NLRP3 inflammasome inhibitors and their applications

Abstract

The present invention belongs to the field of pharmaceutical technology and relates to an NLRP3 inflammasome inhibitor and its application. Specifically, it relates to a compound represented by general formula (A') or its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, where the definitions of each group are as defined in the specification. Research has demonstrated that the compound represented by general formula (A') or its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative has relatively high biological activity against the NLRP3 inflammasome and has important clinical development value for the treatment of NLRP3-related diseases. [C1] TIFF2025534917000447.tif16156

Description

[Technical Field]

[0001] The present invention relates to the field of pharmaceutical technology, specifically to NLRP3 inflammasome inhibitors and their applications. [Background technology]

[0002] Nucleotide-binding oligomerization domain-like receptor protein 3 (NOD-like receptor protein 3, NLRP3) belongs to the nucleotide-binding oligomerization domain-like receptor (NOD-like receptors, NLRs) family and is also known as "pyrin domain-containing protein 3." NLRP3 contains three modules: a pyrin domain (PYD), a nucleotide-binding site domain (NBD), and a leucine-rich repeat (LRR). Upon stimulation with sterile inflammatory danger signals, NLRP3 interacts with the adaptor proteins apoptosis-associated spot-like protein (ASC) and pro-caspase 1 to form the NLRP3 inflammasome. Activation of the NLRP3 inflammasome leads to the release of interleukin-1β (IL-1β) and interleukin-18 (IL-18).

[0003] NLRP3 inflammasome activation typically involves two steps. Step 1 involves signal induction, in which Toll-like receptors recognize pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), transduce the signal into cells, mediate activation of the NF-κB signaling pathway, and upregulate the transcription levels of NLRP3 inflammasome-associated components, including inactive NLRP3 and pro-IL-1β. Step 2 involves signal activation, in which P2X7 receptors, upon signal stimulation by ATP or nigericin, induce oligomerization of NLRP3 monomers to form NLRP3 oligomers, which then recruit ASC and pro-caspase 1 to assemble into the NLRP3 inflammasome complex. This triggers the conversion of pro-caspase 1 to caspase 1 and the production and secretion of mature IL-1β and IL-18.

[0004] NLRP3 inflammasome activation is associated with several diseases, including autoinflammatory fever syndromes such as cryopyrin-associated periodic syndromes (CAPS), sickle cell disease, systemic lupus erythematosus (SLE), chronic liver disease, nonalcoholic steatohepatitis (NASH), gout, pseudogout (chondrocalcinosis), type I and type II diabetes and related complications (e.g., nephropathy, retinopathy), neuroinflammatory disorders (e.g., multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g., hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g., colorectal cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), and myelofibrosis). Treatment options include symptomatic treatment, delaying disease / disorder progression, and surgery as a last resort.

[0005] WO2020234715A1 discloses a series of NLRP3 inhibitors, and the patent is the first to disclose the use of pyridazin-3-ylphenol compounds in the treatment of NLRP3-mediated diseases.

[0006] Currently, there are relatively few types of NLRP3 inflammasome inhibitors being studied, and there is a clinical need to develop NLRP3 inflammasome inhibitors that have relatively high activity and better drug potential. Summary of the Invention [Problem to be solved by the invention]

[0007] The present invention studies the following compound or its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative thereof, and has found that the compound or its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative thereof has relatively high biological activity against NLRP3 inflammasome and has important clinical development value for the treatment of NLRP3-related diseases. [Means for solving the problem]

[0008] A compound represented by general formula (A') or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a deuterated derivative thereof, [ka] Here, W is [ka] Selected from [ka] is selected from a single bond or a double bond, R1 independently represents a hydrogen atom, a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen atom, or C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, -N(C 1-6 Alkyl)2, -SC 1-6alkyl groups or absent; R2 independently represents a hydrogen atom, a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen atom, or C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, -N(C 1-6 Alkyl)2, -SC 1-6 alkyl groups or absent; R1 and R2 each optionally represent a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen, a carbonyl group, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 substituted by 1 to 3 substituents selected from an alkoxy group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group; or R1 and R2 form a 5- to 12-membered ring A together with the C or N atom bonded thereto, and the 5- to 12-membered ring A optionally contains a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen atom, a carbonyl group, an oxo group, a C 1-6 Alkyl group, -NH-C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylsulfonyl group, -N(C 1-6the 5- to 12-membered ring is selected from a 5- to 12-membered cycloalkyl group, a 5- to 7-membered cycloalkyl group, a 5- to 12-membered cycloalkenyl group, a 5- to 7-membered cycloalkenyl group, a 6- to 12-membered fused cycloalkyl group, a 5- to 12-membered heterocyclic group, a 5- to 7-membered heterocyclic group, a 6- to 12-membered fused heterocyclic ring, an aryl group, a 5- to 12-membered heteroaryl group, an 8- to 12-membered fused heteroaryl group, and a 5- to 7-membered heteroaryl group; R3 is -(C 1-6 alkylene) 0-2 -NR4R5, -(C 1-6 alkylene) 0-2 -NR4-COR5, -(C 1-6 alkylene) 0-2 -CO-NR4-R5, -(C 1-6 alkylene) 0-2 -NR4-C 1-6 alkylene-R5; R4 is hydrogen or C 1-6 alkyl groups, R5 is selected from a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group, and R5 may optionally be a halogen atom, a cyano group, an amino group, a hydroxy group, a C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 2-6 Alkenylcarbonyl group, sulfonyl group, C 1-6 Alkylcarbonyl group, ureido C 1-6 Alkyl group, hydroxy C 1-6 Alkyl group, hydrazino group, C 1-6 Alkyl Sulfonyl C 1-6 substituted with 1 to 4 substituents selected from alkyl groups; The substituents in R5 are C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6alkoxy groups, 3- to 7-membered heterocyclic groups, 3- to 7-membered cycloalkyl groups, aryl groups, 5- to 7-membered heteroaryl groups, and sulfonyl groups, and the substituents are optionally selected from halogen, cyano groups, amino groups, hydroxy groups, carbonyl groups, C 1-6 Alkyl groups, 3- to 6-membered cycloalkyl groups, C 1-6 substituted by 1 to 3 substituents selected from alkylsulfonyl groups; Y is selected from an aryl group, a 5- to 14-membered heteroaryl group, a 3- to 14-membered heterocyclic group, and a 3- to 12-membered cycloalkyl group; The above Y is C 2-6 Alkenyl group, C 2-6 alkynyl groups, and optionally further substituted with 1 to 2 substituents selected from halogen, cyano group, amino group, hydroxy group, carbonyl group, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylamino group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkyl sulfonyl group, amino carbonyl group, C 1-6 Alkylaminocarbonyl group, sulfonyl group, -N(C 1-6 Alkyl)2, -SC 1-6 may be substituted with 1 to 2 substituents selected from alkyl groups, The substituent on Y is C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 When the substituent is selected from an alkoxy group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, a 5- to 7-membered heteroaryl group, and a sulfonyl group, the substituent may optionally be a halogen, a cyano group, an amino group, a hydroxy group, a carbonyl group, a C 1-6 substituted with 1 to 3 substituents selected from an alkyl group and a 3- to 6-membered cycloalkyl group; The substituent on Y is C 2-6 Alkenyl group, C 2-6When selected from alkynyl groups, the substituents are optionally selected from halogen, cyano, amino, hydroxy, carbonyl, C 1-6 Alkyl groups, 3-6 membered cycloalkyl groups, halogenated C 1-6 substituted with 1 to 3 substituents selected from alkyl groups; W is, [ka] When R1 and R2 are selected from the group consisting of: W is [ka] Selected from R1 is hydrogen, hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen, carbonyl group, halogenated C 1-6 Alkyl groups, halogenated C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 R1 is selected from the group consisting of an alkynyl group, a 3- to 7-membered heterocyclic group, a 4- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group, and preferably R1 is selected from the group consisting of hydrogen, a cyano group, a halogenated C 1-6 It is selected from alkyl groups.

[0009] In any one of the above technical proposals, W is [ka] Selected from Y is selected from an aryl group, a 5- to 14-membered heteroaryl group, a 3- to 14-membered heterocyclic group, and a 3- to 12-membered cycloalkyl group; The above Y is C 2-6 alkynyl groups, and optionally further substituted with halogen, cyano, amino, hydroxy, carbonyl, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylamino group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkyl sulfonyl group, amino carbonyl group, C 1-6 Alkylaminocarbonyl group, sulfonyl group, -N(C 1-6 Alkyl)2, -SC 1-6 may be substituted with 1 to 2 substituents selected from alkyl groups, The substituents on Y are C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 alkoxy groups, 3- to 7-membered heterocyclic groups, 3- to 7-membered cycloalkyl groups, aryl groups, 5- to 7-membered heteroaryl groups, and sulfonyl groups, and the substituents are optionally selected from halogen, cyano groups, amino groups, hydroxy groups, carbonyl groups, C 1-6 substituted with 1 to 3 substituents selected from an alkyl group and a 3- to 6-membered cycloalkyl group; The substituents on Y are C 2-6 alkynyl groups, the substituents being optionally selected from halogen, cyano, amino, hydroxy, carbonyl, C 1-6 Alkyl groups, 3-6 membered cycloalkyl groups, halogenated C 1-6 substituted with 1 to 3 substituents selected from alkyl groups; R5 is optionally hydroxy C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkyl group, hydrazino group, ureido C 1-6 R5 is substituted with a substituent selected from an alkyl group, and preferably R5 is hydroxy C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 It is substituted with an alkyl group.

[0010] In any one of the above technical proposals, W is [ka] Selected from Y is selected from an aryl group, a 5- to 14-membered heteroaryl group, a 3- to 14-membered heterocyclic group, and a 3- to 12-membered cycloalkyl group; The above Y is C 2-6 and optionally further substituted with halogen, cyano, amino, hydroxy, carbonyl, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylamino group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkyl sulfonyl group, amino carbonyl group, C 1-6 Alkylaminocarbonyl group, sulfonyl group, -N(C 1-6 Alkyl)2, -SC 1-6 may be substituted with 1 to 2 substituents selected from alkyl groups, The substituents on Y are C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 alkoxy groups, 3- to 7-membered heterocyclic groups, 3- to 7-membered cycloalkyl groups, aryl groups, 5- to 7-membered heteroaryl groups, and sulfonyl groups, and the substituents are optionally selected from halogen, cyano groups, amino groups, hydroxy groups, carbonyl groups, C 1-6 substituted with 1 to 3 substituents selected from an alkyl group and a 3- to 6-membered cycloalkyl group; The substituents on Y are C 2-6 alkenyl groups, the substituents being optionally selected from halogen, cyano, amino, hydroxy, carbonyl, C 1-6 Alkyl groups, 3-6 membered cycloalkyl groups, halogenated C 1-6 substituted with 1 to 3 substituents selected from alkyl groups; R5 is selected from a 3- to 7-membered heterocyclic group, a 5- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group, and R5 may optionally be a halogen atom, a cyano group, an amino group, a hydroxy group, a C 1-6 Alkyl groups, halogenated C 1-6Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 2-6 Alkenylcarbonyl group, sulfonyl group, C 1-6 Alkylcarbonyl group, ureido C 1-6 Alkyl group, hydroxy C 1-6 Alkyl group, hydrazino group, C 1-6 Alkyl Sulfonyl C 1-6 It is substituted with 1 to 4 substituents selected from alkyl groups.

[0011] In any one of the above technical proposals, W is [ka] Selected from At least one of R1 and R2 is C 2-6 Alkenyl group, C 2-6 alkynyl group, and cyano group, and preferably, at least one of R1 and R2 is selected from C 2-3 Alkenyl group, C 2-3 an alkynyl group, and a cyano group; R1 and R2 each optionally represent a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen, a carbonyl group, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 It is substituted with 1 to 3 substituents selected from an alkoxy group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group.

[0012] In any one of the above technical proposals, W is [ka] Selected from R1 is selected from hydrogen; R2 is selected from hydrogen.

[0013] In any one of the above technical proposals, W is [ka] Selected from Y is selected from an aryl group, a 5- to 14-membered heteroaryl group, a 3- to 14-membered heterocyclic group, and a 3- to 12-membered cycloalkyl group; The Y is substituted with a propynyl group and may further optionally be substituted with a halogen, a cyano group, an amino group, a hydroxy group, a carbonyl group, a C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylamino group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkyl sulfonyl group, amino carbonyl group, C 1-6 Alkylaminocarbonyl group, sulfonyl group, -N(C 1-6 Alkyl)2, -SC 1-6 may be substituted with 1 to 2 substituents selected from alkyl groups, The substituents on Y are C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 alkoxy groups, 3- to 7-membered heterocyclic groups, 3- to 7-membered cycloalkyl groups, aryl groups, 5- to 7-membered heteroaryl groups, and sulfonyl groups, and the substituents are optionally selected from halogen, cyano groups, amino groups, hydroxy groups, carbonyl groups, C 1-6 substituted with 1 to 3 substituents selected from an alkyl group and a 3- to 6-membered cycloalkyl group; The substituents on Y are selected from propynyl groups, and the substituents are optionally selected from halogen, cyano, amino, hydroxy, carbonyl, C 1-6 Alkyl groups, 3-6 membered cycloalkyl groups, halogenated C 1-6 substituted with 1 to 3 substituents selected from alkyl groups; R5 is selected from 3- to 7-membered cycloalkyl groups, and preferably R5 is selected from cyclobutane and cyclohexane.

[0014] In any one of the above technical proposals, R5 is selected from a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group, and R5 is selected from deuterium, deuterated C 1-6 Alkyl group, ethyl group, cyclopropyl group, halogen, halogenated C 1-6 It is substituted with 1 to 2 substituents selected from an alkyl group, and preferably, R5 is substituted with 1 to 2 substituents selected from deuterium, a deuterated methyl group, an ethyl group, a cyclopropyl group, and difluoroethane.

[0015] In any one of the above technical proposals, W is [ka] Selected from R5 is selected from a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group, and R5 is selected from a hydroxy group 1-6 It is substituted with 1 to 2 substituents selected from alkyl groups, and preferably, R5 is substituted with a hydroxyethyl group.

[0016] In any one of the above technical proposals, Y is selected from aryl groups; The above Y is C 2-6 Alkenyl group, C 2-6 alkynyl groups, and further hydroxy groups, halogens, halogenated C 1-6 The Y may be substituted with 1 to 2 substituents selected from alkyl groups, and preferably, the Y may further be substituted with a hydroxy group, a halogenated C 1-6 The Y may be substituted with an alkyl group. Preferably, the Y is C 2-6 alkynyl group, hydroxy group, and the above C 2-6 The alkynyl group may be further halogenated. 1-6The Y may be substituted with an alkyl group. Preferably, the Y is C 2-6 Y is substituted with a substituent selected from an alkynyl group, a hydroxy group, and a halogen, and more preferably, Y is substituted with a substituent selected from a trifluoromethylethynyl group and a hydroxy group, and more preferably, Y is substituted with a substituent selected from an ethynyl group and a propynyl group, and may further be substituted with a hydroxy group and a fluorine substituent.

[0017] In any one of the above technical proposals, W is [ka] Selected from When R2 is hydrogen, R1 is not selected from the group consisting of a methyl group and a cyclopropyl group. In any one of the above technical solutions, R5 is optionally selected from the group consisting of hydroxy C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 The alkyl group is substituted with a substituent selected from the group consisting of alkyl groups, but does not include the following compounds: [ka]

[0018] In any one of the above technical proposals, W is [ka] Selected from R1 is hydrogen, halogen, C 1-6 Alkyl groups, halogenated C 1-6 selected from alkyl groups and 3- to 7-membered cycloalkyl groups; R3 is -(C 1-6 alkylene) 0-2 -NR4R5, R4 is hydrogen or C 1-6 alkyl groups, R5 is selected from a 3- to 7-membered heterocyclic group and a 3- to 7-membered cycloalkyl group, and the R5 is optionally a deuterated C 1-6 Alkyl group, C1-6 Alkyl groups, halogenated C 1-6 Alkyl group, 3- to 7-membered cycloalkyl group, hydroxy group, hydroxy C 1-6 substituted with 1 to 4 substituents selected from alkyl groups; Y is selected from aryl groups; The above Y is C 2-6 alkynyl groups, and optionally further substituted with a substituent selected from a hydroxy group, C 1-6 Alkyl groups, halogenated C 1-6 may be substituted with 1 to 2 substituents selected from an alkyl group and a 3- to 7-membered cycloalkyl group, Above C 2-6 Substituents for the alkynyl group are optionally halogen, C 1-6 Alkyl groups, 3-6 membered cycloalkyl groups, halogenated C 1-6 It is substituted with a substituent selected from alkyl groups.

[0019] In any one of the above technical proposals, R1 and R2 are hydrogen, halogen, or C 1-6 selected from an alkyl group, a trifluoromethyl group, a difluoromethyl group, a cyclopropyl group, and a cyclobutyl group; R3 is selected from -NR4R5; R4 is selected from hydrogen or a methyl group; R5 is selected from piperidine, a cyclohexyl group, a cyclopentyl group, and a cyclobutyl group; Y is selected from a benzene ring; The above Y is substituted with a substituent selected from an ethynyl group and a propynyl group, and further optionally, a hydroxy group, C 1-6 It may be substituted by 1 to 2 substituents selected from an alkyl group, a trifluoromethyl group, a difluoromethyl group, and a cyclopropyl group, The substituents of the ethynyl group and the propynyl group may optionally be halogen, C 1-6 It is substituted with a substituent selected from an alkyl group, a cyclopropyl group, a trifluoromethyl group, and a difluoromethyl group.

[0020] In any one of the above technical proposals, R1 and R2 are selected from a methyl group, a trifluoromethyl group, a difluoromethyl group, and a cyclopropyl group; R3 is selected from -NR4R5; R4 is selected from hydrogen; R5 is selected from piperidinyl groups; Y is selected from a benzene ring; wherein Y is substituted with a substituent selected from an ethynyl group and a propynyl group, and may further optionally be substituted with 1 to 2 substituents selected from a hydroxy group, a methyl group, a trifluoromethyl group, a difluoromethyl group, and a cyclopropyl group; the substituent of the ethynyl group or propynyl group is optionally substituted with a substituent selected from fluorine, a methyl group, a cyclopropyl group, a trifluoromethyl group, and a difluoromethyl group; The substituents in R5 are selected from methyl, ethyl, cyclopropyl, fluorine, chlorine, bromine, difluoroethane, and hydroxyethyl groups.

[0021] In any one of the above technical proposals, W is [ka] Selected from R1 and R2 are each independently hydrogen, a cyano group, or C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, 3- to 7-membered cycloalkyl group, -N(C 1-6 alkyl)2, or absent, and preferably, R1 and R2 are each independently selected from hydrogen, a cyano group, C 1-6 selected from an alkyl group, a trifluoromethyl group, a difluoromethyl group, a cyclopropyl group, a cyclobutyl group, and -N(CH3)2; R3 is -(C 1-6 alkylene) 0-2 -NR4R5, R4 is hydrogen or C 1-6 alkyl groups, Y is selected from aryl groups; The above Y is C 2-6 alkynyl groups, and optionally further substituted with hydroxy groups, C 1-6 Alkyl groups, halogenated C 1-6 may be substituted with 1 to 2 substituents selected from an alkyl group and a 3- to 7-membered cycloalkyl group, Above C 2-6 Substituents for the alkynyl group are optionally halogen, C 1-6 Alkyl groups, 3-6 membered cycloalkyl groups, halogenated C 1-6 It is substituted with a substituent selected from alkyl groups.

[0022] The R5 is selected from a 3- to 7-membered heterocyclic group and a 3- to 7-membered cycloalkyl group, and the R5 is optionally selected from a hydroxy group, 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkyl group, hydrazino group, ureido C 1-6 R5 is substituted with a substituent selected from an alkyl group, and preferably R5 is hydroxy C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 It is substituted with an alkyl group.

[0023] In any one of the above technical solutions, the formula (A') is not the following compound: [ka]

[0024] In any one of the above technical solutions, when R5 is substituted with a hydroxyethyl group, R1 is not a methyl group.

[0025] In any one of the above technical solutions, when R5 is substituted with a hydroxyethyl group, R1 or R2 is selected from a cyclopropyl group. W is [ka] Selected from R1 and R2 are each independently hydrogen, a cyano group, or C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, 3- to 7-membered cycloalkyl group, -N(C 1-6 alkyl)2 or absent; R3 is -(C 1-6 alkylene) 0-2 -NR4R5, R4 is hydrogen or C 1-6 selected from alkyl groups, R5 is selected from a 3- to 7-membered heterocyclic group and a 3- to 7-membered cycloalkyl group, and R5 is selected from a hydroxy group 1-6 substituted with 1 to 2 substituents selected from alkyl groups, Y is selected from aryl groups; The above Y is C 2-6 alkynyl groups, and optionally further substituted with a substituent selected from a hydroxy group, C 1-6 Alkyl groups, halogenated C 1-6 may be substituted with 1 to 2 substituents selected from an alkyl group and a 3- to 7-membered cycloalkyl group, Above C 2-6 Substituents for the alkynyl group are optionally halogen, C 1-6 Alkyl groups, 3-6 membered cycloalkyl groups, halogenated C 1-6 It is substituted with a substituent selected from alkyl groups.

[0026] In any one of the above technical proposals, W is [ka] Selected from R1 and R2 are each independently hydrogen, a cyano group, or C 1-6 selected from an alkyl group, a trifluoromethyl group, a difluoromethyl group, a cyclopropyl group, a cyclobutyl group, and -N(CH3)2; R3 is selected from NR4R5, R4 is selected from hydrogen; R5 is selected from a piperidinyl group, a cyclobutyl group, and a cyclohexyl group, and R5 is optionally selected from a hydroxy group, C 1-6 Alkyl group, cyano C 1-6 Alkyl group, hydroxy C 1-6 substituted with 1 to 4 substituents selected from alkyl groups; Y is selected from a benzene ring; The above Y is substituted with a substituent selected from an ethynyl group and a propynyl group, and further optionally, a hydroxy group, C 1-6 It may be substituted by 1 to 2 substituents selected from an alkyl group, a trifluoromethyl group, a difluoromethyl group, and a cyclopropyl group, The substituents of the ethynyl group and the propynyl group may optionally be halogen, C 1-6 It is substituted with a substituent selected from an alkyl group, a cyclopropyl group, a trifluoromethyl group, and a difluoromethyl group.

[0027] In any one of the above technical proposals, Y is selected from the group consisting of phenyl groups; The above Y is C 2-6 Alkenyl group, C 2-6 alkynyl groups, and further hydroxy groups, halogenated C 1-6 The Y may be substituted with 1 to 2 substituents selected from alkyl groups, and preferably, the Y may further be substituted with a hydroxy group, a halogenated C 1-6 The Y may be substituted with an alkyl group. Preferably, the Y is C 2-6 Substituted with an alkynyl group or a hydroxy group, and 2-6 The alkynyl group may be further halogenated. 1-6 It may be substituted with an alkyl group, and more preferably, Y is substituted with a trifluoromethylethynyl group or a hydroxy group substituent.

[0028] In any one of the above technical proposals, At least one of R1 and R2 is a halogenated C 1-6 Preferably, at least one of R1 and R2 is selected from fluoro-substituted C 1-6Preferably, at least one of R1 and R2 is selected from alkyl groups, and more preferably, at least one of R1 and R2 is selected from trifluoromethyl groups.

[0029] In any one of the above technical proposals, R1 and R2 are each independently hydrogen, a cyano group, or C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, 3- to 7-membered cycloalkyl group, -N(C 1-6 alkyl)2 or absent; R3 is -(C 1-6 alkylene) 0-2 -NR4R5, R4 is hydrogen or C 1-6 alkyl groups, R5 is selected from a 3- to 7-membered heterocyclic group and a 3- to 7-membered cycloalkyl group, and R5 is selected from deuterium, deuterated C 1-6 R5 is substituted with 1 to 2 substituents selected from an alkyl group, an ethyl group, and a cyclopropyl group, and preferably R5 is substituted with 1 to 2 substituents selected from a deuterium atom, a deuterated methyl group, an ethyl group, and a cyclopropyl group; Y is selected from aryl groups; The above Y is C 2-6 alkynyl groups, and optionally further substituted with a substituent selected from a hydroxy group, C 1-6 Alkyl groups, halogenated C 1-6 may be substituted with 1 to 2 substituents selected from an alkyl group and a 3- to 7-membered cycloalkyl group, Above C 2-6 Substituents for the alkynyl group are optionally halogen, C 1-6 Alkyl groups, 3-6 membered cycloalkyl groups, halogenated C 1-6 It is substituted with a substituent selected from alkyl groups.

[0030] In any one of the above technical proposals, R1 and R2 are each independently hydrogen, a cyano group, or C 1-6 selected from an alkyl group, a trifluoromethyl group, a difluoromethyl group, a cyclopropyl group, a cyclobutyl group, and -N(CH3)2; R3 is selected from -NR4R5; R4 is selected from hydrogen; R5 is selected from a piperidinyl group, a cyclobutyl group, and a cyclohexyl group, and R5 is selected from deuterium, deuterated C 1-6 R5 is substituted with 1 to 2 substituents selected from an alkyl group, an ethyl group, and a cyclopropyl group, and preferably R5 is substituted with 1 to 2 substituents selected from a deuterium atom, a deuterated methyl group, an ethyl group, and a cyclopropyl group; Y is selected from the group consisting of phenyl groups; The above Y is substituted with a substituent selected from an ethynyl group and a propynyl group, and further optionally, a hydroxy group, C 1-6 It may be substituted by 1 to 2 substituents selected from an alkyl group, a trifluoromethyl group, a difluoromethyl group, and a cyclopropyl group, The substituents of the ethynyl group and the propynyl group may optionally be halogen, C 1-6 It is substituted with a substituent selected from an alkyl group, a cyclopropyl group, a trifluoromethyl group, and a difluoromethyl group.

[0031] In any one of the above technical proposals, W is [ka] Selected from R1 is hydrogen, halogen, C 1-6 selected from an alkyl group, a trifluoromethyl group, a difluoromethyl group, a cyclopropyl group, and a cyclobutyl group; R3 is selected from -NR4R5; R4 is selected from hydrogen or a methyl group; R5 is selected from piperidine, cyclohexyl, cyclopentyl, and cyclobutyl groups, and R5 is optionally a deuterated C 1-6 Alkyl group, C 1-6 Alkyl group, trifluoromethyl group, cyclopropyl group, hydroxy group, hydroxy C 1-6 substituted with 1 to 3 substituents selected from alkyl groups; Y is selected from a benzene ring; The above Y is substituted with a substituent selected from an ethynyl group and a propynyl group, and further optionally, a hydroxy group, C 1-6 It may be substituted by 1 to 2 substituents selected from an alkyl group, a trifluoromethyl group, a difluoromethyl group, and a cyclopropyl group, The substituents of the ethynyl group and the propynyl group may optionally be halogen, C 1-6 It is substituted with a substituent selected from an alkyl group, a cyclopropyl group, a trifluoromethyl group, and a difluoromethyl group.

[0032] In any one of the above technical proposals, W is [ka] Selected from R1 is selected from a methyl group, a trifluoromethyl group, a difluoromethyl group, and a cyclopropyl group; R3 is selected from -NR4R5; R4 is selected from hydrogen; R5 is selected from a piperidinyl group, and said R5 is optionally substituted with a substituent selected from a deuterated methyl group, a deuterated ethyl group, a methyl group, an ethyl group, a cyclopropyl group, and a hydroxyethyl group; Y is selected from a benzene ring; wherein Y is substituted with a substituent selected from an ethynyl group and a propynyl group, and may further optionally be substituted with 1 to 2 substituents selected from a hydroxy group, a methyl group, a trifluoromethyl group, a difluoromethyl group, and a cyclopropyl group; The substituents of the ethynyl group and propynyl group are optionally substituted with a substituent selected from fluorine, a methyl group, a cyclopropyl group, a trifluoromethyl group, and a difluoromethyl group.

[0033] In any one of the above technical proposals, W is [ka] Selected from [ka] is selected from double bonds, R1 is C 1-6 selected from alkyl groups and 3- to 7-membered cycloalkyl groups; R2 is absent, R3 is -(C 1-6 alkylene) 0-2 -NR4R5, R4 is hydrogen or C 1-6 alkyl groups, R5 is selected from a 3- to 7-membered heterocyclic group and a 3- to 7-membered cycloalkyl group, and the R5 is optionally a deuterated C 1-6 Alkyl group, ethyl group, halogenated C 1-6 Alkyl group, 3- to 7-membered cycloalkyl group, hydroxy group, hydroxy C 1-6 substituted with 1 to 4 substituents selected from alkyl groups; Y is selected from aryl groups; The above Y is C 2-6 alkynyl groups, and optionally further substituted with a substituent selected from a hydroxy group, C 1-6 Alkyl groups, halogenated C 1-6 may be substituted with 1 to 2 substituents selected from an alkyl group and a 3- to 7-membered cycloalkyl group, Above C 2-6 Substituents for the alkynyl group are optionally halogen, C 1-6 Alkyl groups, 3-6 membered cycloalkyl groups, halogenated C 1-6 It is substituted with a substituent selected from alkyl groups.

[0034] In any one of the above technical proposals, W is [ka] Selected from [ka] is selected from double bonds, R1 is C 1-6an alkyl group, a cyclopropyl group, R2 is absent, R3 is selected from -NR4R5; R4 is selected from hydrogen or a methyl group; R5 is selected from piperidine, cyclohexyl, cyclopentyl, and cyclobutyl groups, and R5 is optionally a deuterated C 1-6 Alkyl group, ethyl group, trifluoromethyl group, cyclopropyl group, hydroxy group, hydroxy C 1-6 substituted with 1 to 3 substituents selected from alkyl groups; Y is selected from a benzene ring; The above Y is substituted with a substituent selected from an ethynyl group and a propynyl group, and further optionally, a hydroxy group, C 1-6 It may be substituted by 1 to 2 substituents selected from an alkyl group, a trifluoromethyl group, a difluoromethyl group, and a cyclopropyl group, The substituents of the ethynyl group and the propynyl group may optionally be halogen, C 1-6 It is substituted with a substituent selected from an alkyl group, a cyclopropyl group, a trifluoromethyl group, and a difluoromethyl group.

[0035] In any one of the above technical proposals, W is [ka] Selected from [ka] is selected from double bonds, R1 is selected from a methyl group and a cyclopropyl group; R2 is absent, R3 is selected from -NR4R5; R4 is selected from hydrogen; R5 is selected from a piperidinyl group, and said R5 is optionally substituted with a substituent selected from a deuterated methyl group, a deuterated ethyl group, an ethyl group, a cyclopropyl group, and a hydroxyethyl group; Y is selected from a benzene ring; wherein Y is substituted with a substituent selected from an ethynyl group and a propynyl group, and may further optionally be substituted with 1 to 2 substituents selected from a hydroxy group, a methyl group, a trifluoromethyl group, a difluoromethyl group, and a cyclopropyl group; The substituents of the ethynyl group and propynyl group are optionally substituted with a substituent selected from fluorine, a methyl group, a cyclopropyl group, a trifluoromethyl group, and a difluoromethyl group.

[0036] In any one of the above technical solutions, R1 and R2 are each independently hydrogen, cyano, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, 3- to 7-membered cycloalkyl group, -N(C 1-6 alkyl)2 or absent.

[0037] In any one of the above technical solutions, R1 and R2 are each independently hydrogen, cyano, C 1-6 It is selected from an alkyl group, a trifluoromethyl group, a difluoromethyl group, a cyclopropyl group, a cyclobutyl group, and -N(CH3)2.

[0038] In any one of the above technical solutions, W is: [ka] Selected from.

[0039] In any one of the above technical solutions, the above R3 is -(C 1-6 alkylene) 0-2 -NR4R5, preferably, R3 is selected from NR4R5.

[0040] In any one of the above technical solutions, R4 is hydrogen or C 1-6 Preferably, R4 is selected from hydrogen or a methyl group, and preferably, R4 is selected from hydrogen.

[0041] In any one of the above technical proposals, The R5 is selected from a 3- to 7-membered heterocyclic group and a 3- to 7-membered cycloalkyl group, and the R5 is optionally selected from a halogen, a cyano group, an amino group, a hydroxy group, a C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, 3- to 7-membered heterocyclic group, hydroxy C 1-6 substituted with 1 to 4 substituents selected from alkyl groups; The substituents in R5 are optionally selected from halogen, cyano, amino, hydroxy, carbonyl, C 1-6 Alkyl groups, 3- to 6-membered cycloalkyl groups, C 1-6 It is substituted with 1 to 3 substituents selected from alkylsulfonyl groups.

[0042] In any one of the above technical solutions, R5 is selected from a piperidinyl group, a cyclobutyl group, and a cyclohexyl group; and R5 is optionally selected from a hydroxy group, C 1-6 Alkyl group, cyano C 1-6 Alkyl group, hydroxy C 1-6 It is substituted with 1 to 4 substituents selected from alkyl groups.

[0043] In any one of the above technical solutions, R5 is selected from a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group; R5 is selected from deuterium, deuterated C 1-6 Alkyl group, ethyl group, cyclopropyl group, halogen, halogenated C 1-6 It is substituted with 1 to 2 substituents selected from alkyl groups.

[0044] In any one of the above technical solutions, R5 is selected from a piperidinyl group, a cyclobutyl group, and a cyclohexyl group, and R5 is substituted with 1 to 2 substituents selected from deuterium, a deuterated methyl group, an ethyl group, a cyclopropyl group, fluorine, chlorine, bromine, and difluoroethane.

[0045] In any one of the above technical solutions, R3 is: [ka] Selected from.

[0046] In any one of the above technical proposals, wherein Y is selected from aryl groups; The above Y is C 2-6 alkynyl groups, and optionally further substituted with a substituent selected from a hydroxy group, C 1-6 Alkyl groups, halogens, halogenated C 1-6 may be substituted with 1 to 2 substituents selected from an alkyl group and a 3- to 7-membered cycloalkyl group, Above C 2-6 Substituents for the alkynyl group are optionally halogen, C 1-6 Alkyl groups, 3-6 membered cycloalkyl groups, halogenated C 1-6 It is substituted with a substituent selected from alkyl groups.

[0047] In any one of the above technical proposals, Y is selected from a benzene ring; The above Y is substituted with a substituent selected from an ethynyl group and a propynyl group, and further optionally, a hydroxy group, C 1-6 optionally substituted with 1 to 2 substituents selected from an alkyl group, fluorine, chlorine, bromine, a trifluoromethyl group, a difluoromethyl group, and a cyclopropyl group; The substituents of the ethynyl group and the propynyl group may optionally be halogen, C 1-6 It is substituted with a substituent selected from an alkyl group, a cyclopropyl group, a trifluoromethyl group, and a difluoromethyl group.

[0048] In any one of the above technical proposals, Y is selected from a benzene ring; wherein Y is substituted with a substituent selected from an ethynyl group and a propynyl group, and may further optionally be substituted with 1 to 2 substituents selected from a hydroxy group, a methyl group, fluorine, a trifluoromethyl group, a difluoromethyl group, and a cyclopropyl group; The substituents of the ethynyl group and propynyl group are optionally substituted with a substituent selected from bromine, fluorine, methyl, cyclopropyl, trifluoromethyl and difluoromethyl groups.

[0049] In any one of the above technical solutions, Y is: [ka] Selected from.

[0050] A compound represented by general formula (A) or a pharmaceutically acceptable salt or stereoisomer thereof, [ka] Here, W is [ka] Selected from X1 and X2 are each independently selected from C or N; R1 is hydrogen, hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen, carbonyl group, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, -N(C 1-6 Alkyl)2, -SC 1-6 alkyl groups or absent; R2 is hydrogen, hydroxy group, amino group, carboxy group, cyano group, nitro group, halogen, carbonyl group, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6Alkynyl group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, -N(C 1-6 Alkyl)2, -SC 1-6 alkyl groups or absent; R1 and R2 each optionally represent a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen, a carbonyl group, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 substituted by 1 to 3 substituents selected from an alkoxy group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group; or R1 and R2 form a 5- to 12-membered ring A together with the C or N atom bonded thereto, and the 5- to 12-membered ring A optionally contains a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen atom, a carbonyl group, a C 1-6 Alkyl group, -NH-C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylsulfonyl group, -N(C 1-6 the 5- to 12-membered ring is selected from a 5- to 12-membered cycloalkyl group, a 5- to 7-membered cycloalkyl group, a 5- to 12-membered cycloalkenyl group, a 5- to 7-membered cycloalkenyl group, a 6- to 12-membered fused cycloalkyl group, a 5- to 12-membered heterocyclic group, a 5- to 7-membered heterocyclic group, a 6- to 12-membered fused heterocyclic ring, an aryl group, a 5- to 12-membered heteroaryl group, an 8- to 12-membered fused heteroaryl group, and a 5- to 7-membered heteroaryl group; R3 is -(C 1-6 alkylene) 0-2 -NR4R5, -(C 1-6 alkylene) 0-2 -NR4-COR5, -(C 1-6 alkylene) 0-2-CO-NR4-R5, -(C 1-6 alkylene) 0-2 -NR4-C 1-6 alkylene-R5; R4 is hydrogen or C 1-6 alkyl groups, R5 is selected from a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group, and R5 may optionally be a halogen atom, a cyano group, an amino group, a hydroxy group, a C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 2-6 Alkenylcarbonyl group, sulfonyl group, C 1-6 substituted with 1 to 4 substituents selected from alkylcarbonyl groups; If R5 is substituted, Substituents in R5: C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 The alkoxy group, the 3- to 7-membered heterocyclic group, the 3- to 7-membered cycloalkyl group, the aryl group, the 5- to 7-membered heteroaryl group, and the sulfonyl group may optionally be substituted with a halogen, a cyano group, an amino group, a hydroxy group, a carbonyl group, a C 1-6 Alkyl groups, 3- to 6-membered cycloalkyl groups, C 1-6 substituted by 1 to 3 substituents selected from alkylsulfonyl groups; Y is selected from an aryl group, a 5- to 14-membered heteroaryl group, a 3- to 14-membered heterocyclic group, and a 3- to 12-membered cycloalkyl group; (1) When X1 and X2 are each selected from C, The above Y is C 2-6 Alkenyl group, C 2-6 alkynyl groups, and optionally halogen, cyano groups, amino groups, hydroxy groups, carbonyl groups, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylamino group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkyl sulfonyl group, amino carbonyl group, C 1-6 substituted with 1 to 2 substituents selected from an alkylaminocarbonyl group and a sulfonyl group; (2) W is [ka] or when any one or two of X1 and X2 are selected from N, The Y is optionally selected from C 2-6 Alkenyl group, C 2-6 Alkynyl group, halogen, cyano group, amino group, hydroxy group, carbonyl group, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylamino group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkyl sulfonyl group, amino carbonyl group, C 1-6 Alkylaminocarbonyl group, sulfonyl group, -N(C 1-6 Alkyl)2, -SC 1-6 substituted with 1 to 3 substituents selected from alkyl groups; If Y is substituted, Substituents in Y: C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 The alkoxy group, the 3- to 7-membered heterocyclic group, the 3- to 7-membered cycloalkyl group, the aryl group, the 5- to 7-membered heteroaryl group, and the sulfonyl group may optionally be substituted with a halogen, a cyano group, an amino group, a hydroxy group, a carbonyl group, a C 1-6 substituted with 1 to 3 substituents selected from an alkyl group and a 3- to 6-membered cycloalkyl group; Substituents in Y: C 2-6 Alkenyl group, C2-6 The alkynyl group may optionally be substituted with a halogen, a cyano group, an amino group, a hydroxy group, a carbonyl group, a C 1-6 Alkyl groups, 3-6 membered cycloalkyl groups, halogenated C 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups.

[0051] In any one of the above technical solutions, the general formula after Y and R3 are bonded to W is: [ka] Selected from.

[0052] The present invention further provides a compound represented by general formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof: [ka] where: R1 is hydrogen, hydroxy group, amino group, carboxy group, cyano group, nitro group, halogen, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 selected from an alkynyl group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group; R2 is hydrogen, hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 selected from an alkynyl group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group; R1 and R2 each optionally represent a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen, a carbonyl group, C 1-6Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 substituted by 1 to 3 substituents selected from an alkoxy group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group; or R1 and R2 form a 5- to 12-membered ring A together with the carbon atom bonded thereto, and the 5- to 12-membered ring A optionally contains a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen atom, a carbonyl group, C 1-6 Alkyl group, -NH-C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylsulfonyl group, -N(C 1-6 the 5- to 12-membered ring is selected from a 5- to 12-membered cycloalkyl group, a 5- to 7-membered cycloalkyl group, a 5- to 12-membered cycloalkenyl group, a 5- to 7-membered cycloalkenyl group, a 6- to 12-membered fused cycloalkyl group, a 5- to 12-membered heterocyclic group, a 5- to 7-membered heterocyclic group, a 6- to 12-membered fused heterocyclic ring, an aryl group, a 5- to 12-membered heteroaryl group, an 8- to 12-membered fused heteroaryl group, and a 5- to 7-membered heteroaryl group; R3 is -(C 1-6 alkylene) 0-2 -NR4R5, -(C 1-6 alkylene) 0-2 -NR4-COR5, -(C 1-6 alkylene) 0-2 -CO-NR4-R5, -(C 1-6 alkylene) 0-2 -NR4-C 1-6 alkylene-R5; R4 is hydrogen or C 1-6 alkyl groups, R5 is selected from a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group, and R5 may optionally be a halogen atom, a cyano group, an amino group, a hydroxy group, a C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 2-6 Alkenylcarbonyl group, sulfonyl group, C 1-6 substituted with 1 to 4 substituents selected from alkylcarbonyl groups; Y is selected from an aryl group, a 5- to 14-membered heteroaryl group, a 3- to 14-membered heterocyclic group, and a 3- to 12-membered cycloalkyl group, and the Y is C 2-6 Alkenyl group, C 2-6 alkynyl groups, and optionally halogen, cyano groups, amino groups, hydroxy groups, carbonyl groups, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylamino group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkyl sulfonyl group, amino carbonyl group, C 1-6 substituted with 1 to 2 substituents selected from an alkylaminocarbonyl group and a sulfonyl group; If R5 is substituted, Substituents in R5: C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 The alkoxy group, the 3- to 7-membered heterocyclic group, the 3- to 7-membered cycloalkyl group, the aryl group, the 5- to 7-membered heteroaryl group, and the sulfonyl group may optionally be substituted with a halogen, a cyano group, an amino group, a hydroxy group, a carbonyl group, a C 1-6 Alkyl groups, 3- to 6-membered cycloalkyl groups, C 1-6 substituted by 1 to 3 substituents selected from alkylsulfonyl groups; If Y is substituted, Substituents in Y: C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 The alkoxy group, the 3- to 7-membered heterocyclic group, the 3- to 7-membered cycloalkyl group, the aryl group, the 5- to 7-membered heteroaryl group, and the sulfonyl group may optionally be substituted with a halogen, a cyano group, an amino group, a hydroxy group, a carbonyl group, a C 1-6 substituted with 1 to 3 substituents selected from an alkyl group and a 3- to 6-membered cycloalkyl group; Substituents in Y: C 2-6 Alkenyl group, C 2-6 The alkynyl group may optionally be substituted with a halogen, a cyano group, an amino group, a hydroxy group, a carbonyl group, a C 1-6 Alkyl groups, 3-6 membered cycloalkyl groups, halogenated C 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups.

[0053] Furthermore, the present invention provides a compound represented by general formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, [ka] where: R1 is hydrogen, hydroxy group, amino group, carboxy group, cyano group, nitro group, halogen, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 selected from an alkynyl group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group; R2 is hydrogen, hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6selected from an alkynyl group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group; R1 and R2 each optionally represent a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen, a carbonyl group, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 substituted by 1 to 3 substituents selected from an alkoxy group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group; or R1 and R2 form a 5- to 12-membered ring A together with the carbon atom bonded thereto, and the 5- to 12-membered ring A optionally contains a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen atom, a carbonyl group, C 1-6 Alkyl group, -NH-C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylsulfonyl group, -N(C 1-6 the 5- to 12-membered ring is selected from a 5- to 12-membered cycloalkyl group, a 5- to 7-membered cycloalkyl group, a 5- to 12-membered cycloalkenyl group, a 5- to 7-membered cycloalkenyl group, a 6- to 12-membered fused cycloalkyl group, a 5- to 12-membered heterocyclic group, a 5- to 7-membered heterocyclic group, a 6- to 12-membered fused heterocyclic ring, an aryl group, a 5- to 12-membered heteroaryl group, an 8- to 12-membered fused heteroaryl group, and a 5- to 7-membered heteroaryl group; R3 is -(C 1-6 alkylene) 0-2 -NR4R5, -(C 1-6 alkylene) 0-2 -NR4-COR5, -(C 1-6 alkylene) 0-2 -CO-NR4-R5, R4 is hydrogen or C 1-6 alkyl groups, R5 is selected from a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group, and R5 may optionally be a halogen atom, a cyano group, an amino group, a hydroxy group, a C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 2-6 Alkenylcarbonyl group, sulfonyl group, C 1-6 substituted with 1 to 4 substituents selected from alkylcarbonyl groups; Y is selected from an aryl group, a 5- to 14-membered heteroaryl group, a 3- to 14-membered heterocyclic group, and a 3- to 12-membered cycloalkyl group, and the Y is C 2-6 Alkenyl group, C 2-6 alkynyl groups, and optionally halogen, cyano groups, amino groups, hydroxy groups, carbonyl groups, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylamino group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkyl sulfonyl group, amino carbonyl group, C 1-6 substituted with 1 to 2 substituents selected from an alkylaminocarbonyl group and a sulfonyl group; If R5 is substituted, Substituents in R5: C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 The alkoxy group, the 3- to 7-membered heterocyclic group, the 3- to 7-membered cycloalkyl group, the aryl group, the 5- to 7-membered heteroaryl group, and the sulfonyl group may optionally be substituted with a halogen, a cyano group, an amino group, a hydroxy group, a carbonyl group, a C 1-6 substituted with 1 to 3 substituents selected from an alkyl group and a 3- to 6-membered cycloalkyl group; If Y is substituted, Substituents in Y: C 1-6Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 The alkoxy group, the 3- to 7-membered heterocyclic group, the 3- to 7-membered cycloalkyl group, the aryl group, the 5- to 7-membered heteroaryl group, and the sulfonyl group may optionally be substituted with a halogen, a cyano group, an amino group, a hydroxy group, a carbonyl group, a C 1-6 substituted with 1 to 3 substituents selected from an alkyl group and a 3- to 6-membered cycloalkyl group; Substituents in Y: C 2-6 Alkenyl group, C 2-6 An alkynyl group is unsubstituted.

[0054] The present invention further provides the above compound having a structure represented by general formula (B) or a pharmaceutically acceptable salt or stereoisomer thereof, [ka] R1 is hydrogen, hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen, carbonyl group, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, -N(C 1-6 Alkyl)2, -SC 1-6 alkyl groups or absent; R2 is hydrogen, hydroxy group, amino group, carboxy group, cyano group, nitro group, halogen, carbonyl group, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, -N(C 1-6 Alkyl)2, -SC 1-6alkyl groups or absent; R1 and R2 each optionally represent a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen, a carbonyl group, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 substituted by 1 to 3 substituents selected from an alkoxy group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group; Any one or two of X1 and X2 are selected from N; Y is substituted with a hydroxy group and optionally C 2-6 Alkenyl group, C 2-6 Alkynyl group, halogen, cyano group, amino group, hydroxy group, carbonyl group, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, C 1-6 Alkylamino group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkyl sulfonyl group, amino carbonyl group, C 1-6 Alkylaminocarbonyl group, sulfonyl group, -N(C 1-6 Alkyl)2, -SC 1-6 It is substituted with 1 to 2 substituents selected from alkyl groups.

[0055] In any one of the above technical solutions, Y is selected from a phenyl group, a 5- to 7-membered heteroaryl group, a 3- to 8-membered heterocyclic group, and a 3- to 7-membered cycloalkyl group; 2-6 Alkenyl group, C 2-6 alkynyl groups, and optionally halogen, cyano, amino, hydroxy, carbonyl, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, C 1-6 Alkylamino group, C 1-6Alkylcarbonylamino group, C 1-6 Alkyl sulfonyl group, amino carbonyl group, C 1-6 substituted with 1 to 2 substituents selected from an alkylaminocarbonyl group and a sulfonyl group; When Y is substituted, the substituents on Y are: 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 The alkoxy group, the 3- to 7-membered heterocyclic group, the 3- to 7-membered cycloalkyl group, and the sulfonyl group may optionally be substituted with a halogen, a cyano group, an amino group, a hydroxy group, a carbonyl group, a C 1-6 substituted with 1 to 3 substituents selected from alkyl groups; R3 is selected from -NH-R5, and R5 is C 1-6 It is a 3- to 7-membered heterocyclic group substituted with 1 or 2 substituents selected from alkyl groups.

[0056] In any one of the above technical solutions, the compound provided by the present invention or its pharmaceutically acceptable salt or stereoisomer has a structure represented by general formula (B): [ka] R1 and R2 together with the C or N atom bonded thereto form a 5- to 8-membered cycloalkyl group, a 5- to 8-membered cycloalkenyl group, a 5- to 8-membered heterocyclic group, a phenyl group, or a 5- to 8-membered heteroaryl group, and the 5- to 8-membered cycloalkyl group, the 5- to 8-membered cycloalkenyl group, the 5- to 8-membered heterocyclic group, the phenyl group, or the 5- to 8-membered heteroaryl group may optionally be substituted with a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen atom, a carbonyl group, a C 1-6 Alkyl group, -NH-C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylsulfonyl group, -N(C 1-6 alkyl)2, Any one or two of X1 and X2 are selected from N; Y is substituted with a hydroxy group and optionally C 2-6 Alkenyl group, C 2-6 Alkynyl group, halogen, cyano group, amino group, hydroxy group, carbonyl group, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, C 1-6 Alkylamino group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkyl sulfonyl group, amino carbonyl group, C 1-6 Alkylaminocarbonyl group, sulfonyl group, -N(C 1-6 Alkyl)2, -SC 1-6 It is substituted with 1 to 2 substituents selected from alkyl groups.

[0057] In any one of the above technical solutions, ring A is selected from a 5- to 12-membered cycloalkyl group, a 5- to 12-membered cycloalkenyl group, a 5- to 12-membered heterocyclic group, an aryl group, and a 5- to 12-membered heteroaryl group.

[0058] In any one of the above technical solutions, ring A is selected from a 5- to 8-membered cycloalkyl group, a 5- to 8-membered cycloalkenyl group, a 5- to 8-membered heterocyclic group, a phenyl group, and a 5- to 8-membered heteroaryl group.

[0059] In any one of the above technical solutions, ring A is selected from a phenyl group and a 5- to 7-membered heteroaryl group, and ring A optionally contains a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen atom, a C 1-6 Alkyl group, -NH-C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, C 1-6 Alkylsulfonyl group, -N(C 1-6 alkyl)2.

[0060] In any one of the above technical solutions, ring A is selected from a phenyl group, a 5- to 6-membered heteroaryl group containing 1 to 2 heteroatoms selected from O, S, and N, and a 5- to 6-membered saturated ring.

[0061] In any one of the above technical solutions, ring A optionally represents a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen atom, a carbonyl group, C 1-6 Alkyl group, -NH-C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylsulfonyl group, -N(C 1-6 alkyl)2.

[0062] In any one of the above technical solutions, ring A is unsubstituted.

[0063] In any one of the above technical solutions, ring A is a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen, C 1-6 Alkyl group, -NH-C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylsulfonyl group, -N(C 1-6 alkyl)2.

[0064] In any one of the above technical solutions, ring A is a cyano group, C 1-6 Alkoxy group, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkylsulfonyl group, -N(C1-6 alkyl)2.

[0065] In any one of the above technical solutions, ring A is a cyano group, C 1-6 Alkoxy group, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkylsulfonyl group, -N(C 1-6 alkyl)2.

[0066] In any one of the above technical solutions, ring A is selected from a phenyl group, a 5- to 6-membered heteroaryl group containing 1 to 2 heteroatoms selected from O, S, and N, and a 5- to 6-membered saturated ring, and ring A is unsubstituted or is selected from a cyano group, C 1-6 Alkoxy group, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkylsulfonyl group, -N(C 1-6 alkyl)2.

[0067] In any one of the above technical solutions, ring A is: [ka] and ring A is optionally selected from a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen, C 1-6 Alkyl group, -NH-C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, C 1-6 Alkylsulfonyl group, -N(C 1-6 alkyl)2.

[0068] In any one of the above technical solutions, ring A is: [ka] and ring A is optionally selected from a cyano group, a nitro group, a halogen, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered cycloalkyl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylsulfonyl group, -N(C 1-6 alkyl)2.

[0069] In any one of the above technical solutions, ring A is: [ka] is.

[0070] In any one of the above technical solutions, R3 is -(C 1-6 alkylene) 0-2 -NR4R5, -(C 1-6 alkylene) 0-2 -NR4-COR5, -(C 1-6 alkylene) 0-2 -CO-NR4-R5, where R4 is hydrogen or C 1-6 R5 is selected from a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group.

[0071] In any one of the above technical solutions, R4 is selected from hydrogen.

[0072] In any one of the above technical solutions, R4 is C 1-6 It is selected from alkyl groups.

[0073] In any one of the above technical solutions, R4 is selected from a methyl group and an ethyl group.

[0074] In any one of the above technical solutions, R3 is -NR4R5, -NR4-C 1-6alkylene-R5, R4 is selected from hydrogen, and R5 is selected from a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group.

[0075] In any one of the above technical solutions, R3 is -NR4R5, -NR4-C 1-6 alkylene-R5, where R4 is selected from hydrogen, and R5 is selected from a 3- to 7-membered cycloalkyl group and a 3- to 7-membered heterocyclic group, preferably, R3 is selected from —NHR5, and R5 is selected from a 4- to 6-membered cycloalkyl group and a 4- to 6-membered heterocyclic group.

[0076] In any one of the above technical solutions, R5 is selected from a 4- to 6-membered cycloalkyl group and a 4- to 6-membered heterocyclic group containing one heteroatom selected from O, N, and S.

[0077] In any one of the above technical solutions, R5 is optionally selected from halogen, cyano, amino, hydroxy, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 2-6 Alkenylcarbonyl group, sulfonyl group, C 1-6 alkylcarbonyl group, and when R5 is substituted, the substituents in R5 are: C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 The alkoxy group, the 3- to 7-membered heterocyclic group, the 3- to 7-membered cycloalkyl group, the aryl group, the 5- to 7-membered heteroaryl group, and the sulfonyl group may optionally be substituted with a halogen, a cyano group, an amino group, a hydroxy group, a carbonyl group, a C 1-6 It is substituted with 1 to 3 substituents selected from an alkyl group and a 3- to 6-membered cycloalkyl group.

[0078] In any one of the above technical solutions, R5 is unsubstituted.

[0079] In any one of the above technical solutions, R5 is a halogen, a cyano group, an amino group, a hydroxy group, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 2-6 Alkenylcarbonyl group, sulfonyl group, C 1-6 substituted with 1 to 2 substituents selected from alkylcarbonyl groups; In any one of the above technical solutions, when R5 is substituted, the substituent in R5 is: C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 The alkoxy group, the 3- to 7-membered heterocyclic group, the 3- to 7-membered cycloalkyl group, the aryl group, the 5- to 7-membered heteroaryl group, and the sulfonyl group are unsubstituted.

[0080] In any one of the above technical solutions, when R5 is substituted, the substituent in R5 is: C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy groups, 3- to 7-membered heterocyclic groups, 3- to 7-membered cycloalkyl groups, aryl groups, 5- to 7-membered heteroaryl groups, sulfonyl groups, halogens, cyano groups, amino groups, hydroxy groups, carbonyl groups, C 1-6 It is substituted with 1 to 3 substituents selected from an alkyl group and a 3- to 6-membered cycloalkyl group.

[0081] In any one of the above technical solutions, R5 is: [ka] Selected from.

[0082] Preferably, R5 is [ka] Selected from.

[0083] In any one of the above technical solutions, Y is selected from an aryl group, a 5- to 14-membered heteroaryl group, a 3- to 14-membered heterocyclic group, and a 3- to 12-membered cycloalkyl group, and the Y is C 2-6 Alkenyl group, C 2-6 alkynyl groups, and optionally halogen, cyano groups, amino groups, hydroxy groups, carbonyl groups, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylamino group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkyl sulfonyl group, amino carbonyl group, C 1-6 It is substituted with 1 to 2 substituents selected from an alkylaminocarbonyl group and a sulfonyl group.

[0084] In any one of the above technical solutions, Y is selected from a phenyl group, a 5- to 7-membered heteroaryl group, a 3- to 8-membered heterocyclic group, and a 3- to 7-membered cycloalkyl group; 2-6 Alkenyl group, C 2-6 alkynyl groups, and optionally halogen, cyano, amino, hydroxy, carbonyl, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, C 1-6 Alkylamino group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkyl sulfonyl group, amino carbonyl group, C 1-6 It is substituted with 1 to 2 substituents selected from an alkylaminocarbonyl group and a sulfonyl group.

[0085] In any one of the above technical solutions, Y is selected from a phenyl group, a 5- to 8-membered heteroaryl group, a 3- to 8-membered heterocyclic group, and a 3- to 7-membered cycloalkyl group.

[0086] In any one of the above technical solutions, Y is selected from a phenyl group and a 5- to 6-membered heteroaryl group.

[0087] In any one of the above technical solutions, Y is selected from a phenyl group and a 5-6 membered heteroaryl group containing 1-2 N heteroatoms.

[0088] In any one of the above technical solutions, Y is C 2-6 Alkenyl group, C 2-6 alkynyl groups, and optionally halogen, cyano, amino, hydroxy, carbonyl, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 It is substituted with 1 or 2 substituents selected from an alkoxy group, a 3- to 7-membered heterocyclic group, and a 3- to 7-membered cycloalkyl group.

[0089] In any one of the above technical solutions, Y is C 2-6 Alkenyl group, C 2-6 It is substituted with 1 to 2 substituents selected from alkynyl groups.

[0090] In any one of the above technical solutions, Y is C 2-6 Alkenyl group, C 2-6 It is substituted with one substituent selected from an alkynyl group.

[0091] In any one of the above technical solutions, Y is optionally selected from the group consisting of halogen, cyano, amino, hydroxy, carbonyl, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 It is substituted with 1 to 3 substituents selected from an alkoxy group, a 3- to 7-membered heterocyclic group, and a 3- to 7-membered cycloalkyl group.

[0092] In any one of the above technical solutions, Y is optionally a halogen, a cyano group, an amino group, a hydroxy group, a carbonyl group, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C1-6 It is substituted with 1 or 2 substituents selected from an alkoxy group, a 3- to 7-membered heterocyclic group, and a 3- to 7-membered cycloalkyl group.

[0093] In any one of the above technical solutions, Y is C 2-6 Alkenyl group, C 2-6 alkynyl groups, and optionally halogen, cyano group, amino group, hydroxy group, carbonyl group, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 It is substituted with 1 to 3 substituents selected from an alkoxy group, a 3- to 7-membered heterocyclic group, and a 3- to 7-membered cycloalkyl group.

[0094] In any one of the above technical solutions, Y is C 2-6 Alkenyl group, C 2-6 and Y is optionally substituted with one substituent selected from a halogen, a cyano group, an amino group, a hydroxy group, a carbonyl group, a C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 It is substituted with one substituent selected from an alkoxy group, a 3- to 7-membered heterocyclic group, and a 3- to 7-membered cycloalkyl group.

[0095] In any one of the above technical solutions, Y is C 2-6 Alkenyl group, C 2-6 alkynyl groups, and optionally halogen, cyano, amino, hydroxy, carbonyl, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylamino group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkyl sulfonyl group, amino carbonyl group, C 1-6 It is substituted with 1 to 2 substituents selected from an alkylaminocarbonyl group and a sulfonyl group.

[0096] In any one of the above technical solutions, when Y is substituted, the substituent on Y is: C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 The alkoxy group, the 3- to 7-membered heterocyclic group, the 3- to 7-membered cycloalkyl group, the aryl group, the 5- to 7-membered heteroaryl group, and the sulfonyl group may optionally be substituted with a halogen, a cyano group, an amino group, a hydroxy group, a carbonyl group, a C 1-6 It is substituted with 1 to 3 substituents selected from an alkyl group and a 3- to 6-membered cycloalkyl group.

[0097] In any one of the above technical solutions, the substituent in Y is: C 2-6 Alkenyl group, C 2-6 Alkynyl groups are substituted with halogens, cyano groups, amino groups, hydroxy groups, carbonyl groups, and C 1-6 Alkyl groups, 3-6 membered cycloalkyl groups, halogenated C 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups.

[0098] In any one of the above technical solutions, the substituent in Y is: C 2-6 Alkenyl group, C 2-6 An alkynyl group is unsubstituted.

[0099] In any one of the above technical solutions, Y is selected from a phenyl group and a 5- to 6-membered heteroaryl group, and the Y is C 2-6 Alkenyl group, C 2-6 alkynyl groups, and optionally halogen, cyano groups, amino groups, hydroxy groups, carbonyl groups, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 1-6 substituted with 1 to 2 groups selected from an alkoxy group, a 3- to 7-membered heterocyclic group, and a 3- to 7-membered cycloalkyl group; 2-6 Alkenyl group, C 2-6 Alkynyl groups are substituted with halogens, cyano groups, amino groups, hydroxy groups, carbonyl groups, and C 1-6 Alkyl groups, 3-6 membered cycloalkyl groups, halogenated C1-6 It is substituted with 1 to 3 substituents selected from alkyl groups.

[0100] In any one of the above technical solutions, Y is: [ka] Selected from.

[0101] In any one of the above technical solutions, when Y is substituted, the substituent on Y is: [ka] Selected from.

[0102] In any one of the above technical solutions, the hydrogen in the compound structure further includes a deuteride formed after deuteration.

[0103] In any one of the above technical solutions, the hydrogen in each optional substituent of Y, W, and R3 may further include a deuterated compound formed after deuteration.

[0104] In one embodiment of the present invention, the compound represented by the above formula (A'), its pharmaceutically acceptable salt or its stereoisomer, or its deuterated derivative is shown in Table 1.

[0105] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18]

[0106] In one embodiment of the present invention, there is provided a pharmaceutical composition comprising any one of the compounds described above or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, and a pharmaceutically acceptable carrier.

[0107] In one embodiment of the present invention, the pharmaceutical composition may contain one or more pharmaceutical carriers and may be administered to patients or test subjects in need of such treatment via oral, parenteral, rectal, or pulmonary administration. For oral administration, the pharmaceutical composition may be formulated into conventional solid preparations such as tablets, capsules, pills, and granules, or into oral liquid preparations such as oral solutions, oral suspensions, and syrups. For oral preparations, appropriate fillers, adhesives, disintegrants, lubricants, and the like may be added. For parenteral administration, the pharmaceutical composition may be formulated into injections, including injection solutions, sterile powders for injections, and concentrated solutions for injections. For injections, the pharmaceutical composition may be produced using conventional methods in the pharmaceutical industry. For injections, additives may be omitted or appropriate additives may be added depending on the properties of the drug. For rectal administration, the pharmaceutical composition may be formulated into suppositories, etc. For pulmonary administration, the pharmaceutical composition may be formulated into inhalants or sprays, etc.

[0108] The present invention further provides use of a compound represented by the above general formula (A') or a pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof, or the above pharmaceutical composition, in the manufacture of a drug for preventing and / or treating a disease associated with NLRP3 inflammasome.

[0109] The present invention further provides use of the above-mentioned compound or a pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof, or the above-mentioned pharmaceutical composition in the manufacture of a medicament for preventing and / or treating an inflammasome-related disease, an immune disease, an inflammatory disease, an autoimmune disease, or an autoinflammatory disease.

[0110] "Halogen" according to the present invention refers to fluorine, chlorine, bromine and iodine.

[0111] The term "hydroxy group" as used herein refers to an --OH group.

[0112] The term "cyano group" as used herein refers to a -CN group.

[0113] The term "amino group" as used herein refers to an -NH2 group.

[0114] The term "carboxy group" as used herein refers to a -COOH group.

[0115] The term "nitro group" as used herein refers to the -NO2 group.

[0116] The term "oxo group" as used herein refers to a =O group.

[0117] The term "ureido group" as used herein refers to a -HNCONH2 group.

[0118] The term "hydrazino group" as used herein refers to the -NHNH2 group.

[0119] The "deuterated C" described in the present invention 1-6 "Alkyl group" refers to an alkyl group substituted with one or more deuterium atoms.

[0120] "C" described in the present invention 1-6 The term "alkyl group" refers to a straight-chain or branched-chain alkyl group derived by removing one hydrogen atom from a hydrocarbon moiety containing 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, and 1-methyl-2-methylpropyl.

[0121] "C" described in the present invention 1-6 The "ren" in the "alkylene group" is C 1-6It refers to a divalent group derived by removing two hydrogen atoms from an alkyl group.

[0122] The "halogenated C" described in the present invention 1-6 The term "alkyl group" refers to a C1-C6 alkyl group substituted with one or more halogen groups as defined above. 1-6 Illustrative examples of alkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,3-dibromoprop-2-yl, 3-bromo-2-fluoropropyl, and 1,4,4-trifluorobut-2-yl.

[0123] "C" described in the present invention 1-6 The term "alkoxy group" refers to a group having the above definition "C 1-6 "C alkyl group" is a group that is bonded to the parent molecule by an oxygen atom, i.e., "C 1-6 alkyl-O- groups, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentyloxy, neopentyloxy, and n-hexyloxy groups;

[0124] The "halogenated C" described in the present invention 1-6 "Alkoxy group" refers to a C1-C6 alkoxy group substituted with one or more halogen groups as defined above, examples of which include, but are not limited to, fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy, and fluoropropoxy groups.

[0125] "C" described in the present invention 2-6The term "alkenyl group" refers to a straight-chain or branched-chain alkene group derived by removing one hydrogen atom from an alkene moiety of 2 to 6 carbon atoms containing at least one carbon-carbon double bond, such as a vinyl group, a 1-propenyl group, a 2-propenyl group, a 1-butenyl group, a 2-butenyl group, a 1,3-butadienyl group, a 1-pentenyl-3-yl group, a 2-pentenyl-1-yl group, a 3-pentenyl-1-yl group, a 3-pentenyl-2-yl group, a 1,3-pentadienyl-1-yl group, a 1,4-pentadienyl-3-yl group, a 1-hexenyl-3-yl group, or a 1,4-hexadienyl-1-yl group. Preferably, "C 2-6 An "alkenyl group" contains one carbon-carbon double bond.

[0126] "C" described in the present invention 2-6 The term "alkynyl group" refers to a straight-chain or branched-chain alkyne group derived by removing one hydrogen atom from an alkyne moiety of 2 to 6 carbon atoms having at least one carbon-carbon triple bond, such as an ethynyl group, a propynyl group, a butynyl group, a pentynyl group, or a hexynyl group. Preferably, "C 2-6 An "alkynyl group" contains one carbon-carbon triple bond.

[0127] "C" described in the present invention 1-6 alkylamino group," "C 1-6 alkylcarbonylamino group," "C 1-6 "Alkylsulfonyl group" and "aminocarbonyl group" are C 1-6 Alkyl-NH-, C 1-6 Alkyl-C(O)-NH-, C 1-6 These refer to groups formed by alkyl-S(O)2- and NH2-C(O)-, respectively.

[0128] In the present invention, [ka] When R1 and R2 in the above formula (I) form a ring together with the C or N atom bonded thereto, it is understood that a double bond or a single bond is formed between X1 and X2 based on the rules for chemical bond formation.

[0129] The "5- to 12-membered ring" described in the present invention refers to a chemically formable carbocyclic ring or heterocyclic ring, for example, a 5- to 12-membered cycloalkyl group, a 5- to 7-membered cycloalkyl group, a 5- to 12-membered cycloalkenyl group, a 5- to 7-membered cycloalkenyl group, a 6- to 12-membered fused cycloalkyl group, a 5- to 12-membered heterocyclic group, a 5- to 7-membered heterocyclic group, a 6- to 12-membered fused heterocyclic ring, an aryl group, a 5- to 12-membered heteroaryl group, an 8- to 12-membered fused heteroaryl group, a 5- to 7-membered heteroaryl group, etc.

[0130] The term "3- to 12-membered cycloalkyl group" as used herein refers to a monovalent or (optionally) divalent group (e.g., 5- to 12-membered cycloalkyl) derived from a 3- to 12-membered cycloalkane, and may be a monocyclic, bicyclic, or polycyclic cycloalkyl group. Unless otherwise specified, this includes all possible monocyclic, fused rings (e.g., 6- to 12-membered fused cycloalkyl groups), including fused rings in the form of bonds, spiro, or bridges. Monocyclic ring systems are typically cyclic hydrocarbon groups containing 3 to 12 carbon atoms, such as 3 to 8 or 3 to 6 carbon atoms. Illustrative examples of cycloalkyl groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclopentane-1,3-diyl, cyclohexane-1,4-diyl, cycloheptane-1,4-diyl, and the like. Fused-ring cycloalkyl groups include bonded cycloalkyl groups, bridged cycloalkyl groups, and spirocycloalkyl groups. The linked cycloalkyl group may be a 6- to 11-membered linked cycloalkyl group, such as a 7- to 10-membered linked cycloalkyl group, representative examples of which include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane groups. The spirocycloalkyl group may be a 7- to 12-membered spirocycloalkyl group, such as a 7- to 11-membered spirocycloalkyl group, illustrative examples of which include: [ka] The bridged cycloalkyl group may be a 6-10 membered bridged cycloalkyl group, such as a 7-10 membered bridged cycloalkyl group, examples of which include: [ka] This includes, but is not limited to:

[0131] The "3- to 7-membered cycloalkyl group" according to the present invention refers to a monovalent group or (optionally) a divalent group derived from a 3- to 7-membered cycloalkane. The "3- to 7-membered cycloalkyl group" may be a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group, and examples of the 3- to 7-membered cycloalkyl group include a cyclopropane group, a cyclobutane group, a cyclopentane group, and a cyclohexane group.

[0132] The "cycloalkenyl group" described in this invention refers to a group obtained by having at least one double bond in the above-mentioned cycloalkyl group. It may be, for example, a "3- to 12-membered cycloalkenyl group," i.e., it may have 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring carbon atoms. Unless otherwise specified, a certain cycloalkenyl group includes all possible single rings and fused rings (including fused in the form of bonds, spiro, or bridges). The cycloalkenyl group may be a 3- to 12-membered cycloalkenyl group, a 3- to 8-membered cycloalkenyl group, a 4- to 6-membered cycloalkenyl group, a 7- to 11-membered spirocycloalkenyl group, a 7- to 11-membered fused cycloalkenyl group, a 6- to 11-membered bridged cycloalkenyl, etc. Illustrative examples of cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, 1,4-cyclohexadien-1-yl, cycloheptenyl, 1,4-cycloheptadien-1-yl, cyclooctenyl, 1,5-cyclooctadien-1-yl, and the like.

[0133] The "5- to 7-membered cycloalkenyl group" described in the present invention refers to a group obtained by having at least one double bond in a 5- to 7-membered cycloalkyl group, such as a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, or a cycloheptenyl group.

[0134] The term "3- to 14-membered heterocyclic group" used in the present invention refers to a monovalent or (optionally) divalent group derived from a 3- to 14-membered heterocycloalkane, i.e., a non-aromatic cyclic group in which at least one ring carbon atom of a 3- to 14-membered heterocyclic group is substituted with a heteroatom selected from O, S, S(O), S(O)2, C(O), and N, and preferably contains 1 to 3 heteroatoms. The term "3- to 14-membered heterocyclic group" (e.g., 5- to 14-membered heterocyclic group, 5- to 12-membered heterocyclic group) includes monocyclic heterocyclic groups, bicyclic heterocyclic groups, and polycyclic heterocyclic groups, in which one or more rings may be saturated or partially saturated, but does not include aromatic rings. Unless otherwise specified, it includes all possible monocyclic and fused rings (including fused rings in the form of bonds, spiro rings, and bridges), saturated and partially saturated cases.

[0135] The monocyclic heterocyclic group may be a 5- to 7-membered heterocyclic group, a 3 ...8-membered heterocyclic group such as a 4- to 7-membered heterocyclic group or a 5- to 6-membered heterocyclic group, a 3- to 8-membered nitrogen-containing heterocyclic group such as a 4- to 7-membered nitrogen-containing heterocyclic group or a 5- to 6-membered nitrogen-containing heterocyclic group, or a 3- to 8-membered saturated heterocyclic group such as a 5- to 6-membered saturated heterocyclic group. Illustrative examples thereof include aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothienyl, imidazolidinyl, pyrazolidinyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, 1,2-thiazolidinyl, 1,3-thiazolidinyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, piperidinyl, piperazine, morpholinyl, 1,4-dioxacyclohexylalkyl, 1,4-oxathiocyclohexylalkyl, 4,5-dihydroisoxazolyl, 4,5-dihydrooxazolyl, 2,5 Examples of aryl groups include, but are not limited to, 2,3-dihydrooxazolyl, 3,4-dihydro-2H-pyrrolyl, 2,3-dihydro-1H-pyrrolyl, 2,5-dihydro-1H-imidazolyl, 4,5-dihydro-1H-imidazolyl, 4,5-dihydro-1H-pyrazolyl, 4,5-dihydro-3H-pyrazolyl, 4,5-dihydrothiazolyl, 2,5-dihydrothiazolyl, 2H-pyranyl, 4H-pyranyl, 2H-thiopyranyl, 4H-thiopyranyl, 2,3,4,5-tetrahydropyridyl, 1,2-isoxazinyl, 1,4-isoxazinyl, or 6H-1,3-oxazinyl.

[0136] Fused heterocyclic groups (e.g., 6- to 12-membered fused heterocyclic groups) include bonded heterocyclic groups, spiro heterocyclic groups, and bridged heterocyclic groups, which may be saturated, partially saturated, or unsaturated, but are not aromatic. The fused heterocyclic group may be a 5- to 6-membered monocyclic cycloalkyl group, a 5- to 6-membered monocyclic cycloalkenyl group, a 5- to 6-membered monocyclic heterocyclic group, or a 5- to 6-membered monocyclic heteroaryl group fused to a benzene ring.

[0137] The above-mentioned bonded heterocyclic group may be a 6- to 12-membered bonded heterocyclic group such as a 6- to 11-membered bonded heterocyclic group or a 7- to 10-membered bonded heterocyclic group, a 6- to 11-membered saturated bonded heterocyclic group, or a 6- to 11-membered nitrogen-containing bonded heterocyclic group, and representative examples thereof include a 3-azabicyclo[3.1.0]hexylalkyl group, a 3,6-diazabicyclo[3.2.0]heptylalkyl group, a 3,8-diazabicyclo[4.2.0]octylalkyl group, a 3,7-diazabicyclo[4.2.0]octylalkyl group, an octahydropyrrolo[3,4-c]pyrrolyl ... Examples of such groups include, but are not limited to, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3,4-b][1,4]oxazinyl, octahydro-1H-pyrrolo[3,4-c]pyridyl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, dihydroindol-1-yl, dihydroindol-2-yl, dihydroindol-3-yl, 2,3-dihydrobenzothiophen-2-yl, octahydro-1H-indolyl, and octahydrobenzofuranyl.

[0138] The spiro heterocyclic group may be a 6- to 12-membered spiro heterocyclic group such as a 7- to 12-membered spiro heterocyclic group, a 7- to 12-membered saturated spiro heterocyclic group, or a 7- to 12-membered nitrogen-containing spiro heterocyclic group, examples of which include: [ka] This includes, but is not limited to:

[0139] The bridged heterocyclic group may be a 6- to 10-membered bridged heterocyclic group (for example, a 6- to 10-membered nitrogen-containing bridged heterocyclic group, particularly a 7-membered nitrogen-containing bridged heterocyclic group), or a 6- to 12-membered bridged heterocyclic group such as a 7- to 10-membered bridged heterocyclic group, examples of which include: [ka] This includes, but is not limited to:

[0140] The term "aryl group" as used herein refers to a monovalent group or, if necessary, a divalent cyclic aromatic group containing 6 to 14 carbon atoms and derived from an aromatic cyclic hydrocarbon, including a phenyl group, a naphthyl group, a phenanthrenyl group, etc.

[0141] The term "5- to 14-membered heteroaryl group" used in the present invention refers to an aromatic 5- to 14-membered cyclic group in which at least one ring carbon atom is substituted with a heteroatom selected from O, S, and N. The "5- to 14-membered heteroaryl group" may be 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered, and preferably contains 1 to 3 heteroatoms. It also includes cases in which the carbon and sulfur atoms are substituted with oxygen and nitrogen, for example, a carbon atom is substituted with C(O) and a sulfur atom is substituted with S(O) or S(O)2. Heteroaryl groups include both single-ring and fused-ring heteroaryl groups, and unless otherwise specified, a single-ring heteroaryl group includes all possible single-ring, fused-ring, fully aromatic, and partially aromatic rings. The single heteroaryl group may be a 5- to 7-membered heteroaryl group, such as a 5- to 6-membered heteroaryl group, examples of which include, but are not limited to, furanyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thienyl, triazolyl, and triazinyl groups.

[0142] In some technical solutions, the term "fused heteroaryl group" refers to a group formed by condensing a monocyclic heteroaryl ring to a phenyl group, a cycloalkenyl group, a heteroaryl group, a cycloalkyl group, or a heterocyclic group. In some technical solutions, the fused heteroaryl group (e.g., an 8- to 14-membered fused heteroaryl) may be an 8- to 14-membered heteroaryl group, such as a 9- to 10-membered heteroaryl group, examples of which include a benzimidazolyl group, a benzofuranyl group, a benzothienyl group, a benzoxadiazolyl group, a benzothiadiazolyl group, a benzothiazolyl group, a cinnolinyl group, a 5,6-dihydroquinolin-2-yl group, a 5,6-dihydroisoquinolin-1-yl group, a furanopyridyl group, an indazolyl group, an indolyl group, and an isoindolinyl group. Examples of aryl groups include, but are not limited to, phenyl, isoquinolinyl, naphthyridinyl, purinyl, quinolinyl, 5,6,7,8-tetrahydroquinolin-2-yl, 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinolin-4-yl, 5,6,7,8-tetrahydroisoquinolin-1-yl, thienopyridinyl, 4,5,6,7-tetrahydro[c][1,2,5]oxadiazolyl, and 6,7-dihydro[c][1,2,5]oxadiazol-4(5H)onyl groups.

[0143] The term "pharmaceutically acceptable salts" as used herein refers to addition salts and solvates of medicaments with acids and bases. Examples of such medicament salts include salts with acids such as hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfurous acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid, hydroiodic acid, and alkanoic acids (e.g., acetic acid, HOOC-(CH)-COOH (where n = 0 to 4)). Examples of such medicament salts further include salts with bases such as sodium, potassium, calcium, and ammonium. A variety of non-toxic medicament addition salts are known to those skilled in the art.

[0144] All numerical ranges described herein include the endpoints of the range, all integers within the range, and subranges formed by these integers. For example, "3 to 7 members" includes 3, 4, 5, 6, and 7 members, "1 to 4" includes 1, 2, 3, and 4, and "1 to 3" includes 1, 2, and 3.

[0145] The term "optionally" or "optionally" refers to the situation described thereafter may or may not occur, and the description includes both the situation occurring and not occurring.

[0146] The "stereoisomer" of the compound described in this invention refers to an isomer resulting from the spatial arrangement of atoms in the molecule. When the compound has an asymmetric carbon atom, an enantiomer occurs, and when the compound has a carbon-carbon double bond or a cyclic structure, a cis-trans isomer occurs.

[0147] The term "tautomer" refers to a special functional group isomer that exists in dynamic equilibrium and can be rapidly converted into another functional group. For example, when a ketone or oxime is present, tautomers occur, and representative examples are keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc.

[0148] All enantiomers, diastereomers, racemic isomers, meso or racemic isomers, tautomers, geometric isomers, epi isomers and mixtures thereof of all compounds are within the scope of the present invention.

[0149] In the chemical configuration of the compound according to the present invention, [ka] represents an unspecified configuration, i.e., when chiral isomers are present in a chemical structure, [ka] teeth, [ka] or [ka] In the chemical structure of the compound according to the present invention, [ka] represents the point of attachment to the parent molecule.

[0150] "Deuterated" according to the present invention refers to the replacement of one or more hydrogen atoms in a compound or group with deuterium.

[0151] General Methods for Preparing the Compounds of the Invention Unless otherwise specified, all raw materials or intermediates not provided in the preparation methods are commercially available or can be synthesized using methods known in the open literature. Suitable work-up methods described in the preparation methods may include one or a combination of conventional work-up methods such as quenching by adding water, concentration, adjusting the pH value, extracting with a suitable solvent (e.g., ethyl acetate, dichloromethane), filtration, drying, etc. Suitable purification methods described in the preparation methods may include one or a combination of purification methods such as silica gel column chromatography, preparative thin-layer chromatography, reverse-phase preparative chromatography, recrystallization, slurrying, etc.

[0152] The compound represented by general formula (A') containing an alkynyl group substitution on Y can be prepared by the route shown in the following reaction scheme 1 or 2.

[0153] [ka] [ka] where: W is [ka] Selected from [ka] is selected from a single bond or a double bond, R3, R1, R2 are as defined above; Ring Y1 is selected from an aryl group, a 5- to 14-membered heteroaryl group, a 3- to 14-membered heterocyclic group, and a 3- to 12-membered cycloalkyl group, wherein the substituents on Y1 are as defined above, and Y is further selected from substituted substituents; PG is selected from a suitable protecting group at O ​​or N (e.g., methyl, ethoxymethyl, methoxymethyl, benzyl, 4-methoxybenzyl, tert-butyl, tert-butoxycarbonyl, benzyloxycarbonyl, trimethylsilyl, tert-butyldimethylsilyl, etc.); Ra1 is H, C 1-6 Ra1 is selected from alkyl groups, and can form a 5- to 7-membered heterocycle with a B or O atom via a carbon atom bond.

[0154] Halo is a halogen (e.g., iodine, bromine, chlorine); Ry1 is hydrogen, halogen, C 1-6 Alkyl groups, 3-6 membered cycloalkyl groups, halogenated C 1-6 Alkyl group, cyano group, amino group, carbonyl group, C 1-6 The silyl group is selected from alkyl tri-substituted silyl groups.

[0155] Hereinafter, a method for preparing a compound having an alkynyl group substitution at Y, represented by general formula (A″), from a compound of formula (IM1), as shown in Reaction Scheme 1, is provided.

[0156] The compound of formula (IM3) can be prepared by Suzuki coupling reaction of the compound of formula (IM1) with the compound of formula (IM2). The compound of formula (IM1) and the compound of formula (IM2) are added to a suitable solvent (e.g., 1,4-dioxane and water), followed by the addition of a suitable catalyst (e.g., 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride or tetrakis(triphenylphosphine)palladium), and a suitable base (e.g., sodium bicarbonate, sodium carbonate, or potassium carbonate). The mixture is heated and stirred under inert gas (e.g., nitrogen gas) at a suitable temperature (e.g., 90°C to 110°C) for a suitable time (e.g., 1 to 20 hours). After the reaction is complete, the compound of formula (IM3) is obtained by separation using appropriate workup and purification methods.

[0157] The compound of formula (IM3) was dissolved in a suitable solvent (e.g., methanol), and a suitable base (e.g., potassium carbonate) and dimethyl (1-diazo-2-oxopropyl)phosphonate were added, followed by stirring at room temperature for a suitable time (e.g., 1 to 5 hours). After completion of the reaction, the compound of formula (IM4) was obtained by separating the compound through appropriate post-treatment and purification.

[0158] The compound of formula (IM4) was reacted under appropriate deprotection conditions, and then separated by appropriate work-up and purification methods to obtain a compound of formula (A''). For example, when the protecting group PG in formula (IM4) is an ethoxymethyl group, the compound of formula (IM4) is added to an appropriate solvent (e.g., dichloromethane), and an appropriate amount of acid (e.g., hydrogen chloride in 1,4-dioxane or trifluoroacetic acid) is added. The deprotection reaction is completed after reacting at an appropriate temperature (e.g., room temperature) for an appropriate time (e.g., 5 minutes to 2.5 hours). When the protecting group PG in formula (IM4) is a methyl group, the compound of formula (IM4) is added to an appropriate solvent (e.g., dichloromethane), and an appropriate amount of boron tribromide is added at an appropriate temperature (e.g., 0°C). The deprotection reaction is completed after reacting at an appropriate temperature (e.g., room temperature) for an appropriate time (e.g., 17 hours).

[0159] When the substituent Ry1 in the alkynyl group is not hydrogen, the compound represented by general formula (A''') can be produced by the route shown in the following reaction scheme 2. Hereinafter, a method for producing a compound having a substituent in the alkynyl group represented by general formula (A''') from a compound of formula (IM4), as shown in reaction scheme 2, is provided.

[0160] The compound of formula (IM4) can be used to produce compounds of formula (IM5) with different substitutions under different reaction conditions. For example, the compound of formula (IM4) and an alkyl halide (e.g., iodomethane) can be alkylated in the presence of a base (e.g., sodium di(trimethylsilyl)amino) to produce a compound of formula (IM5) containing an alkynyl group substituted with an alkyl group or alkyl halide. The compound of formula (IM5) containing an alkynyl group substituted with a halogen group can be produced by reacting the compound of formula (IM4) with a halogenating reagent (e.g., N-bromosuccinimide) in the presence of a suitable catalyst (e.g., silver nitrate). The compound of formula (IM5) containing an alkynyl group substituted with a trifluoromethyl group can be produced by reacting the compound of formula (IM4) with a trifluoromethylating reagent (e.g., Togni reagent, Umemoto reagent, etc.) in the presence of a suitable catalyst (e.g., cuprous iodide), a ligand (e.g., o-phenanthroline), and a base (e.g., potassium bicarbonate).

[0161] Compounds of formula (IM1) can be prepared by the route shown in Scheme 3.

[0162] [ka] where: Y1, Halo, PG, and Ra1 are as defined above.

[0163] A method for preparing a compound of formula (IM1) from a compound of formula (IM1a), as shown in Reaction Scheme 3, is provided below.

[0164] The compound of formula (IM1a) is dissolved in a suitable solvent (e.g., dichloromethane), and a suitable protecting group reagent (e.g., chloromethoxyethane) and a suitable base (e.g., sodium hydride) are added, followed by stirring at a suitable temperature (e.g., 0°C to room temperature) for a suitable time (e.g., 2 to 16 hours). After completion of the reaction, the compound of formula (IM1b) is obtained by separation using a suitable work-up and purification method.

[0165] The compound of formula (IM1) can be prepared by Miyaura coupling reaction of the compound of formula (IM1b) with an appropriate boric acid ester (e.g., bis(pinacolato)diboron). The compound of formula (IM1b) and bis(pinacolato)diboron are added to an appropriate solvent (e.g., 1,4-dioxane), followed by the addition of an appropriate catalyst (e.g., 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride) and an appropriate base (e.g., potassium acetate). The mixture is heated and stirred under inert gas (e.g., nitrogen) protection at an appropriate temperature (e.g., 100°C) for an appropriate time (e.g., 20 hours). After the reaction is complete, the compound of formula (IM1) is isolated by appropriate workup and purification.

[0166] Compounds of formula (IM1) can be prepared by the route shown in Scheme 4 or Scheme 5.

[0167] [ka] [ka] where: W is [ka] Selected from [ka] is selected from a single bond or a double bond, Halo, R3, R4, R5, and PG are as defined above; R 5ais selected from R5 as defined above, and R 5a contains O or N which may be protected by a protecting group, R 5b , R 5c is hydrogen, C 1-6 Alkyl group, C 3-7 Cycloalkyl groups, halogenated C 1-6 Alkyl groups, halogenated C 3-6 A cycloalkyl group, a 3- to 7-membered heterocyclic group, an aryl group, a 5- to 7-membered heteroaryl group, and the substituents are optionally selected from halogen, cyano group, amino group, hydroxy group, carbonyl group, C 1-6 Alkyl groups, 3- to 6-membered cycloalkyl groups, C 1-6 substituted by 1 to 3 substituents selected from alkylsulfonyl groups; R 5b , R 5c can be linked to form a 3- to 7-membered carbocyclic ring or a 3- to 7-membered heterocyclic ring, A method for preparing a compound of formula (IM2) from a compound of formula (IM2a) is provided below.

[0168] For example, as shown in Reaction Scheme 4, the compound of formula (IM2a) and the compound of formula (IM2b) are added to an appropriate solvent (e.g., 1,4-dioxane, N,N-dimethylacetamide, or n-butanol), and an appropriate base (e.g., N,N-diisopropylethylamine) is added, followed by heating and stirring at an appropriate temperature (e.g., 100°C to 120°C) for an appropriate time (e.g., 1 to 72 hours). After completion of the reaction, the compound of formula (IM2) is obtained by separation using an appropriate post-treatment and purification method.

[0169] In some embodiments, compounds of formula (IM2) can be prepared by the route shown in Scheme 5: For example, the compound of formula (IM2a) and the compound of formula (IM2c) are added to an appropriate solvent (e.g., N,N-dimethylacetamide, toluene, or n-butanol), and an appropriate base (e.g., N,N-diisopropylethylamine) is added, followed by heating and stirring at an appropriate temperature (e.g., 120°C) for an appropriate time (e.g., 1 to 72 hours). After the reaction is complete, the compound of formula (IM2d) is obtained by separation using an appropriate post-treatment and purification method.

[0170] The compound of formula (IM2d) can be deprotected to give the compound of formula (IM2e). For example, the compound of formula (IM2d) can be dissolved in a suitable solvent (e.g., dichloromethane), and an appropriate amount of acid (e.g., hydrogen chloride in 1,4-dioxane or trifluoroacetic acid) is added. The deprotection reaction is completed after the reaction is continued at a suitable temperature (e.g., room temperature) for a suitable time (e.g., 5 minutes to 2.5 hours).

[0171] Furthermore, the compound of formula (IM2e) can be subjected to a reductive amination reaction or an alkylation reaction to produce the compound of formula (IM2). For example, the compound of formula (IM2e) can be dissolved in a suitable solvent (e.g., methanol), and then the corresponding aldehyde, ketone, or its corresponding acetal or ketal is added. A suitable reducing agent (e.g., sodium cyanoborohydride) is added, and the resulting product is converted to the corresponding target product at a suitable temperature (e.g., room temperature). Alternatively, the compound of formula (IM2e) can be dissolved in a suitable solvent (e.g., dichloromethane), and then the corresponding alkyl halide is added. The resulting product is converted to the corresponding target product by reaction in the presence of a suitable base (e.g., triethylamine or potassium carbonate). After the reaction is complete, the compound of formula (IM2) is isolated by appropriate workup and purification.

[0172] In the compound of formula (A'), W is [ka] When selected from the following, the compound of formula (IM2d) in Scheme 5 above can also be prepared by the route shown in Scheme 6.

[0173] [ka] where: R1, R4, R 5a , PG, and Halo are as defined above.

[0174] The manufacturing method was as follows.

[0175] Compound (IM2d) can be prepared by oxidizing compound (IM2d1) to compound (IM2d2) using the oxidizing agent selenium dioxide, followed by ring closure with S-methylisothiaminocarbazide hydroiodide to produce compound (IM2d3), oxidizing compound (IM2d3) with m-chloroperbenzoic acid to produce a methylsulfone-group compound (IM2d4), reacting compound (IM2d4) with compound (IM2c) under a suitable base (e.g., N,N-diisopropylethylamine) to produce compound (IM2d5), and further reacting compound (IM2d5) with a halogenating reagent (e.g., N-bromosuccinimide or dibromohydantoin).

[0176] In the compound of formula (A'), W is [ka] When selected from the following, the compound of formula (IM2e) in Scheme 5 above can also be prepared by the route shown in Scheme 7.

[0177] [ka] where: R4, R 5a , PG is as defined above, and Halo is bromine.

[0178] The manufacturing method was as follows.

[0179] Compound of formula (IM2f) can be subjected to a Buchwald coupling reaction with compound of formula (IM2c) under suitable conditions such as a suitable catalyst (tris(dibenzylideneacetone)dipalladium), a ligand (e.g., 1,1'-binaphthyl-2,2'-bisdiphenylphosphine) and a base (e.g., cesium carbonate) to produce compound of formula (IM2g), which can be oxidized under m-chloroperbenzoic acid conditions to produce compound of formula (IM2h), which can then be reacted with boron tribromide to produce compound of formula (IM2e).

[0180] In some embodiments, the compound of formula (IM4) described in Scheme 1 and Scheme 2 can be prepared by the route shown in Scheme 8.

[0181] [ka] where: W is [ka] Selected from [ka] is selected from a single bond or a double bond, Y1, Halo, R1, R2, Ra1, R3, R4, R5, PG, R 5a , R 5b , R 5c is as defined above, Hereinafter, a method for preparing a compound of formula (IM4) from a compound of formula (IM1) is provided.

[0182] The compound of formula (IM4a) can be prepared by Suzuki coupling reaction of the compound of formula (IM1) with the compound of formula (IM2d). The compound of formula (IM1) and the compound of formula (IM2) are added to a suitable solvent (e.g., 1,4-dioxane and water), followed by the addition of a suitable catalyst (e.g., 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride or tetrakis(triphenylphosphine)palladium), a suitable base (e.g., sodium bicarbonate, sodium carbonate, or potassium carbonate), and the mixture is heated and stirred under inert gas (e.g., nitrogen gas) at a suitable temperature (e.g., 90°C to 110°C) for a suitable time (e.g., 1 to 20 hours). After the reaction is complete, the compound of formula (IM4a) is obtained by separation using appropriate workup and purification methods.

[0183] The compound of formula (IM4a) was dissolved in a suitable solvent (e.g., methanol), and a suitable base (e.g., potassium carbonate) and dimethyl (1-diazo-2-oxopropyl)phosphonate were added, followed by stirring at room temperature for a suitable time (e.g., 1 to 5 hours). After the reaction was completed, the compound of formula (IM4b) was obtained by separating the compound through appropriate post-treatment and purification.

[0184] The compound of formula (IM4b) was reacted under appropriate deprotection conditions (e.g., hydrogen chloride in 1,4-dioxane or trifluoroacetic acid), and then separated by appropriate work-up and purification methods to obtain the compound of formula (IM4c).

[0185] The compound of formula (IM4c) can be prepared by a reductive amination reaction or an alkylation reaction to produce the compound of formula (IM4). For example, the compound of formula (IM4c) can be dissolved in a suitable solvent (e.g., methanol), and then the corresponding aldehyde, ketone, or its corresponding acetal or ketal is added. A suitable reducing agent (e.g., sodium cyanoborohydride) is added, and the resulting product is converted to the corresponding target product at a suitable temperature (e.g., room temperature). Alternatively, the compound of formula (IM4c) can be dissolved in a suitable solvent (e.g., dichloromethane), and then the corresponding alkyl halide is added. The resulting product is converted to the corresponding target product in the presence of a suitable base (e.g., triethylamine or potassium carbonate). After the reaction is complete, the compound of formula (IM4) can be separated by appropriate workup and purification methods to obtain the compound of formula (IM4).

[0186] When the substituent Ry1 in the alkynyl group is not hydrogen, the compound of formula (IM5) shown in Reaction Scheme 2 can be prepared by the route shown in Reaction Scheme 9 below.

[0187] [ka] where: W is [ka] Selected from [ka] is selected from a single bond or a double bond, Y1, R1, R2, R3, R4, PG, R 5a , R 5b , R 5c , Halo is as defined above, Ry1 is as defined above, and Ry1 is not hydrogen, A method for preparing a compound of formula (IM5) from a compound of formula (IM4b), as shown in Reaction Scheme 9, is provided below.

[0188] The compound of formula (IM4b) can be converted to a compound of formula (IM5a) with different substitutions at the alkynyl group under different reaction conditions as described in step 1 of reaction scheme 2. After reacting the compound of formula (IM5a) with appropriate deprotection conditions (e.g., hydrogen chloride in 1,4-dioxane or trifluoroacetic acid), the compound of formula (IM5b) can be obtained, and the compound of formula (IM5b) can be converted to a compound of formula (IM5) by reductive amination or alkylation.

[0189] In some embodiments, compounds of formula (IM5) can be prepared by the route shown in Scheme 10.

[0190] [ka] where Y1, Halo, W, Ry1, Ra1, R, and PG are as defined above; A method for preparing a compound of formula (IM5) from a compound of formula (IM5c), as shown in Reaction Scheme 10, is provided below.

[0191] Under nitrogen gas protection, the compound of formula (IM5c) and the compound of formula (IM5d) can be subjected to a Sonogashira cross-coupling reaction under suitable palladium catalyst (e.g., bis(triphenylphosphine)palladium dichloride), copper catalyst (e.g., cuprous iodide) and base (e.g., N,N-diisopropylethylamine) conditions to prepare the compound of formula (IM5e), and the compound of formula (IM5e) can be prepared by Miyaur reaction of the compound of formula (IM5e) with a suitable boric acid ester (e.g., bis(pinacolato)diboron). Compounds of formula (IM5f) can be prepared by a coupling reaction, compounds of formula (IM5e) can be further lithiated with an organolithium reagent (e.g., n-butyllithium) followed by reaction with a suitable borate ester (e.g., pinacol isopropoxyboronate) to prepare compounds of formula (IM5f), and compounds of formula (IM5) can be prepared by Suzuki reaction of compounds of formula (IM5f) with compounds of formula (IM2) as described in Scheme 1.

[0192] In some embodiments, the compound of Formula (IM5a) in Reaction Scheme 9 can be prepared by the reaction shown in Reaction Scheme 11 below.

[0193] [ka] where Ry1, Y1, Ra1, R4, W, PG, R 5a , Halo is as defined above, The compound of formula (IM5a) can be produced by subjecting the compound of formula (IM5e) and the compound of formula (IM2d) to the above-mentioned Suzuki reaction.

[0194] In the compound represented by the general formula (A'), W is [ka] When selected from the following, the compound of formula (A') can be prepared by reaction scheme 12:

[0195] [ka] where Y1, R1, R2, R3, R4, R5, PG, R 5a , R 5b , R 5c , Halo, Ry1 are as defined above; Hereinafter, a method for preparing a compound of formula (A') from a compound of formula (IM8a) via the route shown in Reaction Scheme 12 is provided.

[0196] The compound of formula (IM8a) is reacted with sulfoxide chloride or oxalyl chloride to give the corresponding acid chloride, which is then reacted with the corresponding amine to give the compound of formula (IM8b), which is then reacted with a sulfurizing reagent (e.g., Lawesson's reagent) to give the compound of formula (IM8c), which is then reacted with iodomethane to give the compound of formula (IM8d), which is then reacted with hydrazine hydrate to give the compound of formula (IM8d). The compound of formula (IM8e) is reacted with ethyl thiooxamate in the presence of triethylamine to form a compound of formula (IM8f), the compound of formula (IM8f) is subjected to a Sandmeyer reaction with tert-butyl nitrite in the presence of a copper salt (e.g., cuprous bromide, cuprous chloride) to form a compound of formula (IM8g), and the compound of formula (IM8g) is reacted with a compound of formula (IM2c) and a suitable base (e.g., N,N- The compound of formula (IM8i) can be prepared by Sonogashira cross-coupling reaction of the compound of formula (IM8h) with the compound of formula (IM5d) under suitable conditions of a palladium catalyst (e.g., bis(triphenylphosphine)palladium dichloride), a copper catalyst (e.g., cuprous iodide) and a base (e.g., N,N-diisopropylethylamine). The compound of formula (IM8i) can be treated with suitable deprotection conditions (e.g., hydrogen chloride in 1,4-dioxane or trifluoroacetic acid) to obtain the compound of formula (IM8j). The compound of formula (IM8j) can be subjected to reductive amination or alkylation to prepare the compound of formula (IM8). The compound of formula (IM8) can be deprotected with suitable deprotection conditions (e.g., boron tribromide / dichloromethane) to obtain the compound of formula (A').

[0197] In some embodiments, compounds of formula (IM8) can also be prepared by the route shown in Scheme 13.

[0198] [ka] where Y1, R1, R4, R5, PG, Halo, and Ry1 are as defined above; Compound of formula (IM8g) can be reacted with compound of formula (IM2b) in the presence of a suitable base (e.g., N,N-diisopropylethylamine) to produce compound of formula (IM8k), which can then be subjected to a Sonogashira cross-coupling reaction with compound of formula (IM5d) in the presence of a suitable palladium catalyst (e.g., bis(triphenylphosphine)palladium dichloride), copper catalyst (e.g., cuprous iodide) and base (e.g., N,N-diisopropylethylamine) to produce compound of formula (IM8).

[0199] When the substituent on Y of the compound represented by general formula (A') is selected from an alkene, the compound of formula (A') can be prepared by the route shown in Reaction Scheme 14 or Reaction Scheme 15.

[0200] [ka] [ka] where: Y1, Y, W, Ry1, R3, and PG are as defined above; Ry2 is selected from the group defined for Ry1; The compound of formula (IM3) can be reacted with the corresponding phosphonium ylide reagent to produce a compound of formula (IM6), which can then be further subjected to suitable deprotection conditions as described above to produce a compound of formula (A-A'); Alternatively, the compound of formula (IM5) is subjected to appropriate deprotection conditions to produce the compound of formula (IM7), which is then reduced with hydrogen gas under Lindlar palladium catalyst conditions to give the compound of formula (A-A'').

[0201] The compound of formula (IM6) shown in Scheme 15 can also be prepared by the route shown in Scheme 16.

[0202] [ka] where: Y1, W, Ry1, Ry2, R3, Ra1, PG, and Halo are as defined above; A method for preparing a compound of formula (IM6) from a compound of formula (IM1d) is provided below.

[0203] Compounds of formula (IM1d) were subjected to a Wittig reaction with the corresponding phosphonium ylide reagent to give compounds of formula (IM6a), which were then subjected to the Miyaura coupling reaction with an appropriate borate ester (e.g., bis(pinacolato)diboron) as described above to give compounds of formula (IM6b), which were then subjected to the Suzuki coupling reaction with compounds of formula (IM2) as described above to give compounds of formula (IM6).

[0204] In some embodiments, compounds of formula (IM6) can also be prepared by the route shown in Scheme 17.

[0205] [ka] where: Y1, W, Ry1, Ry2, R3, Ra1, R 5a , R 5b , R 5c , PG, Halo are as defined above, Hereinafter, a method for preparing a compound of formula (IM6) from a compound of formula (IM6b) is provided.

[0206] The compound of formula (IM6b) is subjected to the above-described Suzuki coupling reaction with the compound of formula (IM2d) to produce the compound of formula (IM6c), which is then subjected to the above-described appropriate deprotection conditions to produce the compound of formula (IM6d), which is then further subjected to a reductive amination or alkylation reaction with an aldehyde, ketone, or alkyl halide to give the compound of formula (IM6). [Effects of the Invention]

[0207] The compounds provided by the present invention or their pharmaceutically acceptable salts, stereoisomers, and deuterated derivatives have good inhibitory activity against NLRP3 inflammasome. At the same time, the compounds of the present invention have obvious advantages in various genera of liver microsomes, PK, hyperbrain activity, safety, etc., and therefore the compounds of the present invention can be safely and effectively used in the prevention and / or treatment of diseases associated with NLRP3 inflammasome. DETAILED DESCRIPTION OF THE INVENTION

[0208] In order to clarify the objectives, technical solutions and advantages of the present invention, the present invention will be described in more detail below. Of course, the described embodiments are only some of the embodiments of the present invention, and are not all of the embodiments. All other embodiments that can be obtained by those skilled in the art based on the embodiments of the present invention without creative efforts shall be included in the scope of the claims of the present invention.

[0209] The abbreviations and English expressions used in this invention have the following meanings:

[0210] "THF" refers to tetrahydrofuran, "DMF" refers to N,N-dimethylformamide, "MeOH" refers to methanol, "EA" refers to ethyl acetate, "DCM" refers to dichloromethane, "DMA" refers to N,N-dimethylacetamide, "MTBE" refers to methyl tert-butyl ether, "EtOH" refers to ethanol, "DMAC" refers to dimethylacetamide, "PE" refers to petroleum ether, "n-BuLi" refers to n-butyllithium, "FBS" refers to fetal bovine serum, "PBS" refers to phosphate buffer solution, "PMA" refers to phorbol ester, "LPS" refers to lipopolysaccharide, and "Nigericin" refers to nigericin. [Example]

[0211] Hereinafter, embodiments of the present invention will be described in detail with reference to examples. However, those skilled in the art will understand that the following examples are merely for the purpose of illustrating the present invention and should not be construed as limiting the scope of the present invention. In the examples, if no specific conditions are specified, the procedures are carried out according to standard conditions or conditions recommended by the manufacturer. Reagents or equipment for which no manufacturer is specified are all ordinary products that are commercially available.

[0212] Example 1: Synthesis of (R)-3-(4-ethyl-2-hydroxyphenyl)-4-methyl-6-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one (Compound 23) [ka]

[0213] Step 1: Synthesis of 4-bromo-2-methoxy-N-methylbenzamide [ka] A solution of 4-bromo-2-methoxybenzoyl chloride (32.4 g, 129.85 mmol, 1.0 eq) in dichloromethane (200 mL) was added dropwise to aqueous methylamine solution (100 mL) and reacted at room temperature for 10 min. After completion of the reaction was confirmed by TLC, the reaction mixture was poured into water (100 mL) and extracted with dichloromethane (100 mL x 2). The organic phase was dried and concentrated to give the product (30 g, yield: 94.6%).

[0214] Step 2: Synthesis of 4-bromo-2-methoxy-N-methylthiobenzamide [ka] 4-Bromo-2-methoxy-N-methylbenzamide (30 g, 122.90 mmol, 1.0 eq) and Lawesson's reagent (34.8 g, 86.03 mmol, 0.7 eq) were dissolved in THF (300 mL) and reacted at 70 °C for 1 h. After completion of the reaction was confirmed by TLC, the reaction mixture was poured into water (300 mL) and extracted with ethyl acetate (300 mL x 3). The organic phase was dried and concentrated to give the product (31.97 g, 100% yield).

[0215] Step 3: Synthesis of methyl 4-bromo-2-methoxy-N-methylthiobenzimidate [ka] 4-Bromo-2-methoxy-N-methylthiobenzamide (31.94 g, 122.90 mmol, 1.0 eq) and iodomethane (26.17 g, 184.35 mmol, 1.5 eq) were dissolved in THF (300 mL) and reacted at room temperature for 19 h. After completion of the reaction was confirmed by TLC, the reaction mixture was poured into water (500 mL), the pH was adjusted to approximately 8 with sodium bicarbonate, and the mixture was extracted with ethyl acetate (300 mL x 2). The organic phase was dried and concentrated to give the product (33.7 g, 100% yield).

[0216] Step 4: Synthesis of N-amino-4-bromo-2-methoxy-N'-methylbenzamidine [ka] Methyl 4-bromo-2-methoxy-N-methylthiobenzimidate (33.7 g, 122.90 mmol, 1.0 eq) and hydrazine hydrate (7.24 g, 122.90 mmol, 1.0 eq) were dissolved in EtOH (300 mL) and reacted at 80° C. for 0.5 h. Completion of the reaction was monitored by LC-MS, and the reaction mixture was concentrated under reduced pressure to give the crude product (31.7 g, 100% yield).

[0217] Step 5: Synthesis of 6-amino-3-(4-bromo-2-methoxyphenyl)-4-methyl-1,2,4-triazin-5(4H)-one [ka] N-amino-4-bromo-2-methoxy-N'-methylbenzamidine (31.7 g, 122.90 mmol, 1.0 eq), ethyl thioxamate (16.37 g, 122.90 mmol, 1.0 eq), and triethylamine (12.44 g, 122.90 mmol, 1.0 eq) were dissolved in EtOH (300 mL) and reacted at 70 °C for 16 h. After completion of the reaction was monitored by LC-MS, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was first purified by silica gel column chromatography (methanol:dichloromethane = 1:100), then slurried in ethyl acetate (100 mL), and vacuum filtered to give the product (15.5 g, yield: 40.6%).

[0218] Step 6: Synthesis of 3-(4-bromo-2-methoxyphenyl)-6-chloro-4-methyl-1,2,4-triazin-5(4H)-one [ka] 6-Amino-3-(4-bromo-2-methoxyphenyl)-4-methyl-1,2,4-triazin-5(4H)-one (5.0 g, 16.07 mmol, 1.0 eq) and CuCl (3.18 g, 32.14 mmol, 2.0 eq) were dispersed in acetonitrile (50 mL) and reacted at 70 °C for 5 min under nitrogen gas protection. tert-Butyl nitrite (3.31 g, 32.14 mmol, 2.0 eq) was added dropwise and reacted at 70 °C for 2 h. Completion of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate:dichloromethane = 1:5) to give the product (1.5 g, yield: 28.2%).

[0219] Step 7: Synthesis of tert-butyl (R)-3-((3-(4-bromo-2-methoxyphenyl)-4-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)amino)piperidine-1-carboxylate [ka] 3-(4-Bromo-2-methoxyphenyl)-6-chloro-4-methyl-1,2,4-triazin-5(4H)-one (1.5 g, 4.54 mmol, 1.0 eq), (R)-tert-butyl 3-aminopiperidine-1-carboxylate (1.09 g, 5.45 mmol, 1.2 eq), and N,N-diisopropylethylamine (880 mg, 6.81 mmol, 1.5 eq) were dissolved in 1,4-dioxane (30 mL) and reacted at 100 °C for 18 h. After completion of the reaction was confirmed by LC-MS, the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL × 2). The organic phase was dried and concentrated. The crude product was purified by silica gel column chromatography (methanol:dichloromethane = 1:100) to give the product (1.2 g, yield: 53.6%).

[0220] Step 8: Synthesis of tert-butyl (R)-3-((3-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)-4-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)amino)piperidine-1-carboxylate [ka] (R)-tert-Butyl 3-((3-(4-bromo-2-methoxyphenyl)-4-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)amino)piperidine-1-carboxylate (0.6 g, 1.21 mmol, 1.0 eq), PdCl(PPh) (84 mg, 0.12 mmol, 0.1 eq), and CuI (68 mg, 0.36 mmol, 0.3 eq) were added to diisopropylamine (20 mL) and reacted at 60 °C for 10 min under nitrogen gas protection. Trimethylsilylacetylene (1.19 g, 12.10 mmol, 10 eq) was added and reacted at 60 °C for 5 h. The completion of the reaction was detected by TLC, and the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol:dichloromethane=1:100) to obtain the product (500 mg, yield: 80.8%).

[0221] Step 9: Synthesis of (R)-3-(4-ethynyl-2-hydroxyphenyl)-4-methyl-6-(piperidin-3-ylamino)-1,2,4-triazin-5(4H)-one [ka] (R)-tert-Butyl 3-((3-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)-4-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)amino)piperidine-1-carboxylate (0.5 g, 0.98 mmol, 1.0 eq.) was dissolved in dichloromethane (10 mL), cooled to -70 °C, and boron tribromide (736 mg, 2.94 mmol, 3.0 eq.) was added. The mixture was allowed to warm to room temperature and react for 17 h. Upon completion of the reaction as detected by LC-MS, the reaction mixture was quenched with an appropriate amount of methanol. The reaction mixture was poured into water (20 mL) and extracted with methanol / dichloromethane (1:10, 30 mL x 6). The organic phase was dried and concentrated to give the crude product (200 mg, yield: 62.9%).

[0222] Step 10: Synthesis of (R)-3-(4-ethyl-2-hydroxyphenyl)-4-methyl-6-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one [ka] (R)-3-(4-ethynyl-2-hydroxyphenyl)-4-methyl-6-(piperidin-3-ylamino)-1,2,4-triazin-5(4H)-one (200 mg, 0.61 mmol, 1.0 eq) and aqueous formaldehyde (37%) (50 mg, 0.61 mmol, 1.0 eq) were dissolved in methanol (30 mL) and stirred at room temperature for 10 min. Sodium cyanoborohydride (38 mg, 0.61 mmol, 1.0 eq) was added and the mixture was stirred at room temperature for 10 min. After completion of the reaction was monitored by TLC, the reaction mixture was concentrated under reduced pressure. The crude product was dispersed in water (10 mL) and extracted with dichloromethane (20 mL x 4). The organic phase was dried, concentrated, and purified by preparative thin-layer chromatography (dichloromethane:methanol = 7:1) to give the product (55 mg, yield: 26.6%).

[0223] 1 HNMR(400MHz, DMSO-d6) δ(ppm): 10.46(s, 1H), 7.32-7.30 (d, 1H), 7.05-7.03 (d, 2H), 6.89 (s, 1H), 4.29 (s, 1H), 4.05 (s, 1H), 3.18 (s, 1H), 2.81 (s, 1H), 2.27 (s, 5H), 1.71-1.56 (d, 5H). Molecular formula:C 18 H 21 N5O2 precise molecular weight: 339.17 LC-MS(Pos, m / z)=340.15 [M+H] + .

[0224] Example 2: Synthesis of (R)-3-(2-hydroxy-4-(prop-1-yn-1-yl)phenyl)-4-methyl-6-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one (Compound 27) [ka]

[0225] Step 1: Synthesis of tert-butyl (R)-3-((3-(2-methoxy-4-(prop-1-yn-1-yl)phenyl)-4-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)amino)piperidine-1-carboxylate [ka] (R)-tert-Butyl 3-((3-(4-bromo-2-methoxyphenyl)-4-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)amino)piperidine-1-carboxylate (0.6 g, 1.21 mmol, 1.0 eq), PdCl(PPh) (84 mg, 0.12 mmol, 0.1 eq), and CuI (68 mg, 0.36 mmol, 0.3 eq) were dissolved in diisopropylamine (10 mL) and reacted at 60 °C for 10 min under nitrogen gas protection. A solution of propyne in tetrahydrofuran (1 mol / L, 12.1 mL, 10 eq) was added, and the reaction was continued at 60 °C for 16 h. The target product was detected by LC-MS, and the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL × 2). The organic phase was dried and concentrated, and the crude product was purified by silica gel column chromatography (ethyl acetate:PE = 1:1) to obtain the product (300 mg, yield: 54.6%).

[0226] Step 2: Synthesis of (R)-3-(2-hydroxy-4-(prop-1-yn-1-yl)phenyl)-4-methyl-6-(piperidin-3-ylamino)-1,2,4-triazin-5(4H)-one [ka] (R)-tert-Butyl 3-((3-(2-methoxy-4-(prop-1-yn-1-yl)phenyl)-4-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)amino)piperidine-1-carboxylate (0.3 g, 0.66 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), cooled to -70 °C, and boron tribromide (496 mg, 1.98 mmol, 3.0 eq) was added and reacted for 3 h. Completion of the reaction was confirmed by LC-MS. The reaction was quenched by adding an appropriate amount of methanol, poured into water (20 mL), and extracted with dichloromethane (10 mL × 4). The organic phase was dried and concentrated to give the crude product (100 mg, yield: 44.6%).

[0227] Step 3: Synthesis of (R)-3-(2-hydroxy-4-(prop-1-yn-1-yl)phenyl)-4-methyl-6-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one [ka] (R)-3-(2-hydroxy-4-(prop-1-yn-1-yl)phenyl)-4-methyl-6-(piperidin-3-ylamino)-1,2,4-triazin-5(4H)-one (100 mg, 0.29 mmol, 1.0 eq) and 37% aqueous formaldehyde (24 mg, 0.29 mmol, 1.0 eq) were dissolved in methanol (3 mL) and stirred at room temperature for 5 min. Sodium cyanoborohydride (18 mg, 0.29 mmol, 1.0 eq) was added and the mixture was allowed to react at room temperature for 5 min. After completion of the reaction was monitored by TLC, the reaction mixture was poured into water (10 mL) and extracted with dichloromethane (20 mL x 3). The organic phase was dried and concentrated. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 8:1) to give the product (10 mg, yield: 9.8%).

[0228] 1HNMR (400MHz, CDCl3) δ(ppm): 7.23-7.21 (d, 1H), 7.12 (s, 1H), 6.99-6.97 (d, 1H), 6.48 (s, 1H), 4.25 (s, 1H), 3.57 (s, 3H), 2.58 (s, 2H), 2.33 (s, 4H), 2.09 (s, 3H), 1.75-1.69 (d, 5H). Molecular formula:C 19 H 23 N5O2 precise molecular weight: 353.19 LC-MS(Pos, m / z)=354.07 [M+H] + .

[0229] Example 3: Synthesis of (R)-3-(2-hydroxy-4-(prop-1-yn-1-yl)phenyl)-6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-4-methyl-1,2,4-triazin-5(4H)-one (Compound 33) [ka]

[0230] Step 1: Synthesis of (R)-3-(2-hydroxy-4-(prop-1-yn-1-yl)phenyl)-6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-4-methyl-1,2,4-triazin-5(4H)-one [ka] (R)-3-(2-hydroxy-4-(prop-1-yn-1-yl)phenyl)-4-methyl-6-(piperidin-3-ylamino)-1,2,4-triazin-5(4H)-one (150 mg, 0.44 mmol, 1.0 eq), bromoethanol (165 mg, 1.32 mmol, 3.0 eq), and TEA (233 mg, 2.20 mmol, 5.0 eq) were dissolved in THF (5 mL) and reacted at 60 °C for 3 h. After completion of the reaction was monitored by LC-MS, the reaction mixture was poured into water (20 mL) and extracted with DCM (20 mL x 3). The organic phase was dried, concentrated, and purified by preparative thin-layer chromatography (DCM:MeOH = 8:1) to give the product (80 mg, yield: 47.6%).

[0231] 1 HNMR (400 MHz, CD3OD) δ(ppm): 7.29-7.27 (d, 1H), 7.00-7.98 (d, 1H), 6.95 (s, 1H), 4.25-4.21 (m, 1H), 3.79-3.76 (t, 2H), 3.34 (s, 3H), 3.28 (s, 1H), 2.97 (s, 1H), 2.84-2.83 (d, 2H), 2.66-2.61 (t, 2H), 2.06 (s, 3H), 1.97-1.95 (d, 1H), 1.93-1.90 (t, 1H), 1.83-1.78 (m, 1H), 1.77-1.68 (m, 1H). Molecular formula:C 20 H 25 N5O3 precise molecular weight: 383.20 LC-MS(Pos, m / z)=384.22 [M+H] + .

[0232] Example 4: Synthesis of (R)-3-(4-ethynyl-2-hydroxyphenyl)-6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-4-methyl-1,2,4-triazin-5(4H)-one (Compound 42) [ka]

[0233] Step 1: Synthesis of (R)-3-(4-ethynyl-2-hydroxyphenyl)-6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-4-methyl-1,2,4-triazin-5(4H)-one [ka] (R)-3-(4-ethynyl-2-hydroxyphenyl)-4-methyl-6-(piperidin-3-ylamino)-1,2,4-triazin-5(4H)-one (300 mg, 0.92 mmol, 1.0 eq), bromoethanol (172 mg, 1.38 mmol, 3.0 eq), and TEA (279 mg, 2.76 mmol, 5.0 eq) were dissolved in 1,4-dioxane (10 mL) and reacted at 100°C for 1 h. After completion of the reaction was monitored by TLC, the reaction mixture was concentrated under reduced pressure, and the crude product was first purified by silica gel column chromatography (DCM:MeOH = 10:1) and then slurried with EA (5 mL) to give the product (170 mg, yield: 50%).

[0234] 1 HNMR(400MHz, CD3OD) δ(ppm): 7.35-7.33(d, 1H), 7.12-7.10(d, 1H), 7.06(s, 1H), 4.29-4.26 (m, 1H), 3.82-3.79 (t, 2H), 3.64 (s, 1H), 3.41 (s, 1H), 3.35 (s, 3H), 3.09 (s, 1H), 2.94 (s, 2H), 2.78-2.68 (m, 2H), 2.00 (s, 1H), 1.98-1.95 (m, 1H), 1.87-1.81 (m, 1H), 1.78-1.68 (m, 1H). Molecular formula:C 19 H 23 N5O3 precise molecular weight: 369.18 LC-MS(Pos, m / z)=370.15 [M+H] + .

[0235] Example 5: Synthesis of 5-(bromoethynyl)-2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazin-3-yl)phenol (Compound 34) [ka]

[0236] Step 1: Synthesis of intermediate (cis)-3-((6-chloro-5-methylpyridazin-3-yl)amino)-1-methylcyclobutan-1-ol [ka] 3,6-Dichloro-4-methylpyridazine (1 g, 6.13 mmol, 1.0 eq) was dissolved in n-butanol (5 mL), and (cis)-3-amino-1-methylcyclobutan-1-ol hydrochloride (844 mg, 6.13 mmol, 1.0 eq) and DIPEA (1.5 g, 12.27 mmol, 2.0 eq) were added sequentially. The mixture was stirred at 150 °C for 2 h in a microwave oven. Completion of the reaction was confirmed by TLC. The reaction mixture was concentrated, water (5 mL) was added, and the mixture was extracted with dichloromethane (5 mL x 3). The organic phase was dried, suction filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 80:1 to 20:1) to give the product (225 mg, yield: 16.1%).

[0237] Step 2: Synthesis of intermediate 3-(ethoxymethoxy)-4-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazin-3-yl)benzaldehyde [ka] (cis)-3-((6-chloro-5-methylpyridazin-3-yl)amino)-1-methylcyclobutan-1-ol (500 mg, 2.20 mmol, 1.0 eq) obtained in the previous step was dissolved in 1,4-dioxane (5 mL) and water (2 mL). 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (874 mg, 2.85 mmol, 1.3 eq), sodium bicarbonate (370 mg, 4.40 mmol, 2.0 eq), and Pd(dppf)Cl (161 mg, 0.22 mmol, 0.1 eq) were added sequentially and the mixture was stirred at 90 °C for 2 h under nitrogen gas protection. The completion of the reaction was confirmed by LC-MS, and the reaction solution was suction filtered through diatomaceous earth and washed with ethyl acetate. The organic phase was dried and suction filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 40:1 to 10:1) to obtain the product (700 mg, yield: 85.7%).

[0238] Step 3: Synthesis of intermediate (cis)-3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylpyridazin-3-yl)amino)-1-methylcyclobutan-1-ol [ka] 3-(Ethoxymethoxy)-4-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazin-3-yl)benzaldehyde (350 mg, 0.94 mmol, 1.0 eq) was dissolved in methanol (4 mL), and dimethyl (1-diazo-2-oxopropyl)phosphonate (217 mg, 1.13 mmol, 1.2 eq) and potassium carbonate (260 mg, 1.88 mmol, 2.0 eq) were added sequentially. The mixture was stirred at room temperature for 2 h. After completion of the reaction was confirmed by LC-MS, the reaction mixture was concentrated, water (5 mL) was added, and the mixture was extracted with dichloromethane (5 mL x 3). The organic phase was dried and concentrated to give the product (330 mg, yield: 95.5%).

[0239] Step 4: Synthesis of intermediate (cis)-3-((6-(4-(bromoethynyl)-2-(ethoxymethoxy)phenyl)-5-methylpyridazin-3-yl)amino)-1-methylcyclobutan-1-ol [ka] (cis)-3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylpyridazin-3-yl)amino)-1-methylcyclobutan-1-ol (200 mg, 0.54 mmol, 1.0 eq)) was dissolved in acetone (3 mL), and silver nitrate (46 mg, 0.27 mmol, 0.5 eq) and NBS (214 mg, 0.65 mmol, 1.2 eq) were added sequentially. The mixture was stirred at room temperature for 3 h. Upon completion of the reaction by LC-MS, the reaction mixture was diluted with dichloromethane, filtered through diatomaceous earth, and the filtrate was concentrated. The crude product was purified by preparative thin-layer chromatography (dichloromethane:7% ammonia in methanol = 20:1) to give the product (160 mg, yield: 66.4%).

[0240] Step 5: Synthesis of compound 5-(bromoethynyl)-2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazin-3-yl)phenol [ka] (cis)-3-((6-(4-(bromoethynyl)-2-(ethoxymethoxy)phenyl)-5-methylpyridazin-3-yl)amino)-1-methylcyclobutan-1-ol (160 mg, 0.36 mmol, 1.0 eq) obtained in the previous step was dissolved in dichloromethane (2 mL), 4 mol / L hydrogen chloride / 1,4-dioxane solution (0.45 mL) was added, and the mixture was stirred at room temperature for 30 min. The reaction was confirmed to be complete by LC-MS. The reaction mixture was poured into water, the pH was adjusted to 8 with solid sodium bicarbonate, the mixture was separated, extracted with dichloromethane (5 mL × 2), dried, suction filtered, and concentrated. The crude product was purified by preparative thin-layer chromatography (dichloromethane:7% ammonia / methanol = 15:1) to give the product (80 mg, yield: 57.2%).

[0241] 1 H-NMR (400 MHz, DMSO-d6) δ(ppm): 10.16 (s, 1H), 7.18-7.17 (m, 1H), 7.04-6.98 (m, 3H), 6.62 (s, 1H), 4.99 (s, 1H), 3.93-3.86 (m, 1H), 2.44-2.39 (m, 2H), 2.03 (s, 3H), 1.98-1.93 (m, 2H), 1.29 (s, 3H). Molecular formula:C 18 H 18 BrN3O2 precise molecular weight: 387.06 LC-MS (m / z): 388.04 [M+H] +

[0242] Example 6: Synthesis of (R)-2-(6-((1-(3-hydroxypropyl)piperidin-3-yl)amino)-4-methylpyridazin-3-yl)-5-(prop-1-yn-1-yl)phenol (Compound 35) [ka]

[0243] Step 1: Synthesis of tert-butyl (R)-3-((6-chloro-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate [ka] 3,6-Dichloro-4-methylpyridazine (5.0 g, 30.67 mmol, 1.0 eq), (R)-tert-butyl 3-aminopiperidine-1-carboxylate (6.1 g, 30.67 mmol, 1.0 eq), and N,N-diisopropylethylamine (7.9 g, 61.34 mmol, 2.0 eq) were added to N,N-dimethylacetamide (20.0 mL) and stirred at 120 °C for 6 h. The reaction was monitored for completion by TLC. The system was cooled to room temperature, water (100.0 mL) was added, and the mixture was extracted with EA (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica gel standard: 100-200 mesh, petroleum ether:ethyl acetate = 10:1-5:1) to give the product (1.5 g, yield: 15.0%).

[0244] Step 2: Synthesis of (R)-6-chloro-5-methyl-N-(piperidin-3-yl)pyridazin-3-amine [ka] (R)-tert-butyl 3-((6-chloro-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate (1.5 g, 4.58 mmol, 1.0 eq) was added to dichloromethane (2.0 mL), and hydrogen chloride-1,4-dioxane solution (4.0 mol / L, 4.0 mL) was added dropwise. The reaction was allowed to proceed at room temperature for 2 h. Completion of the reaction was monitored by TLC. The system was adjusted to pH 7-8 with saturated aqueous sodium bicarbonate, extracted with dichloromethane (100.0 mL), and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the product (980.0 mg, yield: 94.5%).

[0245] Step 3: Synthesis of (R)-6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methyl-N-(piperidin-3-yl)pyridazin-3-amine [ka] (R)-6-Chloro-5-methyl-N-(piperidin-3-yl)pyridazin-3-amine (1.40 g, 6.18 mmol, 1.0 eq), 2-ethoxymethoxy-4-prop-1-ynylphenylboronic acid (1.73 g, 7.42 mmol, 1.2 eq), Pd(dppf)Cl (452 ​​mg, 0.618 mmol, 0.1 eq), and NaHCO (1.04 g, 12.4 mmol, 2.0 eq) were added to 1,4-dioxane (30 mL) in this order, followed by HO (15 mL). The mixture was heated to 110 °C under nitrogen gas protection and reacted for 2 h. The reaction mixture was cooled to room temperature, quenched by the addition of water (50 mL), extracted with EA (40 mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 50:1 to 10:1) to give the product (1.82 g, yield: 77.5%).

[0246] Step 4: Synthesis of (R)-3-(3-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)propan-1-ol [ka] (R)-6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methyl-N-(piperidin-3-yl)pyridazin-3-amine (300 mg, 0.788 mmol, 1.0 eq) was dissolved in DCM (10 mL), triethylamine (353 mg, 3.49 mmol, 5.0 eq) and 3-bromopropanol (548 mg, 3.49 mmol, 5.0 eq) were added, and the mixture was stirred at room temperature for 20 h. After concentration, the crude product was purified by silica gel column chromatography (DCM:MeOH = 50:1 to 10:1) to give the product (165 mg, yield: 47.7%).

[0247] Step 5: Synthesis of (R)-2-(6-((1-(3-hydroxypropyl)piperidin-3-yl)amino)-4-methylpyridazin-3-yl)-5-(prop-1-yn-1-yl)phenol [ka] (R)-3-(3-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)propan-1-ol (160 mg, 0.365 mmol, 1.0 eq) was dissolved in DCM (4 mL). Then, a solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 0.27 mL, 1.85 mmol, 3.0 eq) was added dropwise and stirred at room temperature for 1 h. The pH was adjusted to 8 with saturated aqueous NaHCO3, and the mixture was extracted with DCM (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (DCM:MeOH = 5:1) to give the product (76.0 mg, yield: 54.8%).

[0248] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 10.07 (s, 1H), 7.12 (d, J = 7.8 Hz, 1H), 6.96-6.89 (m, 3H), 6.71 (s, 1H), 4.30 (s, 1H), 3.48-3.45 (m, 3H), 3.35 (s, 4H), 2.95 (s, 2H), 2.05 (s, 3H), 2.03 (s, 3H), 1.94 (s, 2H), 1.79 (s, 3H), 1.51 (s, 1H). Molecular formula:C 22 H 28 N4O2 precise molecular weight: 380.22 LC-MS(Pos,m / z)=381.26[M+H] + .

[0249] Example 7: Synthesis of (R)-2-(6-((1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)amino)-4-methylpyridazin-3-yl)-5-(prop-1-yn-1-yl)phenol (Compound 36) [ka] Step 1: Synthesis of (R)-1-(3-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)-2-methylpropan-2-ol [ka] (R)-6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methyl-N-(piperidin-3-yl)pyridazin-3-amine (300 mg, 0.788 mmol, 1.0 eq) was dissolved in DMF (10 mL), KCO (218 mg, 1.58 mmol, 2.0 eq) and 1-chloro-2-methyl-2-propanol (171 mg, 1.58 mmol, 2.0 eq) were added, and the mixture was heated to 90 °C and reacted for 20 h. The mixture was quenched with water (50 mL) and extracted with EA (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 20:1) to give the product (262 mg, yield: 73.4%).

[0250] Step 2: Synthesis of (R)-2-(6-((1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)amino)-4-methylpyridazin-3-yl)-5-(prop-1-yn-1-yl)phenol [ka] (R)-1-(3-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)-2-methylpropan-2-ol (260 mg, 0.574 mmol, 1.0 eq) was dissolved in DCM (5 mL), and then a solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 0.43 mL, 1.72 mmol, 3.0 eq) was added dropwise. The mixture was stirred at room temperature for 1 h, and the pH was adjusted to 8 with saturated aqueous NaHCO3. The mixture was then extracted with DCM (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 10:1) to give the product (170 mg, yield: 75.0%).

[0251] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 10.02 (s, 1H), 7.13 (d, J = 8.1 Hz, 1H), 6.90-6.88 (m, 2H), 6.67 (s, 1H), 6.56 (d, J = 8.2 Hz, 1H), 4.08 (s, 1H), 4.06-4.03 (m, 1H), 3.00 (d, J = 9.0 Hz, 1H), 2.73 (d, J = 10.6Hz, 1H), 2.27-2.14 (m, 4H), 2.05 (s, 3H), 2.03 (s, 3H), 1.83-1.80 (m, 1H), 1.70-1.67 (m, 1H), 1.56-1.52 (m, 1H), 1.30-1.24 (m, 1H), 1.09 (s, 6H). Molecular formula:C 23 H 30 N4O2 precise molecular weight: 394.24 LC-MS(Pos,m / z)=395.23[M+H] + .

[0252] Example 8: Synthesis of 2-(6-(((3R)-1-(1-hydroxyprop-2-yl)piperidin-3-yl)amino)-4-methylpyridazin-3-yl)-5-(prop-1-yn-1-yl)phenol (Compound 37) [ka] Step 1: Synthesis of 2-((R)-3-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)propan-1-ol [ka] (R)-6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methyl-N-(piperidin-3-yl)pyridazin-3-amine (300 mg, 0.788 mmol, 1.0 eq) was dissolved in MeOH (10 mL), 1-hydroxy-2-acetone (87.4 mg, 1.18 mmol, 1.5 eq) was added, and the mixture was reacted at room temperature for 0.5 h. NaBHCN (74.2 mg, 1.18 mmol, 1.5 eq) was added, and the mixture was reacted at room temperature for 2 h. The mixture was concentrated, saturated aqueous NaHCO was added, and the mixture was extracted with DCM (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 50:1 to 10:1) to give the product (192 mg, yield: 55.5%).

[0253] Step 2: Synthesis of 2-(6-(((3R)-1-(1-hydroxyprop-2-yl)piperidin-3-yl)amino)-4-methylpyridazin-3-yl)-5-(prop-1-yn-1-yl)phenol [ka] 2-((R)-3-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)propan-1-ol (192 mg, 0.438 mmol, 1.0 eq) was dissolved in DCM (4 mL), and then hydrogen chloride in 1,4-dioxane (4 mol / L, 0.33 mL, 1.31 mmol, 3.0 eq) was added dropwise. The mixture was stirred at room temperature for 1 h, and the pH was adjusted to 8 with saturated aqueous NaHCO3. The mixture was then extracted with DCM (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (DCM:MeOH = 80:1) to give the product (125 mg, yield: 75.0%).

[0254] 1 HNMR(400MHz, DMSO-d6) δ(ppm): 10.03(s, 1H), 7.13(d, J=8.2Hz, 1H), 6.90-6.88(m, 2H), 6.68(s, 1H), 6.61-6.56(m, 1H), 4.25(s, 1H), 4.03-4.01 (m, 1H), 3.48-3.41 (m, 1H), 3.26-3.23 (m, 1H), 2.94-2.87 (m, 1H), 2.64-2.63 (m, 2H), 2.23-2.19 (m, 2H), 2.05 (s, 3H), 2.03 (s, 3H), 1.80-1.79(m, 1H), 1.71-1.69(m, 1H), 1.52-1.47 (m, 1H), 1.40-1.34 (m, 1H), 0.91-0.89 (m, 3H). Molecular formula:C 22 H 28 N4O2 precise molecular weight: 380.22 LC-MS(Pos,m / z)=381.22[M+H] + .

[0255] Example 9: Synthesis of (R)-1-(2-(3-((6-(2-hydroxy-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)ethyl)urea (Compound 38) [ka]

[0256] Step 1: Synthesis of (R)-1-(2-(3-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)ethyl)urea [ka] (R)-6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methyl-N-(piperidin-3-yl)pyridazin-3-amine (300 mg, 0.788 mmol, 1.0 eq), 1-(2-chloroethyl)urea (194 mg, 1.58 mmol, 2.0 eq), and K2CO3 (218 mg, 1.58 mmol, 2.0 eq) were added to DMF (10 mL), heated to 90 °C, and reacted for 20 h. The mixture was quenched with water (30 mL) and extracted with DCM (20 mL × 5). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 50:1 to 10:1) to give the product (146 mg, yield: 39.7%).

[0257] Step 2: Synthesis of (R)-1-(2-(3-((6-(2-hydroxy-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)ethyl)urea [ka] (R)-1-(2-(3-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)ethyl)urea (146 mg, 0.313 mmol, 1.0 eq) was dissolved in DCM (4 mL). Hydrogen chloride in 1,4-dioxane (4 mol / L, 1 mL) was added dropwise and stirred at room temperature for 1 h. The pH was adjusted to 8 with saturated aqueous NaHCO3, and the mixture was extracted with DCM (10 mL x 5). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (DCM:MeOH = 6:1) to give the product (62.0 mg, yield: 48.5%).

[0258] 1 HNMR(400MHz, DMSO-d6)δ(ppm): 10.03(s, 1H), 7.14 (d, J=7.8Hz, 1H), 6.90-6.88 (m, 2H), 6.67 (s, 1H), 6.58 (d, J=7.8Hz, 1H), 5.88-5.86 (m, 1H), 5.49 (s, 2H), 4.05-4.03 (m, 1H), 3.14-3.04 (m, 2H), 2.92 (d, J = 8.8 Hz, 1H), 2.66 (d, J=10.0Hz, 1H), 2.36-2.32 (m, 2H), 2.05 (s, 4H), 2.03 (s, 4H), 1.87-1.84 (m, 1H), 1.72-1.69 (m, 1H), 1.55-1.52 (m, 1H), 1.40-1.34 (m, 1H). Molecular formula:C 22 H 28 N6O2 precise molecular weight: 408.23 LC-MS(Pos,m / z)=409.23[M+H] + .

[0259] Example 10: Synthesis of (R)-3-((6-(2-hydroxy-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridazin-3-yl)amino)-1,1-dimethylpiperidine chloride (Compound 49) [ka]

[0260] Step 1: Synthesis of (R)-3-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridazin-3-yl)amino)-1,1-dimethylpiperidine iodide [ka] (R)-6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine (120 mg, 0.304 mmol, 1.0 eq) was dissolved in DCM (3 mL), and iodomethane (216 mg, 1.52 mmol, 5.0 eq) was added. The reaction mixture was allowed to react at room temperature for 5 days. After concentration, the crude product was purified by reverse-phase preparative chromatography (ACN:HO = 3:7) to give the product (115 mg, yield: 70.5%).

[0261] Step 2: Synthesis of (R)-3-((6-(2-hydroxy-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridazin-3-yl)amino)-1,1-dimethylpiperidine chloride [ka] (R)-3-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridazin-3-yl)amino)-1,1-dimethylpiperidine iodide (105 mg, 0.196 mmol, 1.0 eq) was added to DCM (2 mL), followed by dropwise addition of hydrogen chloride in 1,4-dioxane (4 mol / L, 0.15 mL, 3.0 eq) and stirring at room temperature for 1 h. After concentration, the crude product was purified by preparative thin-layer chromatography (DCM:MeOH = 5:1) to give the product (28.0 mg, yield: 37.0%).

[0262] 1HNMR (400 MHz, DMSO-d6) δ(ppm): 11.10 (s, 1H), 8.71 (s, 1H), 7.61 (s, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.22 (d, J = 1.0 Hz, 1H), 7.07-7.05 (m, 1H), 4.48 (s, 2H), 4.12 (s, 1H), 3.99 (s, 3H), 3.39 (s, 4H), 2.08-2.06 (s, 3H), 2.06 (s, 3H), 1.88 (s, 2H), 1.73 (s, 1H), 1.52 (s, 1H). Molecular formula:C 21 H 27 ClNO Precision molecular weight: 386.19 Cationic molecular weight: 351.22 LC-MS (Pos, m / z) = 351.25 [M+H] + .

[0263] Example 11: Synthesis of (R)-5-ethynyl-3-methyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol (Compound 41) [ka]

[0264] Step 1: Synthesis of intermediate methyl 4-amino-3-iodo-5-methylbenzoate [ka] Methyl 4-amino-3-methylbenzoate (20.0 g, 121.07 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (200 mL) and N-iodosuccinimide (29.94 g, 133.18 mmol, 1.1 eq) was added in portions. After the addition was complete, the reaction was allowed to proceed at 25 °C for 30 min, and TLC showed completion. The reaction mixture was poured into water (300 mL) and extracted with methyl tert-butyl ether (200 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1 to 40:1) to give the product (21.3 g, yield: 60.4%).

[0265] Step 2: Synthesis of intermediate methyl 4-bromo-3-iodo-5-methylbenzoate [ka] Methyl 4-amino-3-iodo-5-methylbenzoate (19.22 g, 66.03 mmol, 1.0 eq) was dissolved in hydrobromic acid (100 mL), and a solution of sodium nitrite (5.01 g, 72.63 mmol, 1.1 eq) in water (100 mL) was slowly added dropwise at 0° C. After the addition was complete, the reaction was allowed to proceed for 30 minutes at 0° C. A solution of cuprous bromide (11.37 g, 79.24 mmol, 1.2 eq) in hydrobromic acid (100 mL) was added dropwise, and after the addition was complete, the reaction was allowed to proceed for 10 minutes at 0° C., and completion of the reaction was detected by TLC. The reaction mixture was added dropwise to ice water (400 mL) and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1 to 20:1) to obtain the product (16.2 g, yield: 70.9%).

[0266] Step 3: Synthesis of intermediate 4-bromo-3-hydroxy-5-methylbenzoic acid [ka] Methyl 4-bromo-3-iodo-5-methylbenzoate (12.0 g, 34.68 mmol, 1.0 eq) was dissolved in DMSO (60 mL) and 2-hydroxyacetic acid (791 mg, 10.40 mmol, 0.3 eq), copper hydroxide (338 mg, 3.468 mmol, 0.1 eq), and sodium hydroxide (8.32 g, 208.08 mmol, 6.0 eq) in water (60 mL) were added sequentially. The reaction was conducted under nitrogen gas protection at 120 °C for 6 h, and completion of the reaction was confirmed by TLC. The reaction mixture was poured into ice water (120 mL), the pH was adjusted to 1 with 2 mol / L hydrochloric acid, and the mixture was extracted with methyl tert-butyl ether (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, and concentrated to give the crude product, which was used directly in the next step.

[0267] Step 4: Synthesis of intermediate methyl 4-bromo-3-hydroxy-5-methylbenzoate [ka] The crude 4-bromo-3-hydroxy-5-methylbenzoic acid (34.68 mmol) was dissolved in methanol (80 mL) and chlorosulfoxide (40 mL) was added dropwise. After the addition was complete, the reaction was essentially complete as detected by TLC. The reaction mixture was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1 to 20:1) to give the product (4.18 g, 2-step yield: 49.2%).

[0268] Step 5: Synthesis of intermediate methyl 4-bromo-3-ethoxymethoxy-5-methylbenzoate [ka] Methyl 4-bromo-3-hydroxy-5-methylbenzoate (4.18 g, 17.06 mmol, 1.0 eq) was dissolved in tetrahydrofuran (40 mL) at 0 °C. Sodium hydride (1.03 g, 25.59 mmol, 1.5 eq) was added in portions and the mixture was allowed to react at 0 °C for 30 min. Chloromethyl ethyl ether (2.52 g, 25.59 mmol, 1.5 eq) was slowly added dropwise to the reaction mixture. After the addition was complete, the mixture was allowed to react at 0 °C for 5 min. TLC showed the reaction was complete. The reaction mixture was poured into saturated aqueous ammonium chloride (50 mL) and extracted with methyl tert-butyl ether (40 mL × 3). The organic phases were combined, dried, and concentrated to give the product (5.17 g crude, 100% yield), which was used directly in the next step.

[0269] Step 6: Synthesis of intermediate 4-bromo-3-ethoxymethoxy-5-methylphenylmethanol [ka] Methyl 4-bromo-3-ethoxymethoxy-5-methylbenzoate (3.67 g, 12.11 mmol, 1.0 eq) was dissolved in tetrahydrofuran (30 mL) at -78 °C. 1.5 mol / L diisobutylaluminum hydride toluene solution (25 mL, 36.33 mmol, 3.0 eq) was slowly added dropwise. After the addition was complete, the mixture was heated to 25 °C and reacted for 30 min. TLC indicated completion. The reaction mixture was cooled to 0 °C, diluted with methyl tert-butyl ether (30 mL), quenched by the dropwise addition of water (1.5 mL), 15% aqueous sodium hydroxide (1.5 mL), and water (3.6 mL). The mixture was heated to 25 °C and stirred for 15 min. The mixture was dried over anhydrous magnesium sulfate and stirred for 15 min. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated to give the crude product, which was used directly in the next step.

[0270] Step 7: Synthesis of intermediate 4-bromo-3-ethoxymethoxy-5-methylbenzaldehyde [ka] 4-Bromo-3-ethoxymethoxy-5-methylphenylmethanol (crude, 12.11 mmol, 1.0 eq) was dissolved in dichloromethane (40 mL), manganese dioxide (10.53 g, 121.1 mmol, 10.0 eq) was added, and the reaction was allowed to proceed at room temperature (25°C) for 5 hours, at which point TLC showed completion of the reaction. The reaction mixture was filtered through diatomaceous earth and concentrated to give the crude product, which was used directly in the next step.

[0271] Step 8: Synthesis of intermediate 3-ethoxymethoxy-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde [ka] The crude 4-bromo-3-ethoxymethoxy-5-methylbenzaldehyde (12.11 mmol, 1.0 eq) was dissolved in 1,4-dioxane (35 mL). Bis(pinacolato)diboron (4.61 g, 18.17 mmol, 1.5 eq), potassium acetate (2.38 g, 24.22 mmol, 2.0 eq), and PdCl(dppf) (886 mg, 1.211 mmol, 0.1 eq) were added sequentially. The mixture was heated to 110 °C under nitrogen gas protection and reacted for 13 h. TLC showed completion. The reaction mixture was filtered through diatomaceous earth and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 90:1 to 5:1) to give the product (1.36 g, 35.8% yield for three steps).

[0272] Step 9: Synthesis of intermediate (R)-3-ethoxymethoxy-5-methyl-4-(6-(1-methylpiperidin-3-amino)pyridazin-3-yl)benzaldehyde [ka] 6-Chloro-N-(1-methylpiperidin-3-yl)pyridazin-3-amine (400 mg, 1.76 mmol, 1.0 eq) was dissolved in 1,4-dioxane (10 mL), and 3-ethoxymethoxy-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (788 mg, 2.46 mmol, 1.4 eq), potassium carbonate (487 mg, 3.52 mmol, 2.0 eq) in water (2 mL), and PdCl(dppf) (322 mg, 0.44 mmol, 0.25 eq) were added sequentially. Under nitrogen gas protection, the mixture was heated to 95 °C and reacted for 13 h, at which point the reaction was complete as detected by TLC. The reaction mixture was filtered through diatomaceous earth and concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol=100:1 to 10:1) to obtain the product (265 mg, yield: 39.1%).

[0273] Step 10: Synthesis of intermediate (R)-6-(2-(ethoxymethoxy)-4-ethynyl-6-methylphenyl)-N-(1-methylpiperidin-3-yl)pyridazin-3-amine [ka] (R)-3-Ethoxymethoxy-5-methyl-4-(6-(1-methylpiperidin-3-amino)pyridazin-3-yl)benzaldehyde (265 mg, 0.689 mmol, 1.0 eq) was dissolved in methanol (3 mL), and potassium carbonate (191 mg, 1.378 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (199 mg, 1.034 mmol, 1.5 eq) were added sequentially. The reaction was allowed to proceed at 25 °C for 0.5 h, and completion of the reaction was confirmed by TLC. The reaction mixture was concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 50:1 to 10:1) to give the product (230 mg, yield: 87.8%).

[0274] Step 11: Synthesis of compound (R)-5-ethynyl-3-methyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol [ka] (R)-3-Ethoxymethoxy-5-methyl-4-(6-(1-methylpiperidin-3-amino)pyridazin-3-yl)benzaldehyde (230 mg, 0.605 mmol, 1.0 eq) was dissolved in dichloromethane (3 mL) and slowly added dropwise to a 4 mol / L hydrogen chloride / 1,4-dioxane solution (3 mL). The reaction was allowed to proceed at 25 °C for 0.5 h, and TLC showed completion of the reaction. The reaction mixture was concentrated, saturated aqueous sodium bicarbonate (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL x 6). The combined organic phases were dried over anhydrous magnesium sulfate and concentrated. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give the product (91 mg, yield: 46.7%).

[0275] 1 H-NMR (400 MHz, DMSO-d6) δ(ppm): 9.86 (s, 1H), 7.25-7.23 (d, 1H), 7.01 (s, 1H), 6.91-6.88 (m, 3H), 4.25-4.24 (s, 1H), 4.13 (s, 1H), 3.18-3.17 (m, 1H), 2.98 (m, 1H), 2.54 (s, 3H), 2.05 (s, 3H), 1.92-1.86 (m, 2H), 1.73-1.70 (m, 1H), 1.46 (m, 1H), 1.26-1.24 (m, 2H). Molecular formula:C 19 H 22 N4O Precise molecular weight: 322.18 LC-MS(m / z): 323.15 [M+H] +

[0276] Example 12: Synthesis of 2-(6-(((1S,2R)-2-hydroxycyclohexyl)amino)-4-methylpyridazin-3-yl)-5-(prop-1-yn-1-yl)phenol (Compound 43) [ka]

[0277] Step 1: Synthesis of (1R,2S)-2-((6-chloro-5-methylpyridin-3-yl)amino)cyclohexan-1-ol [ka] 3,6-Dichloro-4-methylpyridazine (4.5 g, 27.61 mmol, 1.0 eq.), (1R,2S)-2-aminocyclohexan-1-ol hydrochloride (5.0 g, 33.12 mmol, 1.2 eq.), and N,N-diisopropylethylamine (7.13 g, 55.22 mmol, 2.0 eq.) were added to N,N-dimethylacetamide (15.0 mL) and stirred at 120 °C for 48 h. After incomplete reaction was monitored by TLC, the mixture was cooled to room temperature, water (100.0 mL) was added, and the mixture was extracted with EA (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica gel standard: 100-200 mesh, dichloromethane:methanol = 130:1 to 60:1) to give the product (1.2 g, yield: 18.0%).

[0278] Step 2: Synthesis of (1R,2S)-2-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridazin-3-yl)amino)cyclohexan-1-ol [ka] (1R,2S)-2-((6-chloro-5-methylpyridazin-3-yl)amino)cyclohexan-1-ol (320.0 mg, 1.32 mmol, 1.0 eq), (2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)boronic acid (371.8 mg, 1.58 mmol, 1.2 eq), sodium bicarbonate (222.2 mg, 2.64 mmol, 2.0 eq), and Pd(dppf)Cl2 (96.8 mg, 0.13 mmol, 0.1 eq) were dissolved in 1,4-dioxane (10. The resulting mixture was added to a mixture of 100 mL of ethyl acetate (100 mL) and water (5.0 mL), and the resulting mixture was reacted at 110°C for 3 h under nitrogen gas protection. Completion of the reaction was monitored by TLC. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica gel standard: 100-200 mesh, dichloromethane:methanol = 100:1-60:1) to give the product (400 mg, yield: 76.4%).

[0279] Step 3: Synthesis of 2-(6-(((1S,2R)-2-hydroxycyclohexyl)amino)-4-methylpyridazin-3-yl)-5-(prop-1-yn-1-yl)phenol [ka] (1R,2S)-2-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridazin-3-yl)amino)cyclohexan-1-ol (390.0 mg, 0.98 mmol, 1.0 eq) was added to dichloromethane (4.0 mL), and hydrogen chloride / 1,4-dioxane solution (4.0 mol / L, 4.0 mL) was added dropwise. The reaction was allowed to proceed at room temperature for 2 h, and completion of the reaction was monitored by TLC. The pH was adjusted to 8-9 with saturated aqueous sodium carbonate solution, extracted with dichloromethane (100.0 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica gel standard: 100-200 mesh, dichloromethane:methanol = 100:1-60:1) to obtain the product (130.0 mg, yield: 39.1%).

[0280] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 10.06 (s, 1H), 7.13-7.11 (d, J=8 Hz, 1H), 6.90-6.88 (m, 2H), 6.77 (s, 1H), 6.32-6.30 (d, J=8 Hz, 1H), 4.67-4.66 (d, J=4 Hz, 1H), 3.98-3.90 (m, 2H), 2.05 (s, 3H), 2.02 (s, 3H), 1.75-1.47 (m, 6H), 1.33-1.24 (m, 2H). Molecular formula:C 20 H 23 N3O2 precise molecular weight: 337.18 LC-MS(Pos,m / z)=338.15[M+H] + .

[0281] Example 13: Synthesis of (R)-2-(4-cyclopropyl-6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)pyridazin-3-yl)-5-(prop-1-yn-1-yl)phenol (Compound 44) [ka]

[0282] Step 1: Synthesis of (R)-2-(3-((6-chloro-5-cyclopropylpyridazin-3-yl)amino)piperidin-1-yl)ethan-1-ol [ka] (R)-6-Chloro-5-cyclopropyl-N-(piperidin-3-yl)pyridazin-3-amine (310.0 mg, 1.22 mmol, 1.0 eq), bromoethanol (459.7 mg, 3.67 mmol, 3.0 eq), and triethylamine (372.2 mg, 3.67 mmol, 3.0 eq) were added to dichloromethane (10.0 mL) and stirred at room temperature for 24 h. The reaction was monitored for completion by TLC. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (silica gel standard: 100-200 mesh, dichloromethane:methanol = 40:1 to 10:1) to give the product (300.0 mg, yield: 81.4%).

[0283] Step 2: Synthesis of (R)-2-(3-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)pyridazin-3-yl)amino)piperidin-1-yl)ethan-1-ol [ka] (R)-2-(3-((6-chloro-5-cyclopropylpyridazin-3-yl)amino)piperidin-1-yl)ethan-1-ol (295.0 mg, 0.99 mmol, 1.0 eq.), (2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)boronic acid (279.1 mg, 1.19 mmol, 1.2 eq.), sodium bicarbonate (166.9 mg, 1.98 mmol, 2.0 eq.), and Pd(dppf)Cl2 (72.4 mg, 0.09 mmol, 0.1 eq.) were dissolved in 1,4-dichloro-2-(3-((6-chloro-5-cyclopropylpyridazin-3-yl)amino)piperidin-1-yl)ethan-1-ol. The mixture was added to a mixture of hexane (10.0 mL) and water (5.0 mL) and reacted at 110 °C for 4 hours under nitrogen gas protection. Completion of the reaction was monitored by TLC. Water (100.0 mL) was added, and the mixture was extracted with ethyl acetate (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica gel standard: 100-200 mesh, dichloromethane:methanol = 50:1-10:1) to obtain the product (234.0 mg, yield: 52.3%).

[0284] Step 3: Synthesis of (R)-2-(4-cyclopropyl-6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)pyridazin-3-yl)-5-(prop-1-yn-1-yl)phenol [ka] (R)-2-(3-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)pyridazin-3-yl)amino)piperidin-1-yl)ethan-1-ol (234.0 mg, 0.51 mmol, 1.0 eq) was added to dichloromethane (4.0 mL) and hydrogen chloride / 1,4-dioxane solution (4.0 mol / L, 4.0 mL) was added dropwise. The reaction was allowed to proceed at room temperature for 2 h. Completion was monitored by TLC. The pH was adjusted to 8-9 with saturated aqueous sodium carbonate, and the mixture was extracted with dichloromethane (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography (dichloromethane:methanol = 10:1) to give the product (80.0 mg, yield: 39.4%).

[0285] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 9.99 (s, 1H), 7.20-7.18 (d, J=8 Hz, 1H), 6.91-6.89 (m, 2H), 6.51 (s, 1H), 6.31 (s, 1H), 4.43-4.36 (m, 1H), 4.07 (s, 1H), 3.52-3.51 (m, 2H), 2.94 (s, 1H), 2.67-2.62 (m, 1H), 2.40-2.46 (m, 2H), 2.12-2.05 (m, 5H), 1.80-1.24 (m, 5H), 0.89-0.84 (m, 2H), 0.63-0.59 (m, 2H). Molecular formula:C 23 H 28 N4O2 precise molecular weight: 392.22 LC-MS(Pos,m / z)=393.20[M+H] + .

[0286] Example 14: Synthesis of 2-(6-(((1R,2S)-2-hydroxycyclohexyl)amino)-4-methylpyridazin-3-yl)-5-(prop-1-yn-1-yl)phenol (Compound 48) [ka]

[0287] Step 1: Synthesis of (1S,2R)-2-((6-chloro-5-methylpyridazin-3-yl)amino)cyclohexan-1-ol [ka] 3,6-Dichloro-4-methylpyridazine (3.8 g, 23.31 mmol, 1.0 eq), (1S,2R)-2-aminocyclohexan-1-ol hydrochloride (4.59 g, 30.30 mmol, 1.3 eq) and N,N-diisopropylethylamine (6.0 g, 46.62 mmol, 2.0 eq) were added to N,N-dimethylacetamide (15.0 mL), stirred at 120 °C for 48 h, and the reaction was analyzed by TLC. The reaction was monitored for completion, cooled to room temperature, added with water (100 mL), extracted with EA (100 mL), the organic phase dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica gel standard: 100-200 mesh, dichloromethane:methanol = 130:1-50:1) to give the product (864 mg, yield: 15.4%).

[0288] Step 2: Synthesis of (1S,2R)-2-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridazin-3-yl)amino)cyclohexan-1-ol [ka] (1S,2R)-2-((6-chloro-5-methylpyridazin-3-yl)amino)cyclohexan-1-ol (300.0 mg, 1.24 mmol, 1.0 eq), (2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)boronic acid (348.6 mg, 1.48 mmol, 1.2 eq), sodium bicarbonate (208.5 mg, 2.48 mmol, 2.0 eq), and Pd(dppf)Cl2 (90. The resulting mixture (8 mg, 0.12 mmol, 0.1 eq) was added to a mixture of 1,4-dioxane (10 mL) and water (5 mL) and reacted at 110°C for 3 h under nitrogen gas protection. Completion of the reaction was monitored by TLC. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product (630 mg crude product), which was used directly in the next step.

[0289] Step 3: Synthesis of 2-(6-(((1R,2S)-2-hydroxycyclohexyl)amino)-4-methylpyridazin-3-yl)-5-(prop-1-yn-1-yl)phenol [ka] (1S,2R)-2-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridazin-3-yl)amino)cyclohexan-1-ol (630.0 mg crude product, 1.24 mmol, 1.0 eq) was added to dichloromethane (4.0 mL), and hydrogen chloride / 1,4-dioxane solution (4.0 mol / L, 4.0 mL) was added dropwise. The reaction was allowed to proceed at room temperature for 2 h. The reaction was monitored for completion by TLC. The pH was adjusted to 8-9 with saturated aqueous sodium carbonate, and the mixture was extracted with dichloromethane (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain the product (100.0 mg, yield: 23.9%).

[0290] 1HNMR (400 MHz, DMSO-d6) δ(ppm): 10.05 (s, 1H), 7.13-7.11 (d, J=8 Hz, 1H), 6.90-6.88 (m, 2H), 6.77 (s, 1H), 6.33-6.31 (d, J=8 Hz, 1H), 4.67-4.66 (d, J=4 Hz, 1H), 3.98-3.90 (m, 2H), 2.05 (s, 3H), 2.02 (s, 3H), 1.75-1.46 (m, 6H), 1.33-1.24 (m, 2H). Molecular formula:C 20 H 23 N3O2 precise molecular weight: 337.18 LC-MS(Pos,m / z)=338.17[M+H] + .

[0291] Example 15: Synthesis of (R)-5-(2,2-difluorovinyl)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol (Compound 39) [ka]

[0292] Step 1: Synthesis of 1-bromo-4-(2,2-difluorovinyl)-2-(ethoxymethoxy)benzene [ka] 4-Bromo-3-(ethoxymethoxy)benzaldehyde (2.0 g, 7.71 mmol, 1.0 eq) and ethyl 2,2-difluoro-2-(triphenylphosphonyl)acetate (3.3 g, 9.26 mmol, 1.2 eq) were added to N,N-dimethylformamide (10.0 mL) and stirred at 40 °C for 12 h. After completion of the reaction was monitored by TLC, water (50.0 mL) was added, and the mixture was extracted with ethyl acetate (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica gel standard: 100-200 mesh, petroleum ether:ethyl acetate = 100:1) to give the product (1.0 g, yield: 44.2%).

[0293] Step 2: Synthesis of 2-(4-(2,2-difluorovinyl)-2-(ethoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] 1-Bromo-4-(2,2-difluorovinyl)-2-(ethoxymethoxy)benzene (1.0 g, 3.41 mmol, 1.0 eq), bis(pinacolato)diboron (1.3 g, 5.11 mmol, 1.5 eq), potassium acetate (669.5 mg, 6.82 mmol, 2.0 eq), and Pd(dppf)Cl2 (249.5 mg, 0.34 mmol, 0.1 eq) were added to 1,4-dioxane (15.0 mL) and the mixture was heated under nitrogen gas. The reaction mixture was heated at 100°C for 4 h under reduced pressure, and the reaction completion was monitored by TLC. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica gel standard: 100-200 mesh, petroleum ether:ethyl acetate = 20:1) to give the product (630 mg, yield: 54.3%).

[0294] Step 3: Synthesis of (R)-6-chloro-5-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine [ka] (R)-6-Chloro-5-methyl-N-(piperidin-3-yl)pyridazin-3-amine (980.0 mg, 4.32 mmol, 1.0 eq), aqueous formaldehyde solution (37%, 526.2 mg, 6.48 mmol, 1.5 eq), and acetic acid (0.5 mL) were added to methanol (20.0 mL) and stirred at room temperature for 0.5 h. Then, sodium cyanoborohydride (407.4 mg, 6.48 mmol, 1.5 eq) was added and the mixture was allowed to react at room temperature for 2 h. The reaction was monitored for completion by TLC, concentrated under reduced pressure, and saturated aqueous sodium bicarbonate (100.0 mL) was added. The mixture was stirred for 0.5 h and extracted with dichloromethane (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 40:1 to 20:1) to give the product (750.0 mg, yield: 72.1%).

[0295] Step 4: Synthesis of (R)-6-(4-(2,2-difluorovinyl)-2-(ethoxymethoxy)phenyl)-5-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine [ka] (R)-6-chloro-5-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine (230.0 mg, 0.95 mmol, 1.0 eq.), 2-(4-(2,2-difluorovinyl)-2-(ethoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (389.9 mg, 1.14 mmol, 1.2 eq.), sodium bicarbonate (160.4 mg, 1.91 mmol, 2.0 eq.), and Pd(dppf)Cl (34.9 mg, 0.04 mmol, 0.05 eq.). The residue was added to a mixture of 1,4-dioxane (10.0 mL) and water (5.0 mL) and reacted at 110°C for 4 h under nitrogen gas protection. Completion of the reaction was monitored by TLC. Water (100.0 mL) was added, and the mixture was extracted with ethyl acetate (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica gel standard: 100-200 mesh, dichloromethane:methanol = 40:1-10:1) to give the product (160.0 mg, yield: 40.0%).

[0296] Step 5: Synthesis of (R)-5-(2,2-difluorovinyl)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol [ka] (R)-6-(4-(2,2-difluorovinyl)-2-(ethoxymethoxy)phenyl)-5-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine (140.0 mg, 0.33 mmol, 1.0 eq.) was added to dichloromethane (4.0 mL) and hydrogen chloride / 1,4-dioxane solution (4.0 mol / L, 2.0 mL) was added dropwise. The reaction was allowed to proceed at room temperature for 2 h. Completion was monitored by TLC. The pH was adjusted to 8-9 with saturated aqueous sodium carbonate, and the mixture was extracted with dichloromethane (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give the product (60.0 mg, yield: 49.8%).

[0297] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 10.00 (s, 1H), 7.19-7.17 (d, J=8 Hz, 1H), 6.97 (s, 1H), 76.91-6.89 (d, J=8 Hz, 1H), 6.68 (s, 1H), 6.64-6.62 (d, J=8 Hz, 1H), 5.83-5.75 (m, 1H), 4.06 (s, 1H), 2.95 (s, 1H), 2.66 (s, 1H), 2.25 (s, 3H), 2.12-1.95 (m, 5H), 1.87-1.34 (m, 4H). Molecular formula:C 19 H 22 F2N4O Precise molecular weight: 360.18 LC-MS(Pos,m / z)=361.19[M+H] + .

[0298] Example 16: Synthesis of (R)-2-(7-(1-methylpiperidin-3-yl)amino)pyrazolo[1,5-d][1,2,4]triazin-4-yl)-5-(prop-1-yn-1-yl)phenol (Compound 40) [ka]

[0299] Step 1: Synthesis of 1-bromo-2-methoxy-4-(prop-1-yn-1-yl)benzene [ka] 1-Bromo-4-iodo-2-methoxybenzene (15.65 g, 50 mmol, 1.0 eq), DIPEA (9.7 g, 75 mmol, 1.5 eq), bis(triphenylphosphine)palladium dichloride (3.5 g, 5 mmol, 0.1 eq), and cuprous iodide (1.9 g, 10 mmol, 0.2 eq) were added to anhydrous THF (150 mL). Under nitrogen gas protection, a 1 mol / L THF solution (55 mL) of propyne was added and the reaction was carried out at room temperature for 64 h. The disappearance of the raw materials was monitored by TLC, and water (100 mL) and ethyl acetate (100 mL) were added, stirred for 5 min, filtered, the filter cake was rinsed with ethyl acetate, and the layers were separated. The organic phase was retained, and the aqueous phase was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE = 1:100) to give the product (11.1 g, yield: 99.1%).

[0300] Step 2: Synthesis of (2-methoxy-4-(prop-1-yn-1-yl)phenyl)magnesium bromide [ka] Magnesium strips (1.3 g, 52.19 mmol, 1.1 eq) were added to anhydrous THF (50 mL) and heated to 70 °C under nitrogen gas protection. 1,2-Dibromoethane (1 mL) was added, and a solution of 1-bromo-2-methoxy-4-(prop-1-yn-1-yl)benzene (10.68 g, 47.45 mmol, 1.0 eq) in anhydrous THF (30 mL) was added dropwise. After the addition was complete, the reaction was continued at 70 °C for 1 h. The theoretical amount was used in the next step.

[0301] Step 3: Synthesis of (2-methoxy-4-(prop-1-yn-1-yl)phenyl)(1-(4-methoxybenzyl)-1H-pyrazol-5-yl)methanone [ka] A solution of (2-methoxy-4-(prop-1-yn-1-yl)phenyl)magnesium bromide (47.45 mmol, 1.63 eq) in anhydrous THF was heated to 70 °C, and a solution of N-methoxy-1-(4-methoxybenzyl)-N-methyl-1H-pyrazole-5-formamide (8 g, 29.06 mmol, 1.0 eq) in anhydrous THF (20 mL) was added dropwise. The mixture was then incubated at 70 °C for 20 h. After a significant amount of raw material was detected by TLC, the mixture was cooled to room temperature, saturated aqueous ammonium chloride (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE = 1:100 to 1:5) to give the product (1 g, yield: 9.5%).

[0302] Step 4: Synthesis of (2-methoxy-4-(prop-1-yn-1-yl)phenyl)(1H-pyrazol-5-yl)methanone [ka] (2-Methoxy-4-(prop-1-yn-1-yl)phenyl)(1-(4-methoxybenzyl)-1H-pyrazol-5-yl)methanone (1.6 g, 4.44 mmol, 1.0 eq) was added to a mixture of 1,2-dichloroethane (10 mL) and TFA (10 mL) and heated to reflux for 7 h. After TLC showed the disappearance of the starting material, the mixture was concentrated under reduced pressure, saturated aqueous sodium carbonate (50 mL) was added, and the mixture was extracted with DCM (50 mL × 3). The combined organic phases were 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 = 1:10 to 1:3) to give the product (1.0 g, yield: 90.9%).

[0303] Step 5: Synthesis of 4-(2-methoxy-4-(prop-1-yn-1-yl)phenyl)pyrazolo[1,5-d][1,2,4]triazin-7-ol [ka] (2-Methoxy-4-(prop-1-yn-1-yl)phenyl)(1H-pyrazol-5-yl)methanone (1.0 g, 4.16 mmol, 1.0 eq), methyl hydrazinoformate (1.1 g, 12.48 mmol, 3.0 eq), and acetic acid (249.6 mg, 4.16 mmol, 1.0 eq) were added to anhydrous methanol (50 mL) and heated to reflux for 72 h. After LC-MS showed the disappearance of the starting material, the mixture was concentrated under reduced pressure, and anhydrous ethanol (50 mL) was added. 60% by mass sodium hydride (499.2 mg, 12.48 mmol, 3.0 eq) was further added, and the mixture was heated to reflux for 16 h. The disappearance of the raw materials was monitored by LC-MS, and the mixture was concentrated under reduced pressure. Water (50 mL) was added, and 2 mol / L hydrochloric acid was added dropwise until the pH reached about 3. The mixture was extracted with DCM (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product (1.2 g, yield: 100%).

[0304] Step 6: Synthesis of 4-(2-methoxy-4-(prop-1-yn-1-yl)phenyl)pyrazolo[1,5-d][1,2,4]triazine-7-thiol [ka] 4-(2-Methoxy-4-(prop-1-yn-1-yl)phenyl)pyrazolo[1,5-d][1,2,4]triazin-7-ol (1.2 g, 14.16 mmol, 1.0 eq) and Lawesson's reagent (1.7 g, 4.16 mmol, 1.0 eq) were added to xylene (150 mL), and the mixture was heated to 110 °C under nitrogen gas protection for 19 h. After TLC showed the disappearance of the starting material, the mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (MeOH:DCM = 1:100) to give the product (1.1 g, yield: 91.6%).

[0305] Step 7: Synthesis of 4-(2-methoxy-4-(prop-1-yn-1-yl)phenyl)-7-(methylthio)pyrazolo[1,5-d][1,2,4]triazine [ka] 4-(2-Methoxy-4-(prop-1-yn-1-yl)phenyl)pyrazolo[1,5-d][1,2,4]triazine-7-thiol (1.1 g, 3.71 mmol, 1.0 eq) was added to DMA (5 mL), anhydrous potassium carbonate (512 mg, 3.71 mmol, 1.0 eq) and iodomethane (1 g, 7.42 mmol, 2.0 eq) were added, and the mixture was heated to 60 °C for 3 h. After TLC confirmed the disappearance of the starting material, the reaction mixture was poured into ice water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were 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 = 1:10) to give the product (200 mg, yield: 18.2%).

[0306] Step 8: Synthesis of tert-butyl (R)-3-((4-(2-methoxy-4-(prop-1-yn-1-yl)phenyl)pyrazolo[1,5-d][1,2,4]triazin-7-yl)amino)piperidine-1-carboxylate [ka] 4-(2-Methoxy-4-(prop-1-yn-1-yl)phenyl)-7-(methylthio)pyrazolo[1,5-d][1,2,4]triazine (200 mg, 0.64 mmol, 1.0 eq) and 3A molecular sieves (500 mg) were added to anhydrous DCM (5 mL). A solution of mCPBA (85% by mass, 324.8 mg, 1.6 mmol, 2.5 eq) pre-dried over 3A molecular sieves was added dropwise in DCM (5 mL) and the reaction mixture was allowed to react at room temperature for 1 h. After the disappearance of the starting material was monitored by TLC, a solution of (R)-tert-butyl 3-aminopiperidine-1-carboxylate (897.2 mg, 4.48 mmol, 7.0 eq) in DCM (2 mL) was added and the reaction mixture was allowed to react at room temperature for 16 h. When the raw materials were completely consumed by TLC, water (30 mL) was added and extracted with DCM (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE = 1:10 to 1:2) to obtain the product (146 mg, 2-step yield: 49.3%).

[0307] Step 9: Synthesis of (R)-2-(7-(piperidin-3-ylamino)pyrazolo[1,5-d][1,2,4]triazin-4-yl)-5-(prop-1-yn-1-yl)phenol [ka] (R)-3-((4-(2-methoxy-4-(prop-1-yn-1-yl)phenyl)pyrazolo[1,5-d][1,2,4]triazin-7-yl)amino)piperidine-1-carboxylate tert-butyl ester (146 mg, 0.31 mmol, 1.0 eq) was added to anhydrous DCM (10 mL), the mixture was cooled to -50 ° C, boron tribromide (776.6 mg, 3.1 mmol, 10 eq) was added dropwise, the mixture was allowed to warm to room temperature, and the reaction was continued for 23 h. After the raw materials were consumed by LC-MS, methanol (10 mL) was added dropwise, the mixture was stirred for 10 min, concentrated under reduced pressure, saturated aqueous sodium bicarbonate solution (30 mL) was added, and the mixture was extracted with DCM (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product (108 mg, yield: 100%).

[0308] Step 10: Synthesis of (R)-2-(7-(1-methylpiperidin-3-yl)amino)pyrazolo[1,5-d][1,2,4]triazin-4-yl)-5-(prop-1-yn-1-yl)phenol [ka] (R)-2-(7-(piperidin-3-ylamino)pyrazolo[1,5-d][1,2,4]triazin-4-yl)-5-(prop-1-yn-1-yl)phenol (108 mg, 0.31 mmol, 1.0 eq) was added to methanol (5 mL), and a 37% by weight aqueous formaldehyde solution (25.2 mg, 0.31 mmol, 1.0 eq) was added. The mixture was reacted at room temperature for 0.5 hours. Sodium cyanoborohydride (19.5 mg, 0.31 mmol, 1.0 eq) was added, and the mixture was reacted at room temperature for 1 hour. The disappearance of the raw materials was monitored by TLC, and the mixture was concentrated under reduced pressure. A saturated aqueous solution of sodium bicarbonate (20 mL) was added, and the mixture was extracted with DCM (20 mL × 4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (MeOH:DCM = 1:10) to obtain the product (67 mg, yield: 59.7%).

[0309] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 12.65 (s, 1H), 8.41 (s, 1H), 7.87-7.85 (d, 2H), 7.31 (s, 1H), 6.99 (d, 2H), 4.35-4.33 (m, 1H), 2.83-2.81 (m, 1H), 2.51 (m, 1H), 2.23 (m, 4H), 2.08 (m, 4H), 1.82 (m, 1H), 1.73-1.68 (m, 2H), 1.59-1.56 (m, 1H). Molecular formula:C 20 H 22 NO Accurate mass: 362.19 LC-MS (Pos, m / z) =363.31 [M+H] + .

[0310] Example 17: (R)-2-(4-cyclopropyl-6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)pyridazin-3-yl)-5-ethynylphenol (Compound 45) [ka]

[0311] Step 1: Synthesis of (R)-4-(4-cyclopropyl-6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)pyridazin-3-yl)-3-(ethoxymethoxy)benzaldehyde [ka] (R)-2-(3-((6-chloro-5-cyclopropyl-pyridazin-3-yl)amino)piperidin-1-yl)ethan-1-ol (237 mg, 0.799 mmol, 1.0 eq) was dissolved in 1,4-dioxane (4 mL), and 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (318 mg, 1.04 mmol, 1.3 eq), sodium bicarbonate (134 mg, 1.598 mmol, 2.0 eq) in water (1 mL), and PdCl(dppf) (58 mg, 0.0799 mmol, 0.1 eq) were added. The mixture was heated to 90 °C under nitrogen gas protection and reacted for 1 h. The reaction was complete as detected by TLC. The reaction mixture was concentrated, and dichloromethane (10 mL) and water (10 mL) were added to the concentrate. The layers were separated, and the aqueous phase was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 20:1) to obtain the product (120 mg, yield: 34.1%).

[0312] Step 2: Synthesis of (R)-2-(3-((5-cyclopropyl-6-(2-ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-yl)amino)piperidin-1-yl)ethan-1-ol [ka] (R)-4-(4-cyclopropyl-6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)pyridazin-3-yl)-3-(ethoxymethoxy)benzaldehyde (120 mg, 0.273 mmol, 1.0 eq) was dissolved in methanol (2 mL), and potassium carbonate (75 mg, 0.546 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (79 mg, 0.41 mmol, 1.5 eq) were added in sequence. The reaction mixture was allowed to react at 25 °C for 30 min, and completion of the reaction was confirmed by TLC. The reaction mixture was concentrated, and saturated aqueous sodium chloride solution (5 mL) was added to the concentrate. The mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was used directly in the next step.

[0313] Step 3: Synthesis of (R)-2-(4-cyclopropyl-6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)pyridazin-3-yl)-5-ethynylphenol [ka] (R)-2-(3-((5-cyclopropyl-6-(2-ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-yl)amino)piperidin-1-yl)ethan-1-ol (crude, 0.273 mmol) was dissolved in dichloromethane (1 mL) and added dropwise to trifluoroacetic acid (1 mL). The mixture was reacted at 25 °C for 15 min, and completion of the reaction was detected by TLC. The reaction mixture was concentrated, and the crude product was purified by preparative thin-layer chromatography (dichloromethane:ammonia in methanol = 15:1) to give the product (21 mg, 20.4% yield over two steps).

[0314] 1H-NMR (400 MHz, DMSO-d6) δ(ppm): 10.08 (s, 1H), 7.24-7.22 (m, 1H), 7.01-7.00 (m, 2H), 6.63 (s, 1H), 6.32 (s, 1H), 4.19 (d, 2H), 3.59 (s, 2H), 3.11-2.77 (m, 2H), 2.69-2.57 (m, 1H), 2.39-2.18 (m, 2H), 1.91-1.71 (m, 2H), 1.67-1.65 (m, 1H), 1.59-1.53 ​​(m, 1H), 1.40-1.39 (m, 1H), 1.34-1.17 (m, 2H), 0.90-0.86 (m, 2H), 0.63-0.60 (m, 2H). Molecular formula:C 22 H 26 N4O2 precise molecular weight: 378.21 LC-MS (m / z): 379.26 [M+H] + .

[0315] Example 18: Synthesis of (R)-2-(4-cyclopropyl-6-((1-ethylpiperidin-3-yl)amino)pyridazin-3-yl)-5-ethynylphenol (Compound 90) [ka]

[0316] Step 1: Synthesis of (R)-5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenol)-N-(piperidin-3-yl)pyridazin-3-amine [ka] (R)-tert-Butyl 3-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-yl)amino)piperidine-1-carboxylate (1.0 g, 2.03 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), and 2,6-dimethylpyridine (1.74 g, 16.24 mmol, 8.0 eq) and trimethylsilyl trifluoromethanesulfonate (1.8 g, 8.12 mmol, 4.0 eq) were added dropwise thereto at 0° C., and the completion of the reaction was detected by TLC. Water (20 mL) was added to the reaction mixture, the layers were separated, the aqueous phase was extracted with dichloromethane (20 mL × 2), the organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 50:1 to 10:1) to obtain 1.15 g of the product (crude product).

[0317] Step 2: Synthesis of (R)-5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenol)-N-(1-ethylpiperidin-3-yl)pyridazin-3-amine [ka] (R)-5-Cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenol)-N-(piperidin-3-yl)pyridazin-3-amine (400 mg crude product, 0.703 mmol, 1.0 eq) was dissolved in dichloromethane (3 mL), triethylamine (356 mg, 3.515 mmol, 5.0 eq) and iodoethane (548 mg, 3.515 mmol, 5.0 eq) were added, and the mixture was reacted at 25 °C for 16 h. TLC showed completion of the reaction. Dichloromethane (7 mL) and water (10 mL) were added to the reaction mixture, and the aqueous phase was extracted with dichloromethane (10 mL x 2). The organic phases were combined and dried. The crude product was purified by preparative thin-layer chromatography (dichloromethane:ammonia in methanol = 15:1) to give the product (150 mg, yield: 50.7%).

[0318] Step 3: Synthesis of (R)-2-(4-cyclopropyl-6-((1-ethylpiperidin-3-yl)amino)pyridazin-3-yl)-5-ethynylphenol [ka] (R)-5-Cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenol)-N-(1-ethylpiperidin-3-yl)pyridazin-3-amine (150 mg, 0.357 mmol, 1.0 eq) was dissolved in dichloromethane (1 mL) and added dropwise to trifluoroacetic acid (1 mL). The mixture was reacted at 25°C for 5 minutes, and completion of the reaction was detected by TLC. The reaction mixture was concentrated, and the crude product was purified by preparative thin-layer chromatography (dichloromethane:ammonia in methanol = 10:1) to give the product (28 mg, yield: 21.7%).

[0319] 1 H-NMR (400 MHz, DMSO-d6) δ(ppm): 10.09 (s, 1H), 7.25-7.23 (d, 1H), 7.01-7.00 (m, 2H), 6.47-6.45 (d, 1H), 6.33 (s, 1H), 4.18 (s, 1H), 4.03-4.01 (m, 1H), 2.93-2.91 (m, 1H), 2.61 (m, 1H), 2.37-2.32 (m, 2H), 2.03-2.02 (m, 1H), 1.91-1.81 (m, 2H), 1.71-1.69 (m, 1H), 1.59-1.48 (m, 2H), 1.34-1.26 (m, 1H), 1.02-0.98 (t, 3H), 0.89-0.84 (m, 2H), 0.63-0.59 (m, 2H). Molecular formula:C 22 H 26 N4O Exact molecular weight: 362.21 LC-MS(m / z): 363.29 [M+H] + .

[0320] Example 19: Synthesis of (R)-2-(4-cyclopropyl-6-((1-cyclopropylpiperidin-3-yl)amino)pyridazin-3-yl)-5-ethynylphenol (Compound 95) [ka]

[0321] Step 1: [ka] (R)-2-(4-Cyclopropyl-6-(piperidin-3-ylamino)pyridazin-3-yl)-5-ethynylphenol (crude product, 0.75 mmol, 1.0 eq) was dissolved in methanol (3 mL), and 1-ethoxy-1-trimethylsilyloxycyclopropane (523 mg, 3.0 mmol, 4.0 eq) and cesium fluoride (228 mg, 1.5 mmol, 2.0 eq) were added thereto. The mixture was heated to 50°C and reacted for 1 hour. Sodium cyanoborohydride (189 mg, 3.0 mmol, 4.0 eq) was added thereto and reacted at 50°C for 10 minutes. Completion of the reaction was detected by TLC. The reaction mixture was concentrated, saturated aqueous sodium bicarbonate solution (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol solution of ammonia = 10:1) to obtain the product (15 mg, yield: 5.3%).

[0322] 1H-NMR (400 MHz, DMSO-d6) δ(ppm): 10.08 (s, 1H), 7.24-7.22 (m, 1H), 7.01-7.00 (m, 2H), 6.46 (s, 1H), 6.32 (s, 1H), 4.18 (s, 1H), 3.97 (s, 1H), 3.07 (s, 1H), 2.76 (s, 1H), 2.33 (s, 1H), 2.19 (s, 1H), 1.82 (s, 1H), 1.67 (s, 2H), 1.59-1.50 (m, 1H), 1.48 (m, 1H), 1.34-1.33 (m, 1H), 0.89-0.85 (m, 2H), 0.63-0.60 (m, 2H), 0.44-0.35 (m, 4H). Molecular formula:C 23 H 26 N4O exact molecular weight: 374.21 LC-MS(m / z): 375.29 [M+H] + .

[0323] Example 20: Synthesis of (R)-2-(4-cyclopropyl-6-((1-(methyl-d3)piperidin-3-yl)amino)pyridazin-3-yl)-5-ethynylphenol (Compound 85) [ka]

[0324] Step 1: Synthesis of compound (R)-5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenol)-N-(1-(methyl-d3)piperidin-3-yl)pyridazin-3-amine [ka] (R)-5-Cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenol)-N-(piperidin-3-yl)pyridazin-3-amine (400 mg crude product, 0.703 mmol, 1.0 eq) was dissolved in dichloromethane (3 mL), and triethylamine (356 mg, 3.515 mmol, 5.0 eq) and deuterated iodomethane (296 mg, 3.515 mmol, 5.0 eq) were added thereto, and the reaction was carried out at 25°C for 2 hours (LC-MS showed that 60% of the raw material had reacted). Water (10 mL) was added to the reaction mixture, which was then extracted with dichloromethane (10 mL). The aqueous phase was further extracted with dichloromethane (10 mL × 2). The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by preparative thin-layer chromatography (dichloromethane:ammonia methanol solution = 15:1) to obtain the product (125 mg, yield: 43.4%).

[0325] Step 2: Synthesis of compound (R)-2-(4-cyclopropyl-6-((1-(methyl-d3)piperidin-3-yl)amino)pyridazin-3-yl)-5-ethynylphenol [ka] (R)-5-Cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenol)-N-(1-(methyl-d3)piperidin-3-yl)pyridazin-3-amine (125 mg, 0.305 mmol, 1.0 eq) was dissolved in dichloromethane (1 mL) and added dropwise to trifluoroacetic acid (1 mL). The reaction was allowed to proceed at 25°C for 15 minutes, and completion of the reaction was detected by TLC. The reaction mixture was concentrated, and the crude product was purified by preparative thin-layer chromatography (dichloromethane:ammonia in methanol = 10:1) to give the product (40 mg, yield: 37.4%).

[0326] 1H-NMR (400 MHz, DMSO-d6) δ(ppm): 10.11 (s, 1H), 7.23-7.21 (d, 1H), 7.02-7.00 (m, 2H), 6.68-6.67 (d, 1H), 6.34 (s, 1H), 4.19 (s, 1H), 4.15 (m, 1H), 3.11 (m, 1H), 2.83 (m, 1H), 2.41-2.29 (m, 2H), 1.84-1.79 (m, 2H), 1.66-1.63 (m, 1H), 1.59-1.53 ​​(m, 1H), 1.44-1.30 (m, 1H), 0.91-0.83 (m, 2H), 0.65-0.58 (m, 2H). Molecular formula:C 21 H 21 D3N4O Precise molecular weight: 351.21 LC-MS(m / z): 352.22 [M+H] + .

[0327] Example 21: Synthesis of (R)-3-((6-(2-hydroxy-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridazin-3-yl)amino)piperidine-1-carboximidamide trifluoroacetate (Compound 46) [ka]

[0328] Step 1: Synthesis of tert-butyl (R)-(((tert-butoxycarbonyl)imino)(3-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)methyl)carbamate [ka] (R)-6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methyl-N-(piperidin-3-yl)pyridazin-3-amine (400.0 mg, 1.05 mmol, 1.0 eq.) and tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (391.5 mg, 1.26 mmol, 1.2 eq.) were added to methanol (10.0 mL) and stirred at room temperature for 3 h. The reaction was monitored for completion by TLC. After concentration under reduced pressure, the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 60:1) to give the product (400.0 mg, yield: 61.1%).

[0329] Step 2: Synthesis of (R)-3-((6-(2-hydroxy-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridazin-3-yl)amino)piperidine-1-carboximidamide trifluoroacetate [ka] (R)-(((tert-butoxycarbonyl)imino)(3-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)methyl) tert-butyl carbamate (340.0 mg, 0.54 mmol, 1.0 eq) was added to dichloromethane (5.0 mL), trifluoroacetic acid (5.0 mL) was added dropwise, and the reaction was carried out at room temperature for 4 h. Completion of the reaction was monitored by LC-MS. Water (30.0 mL) was added, and the mixture was extracted with dichloromethane (100.0 mL). The aqueous phase was purified by reverse phase column chromatography (water:acetonitrile = 4:6) to obtain the product (180.0 mg, yield: 69.2%).

[0330] 1HNMR(400MHz, DMSO-d6) δ(ppm): 10.55(s,1H), 8.72(s,1H), 7.57(s,4H), 7.37-7.36(m,1H), 7.20-7.18(d,J=8Hz,1H), 6.98-6.95(m,2H), 3.99-3.98(m,1H),3.90-3.87(m,1H), 3.69-3.66(m,1H), 3.24-3.13(m,2H), 2.17(s,3H), 2.06(s,4H), 1.85-1.83(m,1H), 1.67-1.55(m,2H). Molecular formula:C 22 H 25 Accurate molecular weight of F3N6O3 free base: 364.20 LC-MS (Pos, m / z) = 365.21 [M+H] + .

[0331] Example 22: Synthesis of (R)-5-ethynyl-2-(4-isopropyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol (Compound 81) [ka]

[0332] Step 1: Synthesis of 3,6-dichloro-4-isopropylpyridazine [ka] 3,6-Dichloropyridazine (10.0 g, 67.12 mmol, 1.0 eq), isobutyric acid (5.9 g, 67.12 mmol, 1.0 eq), and silver nitrate (11.4 g, 67.12 mmol, 1.0 eq) were added to water (100 mL), the mixture was heated to 50 °C, concentrated sulfuric acid (11.0 mL) was added dropwise, and then an aqueous solution (100.0 mL) of ammonium persulfate (45.9 g, 201.36 mmol, 3.0 eq) was added dropwise. The mixture was heated to 70 °C and reacted for 2 h. When the reaction was complete, the mixture was cooled and suction filtered. The filtrate was adjusted to pH 9 with 2.0 mol / L aqueous sodium hydroxide solution and extracted with ethyl acetate (400 mL). The organic phase was dried, filtered, and the filtrate was concentrated under reduced pressure to give the product (10.1 g, yield: 78.9%).

[0333] Step 2: Synthesis of tert-butyl (R)-3-((6-chloro-5-isopropylpyridazin-3-yl)amino)piperidine-1-carboxylate [ka] 3,6-Dichloro-4-isopropylpyridazine (5.0 g, 26.17 mmol, 1.0 eq), (R)-1-tert-butoxycarbonyl-3-aminopiperidine (5.76 g, 28.79 mmol, 1.1 eq), and N,N-diisopropylethylamine (6.7 g, 52.34 mmol, 2.0 eq) were added to N,N-dimethylacetamide (50.0 mL) and reacted at 120 °C for 72 h. When the reaction was complete, ethyl acetate (200.0 mL) was added, washed with water (100 mL), dried, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 200:1 to 20:1) to give the product (3.8 g, yield: 40.9%).

[0334] Step 3: Synthesis of (R)-6-chloro-5-isopropyl-N-(piperidin-3-yl)pyridazin-3-amine [ka] (R)-tert-Butyl 3-((6-chloro-5-isopropylpyridazin-3-yl)amino)piperidine-1-carboxylate (3.7 g, 10.43 mmol, 1.0 eq.) was added to dichloromethane (10.0 mL) and a solution of hydrogen chloride in 1,4-dioxane (4.0 mol / L, 10.0 mL) was added dropwise. The reaction was allowed to proceed at room temperature for 2 h, and completion was monitored by TLC. The pH was adjusted to 8-9 with saturated aqueous sodium carbonate, and the mixture was extracted with dichloromethane (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product (2.5 g, yield: 96.1%).

[0335] Step 4: Synthesis of (R)-6-chloro-5-isopropyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine [ka] (R)-6-Chloro-5-isopropyl-N-(piperidin-3-yl)pyridazin-3-amine (860.0 mg, 3.37 mmol, 1.0 eq) and aqueous formaldehyde solution (37% by mass, 356.1 mg, 4.38 mmol, 1.3 eq) were added to methanol (12.0 mL) and stirred at room temperature for 1 h. Sodium cyanoborohydride (318.1 mg, 5.05 mmol, 1.5 eq) was then added and the reaction was continued at room temperature for 2 h. The reaction was monitored for completion by TLC, concentrated under reduced pressure, saturated aqueous sodium bicarbonate (100.0 mL) was added, stirred for 0.5 h, extracted with dichloromethane (100.0 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 50:1 to 10:1) to give the product (770.0 mg, yield: 84.9%).

[0336] Step 5: Synthesis of (R)-3-(ethoxymethoxy)-4-(4-isopropyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)benzaldehyde [ka] (R)-6-chloro-5-isopropyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine (352.5 mg, 1.31 mmol, 1.0 eq), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (441.6 mg, 1.44 mmol, 1.1 eq), sodium bicarbonate (220.0 mg, 2.62 mmol, 2.0 eq), and Pd(dppf)Cl (47.9 mg, 0.06 mmol, 0.0 The resulting mixture (5 eq.) was added to a mixture of 1,4-dioxane (10.0 mL) and water (5.0 mL), and the reaction was carried out at 110°C for 4 h under nitrogen gas protection. Completion of the reaction was monitored by TLC. Water (100.0 mL) was added, and the mixture was extracted with ethyl acetate (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 50:1 to 10:1) to give the product (230.0 mg, yield: 42.6%).

[0337] Step 6: Synthesis of (R)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-isopropyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine [ka] (R)-3-(Ethoxymethoxy)-4-(4-isopropyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)benzaldehyde (223.0 mg, 0.54 mmol, 1.0 eq), dimethyl (1-diazo-2-oxopropyl)phosphonate (155.7 mg, 0.81 mmol, 1.5 eq), and anhydrous potassium carbonate (149.2 mg, 1.08 mmol, 2.0 eq) were added to methanol (10.0 mL) and reacted at room temperature for 12 h. The reaction was monitored for completion by LC-MS. After concentration under reduced pressure, the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 50:1 to 10:1) to give the product (200.0 mg, yield: 90.9%).

[0338] Step 7: Synthesis of (R)-5-ethynyl-2-(4-isopropyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol [ka] (R)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-isopropyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine (200.0 mg, 0.49 mmol, 1.0 eq) was added to dichloromethane (5.0 mL) and a solution of hydrogen chloride in 1,4-dioxane (4.0 mol / L, 5.0 mL) was added dropwise. The reaction was allowed to proceed at room temperature for 2 h. Completion was monitored by TLC. The pH was adjusted to 8-9 with saturated aqueous sodium carbonate, and the mixture was extracted with dichloromethane (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give the product (110.0 mg, yield: 64.3%).

[0339] 1 H-NMR (400 MHz, DMSO-d6) δ(ppm): 9.90 (s, 1H), 7.15-7.13 (d, J=8Hz, 1H), 7.00-6.99 (m, 2H), 6.77-6.73 (m, 2H), 4.17 (s, 2H), 3.13 (s, 1H), 2.82(s, 1H), 2.65-2.59 (m, 1H), 2.50 (s, 3H), 2.41 (s, 3H), 1.89-1.80 (m, 2H), 1.66-1.64 (m, 1H), 1.03-1.01 (m, 6H). Molecular formula:C 21 H 26 N4O Precise molecular weight: 350.21 LC-MS(m / z): 351.25 [M+H] + .

[0340] Example 23: Synthesis of (R)-5-ethynyl-2-(4-cyclobutyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol (Compound 82) [ka]

[0341] Step 1: Synthesis of 3,6-dichloro-4-cyclobutylpyridazine [ka] 3,6-Dichloropyridazine (10.0 g, 67.12 mmol, 1.0 eq), cyclobutyric acid (6.7 g, 67.12 mmol, 1.0 eq), and silver nitrate (11.4 g, 67.12 mmol, 1.0 eq) were added to water (100 mL), the mixture was heated to 50 °C, concentrated sulfuric acid (11.0 mL) was added dropwise, and an aqueous solution (100.0 mL) of ammonium persulfate (45.9 g, 201.36 mmol, 3.0 eq) was added dropwise. The mixture was heated to 70 °C and reacted for 2 h. When the reaction was complete, the mixture was cooled and suction filtered. The filtrate was adjusted to pH 9 with 2.0 mol / L aqueous sodium hydroxide solution and extracted with ethyl acetate (400 mL). The organic phase was dried, filtered, and the filtrate was concentrated under reduced pressure to give the product (9.8 g, yield: 72.0%).

[0342] Step 2: Synthesis of tert-butyl (R)-3-((6-chloro-5-cyclobutylpyridazin-3-yl)amino)piperidine-1-carboxylate [ka] 3,6-Dichloro-4-cyclobutylpyridazine (5.0 g, 24.62 mmol, 1.0 eq), (R)-1-tert-butoxycarbonyl-3-aminopiperidine (7.4 g, 36.93 mmol, 1.5 eq), and N,N-diisopropylethylamine (6.3 g, 49.24 mmol, 2.0 eq) were added to N,N-dimethylacetamide (50.0 mL) and reacted at 120 °C for 72 h. When the reaction was complete by TLC, ethyl acetate (200.0 mL) was added, washed with water (100 mL), and then washed with saturated aqueous ammonium chloride (100 mL). The organic phase was dried, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 200:1 to 100:1) to give the product (1.8 g, yield: 20.0%).

[0343] Step 3: Synthesis of (R)-6-chloro-5-cyclobutyl-N-(piperidin-3-yl)pyridazin-3-amine [ka] (R)-tert-Butyl 3-((6-chloro-5-cyclobutylpyridazin-3-yl)amino)piperidine-1-carboxylate (1.8 g, 4.91 mmol, 1.0 eq) was added to dichloromethane (10 mL) and a solution of hydrogen chloride in 1,4-dioxane (4.0 mol / L, 10 mL) was added dropwise. The reaction was allowed to proceed at room temperature for 2 h, and completion was monitored by TLC. The pH was adjusted to 8-9 with saturated aqueous sodium carbonate, and the mixture was extracted with dichloromethane (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product (1.2 g, yield: 92.3%).

[0344] Step 4: Synthesis of (R)-6-chloro-5-cyclobutyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine [ka] (R)-6-Chloro-5-cyclobutyl-N-(piperidin-3-yl)pyridazin-3-amine (1.17 g, 4.38 mmol, 1.0 eq) and aqueous formaldehyde solution (37% by mass, 462.7 mg, 5.69 mmol, 1.3 eq) were added to methanol (15.0 mL) and stirred at room temperature for 1 h. Sodium cyanoborohydride (413.3 mg, 6.57 mmol, 1.5 eq) was added and the mixture was allowed to react at room temperature for 2 h. The reaction was monitored for completion by TLC, concentrated under reduced pressure, saturated aqueous sodium bicarbonate (100.0 mL) was added, stirred for 0.5 h, extracted with dichloromethane (100.0 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 50:1 to 10:1) to give the product (1.1 mg, yield: 91.6%).

[0345] Step 5: Synthesis of (R)-3-(ethoxymethoxy)-4-(4-cyclobutyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)benzaldehyde [ka] (R)-6-chloro-5-cyclobutyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine (330.0 mg, 1.17 mmol, 1.0 eq), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (395.8 mg, 1.28 mmol, 1.1 eq), sodium bicarbonate (197.4 mg, 2.34 mmol, 2.0 eq), and Pd(dppf)Cl (42.9 mg, 0.06 mmol, 0.0 The resulting mixture (5 eq.) was added to a mixture of 1,4-dioxane (10.0 mL) and water (5.0 mL), and the reaction was carried out at 110°C for 4 h under nitrogen gas protection. Completion of the reaction was monitored by TLC. Water (100.0 mL) was added, and the mixture was extracted with ethyl acetate (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 50:1 to 10:1) to give the product (317.2 mg, yield: 63.5%).

[0346] Step 6: Synthesis of (R)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-cyclobutyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine [ka] (R)-3-(Ethoxymethoxy)-4-(4-cyclobutyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)benzaldehyde (314.0 mg, 0.74 mmol, 1.0 eq), dimethyl (1-diazo-2-oxopropyl)phosphonate (213.1 mg, 1.11 mmol, 1.5 eq), and anhydrous potassium carbonate (204.2 mg, 1.48 mmol, 2.0 eq) were added to methanol (10.0 mL) and reacted at room temperature for 12 h. Completion was monitored by LC-MS. After concentration under reduced pressure, the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 50:1 to 10:1) to give the product (280.0 mg, yield: 90.1%).

[0347] Step 7: Synthesis of (R)-5-ethynyl-2-(4-cyclobutyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol [ka] (R)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-cyclobutyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine (280.0 mg, 0.66 mmol, 1.0 eq.) was added to dichloromethane (10.0 mL) and a solution of hydrogen chloride in 1,4-dioxane (4.0 mol / L, 5.0 mL) was added dropwise. The reaction was allowed to proceed at room temperature for 2 h. Completion was monitored by TLC. The pH was adjusted to 8-9 with saturated aqueous sodium carbonate, and the mixture was extracted with dichloromethane (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give the product (140.0 mg, yield: 58.0%).

[0348] 1 H-NMR(400MHz, DMSO-d6) δ(ppm): 9.89 (s, 1H), 7.10-7.08 (d, J=8Hz, 1H), 6.97-6.96 (m, 2H), 6.75 (s, 1H), 6.64-6.63 (m, 1H), 4.17 (s, 1H), 4.10-4.08 (m, 1H), 3.39-3.35 (m, 1H), 2.91 (s, 1H), 2.59(s, 1H), 2.23(s, 3H), 2.11(s, 1H), 1.99(s, 1H), 1.88-1.83(m, 6H), 1.81-1.52(m, 4H). Molecular formula:C 22 H 26 N4O Precise molecular weight: 362.21 LC-MS(m / z): 363.26 [M+H] + .

[0349] Example 24: Synthesis of 5-ethynyl-2-(6-(((1R,2R)-2-hydroxycyclohexyl)amino)-4-methylpyridazin-3-yl)phenol (Compound 83) [ka] Step 1: Synthesis of (1R,2R)-2-((6-chloro-5-methylpyridazin-3-yl)amino)cyclohexan-1-ol [ka] 3,6-Dichloro-4-methylpyridazine (3.2 g, 19.63 mmol, 1.0 eq), (1R,2R)-2-aminocyclohexan-1-ol hydrochloride (3.8 g, 25.52 mmol, 1.3 eq), and N,N-diisopropylethylamine (5.0 g, 39.26 mmol, 2.0 eq) were added to N,N-dimethylacetamide (20.0 mL) and stirred at 120 °C for 72 h. The reaction was monitored for completion by TLC. After cooling to room temperature, ethyl acetate (100.0 mL) was added, washed with water (100.0 mL), and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 200:1 to 50:1) to give the product (1.2 g, yield: 25.5%).

[0350] Step 2: Synthesis of 3-(ethoxymethoxy)-4-(6-(((1R,2R)-2-hydroxycyclohexyl)amino)-4-methylpyridazin-3-yl)benzaldehyde [ka] (1R,2R)-2-((6-chloro-5-methylpyridazin-3-yl)amino)cyclohexan-1-ol (500.0 mg, 2.06 mmol, 1.0 eq), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (696.6 mg, 2.27 mmol, 1.1 eq), sodium bicarbonate (347.4 mg, 4.12 mmol, 2.0 eq), and Pd(dppf)Cl2 (75.6 mg, 0.10 mmol, 0.0 eq). The resulting mixture (0.5 eq.) was added to a mixture of 1,4-dioxane (10.0 mL) and water (5.0 mL), and the reaction was carried out at 110°C for 4 h under nitrogen gas protection. Completion of the reaction was monitored by TLC. Water (100.0 mL) was added, and the mixture was extracted with ethyl acetate (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 80:1 to 30:1) to give the product (454.0 mg, yield: 56.9%).

[0351] Step 3: Synthesis of (1R,2R)-2-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylpyridazin-3-yl)amino)cyclohexan-1-ol [ka] 3-(Ethoxymethoxy)-4-(6-(((1R,2R)-2-hydroxycyclohexyl)amino)-4-methylpyridazin-3-yl)benzaldehyde (454.0 mg, 1.18 mmol, 1.0 eq), dimethyl (1-diazo-2-oxopropyl)phosphonate (339.4 mg, 1.77 mmol, 1.5 eq), and anhydrous potassium carbonate (325.3 mg, 2.36 mmol, 2.0 eq) were added to methanol (15.0 mL) and reacted at room temperature for 12 h. Completion was monitored by TLC. After concentration under reduced pressure, the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 60:1 to 20:1) to give the product (447.0 mg, yield: 99.5%).

[0352] Step 4: Synthesis of 5-ethynyl-2-(6-(((1R,2R)-2-hydroxycyclohexyl)amino)-4-methylpyridazin-3-yl)phenol [ka] (1R,2R)-2-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylpyridazin-3-yl)amino)cyclohexan-1-ol (447.0 mg, 1.17 mmol, 1.0 eq) was added to dichloromethane (5.0 mL) and a solution of hydrogen chloride in 1,4-dioxane (4.0 mol / L, 5.0 mL) was added dropwise. The reaction was allowed to proceed at room temperature for 2 h. Completion was monitored by TLC. The pH was adjusted to 8-9 with saturated aqueous sodium carbonate, and the mixture was extracted with dichloromethane (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 40:1 to 20:1) to give the product (260.0 mg, yield: 68.6%).

[0353] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 10.13 (s, 1H), 7.19-7.17 (d, J=8 Hz, 1H), 7.00-6.98 (m, 2H), 6.70 (s, 1H), 6.57-6.55 (d, J=8 Hz, 1H), 4.79-4.78 (d, J=4 Hz, 1H), 4.17 (s, 1H), 3.66-3.64 (m, 1H), 3.38-3.36 (m, 1H), 2.05 (s, 1H), 2.03 (s, 3H), 1.92-1.89 (m, 1H), 1.67-1.62 (m, 2H), 1.34-1.16 (m, 4H). Molecular formula:C 19 H 21 N3O2 exact molecular weight: 323.16 LC-MS(Pos, m / z)=324.21[M+H] + .

[0354] Example 25: Synthesis of 2-(6-(((1S,2R)-2-hydroxy-2-methylcyclohexyl)amino)-4-methylpyridazin-3-yl)-5-(prop-1-yn-1-yl)phenol (Compound 80) [ka]

[0355] Step 1: Synthesis of (1R,2S)-2-((6-chloro-5-methylpyridin-3-yl)amino)cyclohexan-1-ol [ka] 3,6-Dichloro-4-methylpyridazine (3.8 g, 23.33 mmol, 1.0 eq.), (1R,2S)-2-aminocyclohexan-1-ol hydrochloride (4.6 g, 30.33 mmol, 1.3 eq.), and N,N-diisopropylethylamine (9.0 g, 69.99 mmol, 3.0 eq.) were added to N,N-dimethylacetamide (20.0 mL) and stirred at 120 °C for 72 h. The reaction was monitored for completion by TLC. After cooling to room temperature, ethyl acetate (100.0 mL) was added, washed with water (100.0 mL), and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 200:1 to 20:1) to give the product (1.4 g, yield: 25.0%).

[0356] Step 2: Synthesis of (S)-2-((5,6-dimethylpyridazin-3-yl)amino)cyclohexan-1-one [ka] N-chlorosuccinimide (2.25 g, 16.89 mmol, 3.0 eq) was added to dichloromethane (20.0 mL), and the mixture was cooled to 0°C under nitrogen gas protection. Dimethyl sulfide (1.0 g, 16.89 mmol, 3.0 eq) was added dropwise, and the mixture was allowed to react for 0.5 hours. The mixture was then cooled to -40°C, and a dichloromethane solution (20.0 mL) of (1R,2S)-2-((6-chloro-5-methylpyridin-3-yl)amino)cyclohexan-1-ol (1.36 g, 5.63 mmol, 1.0 eq) was added dropwise. The mixture was then cooled to -40°C. After the reaction was continued for 1.5 h, triethylamine (1.7 g, 16.89 mmol, 3.0 eq) was added dropwise, and the temperature was gradually raised to room temperature and the reaction was continued for 14 h. The completion of the reaction was monitored by TLC. Dichloromethane (100 mL) was added, and the mixture was washed with water (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 to 2:1) to obtain the product (1.21 g, yield: 81.4%).

[0357] Step 3: Synthesis of (1R,2S)-2-((6-chloro-5-methylpyridazin-3-yl)amino)-1-methylcyclohexan-1-ol [ka] (S)-2-((5,6-dimethylpyridazin-3-yl)amino)cyclohexan-1-one (995.0 mg, 4.15 mmol, 1.0 eq) was added to dry tetrahydrofuran (15.0 mL), and under nitrogen gas protection, a solution of methylmagnesium chloride in tetrahydrofuran (3.0 mol / L, 5.5 mL, 16.60 mmol, 4.0 eq) was added dropwise. After reacting for 7 h, ethyl acetate (100.0 mL) was added, and the mixture was washed with saturated aqueous ammonium chloride (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 130:1 to 100:1) to obtain the product (380.0 mg, yield: 35.8%).

[0358] Step 4: Synthesis of (1R,2S)-2-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridazin-3-yl)amino)-1-methylcyclohexan-1-ol [ka] (1R,2S)-2-((6-chloro-5-methylpyridazin-3-yl)amino)-1-methylcyclohexan-1-ol (380.0 mg, 1.48 mmol, 1.0 eq), (2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)boronic acid (417.3 mg, 1.77 mmol, 1.2 eq), sodium bicarbonate (249.6 mg, 2.96 mmol, 2.0 eq), and Pd(dppf)Cl (54.3 mg, 0.07 mmol, 0.05 eq) were added to 1 The mixture was added to a mixture of 4-dioxane (10.0 mL) and water (5.0 mL) and reacted at 110°C for 3 hours under nitrogen gas protection. Completion of the reaction was monitored by TLC. Water (100.0 mL) was added, and the mixture was extracted with ethyl acetate (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 150:1 to 100:1) to obtain the product (210.0 mg, yield: 34.5%).

[0359] Step 5: Synthesis of 2-(6-(((1S,2R)-2-hydroxy-2-methylcyclohexyl)amino)-4-methylpyridazin-3-yl)-5-(prop-1-yn-1-yl)phenol [ka] (1R,2S)-2-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridazin-3-yl)amino)-1-methylcyclohexan-1-ol (200.0 mg, 0.49 mmol, 1.0 eq) was added to dichloromethane (4.0 mL) and a solution of hydrogen chloride in 1,4-dioxane (4.0 mol / L, 4.0 mL) was added dropwise. The reaction was allowed to proceed at room temperature for 12 h. Completion was monitored by TLC. The pH was adjusted to 8-9 with saturated aqueous sodium carbonate, and the mixture was extracted with dichloromethane (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give the product (53.0 mg, yield: 30.9%).

[0360] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 10.04 (s, 1H), 7.14-7.12 (d, J=8 Hz, 1H), 6.90-6.88 (m, 2H), 6.81 (s, 1H), 6.50-6.48 (d, J=8 Hz, 1H), 4.91 (s, 1H), 3.93-3.89 (m, 1H), 2.05 (s, 3H), 2.02 (s, 3H), 1.88-1.86 (m, 1H), 1.70-1.60 (m, 3H), 1.46-1.31 (m, 4H), 1.11 (s, 3H). Molecular formula:C 21 H 25 N3O2 precise molecular weight: 351.19 LC-MS (Pos, m / z)=352.18[M+H] + .

[0361] Example 26: Synthesis of (R)-2-(5-cyclopropyl-3-((1-cyclopropylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)-5-ethynylphenol (Compound 97) [ka]

[0362] Step 1: Synthesis of tert-butyl (R)-3-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-formylphenyl)-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate [ka] (R)-tert-Butyl 3-((6-bromo-5-cyclopropyl-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate (4.68 g, 11.75 mmol, 1.0 eq), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (4.67 g, 15.27 mmol, 1.3 eq), sodium bicarbonate (1.97 g, 23.50 mmol, 2.0 eq), and Pd(dppf)Cl (428.9 mg, 0.58 The reaction mixture (0.05 mmol, 0.05 eq) was added to a mixture of 1,4-dioxane (50 mL) and water (25 mL), heated to 110 °C under nitrogen gas protection, and reacted for 14 h. Completion of the reaction was monitored by TLC. Water (150 mL) was added, and the mixture was extracted with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 80:1 to 60:1) to give the product (2.1 g, yield: 36.2%).

[0363] Step 2: Synthesis of tert-butyl (R)-3-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate [ka] (R)-tert-Butyl 3-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-formylphenyl)-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate (2.0 g, 4.02 mmol, 1.0 eq), dimethyl (1-diazo-2-oxopropyl)phosphonate (1.1 g, 6.03 mmol, 1.5 eq), and anhydrous potassium carbonate (1.1 g, 8.04 mmol, 2.0 eq) were added to methanol (20.0 mL) and reacted at room temperature for 2 h. The reaction was monitored for completion by TLC. After concentration under reduced pressure, the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 130:1 to 100:1) to give the product (1.6 g, yield: 80.8%).

[0364] Step 3: Synthesis of (R)-5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-N-(piperidin-3-yl)-1,2,4-triazin-3-amine [ka] (R)-tert-butyl 3-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate (1.6 g, 3.24 mmol, 1.0 eq) was added to dichloromethane (25.0 mL), 2,6-dimethylpyridine (2.0 g, 19.44 mmol, 6.0 eq) was added dropwise, the temperature was lowered to 0°C, and trimethylsilyl trifluoromethanesulfonate (2.1 g) was added. , 9.72 mmol, 3.0 eq) was added dropwise, and the temperature was gradually raised to room temperature and reacted for 2 h. The completion of the reaction was monitored by TLC. Dichloromethane (100.0 mL) was added, and the mixture was washed with water (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 80:1 to 20:1) to obtain the product (603.0 mg, yield: 47.2%).

[0365] Step 4: Synthesis of (R)-5-cyclopropyl-N-(1-cyclopropylpiperidin-3-yl)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-1,2,4-triazin-3-amine [ka] (R)-5-Cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-N-(piperidin-3-yl)-1,2,4-triazin-3-amine (603.0 mg, 1.53 mmol, 1.0 eq), (1-ethoxycyclopropoxy)trimethylsilane (1.0 g, 6.12 mmol, 4.0 eq), cesium fluoride (931.0 mg, 6.12 mol, 4.0 eq), and glacial acetic acid (0.5 mL) were added to methanol (20.0 mL) and stirred at 50°C for 3 hours. Then, sodium cyanoborohydride (481.3 mg, 7.65 mmol, 5.0 eq) was added, and the mixture was reacted at 50°C for 12 hours. The reaction was monitored for completion by TLC, concentrated under reduced pressure, saturated aqueous sodium bicarbonate solution (100.0 mL) was added, stirred for 0.5 h, extracted with dichloromethane (100.0 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product (712.0 mg, calculated as a 100% yield).

[0366] Step 5: Synthesis of (R)-2-(5-cyclopropyl-3-((1-cyclopropylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)-5-ethynylphenol [ka] (R)-5-Cyclopropyl-N-(1-cyclopropylpiperidin-3-yl)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-1,2,4-triazin-3-amine (712.0 mg crude product, 1.53 mmol, 1.0 eq.) was added to dichloromethane (10.0 mL), trifluoroacetic acid (10.0 mL) was added dropwise, and the reaction was allowed to proceed at room temperature for 0.5 h. Completion of the reaction was monitored by TLC. The pH was adjusted to 8-9 with saturated aqueous sodium carbonate, and the mixture was extracted with dichloromethane (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give the product (50.0 mg, yield: 8.7%).

[0367] 1 H-NMR (400 MHz, DMSO-d6) δ(ppm): 10.04 (s, 1H), 7.54 (s, 1H), 7.30-7.28 (d, J=8 Hz, 1H), 7.05-7.02 (m, 2H), 4.21 (s, 1H), 3.98-3.57 (m, 1H), 3.09-3.07 (d, J=8 Hz, 1H), 2.82-2.80 (d, J=8 Hz, 1H), 2.18-1.97 (m, 2H), 1.84-1.82 (m, 1H), 1.70-1.64 (m, 3H), 1.46-1.30 (m, 2H), 1.01-1.09 (m, 4H). Molecular formula:C 22 H 25 N5O exact molecular weight: 375.21 LC-MS (m / z): 376.25 [M+H] + .

[0368] Example 27: Synthesis of (R)-2-(5-cyclopropyl-3-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-1,2,4-triazin-6-yl)-5-ethynylphenol (Compound 100) [ka] Step 1: Synthesis of (R)-6-bromo-5-cyclopropyl-N-(piperidin-3-yl)-1,2,4-triazin-3-amine [ka] (R)-tert-Butyl 3-((6-bromo-5-cyclopropyl-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate (2.4 g, 6.03 mmol, 1.0 eq) was added to dichloromethane (10.0 mL), trifluoroacetic acid (5.0 mL) was added dropwise, and the reaction was allowed to proceed at room temperature for 2 h. Completion of the reaction was monitored by TLC. The pH was adjusted to 8-9 with saturated aqueous sodium carbonate, and the mixture was extracted with dichloromethane (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product (1.75 g, yield: 97.7%).

[0369] Step 2: Synthesis of (R)-2-(3-((6-bromo-5-cyclopropyl-1,2,4-triazin-3-yl)amino)piperidin-1-yl)ethan-1-ol [ka] (R)-6-Bromo-5-cyclopropyl-N-(piperidin-3-yl)-1,2,4-triazin-3-amine (383.0 mg, 1.28 mmol, 1.0 eq), bromoethanol (481.5 mg, 3.84 mmol, 3.0 eq), and triethylamine (519.7 mg, 5.12 mmol, 4.0 eq) were added to dichloromethane (10.0 mL) and stirred at room temperature for 14 h. The reaction was monitored for completion by TLC. Dichloromethane (100.0 mL) was added, and the mixture was washed with saturated aqueous ammonium chloride (50.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 50:1 to 10:1) to give the product (300.0 mg, yield: 68.5%).

[0370] Step 3: Synthesis of (R)-4-(5-cyclopropyl-3-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-1,2,4-triazin-6-yl)-3-(ethoxymethoxy)benzaldehyde [ka] (R)-2-(3-((6-bromo-5-cyclopropyl-1,2,4-triazin-3-yl)amino)piperidin-1-yl)ethan-1-ol (297.3 mg, 0.87 mmol, 1.0 eq.), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (319.0 mg, 1.04 mmol, 1.2 eq.), sodium bicarbonate (145.8 mg, 1.73 mmol, 2.0 eq.), and Pd(dppf)Cl (31.7 mg, 0.001 eq.). The resulting solution (0.04 mmol, 0.05 eq) was added to a mixture of 1,4-dioxane (10.0 mL) and water (5.0 mL) and reacted at 110°C for 5 h under nitrogen gas protection. Completion of the reaction was monitored by TLC, and water (100.0 mL) was added, extracted with ethyl acetate (100.0 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 40:1 to 10:1) to obtain the product (160.0 mg, yield: 41.7%).

[0371] Step 4: Synthesis of (R)-2-(3-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-1,2,4-triazin-3-yl)amino)piperidin-1-yl)ethan-1-ol [ka] (R)-4-(5-cyclopropyl-3-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-1,2,4-triazin-6-yl)-3-(ethoxymethoxy)benzaldehyde (160.0 mg, 0.36 mmol, 1.0 eq), dimethyl (1-diazo-2-oxopropyl)phosphonate (104.4 mg, 0.54 mmol, 1.5 eq), and anhydrous potassium carbonate (100.0 mg, 0.72 mmol, 2.0 eq) were added to methanol (10.0 mL) and reacted at room temperature for 12 h. Completion was monitored by LC-MS. After concentration under reduced pressure, the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 50:1 to 10:1) to give the product (141.0 mg, yield: 89.0%).

[0372] Step 5: Synthesis of (R)-2-(5-cyclopropyl-3-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-1,2,4-triazin-6-yl)-5-ethynylphenol [ka] (R)-2-(3-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-1,2,4-triazin-3-yl)amino)piperidin-1-yl)ethan-1-ol (141.0 mg, 0.32 mmol, 1.0 eq) was added to dichloromethane (5.0 mL), trifluoroacetic acid (1.0 mL) was added dropwise, and the reaction was allowed to proceed at room temperature for 1 h. Completion of the reaction was monitored by TLC. The pH was adjusted to 8-9 with saturated aqueous sodium carbonate, and the mixture was extracted with dichloromethane (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give the product (60.0 mg, yield: 49.5%).

[0373] 1HNMR (400 MHz, DMSO-d6) δ(ppm): 10.03 (s, 1H), 7.61-7.53 (m, 1H), 7.30-7.28 (d, J=8 Hz, 1H), 7.05-7.02 (m, 2H), 4.42 (s, 1H), 4.21 (s, 1H), 4.10-3.72 (m, 1H), 3.51-3.48 (m, 2H), 2.91 (s, 1H), 2.67 (s, 1H), 2.40 (s, 2H), 1.78-1.64 (m, 3H), 1.52-1.36 (m, 2H), 1.02-0.96 (m, 4H). Molecular formula:C 21 H 25 N5O2 precise molecular weight: 379.20 LC-MS (Pos, m / z)=380.24[M+H] + .

[0374] Example 28: Synthesis of (R)-2-(5-cyclopropyl-3-((1-(methyl-d3)piperidin-3-yl)amino)-1,2,4-triazin-6-yl)-5-ethynylphenol (Compound 87) [ka]

[0375] Step 1: Synthesis of (R)-6-bromo-5-cyclopropyl-N-(1-(methyl-d3)piperidin-3-yl)-1,2,4-triazin-3-amine [ka] (R)-6-Bromo-5-cyclopropyl-N-(piperidin-3-yl)-1,2,4-triazin-3-amine (458.6 mg, 1.54 mmol, 1.0 eq), deuterated iodomethane (891.78 mg, 6.15 mmol, 4.0 eq), and triethylamine (778.1 mg, 7.69 mmol, 5.0 eq) were added to dichloromethane (10.0 mL) and stirred at room temperature for 5 h. Dichloromethane (100.0 mL) was added, and the mixture was washed with saturated aqueous ammonium chloride (50.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 40:1 to 10:1) to obtain the product (225.0 mg, yield: 46.4%).

[0376] (R)-6-Bromo-5-cyclopropyl-N-(piperidin-3-yl)-1,2,4-triazin-3-amine (550.0 mg, 1.84 mmol, 1.0 eq), deuterated iodomethane (1.46 g, 10.12 mmol, 5.5 eq), and triethylamine (1.0 g, 10.12 mmol, 5.5 eq) were added to dichloromethane (10.0 mL) and stirred at room temperature for 5 h. Dichloromethane (100.0 mL) was added, and the mixture was washed with saturated aqueous ammonium chloride (50.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 40:1 to 10:1) to give the product (235.5 mg, yield: 40.5%). The product (460.5 mg) was obtained by combining two runs.

[0377] Step 2: Synthesis of (R)-4-(5-cyclopropyl-3-((1-(methyl-d3)piperidin-3-yl)amino)-1,2,4-triazin-6-yl)-3-(ethoxymethoxy)benzaldehyde [ka] (R)-6-bromo-5-cyclopropyl-N-(1-(methyl-d3)piperidin-3-yl)-1,2,4-triazin-3-amine (340.0 mg, 1.08 mmol, 1.0 eq), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (396.2 mg, 1.29 mmol, 1.2 eq), anhydrous potassium carbonate (297.9 mg, 2.16 mmol, 2.0 eq), and Pd(PPh3)4 (124.5 mg, 0.11 mmol). The reaction mixture (0.1 eq) was added to a mixture of 1,4-dioxane (10 mL) and water (5 mL) and reacted at 100°C for 12 h under nitrogen gas protection. Completion of the reaction was monitored by TLC. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 40:1 to 10:1) to give the product (260 mg, yield: 58.2%).

[0378] Step 4: Synthesis of (R)-5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-N-(1-(methyl-d3)piperidin-3-yl)-1,2,4-triazin-3-amine [ka] (R)-4-(5-cyclopropyl-3-((1-(methyl-d3)piperidin-3-yl)amino)-1,2,4-triazin-6-yl)-3-(ethoxymethoxy)benzaldehyde (260.0 mg, 0.63 mmol, 1.0 eq), dimethyl (1-diazo-2-oxopropyl)phosphonate (180.7 mg, 0.95 mmol, 1.5 eq), and anhydrous potassium carbonate (173.3 mg, 1.26 mmol, 2.0 eq) were added to methanol (15.0 mL) and reacted at room temperature for 4 h. Completion was monitored by LC-MS. After concentration under reduced pressure, the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 40:1 to 10:1) to give the product (188.0 mg, yield: 72.7%).

[0379] Step 5: Synthesis of (R)-2-(5-cyclopropyl-3-((1-(methyl-d3)piperidin-3-yl)amino)-1,2,4-triazin-6-yl)-5-ethynylphenol [ka] (R)-5-Cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-N-(1-(methyl-d3)piperidin-3-yl)-1,2,4-triazin-3-amine (188.0 mg, 0.46 mmol, 1.0 eq) was added to dichloromethane (5.0 mL), trifluoroacetic acid (2.0 mL) was added dropwise, and the reaction was allowed to proceed at room temperature for 1 h. Completion was monitored by TLC. The pH was adjusted to 8-9 with saturated aqueous sodium carbonate, and the mixture was extracted with dichloromethane (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give the product (110.0 mg, yield: 67.9%).

[0380] 1 HNMR(400MHz, DMSO-d6) δ(ppm): 10.04 (s, 1H), 7.55-7.43 (m, 1H), 7.30-7.28 (d, J=8 Hz, 1H), 7.05-7.01 (m, 2H), 4.21 (s, 1H), 3.92-3.85 (m, 1H), 2.85-2.84 (m, 1H), 2.62 (s, 1H), 1.92-1.80 (m, 3H), 1.70-1.64 (m, 2H), 1.53-1.50(m, 1H), 1.34-1.23(m, 1H), 1.03-0.95(m, 4H). Molecular formula:C 20 H 20 D3N5O Precise molecular weight: 352.21 LC-MS(Pos, m / z)=353.23[M+H] + .

[0381] Example 29: Synthesis of (R)-2-(5-cyclopropyl-3-((1-ethylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)-5-ethynylphenol (Compound 92) [ka]

[0382] Step 1: Synthesis of (R)-6-bromo-5-cyclopropyl-N-(1-ethylpiperidin-3-yl)-1,2,4-triazin-3-amine [ka] (R)-6-Bromo-5-cyclopropyl-N-(piperidin-3-yl)-1,2,4-triazin-3-amine (920.0 mg, 3.08 mmol, 1.0 eq), iodoethane (4.8 g, 30.8 mmol, 10.0 eq), and triethylamine (3.1 g, 30.8 mmol, 10.0 eq) were added to dichloromethane (20.0 mL) and stirred at room temperature for 14 h. Dichloromethane (100.0 mL) was added, and the mixture was washed with saturated aqueous ammonium chloride (50.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 40:1 to 10:1) to obtain the product (970.0 mg, yield: 96.4%).

[0383] Step 2: Synthesis of (R)-4-(5-cyclopropyl-3-((1-ethylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)-3-(ethoxymethoxy)benzaldehyde [ka] (R)-6-Bromo-5-cyclopropyl-N-(1-ethylpiperidin-3-yl)-1,2,4-triazin-3-amine (390.0 mg, 1.19 mmol, 1.0 eq.), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (366.0 mg, 1.19 mmol, 1.0 eq.), anhydrous potassium carbonate (330.3 mg, 2.38 mmol, 2.0 eq.), and Pd(PPh3)4 (138.0 mg, 0.11 mmol). The resulting mixture (1,0.1 eq) was added to a mixture of 1,4-dioxane (10.0 mL) and water (4.0 mL) and reacted at 100°C for 4 h under nitrogen gas protection. Completion of the reaction was monitored by TLC. Water (100.0 mL) was added, and the mixture was extracted with ethyl acetate (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 40:1 to 10:1) to give the product (285.0 mg, yield: 56.1%).

[0384] Step 3: Synthesis of (R)-5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-N-(1-ethylpiperidin-3-yl)-1,2,4-triazin-3-amine [ka] (R)-4-(5-cyclopropyl-3-((1-ethylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)-3-(ethoxymethoxy)benzaldehyde (285.0 mg, 0.67 mmol, 1.0 eq), dimethyl (1-diazo-2-oxopropyl)phosphonate (192.9 mg, 1.00 mmol, 1.5 eq), and anhydrous potassium carbonate (184.9 mg, 1.34 mmol, 2.0 eq) were added to methanol (15.0 mL) and reacted at room temperature for 4 h. Completion was monitored by LC-MS. After concentration under reduced pressure, the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 40:1 to 10:1) to give the product (170.0 mg, yield: 60.2%).

[0385] Step 4: Synthesis of (R)-2-(5-cyclopropyl-3-((1-ethylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)-5-ethynylphenol [ka] (R)-5-Cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-N-(1-ethylpiperidin-3-yl)-1,2,4-triazin-3-amine (170.0 mg, 0.40 mmol, 1.0 eq) was added to dichloromethane (10.0 mL), trifluoroacetic acid (2.0 mL) was added dropwise, and the reaction was allowed to proceed at room temperature for 1 h. Completion of the reaction was monitored by TLC. The pH was adjusted to 8-9 with saturated aqueous sodium carbonate, and the mixture was extracted with dichloromethane (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give the product (80.0 mg, yield: 55.1%).

[0386] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 10.04 (s, 1H), 7.58-7.56 (m, 1H), 7.30-7.28 (d, J=8 Hz, 1H), 7.05-7.01 (m, 2H), 4.22 (s, 1H), 3.94-3.86 (m, 1H), 2.99-2.97 (m, 1H), 2.72 (s, 1H), 2.36 (s, 2H), 1.93-1.83 (m, 3H), 1.70-1.64 (m, 2H), 1.53-1.47 (m, 1H), 1.40-1.30 (m, 2H),1.02-1.98 (m, 5H), 0.86-0.81 (m, 1H). Molecular formula:C 21 H 25 N5O Precise molecular weight: 363.21 LC-MS(Pos, m / z)=364.22[M+H] + .

[0387] Example 30: Synthesis of (R)-6-((1-ethylpiperidin-3-yl)amino)-3-(4-ethynyl-2-hydroxyphenyl)-4-methyl-1,2,4-triazin-5(4H)-one (Compound 93) [ka]

[0388] Step 1: Synthesis of (R)-6-((1-ethylpiperidin-3-yl)amino)-3-(4-ethynyl-2-hydroxyphenyl)-4-methyl-1,2,4-triazin-5(4H)-one [ka] (R)-3-(4-ethynyl-2-hydroxyphenyl)-4-methyl-6-(piperidin-3-ylamino)-1,2,4-triazin-5(4H)-one (200 mg, 0.61 mmol, 1.0 eq) and a solution of acetaldehyde in tetrahydrofuran (5 mol / L, 0.18 mL, 0.92 mmol, 1.5 eq) were dissolved in methanol (10 mL) and stirred at room temperature for 18 h. Sodium cyanoborohydride (38 mg, 0.61 mmol, 1.0 eq) was added and the mixture was stirred at room temperature for 1 h. After completion of the reaction was monitored by TLC, the reaction mixture was concentrated under reduced pressure. The crude product was dispersed in water (10 mL) and extracted with DCM (10 mL x 4). The organic phase was dried, concentrated, and purified by preparative thin-layer chromatography (DCM:MeOH = 10:1) to give the product (50 mg, yield: 23.2%).

[0389] 1HNMR (400MHz, DMSO-d6) δ(ppm): 10.47 (s, 1H), 7.32-7.30 (d, 1H), 7.05-7.03 (d, 2H), 6.86 (s, 1H), 4.29 (s, 1H), 4.04-4.03 (d, 1H), 3.18 (s, 3H), 2.82 (s, 1H), 2.59 (s, 1H), 2.42 (s, 2H), 2.19 (s, 2H), 1.71-1.67 (d, 2H), 1.60-1.56 (t, 2H), 1.06-1.00 (t, 3H). Molecular formula:C 19 H 23 N5O2 precise molecular weight: 353.19 LC-MS(Pos, m / z)=354.22 [M+H] + .

[0390] Example 31: Synthesis of (R)-6-((1-cyclopropylpiperidin-3-yl)amino)-3-(4-ethynyl-2-hydroxyphenyl)-4-methyl-1,2,4-triazin-5(4H)-one (Compound 98) [ka]

[0391] Step 1: Synthesis of (R)-6-((1-cyclopropylpiperidin-3-yl)amino)-3-(4-ethynyl-2-hydroxyphenyl)-4-methyl-1,2,4-triazin-5(4H)-one [ka] (R)-3-(4-ethynyl-2-hydroxyphenyl)-4-methyl-6-(piperidin-3-ylamino)-1,2,4-triazin-5(4H)-one (200 mg, 0.61 mmol, 1.0 eq), 1-ethoxy-1-trimethylsilyloxycyclopropane (532 mg, 3.05 mmol, 5.0 eq), and CsF (140 mg, 0.92 mmol, 1.5 eq) were dissolved in methanol (10 mL) and AcOH (0.5 mL). The mixture was allowed to react at 50°C for 2 h, and sodium cyanoborohydride (153 mg, 2.44 mmol, 4.0 eq) was added. The mixture was then allowed to react at 50°C for 1 h. The reaction was monitored for completion by TLC, concentrated under reduced pressure, and the crude product was dispersed in water (20 mL), adjusted to a pH of about 8 with sodium bicarbonate, and extracted with DCM (20 mL × 3). The organic phase was dried, concentrated, and purified by preparative thin-layer chromatography (DCM:MeOH = 10:1) to give the product (70 mg, yield: 31.4%).

[0392] 1 HNMR (400MHz, DMSO-d6) δ(ppm): 10.42 (s, 1H), 7.32-7.31 (d, 1H), 7.05-7.02 (t, 2H), 6.78-6.76 (d, 1H), 4.29 (s, 1H), 3.96-3.94 (t, 1H), 3.17 (s, 3H), 2.95-2.93 (d, 1H), 2.68 (s, 1H), 2.33-2.32 (d, 2H), 1.72-1.70 (d, 1H), 1.65-1.55 (m, 3H), 1.49-1.44 (m, 1H), 0.43-0.41 (t, 2H), 0.31 (s, 2H). Molecular formula:C 20 H 23 N5O2 exact molecular weight: 365.19 LC-MS(Pos, m / z)=366.24 [M+H] + .

[0393] Example 32: Synthesis of (R)-4-cyclopropyl-6-((1-ethylpiperidin-3-yl)amino)-3-(4-ethynyl-2-hydroxyphenyl)-1,2,4-triazin-5(4H)-one (Compound 109) [ka]

[0394] Step 1: Synthesis of N-cyclopropyl-4-iodo-2-methoxybenzamide [ka] A solution of cyclopropylamine (15.3 g, 267.93 mmol, 3.0 eq) in DCM (100 mL) was added dropwise with a solution of 4-iodo-2-methoxybenzoyl chloride (26.66 g, 89.91 mmol, 1.0 eq) in DCM (200 mL) and the mixture was allowed to react at room temperature for 10 min. After completion of the reaction was confirmed by TLC, the reaction mixture was poured into water (200 mL) and extracted with DCM (100 mL x 2). The organic phase was dried and concentrated to give the product (28.51 g, 100% yield).

[0395] Step 2: Synthesis of N-cyclopropyl-4-iodo-2-methoxythiobenzamide [ka] N-Cyclopropyl-4-iodo-2-methoxybenzamide (28.51 g, 89.91 mmol, 1.0 eq) and Lawesson's reagent (20.0 g, 49.45 mmol, 0.55 eq) were dissolved in THF (300 mL) and reacted at 60°C for 1 h. Completion of the reaction was confirmed by TLC. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (EA:PE = 1:10) to give the product (25 g, yield: 83.4%).

[0396] Step 3: Synthesis of methyl N-cyclopropyl-4-iodo-2-methoxythiobenzimidate [ka] N-Cyclopropyl-4-iodo-2-methoxythiobenzamide (25 g, 75.03 mmol, 1.0 eq) and iodomethane (21.3 g, 150.06 mmol, 2.0 eq) were dissolved in THF (300 mL). The reaction was allowed to proceed at room temperature for 17 h. Upon completion of the reaction as determined by TLC, the reaction mixture was poured into water (500 mL), the pH was adjusted to approximately 9 with potassium carbonate, and the mixture was extracted with EA (200 mL x 2). The organic phase was dried and concentrated to give the product (26.05 g, 100% yield).

[0397] Step 4: Synthesis of N-amino-N'-cyclopropyl-4-iodo-2-methoxybenzamidine [ka] Methyl N-cyclopropyl-4-iodo-2-methoxythiobenzimidate (26.05 g, 122.90 mmol, 1.0 eq.) and hydrazine hydrate (8.84 g, 150.06 mmol, 2.0 eq.) were dissolved in EtOH (300 mL) and reacted at 80° C. for 1 h. Completion of the reaction was monitored by LC-MS, and the reaction mixture was concentrated under reduced pressure to give the product (24.85 g, 100% yield).

[0398] Step 5: Synthesis of 6-amino-4-cyclopropyl-3-(4-iodo-2-methoxyphenyl)-1,2,4-triazin-5(4H)-one [ka] N-amino-N'-cyclopropyl-4-iodo-2-methoxybenzamidine (15 g, 45.29 mmol, 1.0 eq), ethyl thioxamate (9.05 g, 67.94 mmol, 1.5 eq), and TEA (13.75 g, 135.87 mmol, 3.0 eq) were dissolved in EtOH (150 mL) and reacted at 80 °C for 4 h. Completion of the reaction was monitored by LC-MS. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EA:PE = 1:1) to give the product (9.0 g, yield: 51.7%).

[0399] Step 6: Synthesis of 6-bromo-4-cyclopropyl-3-(4-iodo-2-methoxyphenyl)-1,2,4-triazin-5(4H)-one [ka] 6-Amino-4-cyclopropyl-3-(4-iodo-2-methoxyphenyl)-1,2,4-triazin-5(4H)-one (9.0 g, 23.42 mmol, 1.0 eq) and CuBr (6.72 g, 46.84 mmol, 2.0 eq) were dispersed in ACN (90 mL), and tert-butyl nitrite (4.83 g, 46.84 mmol, 2.0 eq) was added dropwise at 70 °C under nitrogen gas protection. The reaction was allowed to proceed for 0.5 h at 70 °C. Completion was monitored by TLC, and the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EA:DCM = 1:10) to give the product (3.0 g, yield: 28.6%).

[0400] Step 7: Synthesis of tert-butyl (R)-3-((4-cyclopropyl-3-(4-iodo-2-methoxyphenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)amino)piperidine-1-carboxylate [ka] 6-Bromo-4-cyclopropyl-3-(4-iodo-2-methoxyphenyl)-1,2,4-triazin-5(4H)-one (3.0 g, 6.69 mmol, 1.0 eq), (R)-tert-butyl 3-aminopiperidine-1-carboxylate (2.0 g, 10.03 mmol, 1.5 eq), and DIPEA (1.30 g, 10.03 mmol, 1.5 eq) were dissolved in 1,4-dioxane (30 mL) and reacted at 100 °C for 18 h. After completion of the reaction by TLC, the reaction mixture was concentrated under reduced pressure. The crude product was dispersed in water (30 mL) and extracted with EA (30 mL × 3). The organic phase was dried and concentrated to give the product (3.8 g, yield: 100%).

[0401] Step 8: Synthesis of tert-butyl (R)-3-((4-cyclopropyl-3-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)amino)piperidine-1-carboxylate [ka] (R)-tert-Butyl 3-((4-cyclopropyl-3-(4-iodo-2-methoxyphenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)amino)piperidine-1-carboxylate (3.8 g, 6.69 mmol, 1.0 eq), trimethylsilylacetylene (3.28 g, 33.45 mmol, 5.0 eq), PdCl(PPh) (470 mg, 0.67 mmol, 0.1 eq), and CuI (383 mg, 2.01 mmol, 0.3 eq) were dispersed in diisopropylamine (20 mL) and THF (20 mL). The reaction was carried out at 40 °C for 1 h under nitrogen gas protection. The completion of the reaction was detected by TLC, and the reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE=1:2) to obtain the product (3.0 g, yield: 83.3%).

[0402] Step 9: Synthesis of (R)-4-cyclopropyl-3-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)-6-(piperidin-3-ylamino)-1,2,4-triazin-5(4H)-one [ka] (R)-tert-Butyl 3-((4-cyclopropyl-3-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)amino)piperidine-1-carboxylate (3.0 g, 5.57 mmol, 1.0 eq) was dissolved in EA (30 mL). A solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 10 mL) was added and the mixture was allowed to react at room temperature for 3 h. Upon completion of the reaction by TLC, the reaction mixture was concentrated under reduced pressure. The crude product was dispersed in water (20 mL) and extracted with EA (20 mL × 2). The aqueous phase was retained, adjusted to pH 8 with sodium bicarbonate, and extracted with EA (20 mL × 4). The organic phase was dried and concentrated to give the product (1.7 g, yield: 70%).

[0403] Step 10: Synthesis of (R)-4-cyclopropyl-6-((1-ethylpiperidin-3-yl)amino)-3-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)-1,2,4-triazin-5(4H)-one [ka] (R)-4-Cyclopropyl-3-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)-6-(piperidin-3-ylamino)-1,2,4-triazin-5(4H)-one (0.5 g, 1.14 mmol, 1.0 eq), TEA (577 mg, 5.70 mmol, 5.0 eq), and iodoethane (889 mg, 5.70 mmol, 5.0 eq) were dissolved in DCM (10 mL) and reacted at room temperature for 19 h. After completion of the reaction as determined by LC-MS, the reaction mixture was poured into water (10 mL) and extracted with DCM (10 mL x 3). The organic phase was dried and concentrated to give the product (530 mg, 100% yield).

[0404] Step 11: Synthesis of (R)-4-cyclopropyl-6-((1-ethylpiperidin-3-yl)amino)-3-(4-ethynyl-2-hydroxyphenyl)-1,2,4-triazin-5(4H)-one [ka] (R)-4-Cyclopropyl-6-((1-ethylpiperidin-3-yl)amino)-3-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)-1,2,4-triazin-5(4H)-one (530 mg, 1.14 mmol, 1.0 eq) was dissolved in DCM (10 mL), the temperature was lowered to -60°C, boron tribromide (857 mg, 3.42 mmol, 3.0 eq) was added, the temperature was naturally raised to room temperature, and the reaction was carried out for 3 hours. The completion of the reaction was detected by TLC, and the reaction solution was quenched by adding an appropriate amount of methanol. The reaction solution was concentrated under reduced pressure, and the crude product was dispersed in water (10 mL), adjusted to a pH of about 8 with sodium bicarbonate, and extracted with DCM (20 mL × 3). The organic phase was dried and concentrated. The crude product was first purified by silica gel column chromatography (DCM:MeOH = 20:1) and then further purified by preparative thin-layer chromatography (DCM:MeOH = 10:1) to obtain the product (240 mg, yield: 55.6%).

[0405] 1 HNMR (400MHz, DMSO-d6) δ(ppm): 10.34 (s, 1H), 7.34-7.32 (d, 1H), 7.03-6.99 (d, 2H), 6.78-6.76 (d, 1H), 4.26 (s, 1H), 3.97 (s, 1H), 2.99 (s, 1H), 2.77 (s, 1H), 2.51 (s, 1H), 2.36-2.35 (d, 2H), 2.14 (s, 2H), 1.68-1.64 (d, 2H), 1.58-1.51 (m, 2H), 1.01-1.00 (d, 3H), 0.67-0.66 (d, 2H), 0.50 (s, 2H). Molecular formula:C 21 H 25 N5O2 precise molecular weight: 379.20 LC-MS(Pos,m / z)=380.24 [M+H] + .

[0406] Example 33: Synthesis of (R)-3-(4-ethyl-2-hydroxyphenyl)-4-methyl-6-((1-(methyl-d3)piperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one (Compound 88) [ka]

[0407] Step 1: Synthesis of (R)-3-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)-4-methyl-6-(piperidin-3-ylamino)-1,2,4-triazin-5(4H)-one [ka] (R)-tert-Butyl 3-((3-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)-4-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)amino)piperidine-1-carboxylate (3.0 g, 5.86 mmol, 1.0 eq.) was dissolved in EA (30 mL). A solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 10 mL) was added and the mixture was allowed to react at room temperature for 2.5 h. Upon completion of the reaction by TLC, the reaction mixture was concentrated under reduced pressure. The crude product was dissolved in water (20 mL) and extracted with EA (20 mL × 2). The aqueous phase was retained, adjusted to pH 8 with sodium bicarbonate, and extracted with EA (30 mL × 3). The organic phase was dried and concentrated to give the product (2.25 g, yield: 93.3%).

[0408] Step 2: Synthesis of (R)-3-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)-4-methyl-6-((1-(methyl-d3)piperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one [ka] (R)-3-(2-Methoxy-4-((trimethylsilyl)ethynyl)phenyl)-4-methyl-6-(piperidin-3-ylamino)-1,2,4-triazin-5(4H)-one (1.0 g, 2.43 mmol, 1.0 eq) and TEA (1.76 g, 12.15 mmol, 5.0 eq) were dissolved in DCM (30 mL), deuterated iodomethane (1.23 g, 12.15 mmol, 5.0 eq) was added, and the mixture was allowed to react at room temperature for 10 min. After completion of the reaction by TLC, the reaction mixture was poured into water (20 mL), extracted with DCM (20 mL x 2), and the organic phase was dried and concentrated to give the product (1.04 g, 100% yield).

[0409] Step 3: Synthesis of (R)-3-(4-ethyl-2-hydroxyphenyl)-4-methyl-6-((1-(methyl-d3)piperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one [ka] (R)-3-(2-Methoxy-4-((trimethylsilyl)ethynyl)phenyl)-4-methyl-6-((1-(methyl-d3)piperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one (1.04 g, 2.43 mmol, 1.0 eq) was dissolved in DCM (20 mL), the temperature was lowered to -60 °C, boron tribromide (1.83 g, 7.29 mmol, 3.0 eq) was added, the temperature was naturally raised to room temperature, and the reaction was carried out for 5 h. The completion of the reaction was detected by LC-MS, and the reaction mixture was quenched by adding an appropriate amount of water, extracted with DCM (20 mL × 2), the aqueous phase was retained, the pH value was adjusted to about 8 with sodium bicarbonate, and extracted with EA (20 mL × 6), the organic phase was dried, concentrated, and purified by preparative thin-layer chromatography (DCM:MeOH = 10:1) to give the product (160 mg, yield: 19.2%).

[0410] 1HNMR (400MHz, DMSO-d6) δ(ppm): 10.44 (s, 1H), 7.32-7.30 (d, 1H), 7.05-7.02 (d, 2H), 6.80-6.78 (d, 1H), 4.28 (s, 1H), 4.04-4.01 (s, 1H), 3.18 (s, 3H), 2.71-2.68 (d, 1H), 2.44 (s, 1H), 2.11 (s, 2H), 1.67 (s, 2H), 1.59-1.48 (m, 2H). Molecular formula:C 18 H 18 D3N5O2 exact molecular weight: 342.19 LC-MS(Pos,m / z)=343.25 [M+H] + .

[0411] Example 34: Synthesis of (R)-2-(6-((1-cyclopropylpiperidin-3-yl)amino)-4-methylpyridazin-3-yl)-5-ethynylphenol (Compound 94): [ka]

[0412] Step 1: Synthesis of tert-butyl (R)-3-((6-(2-(ethoxymethoxy)-4-formylphenyl)-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate [ka] (R)-tert-Butyl 3-((6-chloro-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate (2.20 g, 6.73 mmol, 1.0 eq), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (2.47 g, 8.08 mmol, 1.2 eq), PdCl(dppf) (0.49 g, 0.67 mmol, 0.1 eq), and sodium bicarbonate (1.13 g, 13.46 mmol, 2.0 eq) were added to a mixture of 1,4-dioxane (40 mL) and water (10 mL) and heated to 110 °C under nitrogen gas protection for 2 h. The reaction was monitored for completion by TLC, cooled to room temperature, added with water (50 mL), extracted with EA (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 10:1) to give the product (2.68 g, yield: 84.6%).

[0413] Step 2: Synthesis of tert-butyl (R)-3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate [ka] (R)-tert-Butyl 3-((6-(2-(ethoxymethoxy)-4-formylphenyl)-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate (2.68 g, 5.70 mmol, 1.0 eq) and KCO (1.57 g, 11.39 mmol, 2.0 eq) were added to methanol (30 mL), and dimethyl (1-diazo-2-oxopropyl)phosphonate (1.64 g, 8.54 mmol, 1.5 eq) was added with stirring. The mixture was allowed to react at room temperature for 2 h. The reaction was monitored for completion by TLC, concentrated, added with EA (50 mL), washed with water (25 mL × 2), and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 10:1) to give the product (2.32 g, yield: 87.3%).

[0414] Step 3: Synthesis of (R)-5-ethynyl-2-(4-methyl-6-(piperidin-3-ylamino)pyridazin-3-yl)phenol [ka] (R)-tert-Butyl 3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate (400.0 mg, 0.86 mmol, 1.0 eq) was dissolved in DCM (4 mL) and a 4 mol / L solution of hydrogen chloride in 1,4-dioxane (2.0 mL, 8.14 mmol, 9.5 eq) was added dropwise. The reaction was allowed to proceed at room temperature for 2 h. After completion of the reaction was monitored by TLC, the reaction was quenched by adding water (2 mL), adjusted to pH 8 with saturated NaHCO3 solution, and extracted with DCM (5 mL x 5). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by preparative thin-layer chromatography (DCM:MeOH = 10:1) to give the product (169.8 mg, yield: 64.2%).

[0415] Step 4: Synthesis of (R)-2-(6-((1-cyclopropylpiperidin-3-yl)amino)-4-methylpyridazin-3-yl)-5-ethynylphenol [ka] (R)-5-Ethynyl-2-(4-methyl-6-(piperidin-3-ylamino)pyridazin-3-yl)phenol (169.8 mg, 0.55 mmol, 1.0 eq) was dissolved in MeOH (10 mL), (1-ethoxycyclopropoxy)trimethylsilane (383.9 mg, 2.20 mmol, 4.0 eq) and CsF (167.3 mg, 1.10 mmol, 2.0 eq) were added, and the mixture was stirred at 50 °C for 1 h. NaBH CN (167.3 mg, 1.10 mmol, 2.0 eq) was further added, and stirring was continued for 0.5 h. The reaction was monitored for completion by TLC, cooled to room temperature, concentrated under reduced pressure, and the crude product was added with saturated aqueous NaHCO3 (20 mL) and extracted with DCM (20 mL × 5). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by preparative thin-layer chromatography (DCM:MeOH = 10:1) to give the product (67.3 mg, yield: 35.1%).

[0416] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 10.10 (s, 1H), 7.19-7.17 (m, 1H), 7.00-6.98 (m, 2H), 6.68 (s, 1H), 6.58 (d, J = 6.8 Hz, 1H), 4.19 (s, 1H), 3.96 (s, 1H), 3.10 (s, 1H), 2.79 (s, 1H), 2.27 (s, 1H), 2.17-2.15 (m, 1H), 2.02 (s, 3H), 1.88-1.85 (m, 1H), 1.67 (s, 2H), 0.86-0.82 (m, 2H), 0.43-0.35 (m, 4H). Molecular formula:C 21 H 24 N4O Precise molecular weight: 348.20 LC-MS (Pos, m / z) =349.36[M+H] + .

[0417] Example 35: Synthesis of (R)-5-ethynyl-2-(4-methyl-6-((1-(methyl-d3)piperidin-3-yl)amino)pyridazin-3-yl)phenol (Compound 84): [ka]

[0418] Step 1: Synthesis of (R)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-N-(piperidin-3-yl)pyridazin-3-amine [ka] (R)-tert-Butyl 3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate (0.80 g, 1.71 mmol, 1.0 eq) was dissolved in DCM (8 mL) and cooled to 0 °C. 2,6-dimethylpyridine (1.47 g, 13.72 mmol, 8.0 eq) and TMSOTf (1.52 g, 6.86 mmol, 4.0 eq) were added sequentially and stirred for 5 min. TLC showed the reaction was complete. The mixture was quenched with water (5 mL) and extracted with DCM (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 10:1) to give the product (912.2 mg crude).

[0419] Step 2: Synthesis of (R)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-N-(1-(methyl-d3)piperidin-3-yl)pyridazin-3-amine [ka] (R)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-N-(piperidin-3-yl)pyridazin-3-amine (400.0 mg crude product, 0.75 mmol, 1.0 eq) was dissolved in DCM (3 mL), deuterated iodomethane (317.0 mg, 3.77 mmol, 5.0 eq) was added, and the reaction was allowed to proceed at room temperature for 18 h. After completion of the reaction was monitored by TLC, water (5 mL) was added, followed by extraction with DCM (5 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by preparative thin-layer chromatography (DCM:MeOH = 10:1) to give the product (135.9 mg, yield: 47.0%).

[0420] Step 3: Synthesis of (R)-5-ethynyl-2-(4-methyl-6-((1-(methyl-d3)piperidin-3-yl)amino)pyridazin-3-yl)phenol [ka] (R)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-N-(1-(methyl-d3)piperidin-3-yl)pyridazin-3-amine (135.9 mg, 0.35 mmol) was dissolved in DCM (1 mL) and 4 mol / L hydrogen chloride in 1,4-dioxane (1 mL) was added dropwise and reacted at room temperature for 5 min. The reaction was monitored for completion by TLC, quenched by adding water (1 mL), adjusted to pH = 8 with saturated NaHCO3 solution, extracted with DCM (2 mL x 5), the organic phases combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure and purified by preparative thin-layer chromatography (DCM:MeOH = 10:1) to give the product (67.1 mg, yield: 58.2%).

[0421] 1HNMR (400 MHz, DMSO-d6) δ(ppm): 10.14 (s, 1H), 7.18-7.16 (m, 1H), 7.02-6.98 (m, 2H), 6.75 (d, J=7.2 Hz, 1H), 6.70 (s, 1H), 4.19 (s, 1H), 4.12 (s, 1H), 3.05 (s, 1H), 2.75 (s, 1H), 2.28-2.18(m, 2H), 2.02(s, 3H), 1.86(s, 1H), 1.78-1.77(m, 1H), 1.63-1.60(m, 1H), 1.38(m, 1H). Molecular formula:C 19 H 19 D3N4O Precise molecular weight: 325.20 LC-MS (Pos, m / z) =326.33[M+H] + .

[0422] Example 36: Synthesis of (R)-2-(6-((1-ethylpiperidin-3-yl)amino)-4-methylpyridazin-3-yl)-5-ethynylphenol (Compound 89) [ka]

[0423] Step 1: Synthesis of (R)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-N-(1-ethylpiperidin-3-yl)-5-methylpyridazin-3-amine [ka] (R)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-N-(piperidin-3-yl)pyridazin-3-amine (400.0 mg crude product, 0.75 mmol, 1.0 eq) was dissolved in DCM (3 mL), and iodoethane (587.3 mg, 3.77 mmol, 5.0 eq) was added. The mixture was allowed to react at room temperature for 18 h. After completion of the reaction was monitored by TLC, water (5 mL) was added and the mixture was extracted with DCM (5 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by preparative thin-layer chromatography (DCM:MeOH = 10:1) to give the product (76.7 mg, yield: 25.8%).

[0424] Step 2: Synthesis of (R)-2-(6-((1-ethylpiperidin-3-yl)amino)-4-methylpyridazin-3-yl)-5-ethynylphenol [ka] (R)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-N-(1-ethylpiperidin-3-yl)-5-methylpyridazin-3-amine (76.7 mg, 0.19 mmol) was dissolved in DCM (0.5 mL) and 4 mol / L hydrogen chloride in 1,4-dioxane (0.5 mL) was added dropwise and reacted at room temperature for 5 min. The reaction was monitored for completion by TLC, quenched by adding water (0.5 mL), adjusted to pH 8 with saturated NaHCO3 solution, extracted with DCM (1 mL x 5), the organic phases combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The product was purified by preparative thin-layer chromatography (DCM:MeOH = 10:1) to give the product (29.7 mg, yield: 45.4%).

[0425] 1HNMR (400 MHz, DMSO-d6) δ(ppm): 10.12 (s, 1H), 7.18-7.16 (m, 1H), 7.02-6.99 (m, 2H), 6.70 (m, 2H), 4.19 (m, 2H), 2.90-2.70 (m, 6H), 2.03 (s, 3H), 1.96-1.92 (m, 1H), 1.87-1.82 (m, 1H), 1.66 (s, 1H), 1.41 (s, 1H), 1.10-1.09 (m, 3H). Molecular formula:C 20 H 24 N4O Precise molecular weight: 336.20 LC-MS(Pos, m / z) =337.32[M+H] + .

[0426] Example 37: Synthesis of (R)-3-(3-((6-(2-hydroxy-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)propanenitrile (Compound 78) [ka]

[0427] Step 1: Synthesis of (R)-3-(3-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)propanenitrile [ka] (R)-6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methyl-N-(piperidin-3-yl)pyridazin-3-amine (250 mg, 0.657 mmol, 1.0 eq) was dissolved in DCM (5 mL), triethylamine (333 mg, 3.29 mmol, 5.0 eq) and 3-bromopropionitrile (441 mg, 3.29 mmol, 5.0 eq) were added, and the mixture was stirred at room temperature for 20 h. The mixture was concentrated and purified by silica gel column chromatography (DCM:MeOH = 100:1 to 20:1) to give the product (263 mg, yield: 92.3%).

[0428] Step 3: Synthesis of (R)-3-(3-((6-(2-hydroxy-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)propanenitrile [ka] (R)-3-(3-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)propanenitrile (260 mg, 0.600 mmol, 1.0 eq) was dissolved in DCM (4 mL). Then, a solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 0.45 mL, 1.80 mmol, 3.0 eq) was added dropwise and stirred at room temperature for 2 h. The pH was adjusted to 8 with saturated aqueous NaHCO3, and the mixture was extracted with DCM (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 20:1) to give the product (166 mg, yield: 73.7%).

[0429] 1HNMR(400 MHz, DMSO-d6) δ(ppm): 10.01 (s, 1H), 7.13 (d, J = 8.3 Hz, 1H), 6.96-6.89 (m, 2H), 6.66 (s, 1H), 6.57 (d, J = 8.0 Hz, 1H), 4.03-4.01 (m, 1H), 3.02 (d, J = 8.2 Hz, 1H), 2.73 (d, J = 10.8 Hz, 1H), 2.69-2.66 (m, 2H), 2.64-2.60 (m, 2H), 2.11-1.96 (m, 8H), 1.89-1.86 (m, 1H), 1.73-1.70 (m, 1H), 1.58-1.49 (m, 1H), 1.34-1.24 (m, 1H). Molecular formula:C 22 H 25 N5O Precise molecular weight: 375.21 LC-MS(Pos, m / z)=376.19[M+H] + .

[0430] Example 38: Synthesis of (R)-2-(4-methyl-6-((1-(2,2,2-trifluoroethyl)piperidin-3-yl)amino)pyridazin-3-yl)-5-(prop-1-yn-1-yl)phenol (Compound 79) [ka]

[0431] Step 1: Synthesis of 2,2,2-trifluoroethyl-4-methylbenzenesulfonate [ka] 2,2,2-Trifluoroethanol (5.00 g, 50.0 mmol, 1.0 eq) was dissolved in DCM (100 mL), triethylamine (7.59 g, 75.0 mmol, 1.5 eq) and 4-methylbenzenesulfonyl chloride (9.53 g, 50.0 mmol, 1.0 eq) were added, and the mixture was stirred at room temperature for 20 h. The reaction mixture was washed with water (50 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by silica gel column chromatography (PE:EA = 10:1) to give the product (11.9 g, yield: 93.7%).

[0432] Step 2: Synthesis of (R)-6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methyl-N-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)pyridazin-3-amine [ka] (R)-6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methyl-N-(piperidin-3-yl)pyridazin-3-amine (250 mg, 0.657 mmol, 1.0 eq) was dissolved in DMF (5 mL), and 2,2,2-trifluoroethyl-4-methylbenzenesulfonate (334 mg, 1.31 mmol, 2.0 eq) and KCO (181 mg, 1.31 mmol, 2.0 eq) were added. The mixture was heated to 100 °C and reacted for 48 h. The reaction mixture was quenched by adding water (30 mL) and extracted with EA (30 mL). The organic phase was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 50:1) to give the product (148 mg, yield: 48.7%).

[0433] Step 3: Synthesis of (R)-2-(4-methyl-6-((1-(2,2,2-trifluoroethyl)piperidin-3-yl)amino)pyridazin-3-yl)-5-(prop-1-yn-1-yl)phenol [ka] (R)-6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methyl-N-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)pyridazin-3-amine (148 mg, 0.320 mmol, 1.0 eq) was dissolved in DCM (2 mL). Then, a solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 0.24 mL, 0.960 mmol, 3.0 eq) was added dropwise and stirred at room temperature for 2 h. The pH was adjusted to 8 with saturated aqueous NaHCO3, and the mixture was extracted with DCM (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 50:1) to give the product (67.0 mg, yield: 51.8%).

[0434] 1 HNMR(400 MHz, DMSO-d6) δ(ppm): 10.01 (s, 1H), 7.13 (d, J = 7.6 Hz, 1H), 6.90 (d, J = 7.9 Hz, 2H), 6.66 (s, 1H), 6.61 (d, J = 7.8 Hz, 1H), 4.04-4.01 (m, 1H), 3.25-3.15 (m, 3H), 2.83 (d, J = 10.8 Hz, 1H), 2.40-2.35 (m, 1H), 2.26-2.21 (m, 1H), 2.05 (s, 3H), 2.03 (s, 3H), 1.90 (d, J = 8.8 Hz, 1H), 1.71 (d, J = 13.2 Hz, 1H), 1.60-1.55 (m, 1H), 1.31-1.24 (m, 1H). Molecular formula:C 21 H 23 F3N4O Precise molecular weight: 404.18 LC-MS(Pos, m / z)=405.22[M+H] + .

[0435] Example 39: Synthesis of (R)-2-(3-((1-cyclopropylpiperidin-3-yl)amino)-5-methyl-1,2,4-triazin-6-yl)-5-ethynylphenol (Compound 96) [ka]

[0436] Step 1: Synthesis of 5-methyl-3-(methylsulfinyl)-1,2,4-triazine [ka] 5-Methyl-3-methylthio-1,2,4-triazine (70.0 g, 0.496 mol, 1.0 eq) was dissolved in DCM (700 mL) and stirred at room temperature. m-Chloroperbenzoic acid (101 g, 0.496 mol, 1.0 eq) was added in several portions and stirred at room temperature for 1 h. The mixture was filtered under suction, and the filtrate was concentrated under reduced pressure and used directly in the next step.

[0437] Step 2: Synthesis of tert-butyl (R)-3-((5-methyl-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate [ka] The crude 5-methyl-3-(methylsulfinyl)-1,2,4-triazine obtained in the previous step was dissolved in 1,4-dioxane (200 mL), triethylamine (100 g, 0.992 mol, 2.0 eq) and (R)-tert-butyl 3-aminopiperidine-1-carboxylate (99.3 g, 0.496 mol, 1.0 eq) were added, and the mixture was heated to 100 °C for 1 h. After cooling to room temperature, the mixture was quenched by adding water (600 mL) and extracted with EA (300 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by silica gel column chromatography (PE:EA = 10:1 to 1:1) to give the product (82.5 g, 2-step yield: 56.7%).

[0438] Step 3: Synthesis of tert-butyl (R)-3-((6-bromo-5-methyl-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate [ka] (R)-tert-Butyl 3-((5-methyl-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate (12.0 g, 40.9 mmol, 1.0 eq) was dissolved in DMF (100 mL) and stirred at room temperature. NBS (7.28 g, 40.9 mmol, 1.0 eq) was added in several portions and the reaction was allowed to proceed at room temperature for 4 h. The mixture was quenched with water (300 mL) and extracted with EA (200 mL). The organic phase was washed with water (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by silica gel column chromatography (PE:EA = 20:1 to 2:1) to give the product (6.30 g, yield: 41.4%).

[0439] Step 4: Synthesis of (R)-6-bromo-5-methyl-N-(piperidin-3-yl)-1,2,4-triazin-3-amine [ka] (R)-tert-Butyl 3-((6-bromo-5-methyl-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate (6.30 g, 16.9 mmol, 1.0 eq) was dissolved in DCM (15 mL), TFA (15 mL) was added dropwise, and the mixture was allowed to react at room temperature for 2 h. The pH was adjusted to 8 with saturated aqueous NaHCO3, and the mixture was extracted with a 10:1 DCM:MeOH mixture (40 mL x 5). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by silica gel column chromatography (DCM:MeOH = 50:1 to 10:1) to give the product (4.10 g, yield: 89.0%).

[0440] Step 5: Synthesis of (R)-6-bromo-N-(1-cyclopropylpiperidin-3-yl)-5-methyl-1,2,4-triazin-3-amine [ka] (R)-6-Bromo-5-methyl-N-(piperidin-3-yl)-1,2,4-triazin-3-amine (300 mg, 1.10 mmol, 1.0 eq) was dissolved in MeOH (20 mL), and (1-ethoxycyclopropoxy)trimethylsilane (767 mg, 4.40 mmol, 4.0 eq) and CsF (334 mg, 2.20 mmol, 2.0 eq) were added. The mixture was heated to 50°C and stirred for 1 hour. NaBHCN (276 mg, 4.40 mmol, 4.0 eq) was further added, and the mixture was allowed to react for 0.5 hours. The mixture was cooled to room temperature, concentrated, and saturated aqueous NaHCO3 was added. The mixture was extracted with EA (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 20:1) to give the product (308 mg, yield: 89.5%).

[0441] Step 6: Synthesis of (R)-4-(3-((1-cyclopropylpiperidin-3-yl)amino)-5-methyl-1,2,4-triazin-6-yl)-3-(ethoxymethoxy)benzaldehyde [ka] 3-(Ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (230 mg, 0.751 mmol, 1.3 eq), (R)-6-bromo-N-(1-cyclopropylpiperidin-3-yl)-5-methyl-1,2,4-triazin-3-amine (180 mg, 0.577 mmol, 1.0 eq), Pd(PPh) (42.2 mg, 0.0577 mmol, 0.1 eq), and NaHCO (96.9 mg, 1.15 mmol, 2.0 eq) were added sequentially to 1,4-dioxane (6 mL), followed by HO (3 mL). The mixture was heated to 80 °C under nitrogen gas protection for 24 h. After cooling to room temperature, water (10 mL) was added and extracted with EA (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 20:1) to give the product (112 mg, yield: 49.7%).

[0442] Step 7: Synthesis of (R)-N-(1-cyclopropylpiperidin-3-yl)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-1,2,4-triazin-3-amine [ka] (R)-4-(3-((1-cyclopropylpiperidin-3-yl)amino)-5-methyl-1,2,4-triazin-6-yl)-3-(ethoxymethoxy)benzaldehyde (112 mg, 0.272 mmol, 1.0 eq) was dissolved in MeOH (4 mL), KCO (75.2 mg, 0.544 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (78.4 mg, 0.408 mmol, 1.5 eq) were added, and the mixture was stirred at room temperature for 1 h. Water (20 mL) was added, and the mixture was extracted with EA (15 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 20:1) to give the product (102 mg, yield: 92.0%).

[0443] Step 8: Synthesis of (R)-2-(3-((1-cyclopropylpiperidin-3-yl)amino)-5-methyl-1,2,4-triazin-6-yl)-5-ethynylphenol [ka] (R)-N-(1-cyclopropylpiperidin-3-yl)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-1,2,4-triazin-3-amine (102 mg, 0.250 mmol, 1.0 eq) was dissolved in DCM (3 mL). Then, a solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 0.25 mL, 1.00 mmol, 4.0 eq) was added dropwise and stirred at room temperature for 1 h. The pH was adjusted to 8 with saturated aqueous NaHCO3, and the mixture was extracted with DCM (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 20:1) to give the product (68.5 mg, yield: 78.3%).

[0444] 1 HNMR(400 MHz, DMSO-d6) δ(ppm): 10.09 (s, 1H), 7.40 (s, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 8.0 Hz, 2H), 4.22 (s, 1H), 3.91 (s, 1H), 3.07 (d, J = 7.0 Hz, 1H), 2.81 (d, J = 10.5 Hz, 1H), 2.18-2.10 (m, 5H), 1.86 (d, J = 8.4 Hz, 1H), 1.69-1.63 (m, 2H), 1.50-1.34 (m, 2H), 0.41 (d, J = 6.1 Hz, 2H), 0.31 (s, 2H). Molecular formula:C 20 H 23 N5O Precise molecular weight: 349.19 LC-MS(Pos, m / z)=350.22[M+H] + .

[0445] Example 40: Synthesis of (R)-2-(3-((1-ethylpiperidin-3-yl)amino)-5-methyl-1,2,4-triazin-6-yl)-5-ethynylphenol (Compound 91) [ka]

[0446] Step 1: Synthesis of tert-butyl (R)-3-((6-(2-(ethoxymethoxy)-4-formylphenyl)-5-methyl-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate [ka] 3-(Ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (2.68 g, 8.75 mmol, 1.3 eq), (R)-tert-butyl 3-((6-bromo-5-methyl-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate (2.50 g, 6.72 mmol, 1.0 eq), Pd(dppf)Cl (492 mg, 0.672 mmol, 0.1 eq), and KCO (1.86 g, 13.4 mmol, 2.0 eq) were added sequentially to 1,4-dioxane (40 mL), followed by HO (20 mL). The mixture was heated to 110 °C under nitrogen gas protection for 2 h. The mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with EA (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (PE:EA = 10:1 to 2:1) to give the product (2.62 g, yield: 82.7%).

[0447] Step 2: Synthesis of tert-butyl (R)-3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate [ka] (R)-tert-Butyl 3-((6-(2-(ethoxymethoxy)-4-formylphenyl)-5-methyl-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate (2.62 g, 5.56 mmol, 1.0 eq) was dissolved in MeOH (30 mL). KCO (1.54 g, 11.1 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (1.60 g, 8.34 mmol, 1.5 eq) were added and stirred at room temperature for 1 h. The mixture was concentrated, water (50 mL) was added, and the mixture was extracted with EA (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by silica gel column chromatography (PE:EA = 10:1 to 2:1) to give the product (2.34 g, yield: 90.1%).

[0448] Step 3: Synthesis of (R)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-N-(piperidin-3-yl)-1,2,4-triazin-3-amine [ka] (R)-tert-Butyl 3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate (2.34 g, 5.00 mmol, 1.0 eq) was dissolved in DCM (40 mL), and then 2,6-dimethylpyridine (4.29 g, 40.0 mmol, 8.0 eq) was added. The temperature was lowered to 0°C in an ice-water bath, and TMSOTf (4.45 g, 20.0 mmol, 4.0 eq) was further added dropwise. After the addition was completed, the mixture was immediately quenched with water (50 mL), the layers were separated, the aqueous phase was extracted with DCM (50 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (DCM:MeOH = 50:1 to 10:1) to give the product (1.30 g, yield: 70.7%).

[0449] Step 4: Synthesis of (R)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-N-(1-ethylpiperidin-3-yl)-5-methyl-1,2,4-triazin-3-amine [ka] (R)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-N-(piperidin-3-yl)-1,2,4-triazin-3-amine (250 mg, 0.680 mmol, 1.0 eq) was dissolved in DCM (5 mL), triethylamine (344 mg, 3.40 mmol, 5.0 eq) and iodoethane (530 mg, 3.40 mmol, 5.0 eq) were added, and the mixture was stirred at room temperature for 16 h. Water was added, and the mixture was extracted with DCM (30 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by silica gel column chromatography (DCM:MeOH = 50:1 to 10:1) to give the product (212 mg, yield: 78.8%).

[0450] Step 5: Synthesis of (R)-2-(3-((1-ethylpiperidin-3-yl)amino)-5-methyl-1,2,4-triazin-6-yl)-5-ethynylphenol [ka] (R)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-N-(1-ethylpiperidin-3-yl)-5-methyl-1,2,4-triazin-3-amine (200 mg, 0.506 mmol, 1.0 eq) was dissolved in DCM (3 mL). Then, a solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 0.51 mL, 2.02 mmol, 4.0 eq) was added dropwise and stirred at room temperature for 1 h. The pH was adjusted to 8 with saturated aqueous NaHCO3, and the mixture was extracted with DCM (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by preparative thin-layer chromatography (DCM:MeOH = 10:1) to give the product (102 mg, yield: 59.8%).

[0451] 1HNMR(400 MHz, DMSO-d6) δ(ppm): 10.17 (s, 1H), 7.60 (s, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.04 (d, J = 6.8 Hz, 2H), 4.23 (s, 1H), 4.10 (m, 1H), 3.18 (s, 1H), 2.93 (s, 1H), 2.67-2.60 (m, 2H), 2.19 (s, 4H), 1.91 (d, J = 4.9 Hz, 1H), 1.78 (s, 1H), 1.63 (s, 1H), 1.44 (s, 1H), 1.08 (s, 3H). Molecular formula:C 19 H 23 N5O Precise molecular weight: 337.19 LC-MS(Pos,m / z)=338.22[M+H] + .

[0452] Example 41: Synthesis of (R)-5-ethynyl-2-(3-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-5-methyl-1,2,4-triazin-6-yl)phenol (Compound 99) [ka] Step 1: Synthesis of (R)-2-(3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-1,2,4-triazin-3-yl)amino)piperidin-1-yl)ethan-1-ol [ka] (R)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-N-(piperidin-3-yl)-1,2,4-triazin-3-amine (250 mg, 0.680 mmol, 1.0 eq) was dissolved in DCM (5 mL), triethylamine (344 mg, 3.40 mmol, 5.0 eq) and 2-bromoethanol (425 mg, 3.40 mmol, 5.0 eq) were added, and the mixture was stirred at room temperature for 30 h. Water was added, and the mixture was extracted with DCM (30 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by silica gel column chromatography (DCM:MeOH = 50:1 to 10:1) to give the product (178 mg, yield: 63.6%).

[0453] Step 2: Synthesis of (R)-5-ethynyl-2-(3-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-5-methyl-1,2,4-triazin-6-yl)phenol [ka] (R)-2-(3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-1,2,4-triazin-3-yl)amino)piperidin-1-yl)ethan-1-ol (178 mg, 0.433 mmol, 1.0 eq) was dissolved in DCM (3 mL). Then, a solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 0.43 mL, 1.73 mmol, 4.0 eq) was added dropwise and stirred at room temperature for 1 h. The pH was adjusted to 8 with saturated aqueous NaHCO3, and the mixture was extracted with DCM (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by silica gel column chromatography (DCM:MeOH = 50:1 to 10:1) to give the product (102 mg, yield: 66.7%).

[0454] 1HNMR(400 MHz, DMSO-d6) δ(ppm): 10.22 (s, 1H), 7.72 (s, 1H), 7.26 (d, J = 7.7 Hz, 1H), 7.07-7.03 (m, 2H), 4.25 (s, 1H), 4.91 (s, 1H), 4.23 (s, 2H), 3.64 (s, 2H), 2.85 (s, 3H), 2.20 (s, 3H), 1.89-1.71 (m, 3H), 1.50 (s, 1H), 0.96-0.82 (m, 1H). Molecular formula:C 19 H 23 N5O2 precise molecular weight: 353.19 LC-MS(Pos,m / z)=354.28[M+H] + .

[0455] Example 42: Synthesis of (R)-5-ethynyl-2-(5-methyl-3-((1-(methyl-d3)piperidin-3-yl)amino)-1,2,4-triazin-6-yl)phenol (Compound 86) [ka]

[0456] Step 1: Synthesis of (R)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-N-(1-(methyl-d3)piperidin-3-yl)-1,2,4-triazin-3-amine [ka] (R)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-N-(piperidin-3-yl)-1,2,4-triazin-3-amine (450 mg, 1.22 mmol, 1.0 eq) was dissolved in DCM (20 mL), triethylamine (370 mg, 3.66 mmol, 3.0 eq) and deuterated iodomethane (530 mg, 3.66 mmol, 3.0 eq) were added, and the mixture was stirred at room temperature for 2 h. Water was added, the mixture was separated, and the aqueous phase was extracted with DCM (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by silica gel column chromatography (DCM:MeOH = 50:1 to 10:1) to give the product (192 mg, yield: 40.8%).

[0457] Step 2: Synthesis of (R)-5-ethynyl-2-(5-methyl-3-((1-(methyl-d3)piperidin-3-yl)amino)-1,2,4-triazin-6-yl)phenol [ka] (R)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-N-(1-(methyl-d3)piperidin-3-yl)-1,2,4-triazin-3-amine (192 mg, 0.499 mmol, 1.0 eq) was dissolved in DCM (3 mL). Then, a solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 0.50 mL, 2.00 mmol, 4.0 eq) was added dropwise and stirred at room temperature for 1 h. The pH was adjusted to 8 with saturated aqueous NaHCO3, and the mixture was extracted with DCM (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by silica gel column chromatography (DCM:MeOH = 50:1 to 10:1) to give the product (108 mg, yield: 66.3%).

[0458] 1HNMR (400 MHz, DMSO-d6) δ(ppm): 10.10 (s, 1H), 7.45 (s, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.04-7.02 (m, 2H), 4.22 (s, 1H), 3.99 (s, 1H), 2.87 (s, 1H), 2.63 (d, J = 10.8 Hz, 1H), 2.18 (s, 3H), 1.90-1.84 (m, 3H), 1.72-1.68 (m, 1H), 1.58-1.49 (m, 1H), 1.35-1.29 (m, 1H). Molecular formula:C 18 H 18 D3N5O Precise molecular weight: 326.19 LC-MS(Pos, m / z)=327.24[M+H] + .

[0459] Example 43: Synthesis of 2-(4-difluoromethyl-6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)pyridazin-3-yl)-5-ethynylphenol (Compound 102) [ka]

[0460] Step 1: Synthesis of intermediate 3,6-dichloro-4-difluoromethylpyridazine [ka] 3,6-Dichloropyridazine (30.0 g, 148.98 mmol, 1.0 eq) was dissolved in water (800 mL), difluoroacetic acid (38.6 g, 402 mmol, 2.0 eq) and silver nitrate (34.2 g, 201 mmol, 1.0 eq) were added, and concentrated sulfuric acid (33 mL, 603 mmol, 3.0 eq) was added dropwise to the reaction solution at 50 °C. After the addition was completed, the temperature was raised to 60 °C, and an aqueous solution (400 mL) of ammonium persulfate (137.6 g, 603 mmol, 3.0 eq) was added dropwise to the reaction solution. After the addition was completed, the temperature was raised to 70 °C and the reaction was allowed to proceed for 5 min. The reaction mixture was adjusted to pH 8 with 15% aqueous sodium hydroxide solution and extracted with ethyl acetate (500 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1) to obtain the product (8.98 g, yield: 22.5%).

[0461] Step 2: Synthesis of intermediate (cis)-3-((6-chloro-5-difluoromethylpyridazin-3-yl)amino)-1-methylcyclobutan-1-ol [ka] 3,6-Dichloro-4-difluoromethylpyridazine (3.3 g, 16.58 mmol, 1.0 eq) was dissolved in n-butanol (33 mL), and (cis)-3-amino-1-methylcyclobutan-1-ol hydrochloride (4.56 g, 33.16 mmol, 2.0 eq) and N,N-diisopropylethylamine (8.57 g, 66.32 mmol, 4.0 eq) were added. The mixture was incubated at 120 °C for 1 h, and TLC showed completion of the reaction. The reaction mixture was concentrated, water (50 mL) was added, and the mixture was extracted with dichloromethane (50 mL × 10). The combined organic phases were dried over anhydrous magnesium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 to 1:1) to give the product (1.35 g, yield: 30.9%).

[0462] Step 3: Synthesis of intermediate 4-(4-difluoromethyl-6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)pyridazin-3-yl)-3-(ethoxymethoxy)benzaldehyde [ka] (cis)-3-((6-chloro-5-difluoromethylpyridazin-3-yl)amino)-1-methylcyclobutan-1-ol (200 mg, 0.759 mmol, 1.0 eq) was dissolved in 1,4-dioxane (2 mL), and 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (349 mg, 1.139 mmol, 1.5 eq), potassium carbonate (210 mg, 1.518 mmol, 2.0 eq), tetrakis(triphenylphosphine)palladium (88 mg, 0.0759 mmol, 0.1 eq) and water (0.5 mL) were added. The mixture was heated to 90 °C under nitrogen gas protection and reacted for 6 h. The reaction was complete as detected by TLC. The reaction mixture was filtered through diatomaceous earth, the filter cake was washed with dichloromethane (20 mL), the filtrate was dried over anhydrous magnesium sulfate, filtered, and concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:2) to obtain the product (178 mg, yield: 57.6%).

[0463] Step 4: Synthesis of intermediate (cis)-3-((5-difluoromethyl-6-(2-ethoxymethoxy-4-ethynylphenyl)pyridazin-3-yl)amino)-1-methylcyclobutan-1-ol [ka] 4-(4-Difluoromethyl-6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)pyridazin-3-yl)-3-(ethoxymethoxy)benzaldehyde (178 mg, 0.437 mmol, 1.0 eq) was dissolved in methanol (3 mL), and potassium carbonate (121 mg, 0.874 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (126 mg, 0.656 mmol, 1.5 eq) were added sequentially. The reaction was allowed to proceed at 25 °C for 2 h, and completion of the reaction was confirmed by TLC. The reaction mixture was concentrated, water (20 mL) was added, and the mixture was extracted with dichloromethane (10 mL × 2). The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated to give the product (117 mg, yield: 66.5%).

[0464] Step 5: Synthesis of compound 2-(4-difluoromethyl-6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)pyridazin-3-yl)-5-ethynylphenol [ka] (cis)-3-((5-difluoromethyl-6-(2-ethoxymethoxy-4-ethynylphenyl)pyridazin-3-yl)amino)-1-methylcyclobutan-1-ol (117 mg, 0.29 mmol, 1.0 eq) was dissolved in dichloromethane (1 mL) and added dropwise to trifluoroacetic acid (1 mL). The reaction was allowed to proceed at 25°C for 10 min, and completion of the reaction was detected by TLC. The reaction mixture was concentrated, and the crude product was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 1:2) to give the product (37 mg, yield: 37.0%).

[0465] 1H-NMR (400 MHz, DMSO-d6) δ(ppm): 10.24 (s, 1H), 7.49-7.48 (d, 1H), 7.27-7.25 (d, 1H), 7.04-7.00 (m, 3H), 6.77 (t, J=54.6 Hz, 1H), 5.06 (s, 1H), 4.32 (s, 1H), 4.06-3.98 (m, 1H), 2.47-2.42 (m, 2H), 1.99-1.95 (m, 2H), 1.30 (s, 3H). Molecular formula:C 18 H 17 F2N3O2 precise molecular weight: 345.13 LC-MS(m / z): 346.15 [M+H] + .

[0466] Example 44: Synthesis of 2-(4,5-bis(difluoromethyl)-6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)pyridazin-3-yl)-5-ethynylphenol (Compound 110) [ka]

[0467] Step 1: Synthesis of intermediate 3,6-dichloro-4,5-bis(difluoromethyl)pyridazine [ka] 3,6-Dichloropyridazine (30.0 g, 148.98 mmol, 1.0 eq) was dissolved in water (800 mL), difluoroacetic acid (38.6 g, 402 mmol, 2.0 eq) and silver nitrate (34.2 g, 201 mmol, 1.0 eq) were added, and concentrated sulfuric acid (33 mL, 603 mmol, 3.0 eq) was added dropwise to the reaction solution at 50 °C. After the addition was completed, the temperature was raised to 60 °C, and an aqueous solution (400 mL) of ammonium persulfate (137.6 g, 603 mmol, 3.0 eq) was added dropwise to the reaction solution. After the addition was completed, the temperature was raised to 70 °C and the reaction was allowed to proceed for 5 min. The pH was adjusted to 8 with 15% aqueous sodium hydroxide solution, extracted with ethyl acetate (500 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1) to obtain the product (9.15 g, yield: 18.3%).

[0468] Step 2: Synthesis of intermediate (cis)-3-((6-chloro-4,5-bis(difluoromethyl)pyridazin-3-yl)amino)-1-methylcyclobutan-1-ol [ka] 3,6-Dichloro-4,5-bis(difluoromethyl)pyridazine (2.5 g, 10.04 mmol, 1.0 eq) was dissolved in n-butanol (20 mL), and (cis)-3-amino-1-methylcyclobutan-1-ol hydrochloride (2.76 g, 20.08 mmol, 2.0 eq) and N,N-diisopropylethylamine (5.19 g, 40.16 mmol, 4.0 eq) were added. The mixture was incubated at 120 °C for 0.5 h, and completion of the reaction was confirmed by TLC. The reaction mixture was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 to 2:1) to give the product (232 mg, yield: 7.3%).

[0469] Step 3: Synthesis of intermediate 4-(4,5-bis(difluoromethyl)-6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)pyridazin-3-yl)-3-(ethoxymethoxy)benzaldehyde [ka] (cis)-3-((6-chloro-4,5-bis(difluoromethyl)pyridazin-3-yl)amino)-1-methylcyclobutan-1-ol (212 mg, 0.676 mmol, 1.0 eq) was dissolved in 1,4-dioxane (2 mL), and 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (310 mg, 1.014 mmol, 1.5 eq), potassium carbonate (187 mg, 1.352 mmol, 2.0 eq), tetrakis(triphenylphosphine)palladium (78 mg, 0.0676 mmol, 0.1 eq), and water (0.5 mL) were added. The mixture was heated to 90 °C under nitrogen gas protection and reacted for 1 h. The reaction was complete as detected by TLC. The reaction mixture was filtered through diatomaceous earth, the filter cake was washed with dichloromethane (10 mL), the filtrate was dried over anhydrous magnesium sulfate, filtered, and concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=3:1) to give the product (188 mg, yield: 60.8%).

[0470] Step 4: Synthesis of intermediate (cis)-3-((4,5-bis(difluoromethyl)-6-(2-ethoxymethoxy-4-ethynylphenyl)pyridazin-3-yl)amino)-1-methylcyclobutan-1-ol [ka] 4-(4,5-Bis(difluoromethyl)-6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)pyridazin-3-yl)-3-(ethoxymethoxy)benzaldehyde (188 mg, 0.41 mmol, 1.0 eq) was dissolved in methanol (2 mL)...

Claims

1. A compound represented by general formula (A') or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a deuterated derivative thereof, 【Chemical 1】 Here, W is 【Chemistry 2】 Selected from 【Chemistry 3】 is selected from a single bond or a double bond, R １ are independently hydrogen, a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen, C １－６ Alkyl group, halogenated C １－６ Alkyl group, C １－６ Alkoxy group, halogenated C １－６ Alkoxy group, C ２－６ Alkenyl group, C ２－６ an alkynyl group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, a 5- to 7-membered heteroaryl group, —N(C １－６ alkyl) ２ , -S-C １－６ alkyl groups or absent; R ２ are independently hydrogen, a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen, C １－６ Alkyl group, halogenated C １－６ Alkyl group, C １－６ Alkoxy group, halogenated C １－６ Alkoxy group, C ２－６ Alkenyl group, C ２－６ an alkynyl group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, a 5- to 7-membered heteroaryl group, —N(C １－６ alkyl) ２ , -S-C １－６ alkyl groups or absent; R １ , R ２ each optionally represents a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen, a carbonyl group, C １－６ Alkyl group, halogenated C １－６ Alkyl group, C １－６ Alkoxy group, halogenated C １－６ substituted by 1 to 3 substituents selected from an alkoxy group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group; or R １ , R ２ form a 5- to 12-membered ring A together with the C or N atom bonded thereto, and the 5- to 12-membered ring A optionally contains a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen, a carbonyl group, an oxo group, C １－６ Alkyl group, —NH—C １－６ Alkyl group, halogenated C １－６ Alkyl group, C １－６ Alkoxy group, halogenated C １－６ an alkoxy group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, a 5- to 7-membered heteroaryl group, C １－６ Alkylsulfonyl group, —N(C １－６ alkyl) ２ the 5- to 12-membered ring is selected from a 5- to 12-membered cycloalkyl group, a 5- to 7-membered cycloalkyl group, a 5- to 12-membered cycloalkenyl group, a 5- to 7-membered cycloalkenyl group, a 6- to 12-membered fused cycloalkyl group, a 5- to 12-membered heterocyclic group, a 5- to 7-membered heterocyclic group, a 6- to 12-membered fused heterocycle, an aryl group, a 5- to 12-membered heteroaryl group, an 8- to 12-membered fused heteroaryl group, and a 5- to 7-membered heteroaryl group; R ３ is -(C １－６ alkylene) ０－２ -NR ４ R ５ , -(C １－６ alkylene) ０－２ -NR ４ -COR ５ , -(C １－６ alkylene) ０－２ -CO-NR ４ -R ５ , -(C １－６ alkylene) ０－２ -NR ４ -C １－６ Alkylene-R ５ Selected from R ４ is hydrogen or C １－６ alkyl groups, R ５ is selected from a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group, and ５ is optionally a halogen, a cyano group, an amino group, a hydroxy group, C １－６ Alkyl group, halogenated C １－６ Alkyl group, C １－６ an alkoxy group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, a 5- to 7-membered heteroaryl group, C ２－６ Alkenylcarbonyl group, sulfonyl group, C １－６ Alkylcarbonyl group, ureido C １－６ Alkyl group, hydroxy C １－６ Alkyl group, hydrazino group, C １－６ Alkylsulfonyl C １－６ substituted with 1 to 4 substituents selected from alkyl groups; R ５ The substituent in １－６ Alkyl group, halogenated C １－６ Alkyl group, C １－６ alkoxy groups, 3- to 7-membered heterocyclic groups, 3- to 7-membered cycloalkyl groups, aryl groups, 5- to 7-membered heteroaryl groups, and sulfonyl groups, and the substituents are optionally selected from halogen, cyano groups, amino groups, hydroxy groups, carbonyl groups, C １－６ Alkyl group, 3- to 6-membered cycloalkyl group, C １－６ substituted by 1 to 3 substituents selected from alkylsulfonyl groups; Y is selected from an aryl group, a 5- to 14-membered heteroaryl group, a 3- to 14-membered heterocyclic group, and a 3- to 12-membered cycloalkyl group; The Y is C ２－６ Alkenyl group, C ２－６ alkynyl groups, and optionally further substituted with 1 to 2 substituents selected from halogen, cyano group, amino group, hydroxy group, carbonyl group, C １－６ Alkyl group, halogenated C １－６ Alkyl group, C １－６ an alkoxy group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, a 5- to 7-membered heteroaryl group, C １－６ Alkylamino group, C １－６ Alkylcarbonylamino group, C １－６ Alkyl sulfonyl group, aminocarbonyl group, C １－６ Alkylaminocarbonyl group, sulfonyl group, —N(C １－６ alkyl) ２ , -S-C １－６ may be substituted with 1 to 2 substituents selected from alkyl groups, The substituents on Y are C １－６ Alkyl group, halogenated C １－６ Alkyl group, C １－６ alkoxy groups, 3- to 7-membered heterocyclic groups, 3- to 7-membered cycloalkyl groups, aryl groups, 5- to 7-membered heteroaryl groups, and sulfonyl groups, and the substituents are optionally selected from halogen, cyano groups, amino groups, hydroxy groups, carbonyl groups, C １－６ substituted with 1 to 3 substituents selected from an alkyl group and a 3- to 6-membered cycloalkyl group; The substituents on Y are C ２－６ Alkenyl group, C ２－６ alkynyl groups, the substituents of which are optionally selected from halogen, cyano, amino, hydroxy, carbonyl, C １－６ Alkyl groups, 3- to 6-membered cycloalkyl groups, halogenated C １－６ substituted with 1 to 3 substituents selected from alkyl groups; W is, 【Chemistry 4】 When selected from １ , R ２ do not form a ring with the C bonded thereto, The compound or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a deuterated product thereof.

2. W is 【Chemistry 5】 Selected from R １ represents hydrogen, a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen, a carbonyl group, a halogenated C １－６ Alkyl group, halogenated C １－６ Alkoxy group, C ２－６ Alkenyl group, C ２－６ selected from an alkynyl group, a 3- to 7-membered heterocyclic group, a 4- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group; 2. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof.

3. W is 【Chemistry 6】 Selected from Y is selected from an aryl group, a 5- to 14-membered heteroaryl group, a 3- to 14-membered heterocyclic group, and a 3- to 12-membered cycloalkyl group; The Y is C ２－６ alkynyl groups, and further optionally substituted with halogen, cyano, amino, hydroxy, carbonyl, C １－６ Alkyl group, halogenated C １－６ Alkyl group, C １－６ an alkoxy group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, a 5- to 7-membered heteroaryl group, C １－６ Alkylamino group, C １－６ Alkylcarbonylamino group, C １－６ Alkyl sulfonyl group, aminocarbonyl group, C １－６ Alkylaminocarbonyl group, sulfonyl group, —N(C １－６ alkyl) ２ , -S-C １－６ may be substituted with 1 to 2 substituents selected from alkyl groups, The substituents on Y are C １－６ Alkyl group, halogenated C １－６ Alkyl group, C １－６ alkoxy groups, 3- to 7-membered heterocyclic groups, 3- to 7-membered cycloalkyl groups, aryl groups, 5- to 7-membered heteroaryl groups, and sulfonyl groups, and the substituents are optionally selected from halogen, cyano groups, amino groups, hydroxy groups, carbonyl groups, C １－６ substituted with 1 to 3 substituents selected from an alkyl group and a 3- to 6-membered cycloalkyl group; The substituents on Y are C ２－６ alkynyl groups, the substituents of which are optionally selected from halogen, cyano, amino, hydroxy, carbonyl, C １－６ Alkyl groups, 3- to 6-membered cycloalkyl groups, halogenated C １－６ substituted with 1 to 3 substituents selected from alkyl groups; R ５ is optionally hydroxy C １－６ Alkyl group, C １－６ Alkoxy C １－６ Alkyl group, hydrazino group, ureido C １－６ substituted with a substituent selected from alkyl groups; 2. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof.

4. W is 【Chemistry 7】 Selected from Y is selected from an aryl group, a 5- to 14-membered heteroaryl group, a 3- to 14-membered heterocyclic group, and a 3- to 12-membered cycloalkyl group; The Y is C ２－６ and optionally further substituted with halogen, cyano, amino, hydroxy, carbonyl, C １－６ Alkyl group, halogenated C １－６ Alkyl group, C １－６ an alkoxy group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, a 5- to 7-membered heteroaryl group, C １－６ Alkylamino group, C １－６ Alkylcarbonylamino group, C １－６ Alkyl sulfonyl group, aminocarbonyl group, C １－６ Alkylaminocarbonyl group, sulfonyl group, —N(C １－６ alkyl) ２ , -S-C １－６ may be substituted with 1 to 2 substituents selected from alkyl groups, The substituents on Y are C １－６ Alkyl group, halogenated C １－６ Alkyl group, C １－６ alkoxy groups, 3- to 7-membered heterocyclic groups, 3- to 7-membered cycloalkyl groups, aryl groups, 5- to 7-membered heteroaryl groups, and sulfonyl groups, and the substituents are optionally selected from halogen, cyano groups, amino groups, hydroxy groups, carbonyl groups, C １－６ substituted with 1 to 3 substituents selected from an alkyl group and a 3- to 6-membered cycloalkyl group; The substituents on Y are C ２－６ alkenyl groups, the substituents of which are optionally selected from halogen, cyano, amino, hydroxy, carbonyl, C １－６ Alkyl groups, 3- to 6-membered cycloalkyl groups, halogenated C １－６ substituted with 1 to 3 substituents selected from alkyl groups; R ５ is selected from a 3- to 7-membered heterocyclic group, a 5- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group, and ５ is optionally a halogen, a cyano group, an amino group, a hydroxy group, C １－６ Alkyl group, halogenated C １－６ Alkyl group, C １－６ an alkoxy group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, a 5- to 7-membered heteroaryl group, C ２－６ Alkenylcarbonyl group, sulfonyl group, C １－６ Alkylcarbonyl group, ureido C １－６ Alkyl group, hydroxy C １－６ Alkyl group, hydrazino group, C １－６ Alkylsulfonyl C １－６ substituted with 1 to 4 substituents selected from alkyl groups; 2. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof.

5. W is 【Chemistry 8】 Selected from R １ , R ２ At least one of ２－６ Alkenyl group, C ２－６ an alkynyl group, and a cyano group; R １ , R ２ each optionally represents a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen, a carbonyl group, C １－６ Alkyl group, halogenated C １－６ Alkyl group, C １－６ Alkoxy group, halogenated C １－６ substituted by 1 to 3 substituents selected from an alkoxy group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group; 2. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof.

6. W is 【Chemistry 9】 Selected from R １ is selected from hydrogen, R ２ is selected from hydrogen, 2. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof.

7. W is 【Chemistry 10】 Selected from Y is selected from an aryl group, a 5- to 14-membered heteroaryl group, a 3- to 14-membered heterocyclic group, and a 3- to 12-membered cycloalkyl group; The Y is substituted with a propynyl group and may further optionally be substituted with a halogen, a cyano group, an amino group, a hydroxy group, a carbonyl group, a C １－６ Alkyl group, halogenated C １－６ Alkyl group, C １－６ an alkoxy group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, a 5- to 7-membered heteroaryl group, C １－６ Alkylamino group, C １－６ Alkylcarbonylamino group, C １－６ Alkyl sulfonyl group, aminocarbonyl group, C １－６ Alkylaminocarbonyl group, sulfonyl group, —N(C １－６ alkyl) ２ , -S-C １－６ may be substituted with 1 to 2 substituents selected from alkyl groups, The substituents on Y are C １－６ Alkyl group, halogenated C １－６ Alkyl group, C １－６ alkoxy groups, 3- to 7-membered heterocyclic groups, 3- to 7-membered cycloalkyl groups, aryl groups, 5- to 7-membered heteroaryl groups, and sulfonyl groups, and the substituents are optionally selected from halogen, cyano groups, amino groups, hydroxy groups, carbonyl groups, C １－６ substituted with 1 to 3 substituents selected from an alkyl group and a 3- to 6-membered cycloalkyl group; The substituents on Y are selected from propynyl groups, and the substituents are optionally selected from halogen, cyano, amino, hydroxy, carbonyl, C １－６ Alkyl groups, 3- to 6-membered cycloalkyl groups, halogenated C １－６ substituted with 1 to 3 substituents selected from alkyl groups; R ５ is selected from 3- to 7-membered cycloalkyl groups; 2. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof.

8. R ５ is selected from a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group, and ５ is deuterium, deuterated C １－６ Alkyl group, ethyl group, cyclopropyl group, halogen, halogenated C １－６ substituted with 1 to 2 substituents selected from alkyl groups; 2. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof.

9. W is 【Chemistry 11】 Selected from R ５ is selected from a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group, and ５ is deuterium, hydroxy C １－６ substituted with 1 to 2 substituents selected from alkyl groups; 2. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof.

10. Y is selected from aryl groups; The Y is C ２－６ Alkenyl group, C ２－６ alkynyl groups, and further hydroxy groups, halogens, halogenated C １－６ may be substituted with 1 to 2 substituents selected from alkyl groups; 2. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof.

11. W is 【Chemistry 12】 Selected from R ２ is hydrogen, R １ is not selected from a methyl group and a cyclopropyl group, 2. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof.

12. R ５ is optionally hydroxy C １－６ Alkyl group, C １－６ Alkoxy C １－６ The alkyl group is substituted with a substituent selected from the group consisting of alkyl groups, but does not include the following compounds: 【Chemistry 13】 The compound according to claim 3, or a pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof.

13. W is 【Chemistry 14】 Selected from R １ are independently hydrogen, halogen, C １－６ Alkyl group, halogenated C １－６ selected from alkyl groups and 3- to 7-membered cycloalkyl groups; R ３ is -(C １－６ alkylene) ０－２ -NR ４ R ５ Selected from R ４ is hydrogen or C １－６ alkyl groups, R ５ is selected from a 3- to 7-membered heterocyclic group and a 3- to 7-membered cycloalkyl group, ５ is optionally a deuterated C １－６ Alkyl group, C １－６ Alkyl group, halogenated C １－６ Alkyl group, 3- to 7-membered cycloalkyl group, hydroxy group, hydroxy C １－６ substituted with 1 to 4 substituents selected from alkyl groups; Y is selected from aryl groups; The Y is C ２－６ alkynyl groups, and optionally further substituted with hydroxy groups, C １－６ Alkyl group, halogenated C １－６ It may be substituted with 1 to 2 substituents selected from an alkyl group and a 3- to 7-membered cycloalkyl group, Said C ２－６ Substituents for the alkynyl group are optionally halogen, C １－６ Alkyl groups, 3- to 6-membered cycloalkyl groups, halogenated C １－６ substituted with a substituent selected from alkyl groups; 2. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof.

14. R １ , R ２ is hydrogen, halogen, C １－６ selected from an alkyl group, a trifluoromethyl group, a difluoromethyl group, a cyclopropyl group, and a cyclobutyl group; R ３ is -NR ４ R ５ Selected from R ４ is selected from hydrogen or a methyl group, R ５ is selected from piperidine, a cyclohexyl group, a cyclopentyl group, and a cyclobutyl group; Y is selected from a benzene ring; The Y is substituted with a substituent selected from an ethynyl group and a propynyl group, and further optionally, a hydroxy group, C １－６ optionally substituted with 1 to 2 substituents selected from an alkyl group, a trifluoromethyl group, a difluoromethyl group, and a cyclopropyl group; The substituents of the ethynyl group and the propynyl group may optionally be halogen, C １－６ substituted with a substituent selected from an alkyl group, a cyclopropyl group, a trifluoromethyl group, and a difluoromethyl group; 14. The compound according to claim 12 or 13, or a pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof.

15. R １ , R ２ is selected from a methyl group, a trifluoromethyl group, a difluoromethyl group, and a cyclopropyl group; R ３ is -NR ４ R ５ Selected from R ４ is selected from hydrogen, R ５ is selected from a piperidinyl group, Y is selected from a benzene ring; Y is substituted with a substituent selected from an ethynyl group and a propynyl group, and may further optionally be substituted with 1 to 2 substituents selected from a hydroxy group, a methyl group, a trifluoromethyl group, a difluoromethyl group, and a cyclopropyl group; the substituent of the ethynyl group or propynyl group is optionally substituted with a substituent selected from fluorine, a methyl group, a cyclopropyl group, a trifluoromethyl group, and a difluoromethyl group; R ５ The substituents in are selected from methyl, ethyl, cyclopropyl, fluorine, chlorine, bromine, difluoroethane, and hydroxyethyl groups; 15. The compound according to claim 14, or a pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof.

16. The compounds described below or pharmaceutically acceptable salts thereof, stereoisomers thereof, and deuterated derivatives thereof. 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 【Chemistry 18】 【Chemistry 19】 【Chemistry 20】 【Chemical 21】 【Chemical 22】 【Chemical 23】 【Chemistry 24】 【Chemistry 25】 【Chemical Formula 26】 【Chemical 27】 【Chemical Formula 28】 【Chemical Formula 29】 【Chemistry 30】 【Chemical 31】

17. 17. A pharmaceutical composition comprising the compound of any one of claims 1 to 16 or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, and a pharmaceutically acceptable carrier.

18. Use of a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, stereoisomer, or deuterated derivative thereof, or a pharmaceutical composition according to claim 17, in the manufacture of a drug for preventing and / or treating a disease associated with NLRP3 inflammasome.

19. Use of a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt, stereoisomer, or deuterated derivative thereof, or a pharmaceutical composition according to claim 17, in the manufacture of a drug for preventing and / or treating an inflammasome-related disease, an immune disease, an inflammatory disease, an autoimmune disease, or an autoinflammatory disease.

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