-ketone [ka]

[0289] Referring to Embodiment 4, 3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-6-(7-methyloctahydro-1H-pyrrolo[2,3-b]pyridine-1-yl)-1,2,4-triazine-5(4H)-ketone was prepared. MS / ESI[M+H] + =398.4. 1 H NMR(400MHz,CD3OD)δ7.53(d,J=5.7Hz,1H),7.43-7.37(m,2H),7.21(d,J=8.3Hz,1H),4.21-4.13(m,1H),3.31(s, 3H),2.95-2.87(m,2H),2.67-2.42(m,2H),2.55-2.39(m,3H),2.18(s,3H),1.97-1.78(m,3H),1.53-1.34(m,2H).

[0290] Embodiment 49: 6-(((2R,3R)-1,2-dimethylpiperidine-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazine-5(4H)-ketone [ka]

[0291] Referring to Embodiment 40, 6-(((2R,3R)-1,2-dimethylpiperidine-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazine-5(4H)-ketone was prepared to obtain compound 49 (115 mg, 33.8%). 1H NMR(400MHz,DMSO-d6)δ10.22(brs,1H),7.72(d,J=5.6Hz,1H),7.69(d,J=5.6Hz,1 H),7.59(d,J=8.0Hz,1H),7.29(d,J=8.0Hz,1H),6.39-6.31(m,1H),4.07-3.97(m,1 H),3.20(s,3H),2.87-2.74(m,1H),2.44-2.31(m,1H),2.21(s,3H),2.16-2.02(m,1 H),1.99-1.90(m,1H),1.74-1.58(m,1H),1.55-1.39(m,2H),1.04(d,J=6.4Hz,3H). MS / ESI[M+H] + =386.0.

[0292] Embodiment 50: 6-(((3R,6S)-1,6-dimethylpiperidine-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazine-5(4H)-ketone [ka]

[0293] Referring to Embodiment 40, 6-(((3R,6S)-1,6-dimethylpiperidine-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazine-5(4H)-ketone was prepared. MS / ESI[M+H] + =386.2. 1 H NMR(400MHz,CD3OD)δ7.53(d,J=5.7Hz,1H),7.43-7.37(m,2H),7.21(d,J=8.3Hz,1H),4.03(m,1H),3.27(s, 3H),2.86-2.74(m,2H),2.46-2.41(m,2H),2.18(s,3H),1.84-1.79(m,2H),1.77-1.61(m,2H),1.16(s,3H).

[0294] Embodiment 51: 3-(4-hydroxybenzo[b]thiophen-5-yl)-6-{[(3R)-1-methylpiperidine-3-yl]amino}-4-(2-methoxyethyl)-4H,5H-1,2,4-triazine-5-ketone [ka]

[0295] Referring to Embodiment 12, 3-(4-hydroxybenzo[b]thiophen-5-yl)-6-{[(3R)-1-methylpiperidine-3-yl]amino}-4-(2-methoxyethyl)-4H,5H-1,2,4-triazine-5-ketone was prepared to obtain compound 51 (24 mg, 44.4%). 1 H NMR(400MHz,Methanol-d4)δ7.61(d,J=5.6Hz,1H),7.56-7.51(m,2H),7.29(d,J=8.4Hz,1H),4.23-4.14(m,1H),4.08(t,J=5.6 Hz,2H),3.44(t,J=5.6Hz,2H),3.11-3.01(m,4H),2.76-2.66(m,1H),2.45-2.34(m,5H),2.02-1.81(m,2H),1.77-1.56(m,2H). LC-MS:ESI[M+H] + = 416.0.

[0296] Embodiment 52: 3-(2-fluoro-4-hydroxybenzo[b]thiophen-5-yl)-6-{[(3R,5R)-5-fluoro-1-methylpiperidine-3-yl]amino}-4-methyl-4H,5H-1,2,4-triazine-5-ketone [ka]

[0297] Step 1: Compound INT1d (5.00 g, 20.6 mmol) was dissolved in tetrahydrofuran (25 mL) under a nitrogen atmosphere. The resulting solution was cooled to -70°C, and then LDA (12.4 mL, 2.0 M, 24.7 mmol) was slowly added dropwise. The mixture was then stirred at a constant temperature for 1 hour. Next, a solution of N-fluorodibenzenesulfonamide (7.16 g, 22.7 mmol) in tetrahydrofuran (25 mL) was added dropwise to the resulting mixture. After the dropwise addition, the mixture was reacted at a constant temperature for 1 hour. The reaction mixture was then warmed to room temperature and stirred overnight. After the reaction was complete, saturated ammonium chloride aqueous solution (100 mL) was added to the reaction mixture to stop the reaction. The stopped mixture was extracted with ethyl acetate (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the filtrate was mixed with silica gel, concentrated under reduced pressure, and then purified by column chromatography (PE:HCl = 1:0) to obtain compound 52a (2.80 g, 10.7 mmol, yield: 52%). 1 H NMR (400MHz, CDCl3-d) δ7.41(d,J=8.4Hz,1H),7.23(d,J=6.4Hz,1H),6.80(d,J=2.4Hz,1H),3.91(s,3H).

[0298] Step 2: Compound 52a (2.80 g, 10.7 mmol), bis(pinacolate)diborone (3.25 g, 12.8 mmol), KOAc (2.10 g, 21.4 mmol), and Pd(dppf)Cl2 (751 mg, 1.07 mmol) were added to anhydrous dioxane (30 mL), and the resulting mixture was reacted under a nitrogen atmosphere at 100 °C for 12 hours. After the reaction was complete, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (PE:SiO=30:1) to obtain target compound 52b (2.10 g, 6.81 mmol, colorless solid, yield: 64%). 1 H NMR (400MHz, CDCl3) δ7.63(d,J=8.0Hz,1H),7.40(d,J=8.4Hz,1H),6.84(d,J=2.4Hz,1H),3.94(s,3H),1.38(s,12H).

[0299] Referring to Embodiment 4, 3-(2-fluoro-4-hydroxybenzo[b]thiophen-5-yl)-6-{[(3R,5R)-5-fluoro-1-methylpiperidine-3-yl]amino}-4-methyl-4H,5H-1,2,4-triazine-5-ketone was prepared. 1 H NMR(400MHz,CDCl3-d)δ7.20-7.13(m,2H),6.94(d,J=2.4Hz,1H),6.17(d,J=8.0Hz,1H),4.90-4.71(m,1H),4.42(s,1H),3.54(s,3 H),2.86-2.77(m,1H),2.67-2.61(m,1H),2.55-2.48(m,1H),2.45-2.39(m,1H),2.37(s,3H),2.25-2.17(m,1H),1.89-1.81(m,1H). LC-MS:ESI[M+H] + = 408.0.

[0300] Embodiment 53: 3-(4-cyclopropyl-2-hydroxyphenyl)-6-(((3R,5R)-1-ethyl-5-fluoropiperidine-3-yl)amino)-4-methyl-1,2,4-triazine-5(4H)-ketone [ka]

[0301] Referring to Embodiment 11, 3-(4-cyclopropyl-2-hydroxyphenyl)-6-(((3R,5R)-1-ethyl-5-fluoropiperidine-3-yl)amino)-4-methyl-1,2,4-triazine-5(4H)-ketone was prepared to obtain compound 53 (pale yellow solid, 42.3 mg). 1 H NMR(400MHz,CD3OD)δ7.41(d,J=8.0Hz,1H),6.85(d,J=8.1Hz,1H),6.79(s,1H),4.65(t,J=12.0Hz,1H),3.91-3.72(m ,3H),3.49(s,3H),3.37(m,4H),3.19-3.03(m,1H),2.57(m,1H),1.99(m,1H),1.41(m,4H),1.11(m,2H),0.80(m,2H).

[0302] Embodiment 54: (R)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-isopropyl-6-((1-methylpiperidine-3-yl)amino)-1,2,4-triazine-5(4H)-ketone [ka]

[0303] Referring to Embodiment 12, (R)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-isopropyl-6-((1-methylpiperidine-3-yl)amino)-1,2,4-triazine-5(4H)-ketone was prepared to obtain compound 54 (11 mg, yield: 19.30%). LC-MS:ESI[M+H] + =400.0.NMR(400MHz,MeOD)δ7.53(d,J=5.6Hz),7.47(dd,J=8.2,7.2Hz),7.14(d,J=8.3Hz),4.32(dt,J=12.8,6.4Hz),3.9 6-3.86(m),2.25(s),2.14-2.05(m),1.91(s),1.76(dd,J=9.2,4.4Hz),1.64-1.55(m),1.54-1.40(m),1.29(d,J=6.4Hz).

[0304] Embodiment 55: (R)-6-((1-ethylpiperidine-3-yl)amino)-3-(4-hydroxybenzo[b]thiophen-5-yl)-4-(methyl-d3)-1,2,4-triazine-5(4H)-ketone [ka]

[0305] Referring to Embodiment 12, (R)-6-((1-ethylpiperidine-3-yl)amino)-3-(4-hydroxybenzo[b]thiophene-5-yl)-4-(methyl-d3)-1,2,4-triazine-5(4H)-ketone was prepared to obtain target compound 55 (yellow solid, 37 mg, yield: 14.34%). LC-MS: ESI[M+H] = 389.0. 1 H NMR(400MHz,DMSO)δ7.76(q,J=5.6Hz,2H),7.65(d,J=8.3Hz,1H),7.30(d,J=8.3Hz,1H),3.54(dd,J=25.8,10.7Hz ,2H),3.20(d,J=7.0Hz,2H),2.91-2.75(m,2H),1.99(d,J=10.6Hz,2H),1.84-1.67(m,2H),1.24(t,J=7.2Hz,3H).

[0306] Bioactivity Test 1. Measurement of NLRP3 inflammasome inhibitory activity in human monocytes

[0307] Reagents: THP-1 cells: Wuhan Pricella Biotechnology Co., Ltd., PMA: Sigma-Aldrich, RPMI culture medium: Hyclone, LPS: Sigma-Aldrich, Opti-MEM medium: Gibco, Nigericin: Invivogen, Human IL-1β ELISA assay kit: 4A Biotech, Reference compound MCC950: MedChemExpress (MCE).

[0308] Experimental method: THP-1 cells were cultured in RPMI medium containing PMA (10 μM), and then 2 × 10⁶ cells were placed in a 48-well plate. 5Cells were seeded at a density of cells / mL and incubated overnight at 37°C in a 5% CO2 incubator. The following day, the medium was replaced with Opti-MEM medium containing 1 μg / mL LPS. After 3 hours, the grown cells were simulated with drugs for 40 minutes, then with nigericin (10 μM) 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 Embodiment 63 of patent WO2021193897, Ref-2 was synthesized according to the synthesis method of Embodiment 1 of patent WO2022230912, and Ref-3 was synthesized according to the synthesis method of Embodiment 26 of patent WO2022238347. [ka]

[0309] The experimental results are shown in Table 2. [Table 2]

[0310] Conclusion: The compounds of the present invention exhibit good inhibitory activity against the NLRP3 inflammasome, and preferred compounds have a better inhibitory effect against the NLRP3 inflammasome than MCC950, Ref-1, Ref-2, and Ref-3.

[0311] 2. Measurement of the inhibitory activity of compounds against IL-1β in human PBMC cells Human peripheral blood mononuclear cells (PBMCs) were collected and cultured overnight in RPMI1640 medium containing 10% FBS and antibiotics before stimulation. On day 2, the medium was replaced with serum reducing medium, and the proliferated cells were stimulated with a working concentration of 1 μg / mL LPS for 3 hours, followed by drug stimulation for 40 minutes, and then with a concentration of 10 μM nigericin for 40 minutes. The cell supernatant was collected, and the yield of IL-1β was detected by ELISA.

[0312] The experimental results are shown in Table 3. [Table 3]

[0313] Conclusion: The compounds of the present invention exhibit good inhibitory activity against IL-1β in human PBMC cells, and preferred compounds 3 and 4 exhibit better inhibitory activity against IL-1β than MCC950 in human PBMC cells. 50 It holds.

[0314] 3. Experiments to inhibit compounds against hERG potassium ion channels Cell culture and processing: CHO cells stably expressing hERG were cultured in cell culture flasks and incubated at 37°C in a 5% CO2 incubator. When the cell density reached 60%–80%, the cell culture medium was aspirated, washed once with PBS, and then digested with Detachin. After digestion, the proliferated cells were neutralized with cell culture medium, then centrifuged, the supernatant was aspirated, and the proliferated cells were resuspended by adding cell culture medium again, and the cell density was increased to 2–5 × 10⁶ for later use. 6 The concentration was adjusted to cells / mL.

[0315] Compound preparation: The compound stock solution was diluted with 100% DMSO; that is, 10 μL of the compound stock solution was serially diluted threefold with 20 μL of DMSO to obtain six concentrations. The six concentrations of the compound (4 μL each) were diluted 100-fold with 396 μL of extracellular fluid to obtain six intermediate concentrations. The six intermediate concentrations of the compound (80 μL each) were diluted fivefold with 320 μL of extracellular fluid to obtain the final concentration to be tested. The highest test concentration was 40 μM, followed by six other concentrations: 40 μM, 13.33 μM, 4.44 μM, 1.48 μM, 0.49 μM, and 0.16 μM. The DMSO content of the final test concentration was less than 0.2%, and this concentration of DMSO did not affect hERG potassium channels. The entire dilution process for compound preparation was performed using Bravo instruments.

[0316] Electrophysiological recording process: The processes of single-cell high-impedance sealing and whole-cell mode formation were all automatically completed under whole-cell recording mode by the Qpatch instrument. Cells were clamped at -80mV, and a pre-voltage of -50mV for 50ms was applied to the cells before a 5-second +40mV depolarization stimulus, followed by repolarization to -50mV for 5 seconds, and then back to -80mV. Voltage stimulation was applied every 15 seconds, and after 2 minutes of recording, the extracellular fluid was recorded for 5 minutes, followed by drug administration. Starting from the lowest test concentration, each test concentration of the compound was administered for 2.5 minutes, and after administering all concentrations consecutively, the positive control compound cisapride (3μM) was administered. At least 3 cells were tested for each concentration (n≧3).

[0317] Data Processing: Data analysis and processing were performed using GraphPad Prism 5.0 and Excel software. Compound IC 50 The values ​​were calculated using GraphPad Prism 5 software by fitting with the following formula: Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*hill slope)) In the formula, X is the logarithm of the test sample concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition rates, respectively.

[0318] The experimental results are shown in Table 4. [Table 4]

[0319] Conclusion: Compounds 3, 4, 5, 9, 16, 17, 24, 30, 40, 41, 42, 43, and 54 exhibit a weak inhibitory effect on hERG potassium ion channels, and their inhibitory effect is weaker than that of reference compound Ref-1.

[0320] 4. Pharmacokinetic evaluation of compounds in Balb / c mice

[0321] Experimental objective: To understand the pharmacokinetic properties of the compound.

[0322] Experimental Basis: Technical Guidelines for Nonclinical Pharmacokinetic Studies of Chemical Drugs, 2014

[0323] Experimental protocol: The pharmacokinetic properties of the compound were investigated by intravenous and intragastric administration in Balb / c mice.

[0324] Sample preparation: The compound was weighed and dissolved in DMSO, and then sodium chloride solution for injection was added to prepare a compound solution for administration.

[0325] Sampling: Six Balb / c male mice (Chengdu Dossy Experimental Animals Co., Ltd., License No.: SCXK(Chuan)2020-030) were selected. Three mice were administered intravenously (IV), and the other three were administered gastrically (PO). Approximately 0.05 mL of blood was collected at 5, 15, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 24 hours, and 48 hours after administration. The collected blood was centrifuged at 3500 rpm for 15 minutes, and the supernatant plasma was collected and stored at -40°C until measurement. Blood drug concentrations were quantitatively analyzed by LC-MS / MS, and peak concentration (Cmax) and area under the concentration-time curve (AUC) were determined. (0-t) ), half-life (T 1 / 2 Pharmacokinetic parameters such as pharmacokinetics (F), clearance (CL), steady-state volume of distribution (Vdss), and bioavailability (F) were calculated.

[0326] The results of the pharmacokinetic evaluation are shown in Table 5 below: [Table 5]

[0327] Conclusion: The compounds of the present invention exhibit good pharmacokinetic properties in Balb / c mice after oral administration, including good oral bioavailability, exposure, half-life, and clearance. Compounds 2, 3, 4, 6, 9, 12, 13, 17, 30, 36, 40, 41, 43, 51, 52, 53, 54, 55, etc., exhibit superior PK parameters, e.g., Cmax, AUC, compared to reference compounds Ref-2 and Ref-3. (0-t) and T 1 / 2 It holds.

[0328] 5. Evaluation of LPS-induced mouse models Experimental method: Balb / c mice aged 7-8 weeks were orally administered 25 mg / kg or 50 mg / kg of the compound or a vehicle control (sterile 0.9% NaCl solution). One hour later, the mice were intraperitoneally injected with 10 mg / kg of LPS (Sigma, L2880). The survival status of the mice was observed every 12 hours for 72 hours, and the 72-hour survival rate of the mice was obtained.

[0329] The experimental results are shown in Table 6. [Table 6]

[0330] Conclusion: The compounds of the present invention can increase the survival rate of LPS-induced mice, particularly at the same dose, and compounds 3, 4, 9, 40, 41, etc., have higher survival rates in LPS-induced mice than the reference compounds MCC950 and Ref-2.

[0331] 6. Evaluation of the brain-to-plasma ratio of compounds in vivo

[0332] Experimental objective: To obtain the brain-to-plasma ratio of compounds.

[0333] Experimental protocol: The brain-to-plasma ratio of compounds was investigated by monitoring the content of compounds in the brain and plasma of mice.

[0334] Experimental procedure: Weigh the compound, then add a small amount of DMSO, and finally add sodium chloride solution for injection to administer 10 mg / mL. -1 A compound solution was prepared. Male mice were given 10 mg / kg of the solution. -1 The drug was administered orally, and whole plasma and whole brain tissue were sampled 1 and 6 hours after administration (n=3). Whole plasma was centrifuged at 3500 rpm for 15 minutes, and the supernatant plasma was collected. The centrifuge tube was weighed as M1, the centrifuge tube containing whole brain tissue was weighed as M2, the centrifuge tube containing water for homogenization was weighed as M3, and the centrifuge tube after removing 30 μL of homogenate was weighed as M4. 30 μL of plasma and 30 μL of brain homogenate were sampled and added to the centrifuge tubes, and then 20 ng·mL was added for precipitation. -1 120 μL of acetonitrile containing the internal standard SAHA was added to each sample, vortexed for 30 seconds, and the resulting mixture was centrifuged at 13,000 rpm for 15 minutes. The supernatant was collected and added to the sample vial for measurement. Standard curve range: 10–10,000 ng·mL -1 . Brain drug content = measured value × 0.03 × (M3-M1) / [(M2-M1) × (M3-M4)].

[0335] Table 7 below shows the brain-to-plasma ratio in mice after compound administration: [Table 7]

[0336] Conclusion: Several compounds of the present invention have good brain permeability, and in particular, compounds 3, 4, 12, 17, and 40 have significantly better brain-to-plasma ratios than reference compounds Ref-1 and Ref-2.

[0337] 7. Evaluation of in vivo distribution of cerebrospinal fluid and plasma after compound administration.

[0338] Experimental procedure: Weigh the compound, then add a small amount of DMSO, and then add sodium chloride solution for injection to make a 5 mg / mL dose. -1A compound solution was prepared. 5 mg / kg was administered to large male mice. -1 The drug was administered intravenously, and cerebrospinal fluid and whole plasma were sampled 0.25 hours and 2 hours after administration, respectively (n=1). The whole plasma was centrifuged at 3500 rpm for 15 minutes, and the supernatant plasma was collected. 10 μL of plasma and 10 μL of cerebrospinal fluid were sampled and added to centrifuge tubes, and then 20 ng·mL was added for precipitation. -1 40 μL of acetonitrile containing the internal standard SAHA was added to each sample, vortexed for 30 seconds, and the resulting mixture was centrifuged at 13,000 rpm for 15 minutes. The supernatant was collected and added to the sample vial for measurement. Standard curve range: 1-1000 ng·mL -1 . [Table 8]

[0339] Conclusion: Some of the compounds of the present invention have good brain permeability, and compounds 40 and 43 in particular have high distribution concentrations in cerebrospinal fluid.

[0340] 8. Evaluation of compound affinity for human NLRP3 protein

[0341] Experimental objective: Proteins were immobilized as a solid phase on a CM5 chip, small molecules were diluted in a concentration gradient, and then injected for interaction with the proteins to obtain suitable affinity values.

[0342] Equipment model and specific consumables: Biacore T200 Cytiva (Sweden), Consumables: Series S Sensor Chip CM5 Cytiva (Sweden) BR100012 LOT 10344853, Amine Coupling Kit Cytiva (Sweden) BR100050 LOT 35063.

[0343] Reagents: Buffer solution: PBS 10X (1.37M NaCl, 26.8mM KCl, 81mM Na2HPO4, 17.6mM KH2PO4, pH 7.2~7.4) (Sangon Biotech, Lot No. J806FC0551), Tween20 (Sigma) (Catalog No. P9416), DMSO (Sigma) (Catalog No. 67-68-5, Lot No. WXBF-1310V).

[0344] Experimental procedure: Protein Immobilization: Tip Selection: CM5 Experimental Procedure: Run → Manual Run: Manual run was selected for controlled immobilization. Proteins were immobilized in specific acidic environments (tested at pH values ​​of 4.0, 4.5, and 5.0), ligand proteins were diluted to 10 ug / mL with 10 mM sodium acetate at different pH values, and the samples were sequentially injected in manual mode into the pH environment with the strongest signal response. Protein immobilization parameter settings: Concentration 30-50 ug / mL, pH environment 4.0, flow rate 10 μL / min, temperature 25°C. Solution required for immobilization: 100 μL NHS, 100 μL EDC, 150 μL ethanolamine (NHS and EDC are tip activating reagents to activate dextran groups on the tip surface, and ethanolamine is a blocking reagent used to block groups not bound to the protein). The instrument automatically mixes EDC and NHS to activate the tip surface. After protein immobilization, the reference channel was blocked (using EDC, NHS, or ethanolamine).

[0345] Small molecule injection: Experimental procedure setup: Method - LMW dynamics, injection time setting: 120 seconds contact, 300 seconds dissociation time. All samples and buffers were filtered through a 0.22 μm filter membrane before the experiment.

[0346] Sequence ID 1 of the NLRP3 protein sequence:

[0347] The experimental results show that compound 40 has an affinity Kd value of 62.13 nM for the human NLRP3 protein.

Claims

1. A compound of formula I or a pharmaceutically acceptable form thereof, wherein the structure of formula I is as follows: 【Chemistry 1】 During the ceremony, 【Chemistry 2】 represents a single bond, and Y is NR ７ａ X is selected from C (=O); R １ is hydrogen, deuterium, halogen, -OH, -NH ２ , -CN, or C which is optionally substituted with 0 to 6 substituents １－６ alkyl, -O-C １－６ alkyl, -S-C １－６ alkyl, -NHC(=O)-C １－６ alkyl, -(C=O)NH-C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, and is selected from 3- to 6-membered cycloalkyl; in R １ , the substituents are selected from deuterium, halogen, -OH, -NH ２ , or -CN; R ２ and R ４ These are, independently, hydrogen, deuterium, halogen, -OH, and -NH. ２ C is a group that is optionally substituted with -CN or 0 to 6 substituents. １－６ Alkyl, -O-C １－６ Alkyl, -S-C １－６ Alkyl, -NHC(=O)-C １－６ Alkyl, -(C=O)NH-C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Selected from alkynyls and 3- to 6-membered cycloalkyls; R ２ and R ４ In this, the substituents are deuterium, halogen, -OH, -NH ２ , or selected from -CN; R ３ These are hydrogen, deuterium, halogens, -OH, and -NH ２ C is a group that is optionally substituted with -CN or 0 to 6 substituents. １－６ Alkyl, -O-C １－６ Alkyl, -S-C １－６ Alkyl, -NHC(=O)-C １－６ Alkyl, -(C=O)NH-C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Selected from alkynyl, 3-6 membered cycloalkyl, 5- and 6 membered heterocycloalkyl, phenyl, and 5- and 6 membered heteroaryl; R ３ In this, the substituents are deuterium, halogen, -OH, -NH ２ Selected from , -CN, or 3-6 membered cycloalkyl groups; R ３ In this, 5- and 6-membered heterocycloalkyls and 5- and 6-membered heteroaryls comprise 1 to 3 heteroatoms selected from at least one of N, S, and O; R ５ Hydrogen, deuterium, halogens, -NH ２ C is a group that is optionally substituted with -CN or 0 to 6 substituents. １－６ Alkyl, -O-C １－６ Alkyl, -S-C １－６ Alkyl, -NHC(=O)-C １－６ Alkyl, -(C=O)NH-C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Selected from alkynyls and 3- to 6-membered cycloalkyls; R ５ In this, the substituents are deuterium, halogen, -OH, -NH ２ , or selected from -CN; Or, R ２ and R ３ , R ３ and R ４ , or R ４ and R ５ These groups, together with the atoms to which they are bonded, form a 5- and 6-membered alkane ring, a benzene ring, a 5- and 6-membered alkane heterocyclic ring, or a 5- and 6-membered aromatic heterocyclic ring substituted with 0 to 6 substituents, wherein the substituents are deuterium, halogen, -OH, -NH ２ -CN, oxo group, C １－６ Alkyl, C １－６ Fluoroalkyl, C １－６ Alkyl deuterated, -O-C １－６ Alkyl, -O-C １－６ Fluoroalkyl, -O-C １－６ Alkyl deuterated, C ３－６ Cycloalkyl, C ３－６ Selected from fluorocycloalkyls or 3- to 6-membered cycloalkyls formed by two substituents bonded to the same carbon atom; R ２ and R ３ , R ３ and R ４ , or R ４ and R ５ However, when these groups together with the atoms to which they are bonded form a ring, the five-membered and six-membered alkane heterocyclic rings and the five-membered and six-membered aromatic heterocyclic rings contain one to three heteroatoms selected from at least one of N, S, and O; R １ -OH, R ２ and R ３ When selected from these, these groups, together with the atoms to which they are bonded, form a benzene ring, a 5- to 7-membered alkane heterocyclic ring, or a 5- and 6-membered aromatic heterocyclic ring substituted with 0 to 6 substituents, wherein the substituents are deuterium, halogen, -OH, -NH ２ ,-CN,C １－６ Alkyl, C １－６ Fluoroalkyl, C １－６ Alkyl deuterated, -O-C １－６ Alkyl, -O-C １－６ Fluoroalkyl, -O-C １－６ Alkyl deuterated, C ３－６ Cycloalkyl, C ３－６ Selected from fluorocycloalkyls, or 3- to 6-membered cycloalkyls formed by two substituents bonded to the same carbon atom; R ２ and R ３ However, when these groups together with the atoms to which they are bonded form a ring, the 5- to 7-membered alkane heterocyclic rings and the 5- and 6-membered aromatic heterocyclic rings contain 1 to 3 heteroatoms selected from at least one of N and S, or 2 atoms of O; L is selected from -(CH ２ ), O, -(CH ｎ１ ), -NH-, -NH-(CH ２ ), -NH-CH(CH ｎ１ ), and -NH-CH(CH ２ ), where n1 is an integer selected from 0 to 3;​​​​​​​​ R ６ is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 8-membered heterocycloalkyl, 3- to 8-membered cycloalkyl, 6- to 10-membered spirocycloalkyl, 6- to 10-membered heterospirocycloalkyl, 6- to 10-membered bridged cycloalkyl, 6- to 10-membered heterobridged cycloalkyl, and C １－６ alkyl substituted with 0 to 6 substituents; R ６ in, the substituents are R ８ａ , halogen, oxo group, -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 , -SO ２ R ８ａ , -SO ２ NR ８ａ R ８ｂ , -NR ８ａ SO ２ R ８ｂ , and -CN; R ６ in, 5- to 10-membered heteroaryl, 3- to 8-membered heterocycloalkyl, 6- to 10-membered heterospirocycloalkyl, and 6- to 10-membered bridged cycloalkyl contain 1 to 3 heteroatoms selected from at least one of N, S and O; R ８ａ and R ８ｂ Each of these is independently a C group substituted with hydrogen, deuterium, or 0 to 6 substituents. １－４ Selected from alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5 and 6 membered heteroaryl, (3-6 membered cycloalkyl)-methylene, and (4-6 membered heterocycloalkyl)-methylene; R ８ａ and R ８ｂ In this, the substituents are deuterium, halogen, -N(R １０ａ R １０ｂ ), -OH, -CN, C １－４ Alkyl, C １－４ Alkoxy, C １－４ Selected from deuterated alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, (3-6 membered cycloalkyl)-methylene, or (4-6 membered heterocycloalkyl)-methylene; R ８ａ and R ８ｂ In this, 4-6 membered heterocycloalkyls, 5- and 6 membered heteroaryls, and (4-6 membered heterocycloalkyl)-methylenes each contain 1-3 heteroatoms selected from at least one of N, S, and O; 4-6 membered heterocycloalkyls and (4-6 membered heterocycloalkyl)-methylenes in substituents each contain 1-3 heteroatoms selected from at least one of N, S, and O; Or, R ８ａ and R ８ｂ These groups, together with the atoms to which they are bonded, form a 3-6 membered alkyl heterocyclic ring substituted with 0-6 substituents; R ８ａ and R ８ｂ However, when these groups form a ring together with the atom to which they are bonded, the substituents are deuterium, halogen, -N(R) １１ａ R １１ｂ ), -OH, -CN, C １－４ Selected from alkyl, 3-6 membered cycloalkyl, and 4-6 membered heterocycloalkyl; R ８ａ and R ８ｂ However, when these groups together with the atoms to which they are bonded form a ring, a 3- to 6-membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from at least one of N, S, and O, and a 4- to 6-membered heterocycloalkyl group in the substituent contains 1 to 3 heteroatoms selected from at least one of N, S, and O; R ７ａ C is a group substituted with hydrogen or 0 to 6 substituents. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Selected from alkynyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5- and 6 membered heteroaryl; R ７ａ In this, the substituents are hydrogen, deuterium, halogen, -OH, -NH ２ , or selected from -CN; R ７ａ In this, 4-6 membered heterocycloalkyls and 5-6 membered heteroaryls contain 1-3 heteroatoms selected from at least one of N, S, and O; R １０ａ , R １０ｂ , R １１ａ , and R １１ｂ Each of them is independently of hydrogen or C １－４ Selected from alkyl groups; A pharmaceutically acceptable form is a compound of formula I or any pharmaceutically acceptable form thereof, selected from pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, nitrogen oxides, isotopic markers, metabolites, or prodrugs.

2. R １ However, hydrogen, deuterium, halogens, -OH, -NH ２ C is a group that is optionally substituted with -CN, or 0 to 6 substituents. １－４ Alkyl, -O-C １－４ Alkyl, -S-C １－４ Alkyl, C ２－４ Alkenil, C ２－４ Selected from alkynyls and 3- to 6-membered cycloalkyls, wherein the substituents are deuterium, halogen, -OH, -NH ２ Selected from , or -CN; Preferably, R １ However, hydrogen, deuterium, halogens, F, Cl, -OH, -NH ２ C is a group that is optionally substituted with -CN, or 0 to 3 substituents. １－４ Alkyl, -O-C １－４ Alkyl, -S-C １－４ Selected from alkyl and 3- to 6-membered cycloalkyl groups, wherein the substituents are deuterium, F, Cl, -OH, -NH ２ Selected from , or -CN; More specifically, R １ However, hydrogen, deuterium, F, Cl, -OH, -CH ３ The compound according to claim 1, selected from fluoromethyl, deuterated methyl, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl, and fluorocyclopropyl.

3. R ２ and R ４ However, each is independent of hydrogen, deuterium, halogen, -OH, and -NH. ２ C is a group that is optionally substituted with -CN, or 0 to 6 substituents. １－４ Alkyl, -O-C １－４ Alkyl, -S-C １－４ Alkyl, C ２－４ Alkenil, C ２－４ Selected from alkynyls and 3- to 6-membered cycloalkyls, wherein the substituents are deuterium, halogen, -OH, -NH ２ Selected from , or -CN; Preferably, R ２ and R ４ However, each is independent of hydrogen, deuterium, F, Cl, -OH, and -NH. ２ C is a group that is optionally substituted with -CN, or 0 to 3 substituents. １－４ Alkyl, -O-C １－４ Alkyl, -S-C １－４ Selected from alkyl and 3- to 6-membered cycloalkyl groups, wherein the substituents are deuterium, F, Cl, -OH, -NH ２ Selected from , or -CN; More specifically, R ２ and R ４ However, each is independent of hydrogen, deuterium, F, Cl, -OH, and -CH. ３ , selected from fluoromethyl, deuterated methyl, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl, and fluorocyclopropyl, The compound according to claim 1 or 2.

4. R ３ However, hydrogen, deuterium, halogens, -OH, -NH ２ C is a group that is optionally substituted with -CN, or 0 to 6 substituents. １－４ Alkyl, -O-C １－４ Alkyl, -S-C １－４ Alkyl, C ２－４ Alkenil, C ２－４ Selected from alkynyl, 3-6 membered cycloalkyl, 5- and 6 membered heterocycloalkyl, phenyl, and 5- and 6 membered heteroaryl; R ３ In this, the substituent is deuterium, halogen, -OH, -NH ２ -CN, -CF ３ , or selected from cyclopropyl; R ３ In this, the 5- and 6-membered heterocycloalkyl and 5- and 6-membered heteroaryl contain 1 to 3 heteroatoms selected from at least one of N, S, and O. Preferably, R ３ However, C is a group optionally substituted with hydrogen, deuterium, F, Cl, -CN, or 0 to 3 substituents. １－４ Alkyl, -O-C １－４ Alkyl, -S-C １－４ Alkyl, C ２－４ Alkenil, C ２－４ Selected from alkynyl, 3-6 membered cycloalkyl, 5- and 6 membered heterocycloalkyl, phenyl, and 5- and 6 membered heteroaryl; R ３ In this, the substituent is deuterium, F, Cl, -OH, -NH ２ , -CF ３ Selected from , -CN, or cyclopropyl; R ３ In this, the 5- and 6-membered heterocycloalkyl and 5- and 6-membered heteroaryl contain one to two heteroatoms selected from at least one of N, S, and O. More specifically, R ３ However, selected from hydrogen, deuterium, F, Cl, methyl, fluoromethyl, deuterated methyl, methylthio, fluoromethylthio, deuterated methylthio, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl, fluorocyclopropyl, vinyl, ethynyl, phenyl, fluorophenyl, and deuterated phenyl, The compound according to any one of claims 1 to 3.

5. R ５ However, hydrogen, deuterium, halogens, -NH ２ C is a group that is optionally substituted with -CN, or 0 to 6 substituents. １－４ Alkyl, -O-C １－４ Alkyl, -S-C １－４ Alkyl, C ２－４ Alkenil, C ２－４ Selected from alkynyls and 3- to 6-membered cycloalkyls, wherein the substituents are deuterium, halogen, -OH, -NH ２ Selected from , or -CN; Preferably, R ５ However, hydrogen, deuterium, F, Cl, -NH ２ C is a group that is optionally substituted with -CN, or 0 to 3 substituents. １－４ Alkyl, -O-C １－４ Alkyl, -S-C １－４ Selected from alkyl and 3- to 6-membered cycloalkyl groups, wherein the substituents are deuterium, F, Cl, -OH, -NH ２ Selected from , or -CN; More specifically, R ５ However, hydrogen, deuterium, F, Cl, -CH, -CH ３ , selected from fluoromethyl, deuterated methyl, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl, and fluorocyclopropyl, The compound according to any one of claims 1 to 4.

6. R ２ and R ３ , R ３ and R ４ , or R ４ and R ５ However, these groups, together with the atoms to which they are bonded, form a 5- and 6-membered alkane ring, a benzene ring, a 5- and 6-membered alkane heterocyclic ring, or a 5- and 6-membered aromatic heterocyclic ring substituted with 0 to 6 substituents, wherein the substituents are deuterium, halogen, -OH, -NH ２ -CN, oxo group, C １－４ Alkyl, C １－４ Fluoroalkyl, C １－４ Alkyl deuterated, -O-C １－４ Alkyl, -O-C １－４ Fluoroalkyl, -O-C １－４ Selected from deuterated alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered fluorocycloalkyl, or 3 and 4-membered cycloalkyls formed by two substituents bonded to the same carbon atom; R ２ and R ３ , R ３ and R ４ , or R ４ and R ５ However, when these groups, together with the atoms to which they are bonded, form rings and 5- and 6-membered alkane heterocyclic rings, the 5- and 6-membered aromatic heterocyclic rings contain one or two heteroatoms selected from at least one of N, S, and O. Preferably, R ２ and R ３ , or R ３ and R ４ However, these groups, together with the atoms to which they are bonded, are substituted with 0 to 3 substituents. 【Transformation 3】 The substituents are deuterium, F, Br, Cl, -OH, -NH ２ Selected from -CN, oxo group, methyl, fluoromethyl, deuterated methyl, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl, fluorocyclopropyl, or 3- and 4-membered cycloalkyl groups formed by two substituents bonded to the same carbon atom, The compound according to any one of claims 1 to 5.

7. R １ -OH, R ２ and R ３ If selected from these, these groups, together with the atoms to which they are bonded, form a benzene ring, a 5- and 6-membered alkane heterocyclic ring, or a 5- and 6-membered aromatic heterocyclic ring substituted with 0 to 6 substituents, wherein the substituents are deuterium, halogen, -OH, -NH ２ ,-CN,C １－４ Alkyl, C １－４ Fluoroalkyl, C １－４ Alkyl deuterated, -O-C １－４ Alkyl, -O-C １－４ Fluoroalkyl, -O-C １－４ Selected from deuterated alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered fluorocycloalkyl, or 3 and 4-membered cycloalkyls formed by two substituents bonded to the same carbon atom; R ２ and R ３ However, when these groups together with the atoms to which they are bonded form a ring, five-membered and six-membered alkane heterocyclic rings contain two atoms of oxygen, and five-membered and six-membered aromatic heterocyclic rings contain one or two heteroatoms selected from at least one of N, S, and O; Preferably, R １ -OH, R ２ and R ３ If selected from these, together with the atom to which these groups are bonded, 【Chemistry 4】 A compound according to any one of claims 1 to 5, which forms a compound.

8. Structural unit 【Transformation 5】 but, 【Transformation 6】 A compound selected from any one of claims 1 to 7.

9. R ７ａ However, C is a group that is optionally substituted with hydrogen or 0 to 6 substituents. １－４ Alkyl, C ２－６ Alkenil, C ２－６ Selected from alkynyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5- and 6 membered heteroaryl; R ７ａ In this, the substituent is hydrogen, deuterium, halogen, -OH, -NH ２ Selected from , or -CN; Preferably, R ７ａ However, hydrogen, C １－４ Alkyl, C １－４ Fluoroalkyl, C １－４ Alkyl deuterated, 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, pyridinyl, or 【Transformation 7】 Selected from; X １ and X ２ However, each is independently selected from CH and N; X ３ However, N-C １－４ Selected from alkyl, NH, S, and O; More specifically, R ７ａ However, hydrogen, methyl, deuterated methyl, fluoromethyl, ethyl, fluoroethyl, isopropyl, fluoroisopropyl, cyclopropyl, fluorocyclopropyl, cyclohexyl, fluorocyclohexyl, phenyl, 2-pyridinyl, and 【Transformation 8】 Selected from; X １ However, selected from CH and N; X ３ The compound according to any one of claims 1 to 8, wherein the compound is selected from N-methyl, S, and O.

10. Structural unit 【Chemistry 9】 but, 【Chemistry 10】 A compound according to any one of claims 1 to 9, selected from the above.

11. L is O, -NH-, -NH-CH ２ -, and -NH-CH(CH ３ A compound according to any one of claims 1 to 10, selected from )

12. R ６ In this, the substituents are fluorine, chlorine, hydroxyl group, cyano group, oxo group, C １－４ Alkyl, C １－４ Fluoroalkyl, C １－４ Alkyl deuterated, C １－４ Alkoxy, C １－４ Fluoroalkoxy, C １－４ Deuterated alkoxy, 3-6 membered cycloalkyl, 3-6 membered fluorocycloalkyl, amino group, dimethylamino group, 【Chemistry 11】 A compound according to any one of claims 1 to 11, selected from the above.

13. R ６ However, the structure is as follows: 【Chemistry 12】 Selected from; R １２ａ and R １２ｂ However, each is independent of R ８ａ , halogen, oxo group, -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 , -SO ２ R ８ａ , -SO ２ NR ８ａ R ８ｂ , -NR ８ａ SO ２ R ８ｂ , and -CN are selected, and n2 is an integer selected from 0 to 6; Preferably, R １２ａ and R １２ｂ However, each is independent of R ８ａ , halogen, oxo group, -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 , -SO ２ R ８ａ , -SO ２ NR ８ａ R ８ｂ , -NR ８ａ SO ２ R ８ｂ , and -CN are selected, and n2 is an integer selected from 0 to 6; More specifically, R １２ａ and R １２ｂ However, each is independent of fluorine, chlorine, hydroxyl group, cyano group, oxo group, and C. １－４ Alkyl, C １－４ Fluoroalkyl, C １－４ Alkyl deuterated, C １－４ Alkoxy, C １－４ Fluoroalkoxy, C １－４ Deuterated alkoxy, 3-6 membered cycloalkyl, 3-6 membered fluorocycloalkyl, amino group, dimethylamino group, 【Chemistry 13】 A compound according to any one of claims 1 to 12, selected from the above.

14. R ６ However, the structure is as follows: 【Chemistry 14】 A compound according to any one of claims 1 to 13, selected from the above.

15. The aforementioned compound, 【Chemistry 15】 A compound according to any one of claims 1 to 14, selected from the above.

16. Structural unit 【Chemistry 16】 【Chemistry 17】 A compound according to claim 1, selected from the following.

17. Structural unit [Chemistry 18] but, 【Chemistry 19】 A compound according to claim 16, selected from the above.

18. L is O, -NH-, -NH-CH ２ -, and -NH-CH(CH ３ A compound according to claim 16 or 17, selected from ) -.

19. R ６ However, the structure is as follows: 【Chemistry 20】 A compound according to any one of claims 1 to 18, selected from the above.

20. The aforementioned compound, 【Chemistry 21】 A compound according to any one of claims 16 to 19, selected from the above.

21. Structural unit 【Chemistry 22】 but, 【Chemistry 23】 A compound according to claim 1, selected from the following.

22. Structural unit 【Chemistry 24】 but, 【Chemistry 25】 A compound according to claim 21, selected from the above.

23. L is O, -NH-, -NH-CH ２ -, and -NH-CH(CH ３ A compound according to claim 21 or 22, selected from ) -.

24. R ６ However, the structure is as follows: 【Chemistry 26】 【change】 A compound according to any one of claims 21 to 23, selected from the above.

25. The aforementioned compound, 【Chemistry 27】 A compound according to any one of claims 21 to 24, selected from the above.

26. Structural unit 【Chemistry 28】 but, 【Chemistry 29】 Selected from, The compound according to any one of claims 1 to 14.

27. R ６ However, the structure is as follows: 【Transformation 30】 A compound according to claim 26, selected from the above.

28. The aforementioned compound, 【Chemistry 31】 A compound according to claim 26 or 27, selected from the above.

29. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope marker, metabolite, or prodrug thereof, as an active ingredient.

30. Use of a compound or pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope marker, metabolite, or prodrug according to any one of claims 1 to 28, and the pharmaceutical composition according to claim 29, in the preparation of a drug for the prevention and / or treatment of NLRP3-related disease.

31. The use according to claim 30, wherein the NLRP3-related disease includes inflammatory diseases, autoimmune diseases, cardiovascular diseases, cancer, kidney diseases, gastrointestinal diseases, respiratory diseases, endocrine diseases, or central nervous system diseases.

32. The use according to claim 31, wherein the NLRP3-related disease includes cryopyrin-associated periodic syndrome (CAPS), Mackle-Wells syndrome, familial cold autoinflammatory syndrome, neonatal-onset multiorgan inflammatory disease (NOMID), familial Mediterranean fever, non-alcoholic steatohepatitis, alcoholic liver disease, graft-versus-host disease, multiple sclerosis, rheumatoid arthritis, type 1 / II diabetes and related complications, psoriasis, Alzheimer's disease, atherosclerosis, gout, chronic kidney disease, sepsis, hepatic fibrosis, idiopathic pulmonary fibrosis, epilepsy, neuropathic pain, depressive disorders, Parkinson's disease, asthma, acute myocardial infarction, systemic 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.

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