NLRP3 inhibitors inflammasomes and pharmaceuticals containing these compounds.

Abstract

The invention is in the field of pharmaceutical engineering and relates to an NLRP3 inflammasome inhibitor. Specifically, the invention relates to a compound represented by general formula (I), or its deuterized compound, its stereoisomer, or its pharmaceutical salt. The definition of each group is as defined in the description. Studies show that the compound represented by general formula (I), or its deuterized compound, its stereoisomer, or its pharmaceutical salt has relatively high biological activity against NLRP3 inflammasome, and has significant clinical development value for the treatment of NLRP3 YW-R3(I)-related disease.

Description

NLRP3 inflammasome inhibitors and their applications

[0001] Citation of Related Applications

[0002] The present invention claims priority to invention patent application number 202311008972.0, entitled “NLRP3 inflammasome inhibitors and their applications”, filed in China on August 11, 2023, and the entire contents of the patent application are incorporated herein by reference. Technical Field

[0003] The present invention belongs to the field of medical technology, and specifically relates to NLRP3 inflammasome inhibitors and applications thereof. Background Art

[0004] Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) belongs to the nucleotide-binding oligomerization domain-like receptor (NLR) 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 leucine-rich repeats (LRRs). When stimulated by sterile inflammatory danger signals, NLRP3 interacts with the adaptor proteins apoptosis-associated speck-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).

[0005] The activation of the NLRP3 inflammasome typically requires two steps. The first step involves triggering signals, in which Toll-like receptors recognize pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), which then transmit the signal into the cell, mediating the activation of the NF-κB signaling pathway, and then upregulating the transcriptional levels of NLRP3 inflammasome-related components, including inactive NLRP3 and pro-IL-1β. The second step is the activation signal. After receiving signals such as ATP and nigericin, the P2X7 receptor and other receptors oligomerize the 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, as well as the production and secretion of mature IL-1β and IL-18.

[0006] Activation of the NLRP3 inflammasome is associated with a variety of diseases, including autoinflammatory febrile syndromes such as cryopyrin-associated periodic syndrome (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 scarring, and cancer (e.g., colorectal cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), and myelofibrosis). Most treatments involve symptomatic treatment, slowing the progression of the disease / disorder, and surgery as a last resort.

[0007] Currently, there are relatively few NLRP3 inflammasome inhibitors under development, and developing NLRP3 inflammasome inhibitors with higher activity and better drugability has become a clinical need.

[0008] Summary of the Invention

[0009] The present invention studies the following compound, or a deuterated compound, or a stereoisomer, or a pharmaceutically acceptable salt thereof. The study found that the compound, or a deuterated compound, or a stereoisomer, or a pharmaceutically acceptable salt thereof has high biological activity against the NLRP3 inflammasome and has important clinical development value for the treatment of NLRP3-related diseases.

[0010] To achieve the above object, the present invention provides the following solutions:

[0011] The compound represented by general formula (I), or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0012] YW-R3

[0013] (I)

[0014] Wherein, W is selected from or

[0015] is selected from a single bond or a double bond;

[0016] R1 is independently selected from hydrogen, oxo, thio, hydroxy, amino, carboxyl, cyano, nitro, halogen, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, halogenated C 1-6Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl, aryl, 5-7 membered heteroaryl, sulfonyl, -N(C 1-6 Alkyl)2 or not present;

[0017] R2 is independently selected from hydrogen, oxo, thio, hydroxy, amino, carboxyl, cyano, nitro, halogen, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl, aryl, 5-7 membered heteroaryl, sulfonyl, -N(C 1-6 Alkyl)2 or not present;

[0018] The R1 and R2 are independently optionally replaced by 1-3 groups selected from hydroxyl, C 0-6 Alkylamino, carboxyl, cyano, nitro, halogen, C 0-6 Alkylcarbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl, aryl, 5-7 membered heteroaryl, C 0-6 Substitution of the alkylsulfonyl group by substituents;

[0019] or

[0020] R1, R2 and the C or N atom to which they are attached form a 5-12 membered ring A;

[0021] The 5-12 membered ring A is optionally substituted by 1-4 groups selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen, carbonyl, oxo, C 1-6 Alkyl, -NH-C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C 1-6 Alkylsulfonyl, -N(C 1-6 alkyl)2 is substituted with a substituent;

[0022] R3 is selected from -(CH2) n-NR4-Z-(CH2) m -R5, -(CH2) n -NR4-Z-CR c R d -R5;

[0023] n is an integer from 0 to 6;

[0024] m is an integer from 0 to 3;

[0025] R4 is selected from hydrogen or C 1-6 alkyl;

[0026] Z is selected from C=O, C=S, S(O) or S(O)2;

[0027] R5 is selected from 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl, aryl, 5-7 membered heteroaryl, NR a R b , OR b 、C 1-6 alkyl;

[0028] R a 、R c Selected from hydrogen or C 1-6 alkyl;

[0029] R b 、R d Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl, aryl, 5-7 membered heteroaryl, sulfonyl, -N(C 1-6 Alkyl)2;

[0030] The R b Optionally substituted by 1-2 groups selected from hydroxy, halogen, 3-7 membered cycloalkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy substituent substitution;

[0031] The R d Optionally substituted by 1-2 groups selected from hydroxy, halogen, 3-7 membered cycloalkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, aryl, cyano, and carboxyl substituents;

[0032] or

[0033] R c 、Rd Together with the C atoms to which they are attached, they form a 3-7 membered cycloalkyl group;

[0034] or

[0035] When R5 is selected from NR a R b When R a Connected with R4 to form a 4-7 membered heterocyclic group with R3;

[0036] The R5 is optionally substituted by 1-4 groups selected from oxo, thio, hydroxy, amino, carboxyl, cyano, nitro, halogen, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl, aryl, 5-7 membered heteroaryl, sulfonyl, ureido, hydrazine substituents;

[0037] The substituents on R5 may be further optionally replaced by 1-3 groups selected from hydroxyl, C 0-6 Alkylamino, carboxyl, cyano, nitro, halogen, C 0-6 Alkylcarbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-6 membered heterocyclyl, 3-6 membered cycloalkyl, 5-6 membered cycloalkenyl, aryl, 5-7 membered heteroaryl, C 0-6 Alkylsulfonyl, urea, hydrazine substituents substitution;

[0038] Y is selected from aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl;

[0039] The Y is optionally substituted by 1-4 groups selected from oxo, thio, hydroxy, amino, carboxyl, cyano, nitro, halogen, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl, aryl, 5-7 membered heteroaryl, sulfonyl substituents;

[0040] The substituents on Y may be further optionally substituted by 1-3 groups selected from hydroxyl, C 0-6 Alkylamino, carboxyl, cyano, nitro, halogen, C 0-6 Alkylcarbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-6 membered heterocyclyl, 3-7 membered cycloalkyl, 5-6 membered cycloalkenyl, aryl, 5-7 membered heteroaryl, C 0-6 Alkylsulfonyl substituents are substituted.

[0041] In any of the above technical solutions, wherein W is selected from

[0042] In any of the above technical solutions,

[0043] R1 is independently selected from hydrogen, oxo, thio, hydroxy, amino, carboxyl, cyano, nitro, halogen, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl, aryl, 5-7 membered heteroaryl, sulfonyl;

[0044] R2 is independently selected from hydrogen, oxo, thio, hydroxy, amino, carboxyl, cyano, nitro, halogen, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl, aryl, 5-7 membered heteroaryl, sulfonyl;

[0045] The R1 and R2 are independently optionally replaced by 1-3 groups selected from hydroxyl, C 0-6 Alkylamino, carboxyl, cyano, nitro, halogen, C 0-6 Alkylcarbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl, aryl, 5-7 membered heteroaryl, C 0-6 Alkylsulfonyl substituents are substituted.

[0046] In any of the above technical solutions, R1 and R2 are independently selected from hydrogen, cyano, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-7 membered cycloalkyl, -N(C 1-6 alkyl)2 or not present, preferably, R1, R2 are independently selected from hydrogen, cyano, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, cyclopropyl, cyclobutyl or not present.

[0047] In any of the above technical solutions, R1 and R2 are independently selected from hydrogen, hydroxyl, amino, cyano, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered cycloalkyl, sulfonyl, preferably, R1, R2 are independently selected from hydrogen, amino, cyano, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered cycloalkyl, further preferably, R1, R2 are independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, 3-7 membered cycloalkyl, more preferably, R1, R2 are independently selected from hydrogen, methyl, ethyl, trifluoromethyl, cyclopropyl, cyclobutyl, when R1, R2 are independently selected from amino, R1, R2 can be further C 1-6 In any of the above technical solutions, R1 and R2 are independently selected from hydrogen and halogen, preferably, R1 and R2 are independently selected from hydrogen, fluorine, chlorine and bromine.

[0048] In any of the above technical solutions, R1 and R2 are independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, preferably, R1 and R2 are independently selected from methyl, ethyl, isopropyl, butyl, and methoxy.

[0049] In any of the above technical solutions, R1 and R2 are independently selected from halogenated C 1-6 Alkyl, preferably, R1 and R2 are independently selected from trifluoromethyl and difluoromethyl.

[0050] In any of the above technical solutions, R1 and R2 are independently selected from 3-7 membered cycloalkyl and halogenated 3-7 membered cycloalkyl. Preferably, R1 and R2 are independently selected from cyclopropyl and cyclobutyl.

[0051] In any of the above technical solutions, R1, R2 and the C or N atom to which they are connected form a 5-12 membered ring A;

[0052] In some embodiments, the compound provided by the present invention, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, has a structure represented by formula (II):

[0053] wherein Ring A is selected from 5-7 membered cycloalkenyl, 5-7 membered cycloalkyl, 5-7 membered heterocyclyl, phenyl, 5-7 membered heteroaryl; Ring A is optionally substituted by 1-4 groups selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, -NH-C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C 1-6 Alkylsulfonyl, -N(C 1-6 alkyl)2 is substituted with a substituent.

[0054] Further, the ring A is selected from phenyl, 5-7 membered cycloalkyl, 5-7 membered heteroaryl; the ring A is optionally substituted by 1-4 groups selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, -NH-C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group, C 1-6 Alkylsulfonyl, -N(C 1-6 alkyl)2 is substituted with a substituent.

[0055] Furthermore, the ring A is selected from Ring A is optionally substituted by 1-2 groups selected from cyano, halogen, C 1-6 Alkyl, -NH-C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered cycloalkyl, 5-7 membered heteroaryl, C 1-6 Alkylsulfonyl, -N(C 1-6 alkyl)2 is substituted with a substituent.

[0056] In any of the above technical solutions, wherein R3 is selected from -(CH2) n -NR4-Z-(CH2) m -R5, -(CH2) n -NR4-Z-CR c R d -R5;

[0057] n is an integer from 0 to 2;

[0058] m is an integer from 0 to 2;

[0059] R4 is selected from hydrogen or C 1-6 alkyl;

[0060] Z is selected from C=O;

[0061] R5 is selected from 3-7 membered heterocyclic group, NR a R b , OR b 、C 1-6 alkyl;

[0062] R a 、R c Selected from hydrogen or C 1-6 alkyl;

[0063] R b 、R d Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, halogenated C 1-6 Alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl;

[0064] The R b Optionally substituted by 1-2 groups selected from hydroxy, halogen, 3-7 membered cycloalkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy substituent substitution;

[0065] The R d Optionally substituted by 1-2 groups selected from hydroxy, halogen, 3-7 membered cycloalkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, aryl, cyano, carboxyl substituents.

[0066] Further, among them,

[0067] n is 0;

[0068] m is 0;

[0069] R5 is selected from 3-7 membered heterocyclic group;

[0070] The R5 is optionally substituted by 1-4 groups selected from hydroxyl, amino, carboxyl, cyano, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic, 3-7 membered cycloalkyl, aryl substituents;

[0071] Furthermore, R5 is a 4-7 membered heterocyclic group containing 1 to 2 heteroatoms selected from O, N, and S. Preferably, R5 is a 4-7 membered heterocyclic group containing 1 N heteroatom. Preferably, R5 is selected from

[0072] The substituents on R5 may be further optionally replaced by 1-3 groups selected from hydroxy, halogen, C 1-6 Alkyl substituents are substituted.

[0073] Further, among them,

[0074] n is 0;

[0075] m is 0;

[0076] R5 is selected from NR a R b ;

[0077] R a 、R c Selected from hydrogen or C 1-6 alkyl;

[0078] R b 、R d Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, cyclopropyl, cyclobutyl;

[0079] The R b Optionally substituted by 1-2 groups selected from hydroxy, halogen, cyclopropyl, cyclobutyl, C 1-6 Alkoxy substituent substitution;

[0080] The R d Optionally substituted by 1-2 groups selected from hydroxy, halogen, cyclopropyl, cyclobutyl, halo C 1-6 Alkyl, C 1-6 Alkoxy and phenyl substituents.

[0081] In any of the above technical solutions, wherein R3 is selected from

[0082] Furthermore, m is an integer of 1 to 2, and preferably, m is 1.

[0083] In any of the above technical solutions, R3 is selected from -(CH2) n -NR4-Z-(CH2) m -R5;

[0084] n is an integer from 0 to 6;

[0085] m is an integer from 0 to 3;

[0086] Preferably, n is an integer of 0 to 2, and m is an integer of 1 to 2; more preferably, n is 0, and m is 1.

[0087] In any of the above technical solutions, R3 is selected from -(CH2) n -NR4-Z-(CH2) m -R5, -(CH2) n -NR4-Z-CR c R d -R5;

[0088] n is an integer from 0 to 2;

[0089] m is an integer from 0 to 2;

[0090] Preferably, n is 0, and m is an integer from 0 to 2; preferably, n is 0, and m is 0 or 1.

[0091] In any of the above technical solutions, R4 is selected from hydrogen, methyl or ethyl.

[0092] In any of the above technical solutions,

[0093] R5 is selected from NR a R b , OR b ;

[0094] R a Selected from hydrogen or C 1-6 alkyl;

[0095] R b Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl;

[0096] The R b Optionally substituted by 1-2 groups selected from hydroxy, halogen, 3-7 membered cycloalkyl, halogenated C 1-6 Alkyl substituents are substituted.

[0097] In any of the above technical solutions,

[0098] R a Selected from hydrogen or C 1-6 alkyl;

[0099] R b Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, 3-7 membered cycloalkyl, said R b Optionally substituted by 1-2 groups selected from hydroxy, halogen, 3-7 membered cycloalkyl, halogenated C 1-6 Alkyl substituents are substituted.

[0100] Furthermore, R b is selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, said R b Optionally substituted by 1-2 substituents selected from hydroxy, cyclopropyl, trifluoromethyl.

[0101] In any of the above technical solutions,

[0102] R c Selected from hydrogen or C 1-6 alkyl;

[0103] R d Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, 3-7 membered cycloalkyl, said R d Optionally substituted by 1-2 groups selected from hydroxy, halogen, 3-7 membered cycloalkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, aryl, cyano substituents.

[0104] Furthermore, R d is selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, said R d Optionally substituted with 1-2 substituents selected from hydroxy, halogen, cyclopropyl, cyclobutyl, trifluoromethyl, methoxy, phenyl, cyano.

[0105] In any of the above technical solutions,

[0106] wherein Y is selected from phenyl, 5-14 membered heteroaryl;

[0107] The Y is optionally substituted by 1-4 groups selected from hydroxy, amino, cyano, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, 3-7 membered cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl substitution;

[0108] When the substituents on Y are selected from C 1-6 Alkyl, 3-7 membered cycloalkyl, C 2-6 Alkenyl, C2-6 When alkynyl, the substituent is further optionally substituted by 1-3 substituents selected from hydroxy, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, 3-7 membered cycloalkyl substituents;

[0109] Preferably, Y is substituted by hydroxyl, and Y may be further optionally substituted by 1-3 groups selected from amino, cyano, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, cyclopropyl substituents, the substituents on Y may be further optionally substituted by 1-3 selected from halogen, C 1-6 Alkyl, cyclopropyl, trifluoromethyl, difluoromethyl substituents.

[0110] Further, Y is selected from phenyl and 5-6 membered heteroaryl. Preferably, Y is selected from phenyl and 5-6 membered heteroaryl containing 1-2 N heteroatoms.

[0111] Furthermore, Y is selected from phenyl, pyridine, and pyrimidine.

[0112] Furthermore, Y is selected from

[0113] In any of the above technical solutions, the Y is optionally replaced by 1-4 groups selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl, aryl, 5-7 membered heteroaryl, sulfonyl substituents, preferably, the Y is optionally substituted by 1-4 groups selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, carbonyl, C 1-6 Alkyl, trifluoromethyl, difluoromethyl, methoxy, -S-methyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 4-6 membered heterocyclyl, cyclopropyl, 5-6 membered heteroaryl substituents, preferably, said Y is optionally substituted by 1-4 substituents selected from methyl, hydroxy, cyano, cyclopropyl, halogen, methoxy, trifluoromethyl, vinyl, propenyl, ethynyl, propynyl, -S-methyl.

[0114] In any of the above technical solutions, the substituents on Y can be further optionally replaced by 1-3 groups selected from hydroxyl, C 0-6Alkylamino, carboxyl, cyano, nitro, halogen, C 0-6 Alkylcarbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-6 membered heterocyclyl, 3-7 membered cycloalkyl, 5-6 membered cycloalkenyl, aryl, 5-7 membered heteroaryl, C 0-6 Alkylsulfonyl substituents are substituted.

[0115] Furthermore, the substituents on Y may be further optionally replaced by 1-3 substituents selected from hydroxyl, methylamino, dimethylamino, cyano, fluorine, chlorine, methylcarbonyl, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, vinyl, propenyl, ethynyl, propynyl, 4-6 membered heterocyclic group, cyclopropyl, 5-6 membered heteroaryl, C 0-6 Alkylsulfonyl substituents are substituted.

[0116] In any of the above technical solutions, Y is optionally replaced by 1-4 groups selected from hydroxyl, Methyl, trifluoromethyl, halogen, cyano, cyclopropyl.

[0117] In any of the above technical solutions, the Y is substituted by a hydroxyl group, and the Y may be further optionally substituted by 1-3 groups selected from amino, cyano, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cyclopropyl, sulfonyl substituents, the substituents on Y may be further optionally substituted with 1-3 selected from halogen, C 1-6 Alkyl, 3-7 membered cycloalkyl, halogenated C 1-6 Alkyl substituents are substituted.

[0118] Furthermore, the substituents on Y may be further optionally replaced by 1-3 substituents selected from halogen, C 1-6 Alkyl, cyclopropyl, trifluoromethyl, difluoromethyl substituents.

[0119] In one embodiment of the present invention, the compound as shown above, or its deuterated compound, or its stereoisomer, or its pharmaceutically acceptable salt is shown in Table 1:

[0120] Table 1

[0121] In one embodiment of the present invention, a pharmaceutical composition is provided, comprising any one of the above-mentioned compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof in combination with one or more pharmaceutically acceptable carriers.

[0122] The present invention also provides the use of any one of the above-mentioned compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or the above-mentioned pharmaceutical compositions in the preparation of drugs for preventing and / or treating diseases associated with NLRP3 inflammasome.

[0123] The present invention also provides the use of any one of the above-mentioned compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or the above-mentioned pharmaceutical compositions in the preparation of drugs for preventing and / or treating inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases or autoinflammatory diseases.

[0124] Detailed Description of the Invention

[0125] The "halogen" described in the present invention refers to fluorine, chlorine, bromine and iodine.

[0126] The "hydroxyl group" described in the present invention refers to an -OH group.

[0127] The "cyano group" described in the present invention refers to a -CN group.

[0128] The "amino group" described in the present invention refers to the -NH2 group.

[0129] The "carboxyl group" described in the present invention refers to a -COOH group.

[0130] The "nitro" described in the present invention refers to a -NO2 group.

[0131] The "oxo group" described in the present invention refers to a =O group.

[0132] The "thio" group described in the present invention refers to a =S group.

[0133] The "urea group" described in the present invention refers to a -HNCONH2 group.

[0134] The "hydrazino" group described in the present invention refers to a -NHNH2 group.

[0135] The present invention's "C 1-6The term "alkyl" refers to a straight or branched chain alkyl group derived from a hydrocarbon moiety containing 1 to 6 carbon atoms by removing one hydrogen atom, 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.

[0136] The "C 1-6 The "alkylene" in "alkylene" refers to C 1-6 An alkyl group is a divalent group derived by removing two hydrogen atoms.

[0137] The "halogenated C 1-6 "Alkyl" refers to a C substituted by one or more halogen groups as defined above. 1-6 Alkyl group. HaloC 1-6 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.

[0138] The "C 1-6 "Alkoxy" refers to the "C 1-6 Alkyl" is a group connected to the parent molecule through an oxygen atom, that is, "C 1-6 Alkyl-O-" groups, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy, neopentoxy and n-hexoxy, etc.

[0139] The "halogenated C 1-6 "Alkoxy" refers to a C1-C6 alkoxy group substituted with one or more halo groups as defined above, examples of which include, but are not limited to, fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy, and fluoropropoxy.

[0140] The "C 2-6 "Alkenyl" refers to a straight-chain or branched alkene group derived from an alkene moiety of 2 to 6 carbon atoms containing at least one carbon-carbon double bond by removing one hydrogen atom, such as ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadi-1-enyl, 1-penten-3-yl, 2-penten-1-yl, 3-penten-1-yl, 3-penten-2-yl, 1,3-pentadien-1-yl, 1,4-pentadien-3-yl, 1-hexen-3-yl, 1,4-hexadien-1-yl. Preferably, "C 2-6The alkenyl group contains a carbon-carbon double bond.

[0141] The "C 2-6 "Alkynyl" refers to a straight or branched chain alkynyl group derived from an alkyne moiety of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond by removing a hydrogen atom, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Preferably, "C 2-6 Alkynyl contains a carbon-carbon triple bond.

[0142] The "C 0-6 Alkylamino", "C 0-6 "Alkylsulfonyl" refers to a C 0-6 Alkyl-NH-, C 0-6 The group formed by alkyl-S(O)2-.

[0143] The "5-12 membered ring" described in the present invention includes a carbocyclic ring or heterocyclic ring that may be formed chemically, such as a 5-12 membered cycloalkyl group, a 5-7 membered cycloalkyl group, a 5-12 membered cycloalkenyl group, a 5-7 membered cycloalkenyl group, a 6-12 membered fused cycloalkyl group, a 5-12 membered heterocyclic group, a 5-7 membered heterocyclic group, a 6-12 membered fused heterocyclic group, an aryl group, a 5-12 membered heteroaryl group, an 8-12 membered fused heteroaryl group, a 5-7 membered heteroaryl group, and the like.

[0144] The "3-12 membered cycloalkyl" of the present invention refers to a monovalent group derived from a 3-12 membered cycloalkane or a divalent group (such as a 5-12 membered cycloalkyl) (as needed), which can be a monocyclic, bicyclic, or polycyclic cycloalkyl system. Unless otherwise specified, all possible monocyclic and condensed rings (such as 6-12 membered condensed cycloalkyl) are included, including those fused in the form of para-, spiro-, or bridged rings. The monocyclic system is generally a cyclic hydrocarbon group containing 3-12 carbon atoms, such as 3-8 or 3-6 carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclopentane-1,3-diyl, cyclohexane-1,4-diyl, cycloheptane-1,4-diyl, etc. Condensed ring cycloalkyl includes para-cycloalkyl, bridged cycloalkyl, and spirocycloalkyl. The cycloalkyl group may be a 6-11 membered cycloalkyl group such as a 7-10 membered cycloalkyl group, and its representative examples 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. The spirocycloalkyl group may be a 7-12 membered spirocycloalkyl group such as a 7-11 membered spirocycloalkyl group, and its examples include but are not limited to: The bridged cycloalkyl group may be a 6-10 membered bridged cycloalkyl group, such as a 7-10 membered bridged cycloalkyl group, and examples thereof include but are not limited to: base.

[0145] The "3- to 7-membered cycloalkyl" herein refers to a monovalent group or (if necessary) a divalent group derived from a 3- to 7-membered cycloalkane. "3- to 7-membered cycloalkyl," such as "3- to 6-membered cycloalkyl" or "4- to 6-membered cycloalkyl," can be a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group. Examples of 3- to 7-membered cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0146] "Cycloalkenyl" of the present invention refers to a group having at least one double bond in the group of the above-mentioned cycloalkyl. It can be, for example, a "3-12 membered cycloalkenyl", i.e., it can have 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring-forming carbon atoms. Unless otherwise specified, a certain membered cycloalkenyl includes all possible monocyclic and condensed rings (including those fused in the form of parallel, spiral or bridged) that may be formed. The cycloalkenyl can be a 3-12 membered cycloalkenyl, a 3-8 membered cycloalkenyl, a 3-7 membered cycloalkenyl, a 4-6 membered cycloalkenyl, a 5-6 membered cycloalkenyl, a 5-7 membered cycloalkenyl, a 7-11 membered spirocycloalkenyl, a 7-11 membered parallel cycloalkenyl, a 6-11 membered bridged cycloalkenyl, etc. Examples of the cycloalkenyl group include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, 1,4-cyclohexadien-1-yl, cycloheptenyl, 1,4-cycloheptadien-1-yl, cyclooctenyl, and 1,5-cyclooctadien-1-yl.

[0147] The "5-7 membered cycloalkenyl group" mentioned in the present invention refers to a group obtained by having at least one double bond in a 5-7 membered cycloalkyl group, such as cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, etc.

[0148] The "3-14 membered heterocyclic group" of the present invention refers to a monovalent group or (as needed) divalent group derived from a 3-14 membered heterocycloalkane, i.e., a non-aromatic cyclic group in which at least one of the 3-14 membered ring carbon atoms is replaced by a heteroatom selected from O, S, S(O), S(O)2, C(O), or N, and preferably contains 1-3 heteroatoms. "3-14 membered heterocyclic group" (e.g., 5-14 membered heterocyclic group, 5-12 membered heterocyclic group) includes monocyclic heterocyclic group, bicyclic heterocyclic group system or polycyclic heterocyclic group system, wherein one or more rings may be saturated or partially saturated, but does not include aromatic rings. Unless otherwise specified, all possible monocyclic, fused rings (including those fused in the form of halogenated, spiro-, or bridged rings), saturated and partially saturated rings are included.

[0149] The monocyclic heterocyclic group can be a 3-8 membered heterocyclic group such as a 5-7 membered heterocyclic group, a 3-7 membered heterocyclic group, a 3-6 membered heterocyclic group, a 4-7 membered heterocyclic group or a 5-6 membered heterocyclic group, a 3-8 membered nitrogen-containing heterocyclic group such as a 4-7 membered nitrogen-containing heterocyclic group or a 5-6 membered nitrogen-containing heterocyclic group, a 3-8 membered saturated heterocyclic group such as a 5-6 membered saturated heterocyclic group, etc. Examples include, but are not limited to, aziridine, oxirane, thiirane, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, 1,2-thiazolidinyl, 1,3-thiazolidinyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, piperidinyl, piperazinyl, morpholinyl, 1,4-dioxanyl, 1,4-oxathianyl, 4,5-dihydroisoxazolyl, 4,5-dihydrooxazolyl, 2, 5-dihydrooxazolyl, 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-tetrahydropyridinyl, 1,2-isoxazinyl, 1,4-isoxazinyl or 6H-1,3-oxazinyl, etc.

[0150] Fused heterocyclic groups (e.g., 6-12 membered fused heterocyclic groups) include benzoheterocyclic groups, spiroheterocyclic groups, and bridged heterocyclic groups, which may be saturated, partially saturated, or unsaturated, but not aromatic. The fused heterocyclic group may be a 5-6 membered monocyclic heterocyclic ring fused to a benzene ring, a 5-6 membered monocyclic cycloalkyl group, a 5-6 membered monocyclic cycloalkenyl group, a 5-6 membered monocyclic heterocyclic group, or a 5-6 membered monocyclic heteroaryl group.

[0151] The heterocyclic group can be a 6-12 membered heterocyclic group such as a 6-11 membered heterocyclic group or a 7-10 membered heterocyclic group, a 6-11 membered saturated heterocyclic group, a 6-11 membered nitrogen-containing heterocyclic group, and its representative examples include but are not limited to: 3-azabicyclo[3.1.0]hexane, 3,6-diazabicyclo[3.2.0]heptane, 3,8-diazabicyclo[4.2.0]octane, 3,7-diazabicyclo[4.2.0]octane, octahydropyridine ... Pyrrolyl, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3,4-b][1,4]oxazinyl, octahydro-1H-pyrrolo[3,4-c]pyridinyl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-1-yl, indolin-2-yl, indolin-3-yl, 2,3-dihydrobenzothiophen-2-yl, octahydro-1H-indolyl, octahydrobenzofuranyl.

[0152] The spiro heterocyclic group may be a 6-12 membered spiro heterocyclic group such as a 7-12 membered spiro heterocyclic group, a 7-12 membered saturated spiro heterocyclic group, or a 7-12 membered nitrogen-containing spiro heterocyclic group, examples of which include but are not limited to:

[0153] The bridged heterocyclic group may be a 6-12 membered bridged heterocyclic group, such as a 6-10 membered bridged heterocyclic group (e.g., a 6-10 membered nitrogen-containing bridged heterocyclic group, especially a 7 membered nitrogen-containing bridged heterocyclic group), or a 7-10 membered bridged heterocyclic group, examples of which include but are not limited to:

[0154] The "aryl" mentioned in the present invention refers to a monovalent or, as required, divalent cyclic aromatic group derived from an aromatic carbocyclic hydrocarbon containing 6 to 14 carbon atoms, including benzene, naphthyl, phenanthryl and the like.

[0155] The "5-14 membered heteroaryl" described in the present invention refers to an aromatic 5-14 membered cyclic group in which at least one ring carbon atom is replaced by a heteroatom selected from O, S, and N. The "5-14 membered heteroaryl" can be a 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered heteroaryl group, preferably containing 1-3 heteroatoms, and includes carbon atoms and sulfur atoms replaced by oxygen or nitrogen, for example, carbon atoms replaced by C(O), and sulfur atoms replaced by S(O) or S(O)2. Heteroaryl groups include single heteroaryl groups and fused heteroaryl groups. Unless otherwise specified, a single-membered heteroaryl group includes all possible single-ring, fused-ring, fully aromatic, and partially aromatic groups. The monoheteroaryl group can be a 5-7 membered heteroaryl group such as a 5-6 membered heteroaryl group, examples of which include but are not limited to furyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thienyl, triazolyl and triazinyl.

[0156] In certain embodiments, a fused heteroaryl group refers to a group formed by a monocyclic heteroaryl ring fused to a phenyl group, a cycloalkenyl group, a heteroaryl group, a cycloalkyl group, or a heterocyclic group. In certain embodiments, a fused heteroaryl group (such as an 8-14 membered fused heteroaryl group) can be an 8-14 membered heteroaryl group such as a 9-10 membered heteroaryl group, examples of which include but are not limited to benzimidazolyl, benzofuranyl, benzothiophenyl, benzoxadiazolyl, benzothiadiazolyl, benzothiazolyl, cinnolinyl, 5,6-dihydroquinolin-2-yl, 5,6-dihydroisoquinolin-1-yl, furopyridinyl, indazolyl, indolyl, isoindolyl, 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.

[0157] As used herein, "pharmaceutically acceptable salts" refer to pharmaceutically acceptable acid and base addition salts and solvates. Such pharmaceutically acceptable salts include salts of 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 such as acetic acid and HOOC-(CH2)n-COOH (wherein n=0-4). Such pharmaceutically acceptable salts also include salts of bases such as sodium, potassium, calcium, and ammonium. A wide variety of non-toxic pharmaceutically acceptable addition salts are known to those skilled in the art.

[0158] All numerical ranges described herein are intended to include both endpoints of the range, all integers within the range, and subranges formed by these integers. For example, "3-7" includes 3, 4, 5, 6, and 7; "1-4" includes 1, 2, 3, and 4; and "1-3" includes 1, 2, and 3.

[0159] The term "optional" or "optionally" means that the subsequently described event may or may not occur, and that the description includes both occurring and not occurring.

[0160] "Stereoisomers" of the compounds described herein refer to isomers resulting from differences in the spatial arrangement of atoms in a molecule. Enantiomers are formed when asymmetric carbon atoms are present in a compound, while cis- and trans-isomers are formed when a carbon-carbon double bond or ring structure is present in a compound.

[0161] The term "tautomer" refers to a special type of functional group isomerism in which different functional group isomers are in dynamic equilibrium and can rapidly convert into each other. For example, in the presence of ketones or oximes, tautomers may be produced, representative examples of which include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, and imine-enamine tautomers. Enantiomers, diastereomers, racemates, cis-trans isomers, tautomers, geometric isomers, epimers, and mixtures thereof of all compounds are encompassed within the scope of the present invention.

[0162] In the chemical configuration of the compounds of the present invention, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or include both Two configurations. In the chemical structure of the compound described in the present invention, Indicates a non-fixed point of attachment to the parent molecule.

[0163] It is a single bond or a double bond.

[0164] "Deuterated" means that one or more hydrogen atoms in a compound or group are replaced by deuterium.

[0165] General preparation methods of the compounds of the present invention

[0166] Unless otherwise specified, all raw materials or intermediates in the preparation methods for which the preparation methods are not provided can be purchased or synthesized using methods known in the public literature. Suitable post-treatment methods described in the preparation methods may include one or more of the following conventional post-treatment methods, such as quenching with water, concentration, pH adjustment, extraction with a suitable solvent (such as ethyl acetate, dichloromethane), filtration, drying, etc. Suitable purification methods described in the preparation methods may include one or more of the following purification methods, such as silica gel column chromatography, preparative thin-layer chromatography, reverse-phase preparative chromatography, recrystallization, beating, etc.

[0167] The compound of the present invention can be prepared by the following reaction formula 1

[0168] Reaction 1:

[0169] in,

[0170] X is C or N;

[0171] R1, R2, and R4 are as defined above. When X is N, R2 does not exist.

[0172] Halo is a halogen, or other leaving groups such as sulfonate or alkylsulfonyl;

[0173] PG is a suitable protecting group;

[0174] R4 in the intermediate represented by formula (III-5) can form a 5-7 membered heterocyclic ring with B and O atoms;

[0175] R c 、R d , R5, and Y are as defined above.

[0176] The following provides a method for preparing the compound of the general formula shown in Reaction Scheme 1:

[0177] The intermediate represented by formula (III-2) can be obtained by an aromatic nucleophilic substitution reaction between the intermediate represented by formula (III-1) and the corresponding amine under heating conditions.

[0178] The intermediate represented by formula (III-2) and the intermediate represented by formula (III-3) undergo condensation reaction in the presence of a base (such as triethylamine or N,N-diisopropylethylamine) and a suitable peptide condensation reagent (such as 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate or isopropyl chloroformate) to obtain the intermediate represented by formula (III-4).

[0179] Under the protection of an inert gas (such as nitrogen), the intermediate represented by formula (III-4) and the intermediate represented by formula (III-5) are heated to a suitable temperature (such as 90°C to 110°C) in the presence of a suitable catalyst (such as tetrakis(triphenylphosphine)palladium or [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride) and a suitable base (such as potassium carbonate, sodium carbonate or sodium bicarbonate, etc.) to undergo a Suzuki coupling reaction to obtain the intermediate represented by formula (III-6).

[0180] The intermediate represented by formula (III-6) reacts with the reagent (1-diazo-2-oxopropyl) dimethyl phosphonate in the presence of a suitable base (such as potassium carbonate) to generate the intermediate represented by formula (III-7).

[0181] The intermediate represented by formula (III-7) is subjected to the action of a suitable deprotection reagent (such as a 1,4-dioxane solution of hydrogen chloride, an ethanol solution of hydrogen chloride, an ethyl acetate solution of hydrogen chloride, boron tribromide, piperidine, diethylamine or trifluoroacetic acid, etc.) to remove the protecting group to obtain the compound of the present invention.

[0182] In some embodiments, the intermediate represented by the above formula (III-7) can be prepared by the following reaction formula 2

[0183] Reaction 2:

[0184] Among them, X, R1, R2, Halo, R4, PG, R c 、R d , R5, and Y are as defined above. The following provides a method for preparing the intermediate of formula (III-7) shown in reaction formula 2:

[0185] Under the protection of an inert gas (such as nitrogen), the intermediate represented by formula (III-2) and the intermediate represented by formula (III-5) are heated to a suitable temperature (such as 90°C to 110°C) in the presence of a suitable catalyst (such as tetrakis(triphenylphosphine)palladium or [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride) and a suitable base (such as potassium carbonate, sodium carbonate or sodium bicarbonate, etc.) to undergo a Suzuki coupling reaction to obtain the intermediate represented by formula (III-8).

[0186] The intermediate represented by formula (III-8) reacts with the reagent (1-diazo-2-oxopropyl) dimethyl phosphonate in the presence of a suitable base (such as potassium carbonate) to generate the intermediate represented by formula (III-9).

[0187] The intermediate represented by formula (III-9) and the intermediate represented by formula (III-3) undergo condensation reaction in the presence of a base (such as triethylamine or N,N-diisopropylethylamine) and a suitable peptide condensation reagent (such as 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate or isopropyl chloroformate) to obtain the intermediate represented by formula (III-7).

[0188] The compound of the present invention can also be prepared by the following reaction formula 3

[0189] Reaction 3:

[0190] Among them, X, R1, R2, Halo, R4, PG, R c 、R d , R5, and Y are as defined above. The following provides a method for preparing the compound of the general formula shown in Reaction Scheme 3:

[0191] Under the protection of an inert gas (such as nitrogen), the intermediate represented by formula (III-2) and the intermediate represented by formula (III-10) are heated to a suitable temperature (such as 90°C to 110°C) in the presence of a suitable catalyst (such as tetrakis(triphenylphosphine)palladium or [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride) and a suitable base (such as potassium carbonate, sodium carbonate or sodium bicarbonate, etc.) to undergo a Suzuki coupling reaction to obtain the intermediate represented by formula (III-11).

[0192] The intermediate represented by formula (III-11) and the intermediate represented by formula (III-3) undergo condensation reaction in the presence of a base (such as triethylamine or N,N-diisopropylethylamine) and a suitable peptide condensation reagent (such as 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate or isopropyl chloroformate) to obtain the intermediate represented by formula (III-12).

[0193] The intermediate represented by formula (III-12) is subjected to the action of a suitable deprotection reagent (such as a 1,4-dioxane solution of hydrogen chloride, an ethanol solution of hydrogen chloride, an ethyl acetate solution of hydrogen chloride, boron tribromide, piperidine, diethylamine or trifluoroacetic acid, etc.) to remove the protecting group to obtain the compound of the present invention.

[0194] In some embodiments, the intermediate represented by formula (III-12) can also be prepared by the following reaction formula 4

[0195] Reaction 4:

[0196] Among them, X, R1, R2, Halo, R4, PG, R c 、R d , R5, and Y are as defined above. The following provides a method for preparing the intermediate of formula (III-12) shown in reaction formula 4:

[0197] Under the protection of an inert gas (such as nitrogen), the intermediate represented by formula (III-4) and the intermediate represented by formula (III-10) or the intermediate represented by formula (III-16) are heated to a suitable temperature (such as 90°C to 110°C) in the presence of a suitable catalyst (such as [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, tetrakis(triphenylphosphine)palladium or tetrakis(triphenylphosphine)palladium and cuprous iodide) and a suitable base (such as potassium carbonate, sodium carbonate, sodium bicarbonate or cesium fluoride, etc.) to undergo a Suzuki coupling reaction or a Stille coupling reaction to obtain the intermediate represented by formula (III-12).

[0198] The compound of the present invention can also be prepared by the following reaction formula 5.

[0199] Reaction 5:

[0200] Among them, X, R1, R2, Halo, R4, PG, R c 、R d 、R a 、R b , R5, and Y are as defined above. The following provides a method for preparing the compound of the general formula shown in Reaction Scheme 5:

[0201] The intermediate represented by formula (III-11) and the intermediate represented by formula (III-13) undergo condensation reaction in the presence of a base (such as triethylamine or N,N-diisopropylethylamine) to obtain the intermediate represented by formula (III-14).

[0202] The intermediate represented by formula (III-14) is subjected to the action of a suitable deprotection reagent (such as a 1,4-dioxane solution of hydrogen chloride, an ethanol solution of hydrogen chloride, an ethyl acetate solution of hydrogen chloride, boron tribromide or trifluoroacetic acid, etc.) to remove the protecting group to obtain the intermediate represented by formula (III-15).

[0203] The intermediate represented by formula (III-15) and the intermediate represented by formula (III-16) undergo a substitution reaction in the presence of a suitable base (such as triethylamine or N,N-diisopropylethylamine) to obtain the compound of the present invention.

[0204] Beneficial effects of the present invention

[0205] Studies have found that the compounds provided by the present invention, or their deuterated compounds, or their stereoisomers, or their pharmaceutically acceptable salts, have good inhibitory activity against the NLRP3 inflammasome. Therefore, the compounds of the present invention can be used to prevent and / or treat diseases associated with the NLRP3 inflammasome. At the same time, the compounds of the present invention are metabolically stable, have low toxicity, and have good pharmacokinetic properties and high safety. DETAILED DESCRIPTION

[0206] To make the objectives, technical solutions, and advantages of the present invention more clearly understood, the present invention is described in further detail below. It is apparent that the embodiments described herein are merely a portion of the embodiments of the present invention, and not all of them. All other embodiments derived by persons of ordinary skill in the art based on the embodiments of the present invention without inventive effort are intended to fall within the scope of protection of the present invention.

[0207] The abbreviations and English expressions used in this invention have the following meanings:

[0208] "THF" refers to tetrahydrofuran; "DMF" refers to N,N-dimethylformamide; "MeOH" refers to methanol; "EA" refers to ethyl acetate; "DCM" refers to dichloromethane; "PE" refers to petroleum ether;

[0209] “FBS” refers to fetal bovine serum; “PBS” refers to phosphate-buffered saline; “PMA” refers to phorbol myristate; “LPS” refers to lipopolysaccharide; and “Nigericin” refers to nigericin.

[0210] Intermediate Preparation Example 1: Synthesis of 6-chloro-5-cyclopropylpyridazin-3-amine

[0211] Step 1: Synthesis of 3,6-dichloro-4-cyclopropylpyridazine

[0212] Dissolve 3,6-dichloropyridazine (20.0 g, 134.2 mmol, 1.0 eq) in water (200 mL), add cyclopropylcarboxylic acid (11.56 g, 134.2 mmol, 1.0 eq) and silver nitrate (22.8 g, 134.2 mmol, 1.0 eq), and add concentrated sulfuric acid (21.6 mL, 402.6 mmol, 3.0 eq) dropwise at 50°C. After the addition is complete, raise the temperature to 60°C, and add a 200 mL aqueous solution of ammonium persulfate (91.88 g, 402.6 mmol, 3.0 eq). After the addition is complete, raise the temperature to 70°C and react for 30 min. TLC indicates the reaction is complete. The reaction solution was adjusted to pH 8 with a 1 mol / L aqueous sodium hydroxide solution and extracted with ethyl acetate (400 mL × 2). The organic phases were combined, dried, and concentrated. The crude product was first chromatographed on a silica gel column (petroleum ether: ethyl acetate = 50:1). A large amount of solid precipitated after the product was allowed to stand. The filter cake was slurried with a petroleum ether / ethyl acetate mixed solvent to obtain the product (17 g, yield: 67.1%).

[0213] Step 2: Synthesis of 6-chloro-5-cyclopropylpyridazin-3-amine

[0214] 3,6-Dichloro-4-cyclopropylpyridazine (10.0 g, 52.90 mmol, 1.0 eq.) and aqueous ammonia (30.0 mL) were added to a sealed tube and stirred at 140°C for 14 hours. TLC showed that the reaction was complete. Water (50.0 mL) was added 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 = 100:1-40:1) to obtain the product (4.3 g, yield: 47.9%).

[0215] Intermediate Preparation Example 2: Synthesis of 6-chloro-5-isopropylpyridazin-3-amine

[0216] Step 1: Synthesis of 3,6-dichloro-4-isopropylpyridazine

[0217] The product (10.1 g, yield: 78.9%) was prepared by referring to the method of Step 1 of Intermediate Preparation Example 1.

[0218] Step 2: Synthesis of 6-chloro-5-isopropylpyridazin-3-amine

[0219] The crude product was prepared according to the method of Step 2 of Intermediate Preparation Example 1, and purified by silica gel column chromatography (dichloromethane:methanol=130:1-100:1) to obtain the product (2.0 g, yield: 44.4%).

[0220] Intermediate Preparation Example 3: Synthesis of 6-chloro-5-cyclobutylpyridazin-3-amine

[0221] Step 1: Synthesis of 3,6-dichloro-4-cyclobutylpyridazine

[0222] The product (9.8 g, yield: 72.0%) was prepared by referring to the method of Step 1 of Intermediate Preparation Example 1.

[0223] Step 2: Synthesis of 6-chloro-5-cyclobutylpyridazin-3-amine

[0224] The crude product was prepared according to the method of Step 2 of Intermediate Preparation Example 1, and purified by silica gel column chromatography (dichloromethane:methanol=130:1-100:1) to obtain the product (1.5 g, yield: 33.3%).

[0225] Intermediate Preparation Example 4: Synthesis of 6-chloro-5-cyclobutylpyridazin-3-amine

[0226] Step 1: Synthesis of 4-(tert-butyl)-3,6-dichloropyridazine

[0227] The crude product was prepared according to the method of Step 1 of Intermediate Preparation Example 1, and purified by silica gel column chromatography (PE:EA=20:1) to obtain the product (23.0 g, yield: 66.8%).

[0228] Step 2: Synthesis of 5-(tert-butyl)-6-chloropyridazin-3-amine

[0229] The crude product was prepared according to the method of Step 2 of Intermediate Preparation Example 1, and purified by silica gel column chromatography (DCM:MeOH=200:1-50:1) to obtain the product (14.2 g, yield: 68.2%).

[0230] Intermediate Preparation Example 5: Synthesis of 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde

[0231] Step 1: Synthesis of 4-bromo-3-hydroxybenzaldehyde

[0232] 4-Bromo-3-methoxybenzaldehyde (10.0 g, 46.5 mmol, 1.0 eq) was added to a 40% (mass fraction) aqueous HBr solution (60 mL) and heated to 100°C for 20 hours. The mixture was cooled to room temperature, added with water, and extracted with EA (50 mL x 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 (PE:EA = 50:1 to 5:1) to obtain the product (7.80 g, yield: 83.4%).

[0233] Step 2: Synthesis of 4-bromo-3-(ethoxymethoxy)benzaldehyde

[0234] 4-Bromo-3-hydroxybenzaldehyde (7.80 g, 38.8 mmol, 1.0 eq) was dissolved in THF (100 mL), cooled to 0°C, and 60% (mass fraction) NaH (2.33 g, 58.2 mmol, 1.5 eq) was added portionwise. The mixture was stirred for 20 minutes, followed by the addition of chloromethyl ether (5.50 g, 86.2 mmol, 1.5 eq) and the reaction was allowed to proceed for 2 hours. The mixture was quenched by the addition of saturated aqueous NH4Cl solution. The layers were separated, and the aqueous phase was extracted with EA (30 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 50:1 to 5:1) to obtain the product (7.60 g, yield: 75.6%).

[0235] Step 3: Synthesis of 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde

[0236] 4-Bromo-3-(ethoxymethoxy)benzaldehyde (5.00 g, 19.3 mmol, 1.0 eq), pinacol diboron (7.35 g, 29.0 mmol, 1.5 eq), Pd(dppf)Cl2 (1.41 g, 1.93 mmol, 0.1 eq), and KOAc (3.79 g, 38.6 mmol, 2.0 eq) were added sequentially to 1,4-dioxane (50 mL). The mixture was heated to 100°C under nitrogen and allowed to react for 20 hours. After cooling to room temperature, water (50 mL) was added and the mixture was extracted with EA (50 mL x 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 (PE:EA = 20:1 to 5:1) to obtain the product (5.20 g, yield: 88.0%).

[0237] Intermediate Preparation Example 6: Synthesis of (2-(ethoxymethoxy)-4-(trifluoromethyl)phenyl)boric acid

[0238] Step 1: Synthesis of 1-bromo-2-(ethoxymethoxy)-4-(trifluoromethyl)benzene

[0239] 2-Bromo-5-trifluoromethylphenol (5.00 g, 20.7 mmol, 1.0 eq) was dissolved in THF (50 mL), cooled to 0°C, and NaH (60%, 2.94 g, 31.1 mmol, 1.5 eq) was added portionwise. The mixture was stirred for 20 minutes, and then chloromethyl ether (1.24 g, 31.1 mmol, 1.5 eq) was added. After reacting for 4 hours, the mixture was quenched by adding saturated aqueous NH4Cl solution, and extracted with EA (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product (6.08 g, yield: 98.0%).

[0240] Step 2: Synthesis of (2-(ethoxymethoxy)-4-(trifluoromethyl)phenyl)boronic acid

[0241] 1-Bromo-2-(ethoxymethoxy)-4-(trifluoromethyl)benzene (3.00 g, 10.0 mmol, 1.0 eq) and triisopropyl borate (2.82 g, 15.0 mmol, 1.5 eq) were dissolved in THF (30 mL). Under nitrogen, the temperature was cooled to -60°C. Then, n-butyllithium (1.6 mol / L in THF, 9.4 mL, 15.0 mmol, 1.5 eq) was added dropwise and allowed to react for 3 hours. The mixture was quenched with saturated aqueous NH4Cl solution and extracted with EA (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was slurried with petroleum ether to obtain the product (2.20 g, yield: 83.1%).

[0242] Intermediate Preparation Example 7: Synthesis of (2-methoxy-4-(1-propynyl)phenyl)boronic acid

[0243] Step 1: Synthesis of 1-bromo-2-methoxy-4-(1-propynyl)benzene

[0244] 2-Bromo-5-iodoanisole (6.7 g, 21.41 mmol, 1.0 eq) was dissolved in tetrahydrofuran (60 mL), and N,N-diisopropylethylamine (4.15 g, 32.12 mmol, 1.5 eq), copper iodide (815 mg, 4.28 mmol, 0.2 eq) and bis(triphenylphosphine)palladium dichloride (1.5 g, 2.14 mmol, 0.1 eq) were added sequentially. Under nitrogen protection, 1 mol / L propyne tetrahydrofuran solution (23.6 mL, 23.6 mmol, 1.1 eq) was added dropwise. The reaction was carried out at 25 ° C for 4 h. TLC showed that the reaction was complete. Saturated aqueous ammonium chloride solution (150 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 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 (4.34 g, yield: 90.0%).

[0245] Step 2: Synthesis of intermediate (2-methoxy-4-(1-propynyl)phenyl)boronic acid

[0246] 1-Bromo-2-methoxy-4-(1-propynyl)benzene (3.34 g, 14.84 mmol, 1.0 eq) and triisopropyl borate (3.35 g, 17.81 mmol, 1.2 eq) were dissolved in tetrahydrofuran (35 mL). Under nitrogen at -65°C, a 2.5 mol / L solution of n-butyllithium in tetrahydrofuran (7.2 mL, 17.81 mmol, 1.2 eq) was slowly added dropwise. The mixture was allowed to react at 25°C for 2 hours. TLC indicated the reaction was complete. The reaction mixture was quenched by pouring saturated aqueous ammonium chloride (40 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined and concentrated. The crude product was slurried with petroleum ether (5 mL) and filtered. The filter cake was the product (1.5 g, 53.2% yield).

[0247] Intermediate Preparation Example 8: Synthesis of (2-(ethoxymethoxy)-4-fluorophenyl)boronic acid

[0248] Step 1: Synthesis of 1-bromo-2-(ethoxymethoxy)-4-fluorobenzene

[0249] 2-Bromo-5-fluorophenol (9.0 g, 47.12 mmol, 1.0 eq.) was added to tetrahydrofuran (40.0 mL). Sodium hydride (60%) (2.8 g, 70.68 mmol, 1.5 eq.) was added portionwise under an ice-water bath. After 1 hour of reaction, (chloromethoxy)ethane (6.7 g, 70.68 mmol, 1.5 eq.) was added. TLC indicated the reaction was complete. Ethyl acetate (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 (petroleum ether:ethyl acetate = 100:1) to obtain the product (9.7 g, yield: 82.9%).

[0250] Step 2: Synthesis of (2-(ethoxymethoxy)-4-fluorophenyl)boronic acid

[0251] 1-Bromo-2-(ethoxymethoxy)-4-fluorobenzene (9.0 g, 36.13 mmol, 1.0 eq.) and triisopropyl borate (10.2 g, 54.20 mmol, 1.5 eq.) were added to tetrahydrofuran (50.0 mL). The temperature was lowered to -70°C, and n-butyllithium (2.5 mol / L, 21.0 mL) was added dropwise. The mixture was allowed to warm to room temperature and react for 2 hours. TLC indicated the reaction was complete. 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 to obtain the product (6.1 g, yield: 79.2%).

[0252] Example 1: Synthesis of N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)-2-(methylamino)acetamide (Compound 7)

[0253] Step 1: Synthesis of 6-chloro-5-cyclopropylpyridazin-3-amine

[0254] 3,6-Dichloro-4-cyclopropylpyridazine (9.0 g, 47.60 mmol, 1.0 eq.) and aqueous ammonia (28%) (3.0 g, 238.0 mmol, 5.0 eq.) were mixed in a sealed tube and reacted at 140°C for 14 hours. The reaction was completed after monitoring by TLC. Dichloromethane (100.0 mL) was added and washed with water (50.0 mL). The organic phase was dried and filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 200:1-100:1) to obtain the product (3.5 g, yield: 43.7%).

[0255] Step 2: Synthesis of tert-butyl (2-((6-chloro-5-cyclopropylpyridazin-3-yl)amino)-2-oxoethyl)(methyl)carbamate

[0256] N-(tert-Butyloxycarbonyl)-N-methylglycine (825.5 mg, 4.36 mmol, 2.0 eq.) and triethylamine (662.0 mg, 6.54 mmol, 3.0 eq.) were added to dichloromethane (15.0 mL), and isopropyl chloroformate (668.2 mg, 5.45 mmol, 2.5 eq.) was added dropwise under ice-water bath. The mixture was stirred under ice-water bath for 1 hour, and 6-chloro-5-cyclopropylpyridazin-3-amine (370.0 mg) was added. , 2.18mmol, 1.0eq.) in dichloromethane solution (5.0mL), gradually warm to room temperature for 12 hours. After TLC monitoring, the reaction was complete. Saturated aqueous ammonium chloride solution (50.0mL) was added and extracted with dichloromethane (100.0mL). 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 = 100:1-80:1) to obtain the product (660.0mg, yield: 88.8%).

[0257] Step 3: Synthesis of tert-butyl (2-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-formylphenyl)pyridazin-3-yl)amino)-2-oxoethyl)(methyl)carbamate

[0258] Tert-butyl (2-((6-chloro-5-cyclopropylpyridazin-3-yl)amino)-2-oxoethyl)(methyl)carbamate (625.0 mg, 1.83 mmol, 1.0 eq.), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (673.8 mg, 2.20 mmol, 1.2 eq.), potassium carbonate (506.9 mg, 3.66 mmol, 2.0 eq.) and Pd(PPh3)4(21 To a mixed solution of 1,4-dioxane (1.9 mg, 0.18 mmol, 0.1 eq.) and water (5.0 mL) was added. The mixture was reacted at 100°C for 4 hours under nitrogen protection. The reaction was completed after monitoring by TLC. Water (100.0 mL) was added and extracted with ethyl acetate (100.0 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1-80:1) to obtain the product (504.0 mg, yield: 56.7%).

[0259] Step 4: Synthesis of tert-butyl (2-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-yl)amino)-2-oxoethyl)(methyl)carbamate

[0260] Tert-butyl (2-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-formylphenyl)pyridazin-3-yl)amino)-2-oxoethyl)(methyl)carbamate (504.0 mg, 1.04 mmol, 1.0 eq.), dimethyl (1-diazo-2-oxopropyl)phosphonate (299.6 mg, 1.5 mmol, 1.5 eq.), and anhydrous potassium carbonate (287.4 mg, 2.08 mmol, 2.0 eq.) were added to methanol (10.0 mL) and allowed to react at room temperature for 4 hours. TLC monitored the reaction for completion. The system was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 80:1) to obtain the product (272.0 mg, 56.0% yield).

[0261] Step 5: Synthesis of N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)-2-(methylamino)acetamide

[0262] Tert-butyl (2-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-yl)amino)-2-oxoethyl)(methyl)carbamate (272.0 mg, 0.56 mmol, 1.0 eq.) was added to dichloromethane (10.0 mL), and trifluoroacetic acid (3.0 mL) was added dropwise. The mixture was allowed to react at room temperature for 1 hour. TLC monitored the reaction to be complete. The pH of the system was adjusted to 8-9 with saturated aqueous sodium carbonate solution, 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 = 40:1-10:1) to obtain the product (90.0 mg, yield: 49.4%).

[0263] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 7.82 (s, 1H), 7.27-7.25 (d, J = 8Hz, 1H), 7.06-7.04 (m, 2H), 4. 21(s,1H),3.34(s,3H),2.33(s,3H),1.69-1.65(m,1H),1.02-0.99(m,2H),0.72-0.70(m,2H).

[0264] Molecular formula: C 18 H 18 N4O2 exact molecular weight: 322.14 LC-MS (m / z) = 323.19 [M+H] + .

[0265] Example 2: Synthesis of N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)-2-(dimethylamino)acetamide (Compound 80)

[0266] Step 1: Synthesis of N-(6-chloro-5-cyclopropylpyridazin-3-yl)-2-(dimethylamino)acetamide

[0267] N,N-dimethylglycine (486.3 mg, 4.72 mmol, 2.0 eq.) and triethylamine (954.4 mg, 9.43 mmol, 4.0 eq.) were added to dichloromethane (15.0 mL), and isopropyl chloroformate (866.9 mg, 7.07 mmol, 3.0 eq.) was added dropwise under ice-water bath. The mixture was stirred under ice-water bath for 1 hour, and 6-chloro-5-cyclopropylpyridazin-3-amine (400.0 mg, 2.36 mmol) was added. l, 1.0 eq.) in dichloromethane (5.0 mL), the temperature was gradually raised to room temperature and the reaction was carried out for 14 hours. TLC showed that the reaction was complete. The reaction solution was washed with saturated aqueous ammonium chloride (50.0 mL), and the aqueous phase was extracted with dichloromethane (100.0 mL). 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 (dichloromethane:methanol = 100:1-80:1) to obtain the product (468.2 mg, yield: 78.0%).

[0268] Step 2: Synthesis of N-(5-cyclopropyl-6-(2-(ethoxymethoxy)-4-formylphenyl)pyridazin-3-yl)-2-(dimethylamino)acetamide

[0269] N-(6-chloro-5-cyclopropylpyridazin-3-yl)-2-(dimethylamino)acetamide (468.2 mg, 1.84 mmol, 1.0 eq.), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (731.6 mg, 2.39 mmol, 1.3 eq.), potassium carbonate (508.0 mg, 3.68 mmol, 2.0 eq.), and Pd(PPh3)4 (212.4 mg, To the mixture of 1,4-dioxane (0.18 mmol, 0.1 eq.) and water (5.0 mL), the reaction was carried out at 100°C under nitrogen for 6 hours. TLC showed that the reaction was complete. Water (100.0 mL) was added and extracted with ethyl acetate (100.0 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1-50:1) to obtain the product (450.0 mg, yield: 61.4%).

[0270] Step 3: Synthesis of N-(5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-yl)-2-(dimethylamino)acetamide

[0271] N-(5-cyclopropyl-6-(2-(ethoxymethoxy)-4-formylphenyl)pyridazin-3-yl)-2-(dimethylamino)acetamide (450.0 mg, 1.13 mmol, 1.0 eq.), dimethyl (1-diazo-2-oxopropyl)phosphonate (325.3 mg, 1.69 mmol, 1.5 eq.), and anhydrous potassium carbonate (312.0 mg, 2.26 mmol, 2.0 eq.) were added to methanol (10.0 mL) and allowed to react at room temperature for 4 hours. TLC indicated the reaction was complete. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 50:1) to obtain the product (388.0 mg, 87.2% yield).

[0272] Step 4: Synthesis of N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)-2-(dimethylamino)acetamide

[0273] N-(5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-yl)-2-(dimethylamino)acetamide (380.0 mg, 0.96 mmol, 1.0 eq.) was added to dichloromethane (10.0 mL), and trifluoroacetic acid (4.0 mL) was added dropwise. The reaction was allowed to react at room temperature for 1 hour. TLC indicated the reaction was complete. The pH was adjusted to 8-9 with saturated aqueous sodium carbonate solution, 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 = 100:1-80:1) to obtain the product (160.0 mg, yield: 49.3%).

[0274] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.46 (s, 1H), 10.04 (s, 1H), 7.79 (s, 1H), 7.27-7.25 (d, J = 8Hz, 1H), 7.06-7 .04(m,2H),4.21(s,1H),3.19(s,2H),2.32(s,6H),1.69-1.65(m,1H),1.03-0.98(m,2H),0.74-0.70(m,2H).

[0275] Molecular formula: C 19 H 20N4O2 exact molecular weight: 336.16 LC-MS (m / z) = 337.16 [M+H] + .

[0276] Example 3: Synthesis of N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)-2-(methylamino)propionamide (Compound 27)

[0277] Step 1: Synthesis of tert-butyl (1-((6-chloro-5-cyclopropylpyridazin-3-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0278] N-(tert-Butyloxycarbonyl)-N-methylalanine (838.5 mg, 4.13 mmol, 2.0 eq.) and triethylamine (626.3 mg, 6.19 mmol, 3.0 eq.) were added to dichloromethane (15.0 mL), and isopropyl chloroformate (505.6 mg, 4.13 mmol, 2.0 eq.) was added dropwise under ice-water bath, and stirred for 1 hour, and 6-chloro-5-cyclopropylpyridazin-3-amine (350.0 The temperature was gradually raised to room temperature for 12 hours. TLC showed that the reaction was complete. The reaction solution was washed with saturated aqueous ammonium chloride (50.0 mL), and the aqueous phase was extracted with dichloromethane (50.0 mL). 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 (petroleum ether:ethyl acetate = 10:1-5:1) to obtain the product (354.0 mg, yield: 48.3%).

[0279] Step 2: Synthesis of tert-butyl (1-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-formylphenyl)pyridazin-3-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0280] Tert-butyl (1-((6-chloro-5-cyclopropylpyridazin-3-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (354.0 mg, 0.99 mmol, 1.0 eq.), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (396.8 mg, 1.29 mmol, 1.3 eq.), potassium carbonate (206.6 mg, 1.49 mmol, 1.5 eq.) and Pd(PPh3) were added to a 1% flask. Compound 4 (115.2 mg, 0.09 mmol, 0.1 eq.) was added to a mixed solution of 1,4-dioxane (10.0 mL) and water (5.0 mL). The mixture was reacted at 100°C under nitrogen for 4 hours. TLC showed that the reaction was complete. Water (50.0 mL) was added and the mixture was extracted with ethyl acetate (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 (petroleum ether:ethyl acetate = 10:1-1:1) to obtain the product (270.0 mg, yield: 54.3%).

[0281] Step 3: Synthesis of tert-butyl (1-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0282] Tert-butyl (1-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-formylphenyl)pyridazin-3-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (260.0 mg, 0.52 mmol, 1.0 eq.), dimethyl (1-diazo-2-oxopropyl)phosphonate (150.0 mg, 0.78 mmol, 1.5 eq.), and anhydrous potassium carbonate (144.0 mg, 1.04 mmol, 2.0 eq.) were added to methanol (15.0 mL) and allowed to react at room temperature for 3 hours. TLC indicated the reaction was complete. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:1) to obtain the product (179.0 mg, 69.4% yield).

[0283] Step 4: Synthesis of N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)-2-(methylamino)propionamide

[0284] Tert-butyl (1-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (179.0 mg, 0.36 mmol, 1.0 eq.) was added to dichloromethane (5.0 mL). A solution of hydrogen chloride in 1,4-dioxane (4.0 mol / L, 3.0 mL) was added dropwise. The mixture was allowed to react at room temperature for 3 hours. TLC indicated the reaction was complete. The pH was adjusted to 8-9 with saturated aqueous sodium carbonate solution. The mixture was extracted with dichloromethane (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 preparative thin-layer chromatography to afford the product (20.0 mg, 16.4% yield).

[0285] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.04 (s, 1H), 7.84 (s, 1H), 7.27-7.25 (d, J = 8Hz, 1H), 7.07-7.04 (m, 2H), 4.22 (s, 1H), 3. 30(s,1H),2.29(s,3H),1.69-1.65(m,1H),1.30(s,1H),1.26(s,1H),1.24(s,3H),1.03-0.98(m,2H),0.74-0.70(m,2H).

[0286] Molecular formula: C 19 H 20 N4O2 exact molecular weight: 336.16 LC-MS (m / z) = 337.20 [M+H] + .

[0287] Example 4: Synthesis of N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)pyrrolidine-2-carboxamide (Compound 28)

[0288] Prepared by referring to the synthetic method of Example 3.

[0289] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.73 (s, 1H), 10.10 (s, 1H), 7.83 (s, 1H), 7.27-7.25 (d, J = 8Hz, 1H), 7.06-7.04 (m, 2H), 4.22 (s, 1H), 3.83-3.30(m,1H),2.98-2.85(m,2H),2.12-2.03(m,1H),1.87-1.79(m,1H),1.70-1.63(m,3H),1.03-0.98(m,2H),0.73-0.70(m,2H).

[0290] Molecular formula: C 20 H 20 N4O2 exact molecular weight: 348.16 LC-MS (m / z) = 349.20 [M+H] + .

[0291] Example 5: Synthesis of 3-(6-(4-ethynyl-2-hydroxyphenyl)-5-methylpyridazin-3-yl)-1-methylimidazolidin-4-one (Compound 29)

[0292] Step 1: Synthesis of intermediate 4-(6-amino-4-methylpyridazin-3-yl)-3-(ethoxymethoxy)benzaldehyde

[0293] 3-Amino-5-methyl-6-chloropyridazine (5.0 g, 34.83 mmol, 1.0 eq), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (13.86 g, 45.28 mmol, 1.3 eq), an aqueous solution (15 mL) of potassium carbonate (9.63 g, 69.66 mmol, 2.0 eq) and tetrakis(triphenylphosphine)palladium (4.03 g, 3.483 mmol, 0.1 eq) were added to 1,4-dioxane (50 mL) and reacted at 90 ° C for 17 h under nitrogen protection. TLC showed that the reaction was complete. The reaction solution was filtered through celite, washed with dichloromethane (100 mL), and the filtrate was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane:methanol=50:1-20:1) to obtain the product (8.0 g, yield: 80%).

[0294] Step 2: Synthesis of intermediate 6-(2-(ethoxymethoxy)-4-ethynyl)-5-methylpyridazin-3-amine

[0295] 4-(6-Amino-4-methylpyridazin-3-yl)-3-(ethoxymethoxy)benzaldehyde (8.0 g, 27.84 mmol, 1.0 eq) was dissolved in methanol (80 mL). Potassium carbonate (7.7 g, 55.68 mmol, 2.0 eq) was added and the mixture was allowed to react at 25°C for 2 hours. Dimethyl (1-diazo-2-oxopropyl)phosphonate (8.02 g, 41.76 mmol, 1.5 eq) was then added and the mixture was allowed to react at 25°C for 1.5 hours. TLC indicated the reaction was complete. The reaction solution was filtered through celite, and the filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography (dichloromethane:methanol = 50:1 to 30:1) to obtain the product (4.0 g, 50.7% yield).

[0296] Step 3: Synthesis of intermediate tert-butyl (2-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylpyridazin-3-yl)amino)-2-oxoethyl)(methyl)carbamate

[0297] N-tert-Butoxycarbonylsarcosine (200 mg, 1.058 mmol, 2.0 eq) was dissolved in dichloromethane (2 mL), and triethylamine (161 mg, 1.587 mmol, 3.0 eq) was added thereto. Isopropyl chloroformate (162 mg, 1.323 mmol, 2.5 eq) was added dropwise thereto at 0°C, and the mixture was reacted at 0°C for 1 hour. A solution of 6-(2-(ethoxymethoxy)-4-ethynyl)-5-methylpyridazin-3-amine (150 mg, 0.529 mmol, 1.0 eq) in dichloromethane (2 mL) was added, and the temperature was raised to 25°C for 1 hour. TLC showed that the reaction was complete. The reaction solution was poured into water (2 mL), extracted with dichloromethane (5 mL × 3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by preparative thin-layer chromatography (ethyl acetate) to obtain the product (110 mg, yield: 45.8%).

[0298] Step 4: Synthesis of compound 3-(6-(4-ethynyl-2-hydroxyphenyl)-5-methylpyridazin-3-yl)-1-methylimidazolidin-4-one

[0299] Tert-butyl (2-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylpyridazin-3-yl)amino)-2-oxoethyl)(methyl)carbamate (110 mg, 0.242 mmol, 1.0 eq) was dissolved in dichloromethane (1 mL) and added dropwise to trifluoroacetic acid (1 mL). The mixture was allowed to react at 25°C for 0.5 h. TLC indicated the reaction was complete. The reaction solution was concentrated, poured into saturated aqueous sodium bicarbonate (10 mL), and extracted with a mixed solvent of dichloromethane / methanol (10:1) (10 mL x 6). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to obtain the crude product, which was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to afford the product (11 mg, yield: 14.7%).

[0300] 1 H-NMR(400MHz,DMSO-d6)δ(ppm):10.13(s,1H),8.36(d,1H),7.24-7.22(s,1H),7.07 -7.05(m,2H),4.84(s,2H),4.23(s,1H),3.49(s,2H),2.48(s,3H),2.21-2.20(d,3H).

[0301] Molecular formula: C17 H 16 N4O2 exact molecular weight: 308.13 LC-MS (m / z): 309.13 [M+H] +

[0302] Example 6: Synthesis of N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)-2-methoxyacetamide (Compound 30)

[0303] Step 1: Synthesis of 4-(6-amino-4-cyclopropylpyridazin-3-yl)-3-(ethoxymethoxy)benzaldehyde

[0304] 6-Chloro-5-cyclopropylpyridazin-3-amine (3.0 g, 17.68 mmol, 1.0 eq.), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (6.5 g, 21.22 mmol, 1.2 eq.), potassium carbonate (3.6 g, 26.53 mmol, 1.5 eq.) and Pd(PPh3)4 (1.0 g, 0.88 mmol, 0. 0.5 eq.) was added to a mixed solution of 1,4-dioxane (30.0 mL) and water (15.0 mL), and the reaction was carried out at 90°C under nitrogen protection for 12 hours. TLC showed that the reaction was complete, and ethyl acetate (100.0 mL) was added and 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 (petroleum ether:ethyl acetate = 10:1-2:1) to obtain the product (4.0 g, yield: 72.2%).

[0305] Step 2: Synthesis of 5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-amine

[0306] 4-(6-amino-4-cyclopropylpyridazin-3-yl)-3-(ethoxymethoxy)benzaldehyde (3.95 g, 12.61 mmol, 1.0 eq.), dimethyl (1-diazo-2-oxopropyl)phosphonate (3.6 g, 18.91 mmol, 1.5 eq.), and anhydrous potassium carbonate (3.48 g, 25.21 mmol, 2.0 eq.) were added to methanol (40.0 mL) and allowed to react at room temperature for 4 hours. TLC indicated the reaction was complete. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 80:1 to 40:1) to obtain the product (3.2 g, 82.0% yield).

[0307] Step 3: Synthesis of N-(5-cyclopropyl-6-(2-ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-yl)-2-methoxyacetamide

[0308] 2-Methoxyacetic acid (203.7 mg, 2.26 mmol, 2.0 eq.), N,N-diisopropylethylamine (438.5 mg, 3.39 mmol, 3.0 eq.), and HATU (634.6 mg, 2.26 mmol, 2.0 eq.) were added to DMF (10.0 mL), stirred for 1 hour, and then 5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-amine (350.0 mg, 1.13 mmol, 1.0 eq.) was added. The reaction was allowed to react at room temperature for 12 hours. TLC showed that the reaction was complete. Ethyl acetate (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 (petroleum ether:ethyl acetate = 10:1 to 5:1) to obtain the product (174.0 mg, yield: 40.3%).

[0309] Step 4: Synthesis of N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)-2-methoxyacetamide

[0310] N-(5-cyclopropyl-6-(2-ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-yl)-2-methoxyacetamide (174.0 mg, 0.45 mmol, 1.0 eq.) was added to dichloromethane (10.0 mL), and trifluoroacetic acid (2.0 mL) was added dropwise. The reaction was allowed to react at room temperature for 1 hour. TLC indicated the reaction was complete. The pH was adjusted to 8-9 with saturated aqueous sodium carbonate solution, and the mixture was extracted with dichloromethane (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 preparative thin-layer chromatography to afford the product (85.0 mg, 57.8% yield).

[0311] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.67 (s, 1H), 10.06 (s, 1H), 7.76 (s, 1H), 7.28-7.26 (d, J = 8Hz, 1H), 7.07-7 .04(m,2H),4.21(s,1H),4.12(s,2H),3.38(s,3H),1.70-1.64(m,1H),1.03-0.98(m,2H),0.74-0.70(m,2H).

[0312] Molecular formula: C 18 H 17N3O3 exact molecular weight: 323.13 LC-MS (m / z) = 324.14 [M+H] + .

[0313] Example 7: Synthesis of N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)-2-cyclopropylaminoacetamide (Compound 10)

[0314] Step 1: Synthesis of 2-bromo-N-(5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-yl)acetamide

[0315] 5-Cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-amine (1.0 g, 3.23 mmol, 1.0 eq.) and N,N-diisopropylethylamine (1.25 g, 9.69 mmol, 3.0 eq.) were added to dichloromethane (20.0 mL). Bromoacetyl bromide (1.3 g, 6.46 mmol, 2.0 eq.) was added dropwise under an ice-water bath and allowed to react for 0.5 hour. TLC indicated the reaction was complete. Dichloromethane (50.0 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 (petroleum ether:ethyl acetate = 6:1 to 3:1) to obtain the product (1.0 g, yield: 71.9%).

[0316] Step 2: Synthesis of 2-bromo-N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)acetamide

[0317] 2-Bromo-N-(5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-yl)acetamide (1.0 g, 2.32 mmol, 1.0 eq.) was added to dichloromethane (10.0 mL), and trifluoroacetic acid (2.0 mL) was added dropwise. The reaction was allowed to react at room temperature for 1 hour. TLC indicated the reaction was complete. The pH was adjusted to 7-8 with saturated aqueous sodium bicarbonate solution, and the mixture was extracted with dichloromethane (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 = 40:1-10:1) to obtain the product (575.0 mg, yield: 66.4%).

[0318] Step 3: Synthesis of N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)-2-cyclopropylaminoacetamide

[0319] 2-Bromo-N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)acetamide (130.0 mg, 0.35 mmol, 1.0 eq.), N,N-diisopropylethylamine (135.4 mg, 1.05 mmol, 3.0 eq.), and cyclopropylamine (39.8 mg, 0.70 mmol, 2.0 eq.) were added to DMF (3.0 mL) and reacted for 1 hour. TLC indicated the reaction was complete. Ethyl acetate (50.0 mL) was added and 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 preparative thin-layer chromatography to obtain the product (80.0 mg, 65.7% yield).

[0320] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.70 (s, 1H), 10.03 (s, 1H), 7.81 (s, 1H), 7.28-7.26 (d, J = 8Hz, 1H), 7.06-7.04 (m, 2H), 4.21 (s, 1H), 3.44 (s, 2H) ),3.18-3.16(d,J=8Hz,1H),2.22-2.17(m,1H),1.70-1.64(m,1H),1.03 -0.98(m,2H),0.73-0.69(m,2H),0.41-0.37(m,2H),0.31-0.28(m,2H).

[0321] Molecular formula: C 20 H 20 N4O2 exact molecular weight: 348.16 LC-MS (m / z) = 349.20 [M+H] + .

[0322] Example 8: Synthesis of N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)-2-(ethylamino)acetamide (Compound 8)

[0323] The product was prepared by referring to the synthetic method of step 3 of Example 7 (yield: 55.0%).

[0324] 1HNMR (400MHz, DMSO-d6) δ (ppm): 10.03 (s, 1H), 7.82 (s, 1H), 7.27-7.25 (d, J = 8Hz, 1H), 7.06-7.04 (m, 2H), 4.21 (s, 1H),3.38(s,3H),2.62-2.57(m,2H),1.69-1.64(m,1H),1.07-1.03(m,3H),1.02-0.98(m,2H),0.73-0.69(m,2H).

[0325] Molecular formula: C 19 H 20 N4O2 exact molecular weight: 336.16 LC-MS (m / z) = 337.19 [M+H] + .

[0326] Example 9: Synthesis of N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)-2-((2,2,2-trifluoroethyl)amino)acetamide (Compound 12)

[0327] Prepared by referring to the synthetic method of step 3 in Example 7.

[0328] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.79 (s, 1H), 10.02 (s, 1H), 7.80 (s, 1H), 7.28-7.26 (d, J = 8Hz, 1H), 7.07-7.06 (m, 2H), 4.22 (s ,1H),3.55-3.53(d,J=8Hz,2H),3.42-3.38(m,2H),3.07-3.01(m,1H),1.71-1.64(m,1H),1.03-0.99(m,2H),0.73-0.69(m,2H).

[0329] Molecular formula: C 19 H 17 F3N4O2 exact molecular weight: 390.13 LC-MS (m / z) = 391.15 [M+H] + .

[0330] Example 10: Synthesis of N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)-2-(isopropylamino)acetamide (Compound 9)

[0331] Prepared by referring to the synthetic method of step 3 in Example 7.

[0332] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.03 (s, 1H), 7.82 (s, 1H), 7.27-7.25 (d, J = 8Hz, 1H), 7.06-7.04 (m, 2H) ,4.21(s,1H),3.38(s,4H),2.80-2.74(m,1H),1.71-1.64(m,1H),1.03-0.99(m,8H),0.73-0.69(m,2H).

[0333] Molecular formula: C 20 H 22 N4O2 exact molecular weight: 350.17 LC-MS (m / z) = 351.20 [M+H] + .

[0334] Example 11: Synthesis of N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)-2-((3-hydroxycyclobutyl)amino)acetamide (Compound 33)

[0335] Prepared by referring to the synthetic method of step 3 in Example 7.

[0336] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.04 (s, 1H), 7.79 (s, 1H), 7.28-7.26 (d, J = 8Hz, 1H), 7.06-7.04 (m, 2H), 4.99-4.94 (m, 1H), 4.21 (s, 1H), 3.7 7-3.72(m,1H),3.37(s,4H),2.82-2.74(m,1H),2.47-2.41(m,2H),2.0 7-1.91(m,1H),1.71-1.59(m,2H),1.04-0.99(m,2H),0.72-0.68(m,2H)

[0337] Molecular formula: C 21 H 22 N4O3 exact molecular weight: 378.17 LC-MS (m / z) = 379.21 [M+H] + .

[0338] Example 12: Synthesis of 2-(tert-butylamino)-N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)acetamide (Compound 39)

[0339] Prepared by referring to the synthetic method of step 3 in Example 7.

[0340] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.06 (s, 1H), 7.81 (s, 1H), 7.27-7.25 (d, J = 8Hz, 1H), 7.07-7 .04(m,2H),4.22(s,1H),1.70-1.64(m,1H),1.08(s,9H),1.04-0.99(m,2H),0.73-0.69(m,2H)

[0341] Molecular formula: C 21 H 24 N4O2 exact molecular weight: 364.19 LC-MS (m / z) = 365.25 [M+H] + .

[0342] Example 13: Synthesis of N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)-2-((2-methoxyethyl)amino)acetamide (Compound 40)

[0343] Prepared by referring to the synthetic method of step 3 in Example 7.

[0344] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.05 (s, 1H), 7.82 (s, 1H), 7.27-7.25 (d, J = 8Hz, 1H), 7.06-7.04 (m, 2H), 4.22 (s, 1H),3.42-3.40(m,5H),3.25(s,3H),2.74-2.71(m,2H),1.70-1.63(m,1H),1.03-0.98(m,2H),0.73-0.69(m,2H).

[0345] Molecular formula: C 20 H 20 N4O3 exact molecular weight: 366.17 LC-MS (m / z) = 367.16 [M+H] + .

[0346] Example 14: Synthesis of N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)-3-(methylamino)propionamide (Compound 35)

[0347] Step 1: Synthesis of tert-butyl (3-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-yl)amino)-3-oxopropyl)(methyl)carbamate

[0348] 3-((tert-Butoxycarbonyl)(methyl)amino)propionic acid (743.4 mg, 3.66 mmol, 2.0 eq.), 1-methyl-1H-pyrazole (450.4 mg, 5.48 mmol, 3.0 eq.) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (1.02 g, 3.66 mmol, 2.0 eq.) were added to dichloromethane (15.0 mL) and stirred for 0.5 hours. 5-cyclopropyl-6-(2- (Ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-amine (566.0 mg, 1.83 mmol, 1.0 eq.) was reacted at room temperature for 12 hours. TLC showed the reaction was complete. Dichloromethane (50.0 mL) was added and washed with water (50.0 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 80:1-2:1) to obtain the product (300.0 mg, yield: 33.1%).

[0349] Step 2: Synthesis of N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)-3-(methylamino)propionamide

[0350] Tert-butyl (3-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-yl)amino)-3-oxopropyl)(methyl)carbamate (300.0 mg, 0.61 mmol, 1.0 eq.) was added to dichloromethane (10.0 mL), and trifluoroacetic acid (2.0 mL) was added dropwise. The mixture was allowed to react at room temperature for 1 hour. TLC indicated the reaction was complete. The pH was adjusted to 7-8 with saturated aqueous sodium bicarbonate solution, and the mixture was extracted with dichloromethane (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 preparative thin-layer chromatography to afford the product (37.0 mg, 18.0% yield).

[0351] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 11.30 (s, 1H), 10.21 (s, 1H), 7.91 (s, 1H), 7.26-7.24 (d, J = 8Hz, 1H), 7.13-7.12 (m, 1H), 7.05-7.03 (m,1H),4.22(s,1H),3.18-3.15(m,2H),2.96-2.93(m,2H),2.55(s,3H),1.69-1.64(m,1H),1.03-0.98(m,2H),0.70-0.66(m,2H).

[0352] Molecular formula: C 19 H20 N4O2 exact molecular weight: 336.16 LC-MS (m / z) = 337.19 [M+H] + .

[0353] Example 15: Synthesis of (R)-N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)-2-(methylamino)propionamide (Compound 36)

[0354] Prepared with reference to the synthetic method of Example 14,

[0355] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.03 (s, 1H), 7.84 (s, 1H), 7.27-7.25 (d, J = 8Hz, 1H),7.06-7.04(m,2H),4.22(s,1H),3.29-3.26(m,3H),2.28(s,3H),1.7 0-1.63(m,1H),1.25-1.22(m,3H),1.03-0.98(m,2H),0.74-0.70(m,2H).

[0356] Molecular formula: C 19 H 20 N4O2 exact molecular weight: 336.16 LC-MS (m / z) = 337.20 [M+H] + .

[0357] Example 16: Synthesis of 1-amino-N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)cyclopropane-1-carboxamide (Compound 54)

[0358] Prepared by referring to the synthetic method of Example 14.

[0359] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.06 (s, 1H), 7.80 (s, 1H), 7.28-7.26 (d, J = 8Hz, 1H), 7.06-7.04 (m, 2H), 4.24 (s,1H),3.17-3.16(d,J=4Hz,1H),1.67-1.64(m,1H),1.27-1.23(m,2H),1.00-0.99(m,2H),0.72-0.70(m,2H).

[0360] Molecular formula: C 19 H 18N4O2 exact molecular weight: 334.14 LC-MS (m / z) = 335.18 [M+H] + .

[0361] Example 17: Synthesis of (S)-N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)-2-(methylamino)propionamide (Compound 37)

[0362] Prepared by referring to the synthetic method of Example 14.

[0363] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.03 (s, 1H), 7.84 (s, 1H), 7.27-7.25 (d, J = 8Hz, 1H), 7.06-7.04 (m, 2H), 4.22 (s ,1H),3.29-3.26(m,3H),2.28(s,3H),1.70-1.63(m,1H),1.25-1.22(m,3H),1.03-0.98(m,2H),0.74-0.70(m,2H)

[0364] Molecular formula: C 19 H 20 N4O2 exact molecular weight: 336.16 LC-MS (m / z) = 337.19 [M+H] + .

[0365] Example 18: Synthesis of 2-amino-N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)-2-methylpropanamide (Compound 58)

[0366] Prepared by referring to the synthetic method of Example 14.

[0367] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.04 (s, 1H), 7.83 (s, 1H), 7.27-7.25 (d, J = 8Hz, 1H), 7.06-7.03 (m, 2H),5.24(s,2H),4.23(s,1H),1.69-1.65(m,1H),1.31(s,6H),1.02-1.00(m,2H),0.73-0.72(m,2H).

[0368] Molecular formula: C 19 H 20 N4O2 exact molecular weight: 336.16 LC-MS (m / z) = 337.15 [M+H]+ .

[0369] Example 19: Synthesis of N-(5-cyclopropyl-6-(2-hydroxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)-2-(methylamino)acetamide (Compound 20)

[0370] The intermediate tert-butyl (2-((6-chloro-5-cyclopropylpyridazin-3-yl)amino)-2-oxoethyl)(methyl)carbamate and (2-(ethoxymethoxy)-4-(trifluoromethyl)phenyl)boric acid were used as raw materials and prepared by referring to the synthetic method of steps 2 and 4 of Example 3.

[0371] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 7.78 (s, 1H), 7.50-7.48 (d, J = 8Hz, 1H), 7.30-7.27 (m,2H),2.50-2.47(m,3H),1.66-1.62(m,1H),1.03-1.01(m,2H),0.73-0.71(m,2H)

[0372] Molecular formula: C 17 H 17 F3N4O2 exact molecular weight: 366.13 LC-MS (m / z) = 367.13 [M+H] + .

[0373] Example 20: Synthesis of Compound N-(6-(2-hydroxy-4-trifluoromethylphenyl)-5-methylpyridazin-3-yl)-2-(methylamino)acetamide (Compound 17)

[0374] Step 1: Synthesis of intermediate 6-(2-methoxy-4-trifluoromethylphenyl)-5-methylpyridazin-3-amine

[0375] 3-Amino-5-methyl-6-chloropyridazine (500 mg, 3.48 mmol, 1.0 eq), 2-methoxy-4-(trifluoromethylphenyl)boronic acid (919 mg, 4.18 mmol, 1.2 eq), potassium carbonate (962 mg, 6.96 mmol, 2.0 eq) in 1.5 mL, and tetrakis(triphenylphosphine)palladium (402 mg, 0.348 mmol, 0.1 eq) were added to 1,4-dioxane (5 mL). Under nitrogen, the mixture was reacted at 90°C for 16 hours. TLC indicated the reaction was complete. The reaction mixture was filtered through celite, and the filter cake was washed with dichloromethane (20 mL) and methanol (20 mL). The filtrate was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the crude product, which was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 50:1) to obtain the product (745 mg, yield: 75.6%).

[0376] Step 2: Synthesis of intermediate 2-bromo-N-(6-(2-methoxy-4-trifluoromethylphenyl)-5-methylpyridazin-3-yl)acetamide

[0377] Dissolve 6-(2-methoxy-4-trifluoromethylphenyl)-5-methylpyridazin-3-amine (745 mg, 2.63 mmol, 1.0 eq) in dichloromethane (20 mL). Add N,N-diisopropylethylamine (680 mg, 5.26 mmol, 2.0 eq). Add bromoacetyl bromide (797 mg, 3.95 mmol, 1.5 eq) dropwise at 0°C. Allow to react at 0°C for 5 minutes. TLC indicates the reaction is complete. Pour the reaction solution into water (10 mL) and extract with dichloromethane (15 mL x 3). The organic phases are combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate is concentrated to obtain the crude product, which is directly used in the next step.

[0378] Step 3: Synthesis of intermediate 2-bromo-N-(6-(2-hydroxy-4-trifluoromethylphenyl)-5-methylpyridazin-3-yl)acetamide

[0379] 2-Bromo-N-(6-(2-methoxy-4-trifluoromethylphenyl)-5-methylpyridazin-3-yl)acetamide (crude, 2.63 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL). Boron tribromide (3.3 g, 13.15 mmol, 5.0 eq) was added dropwise. The mixture was allowed to react at 25°C for 3 hours. TLC indicated the reaction was complete. Dichloromethane (40 mL) was added for dilution. Methanol (5 mL) was slowly added dropwise at 0°C to quench the reaction. After the addition was complete, the reaction mixture was poured into saturated aqueous sodium bicarbonate (50 mL) and extracted with dichloromethane (20 mL x 5). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated to afford the product (741 mg, 71.9% yield).

[0380] Step 4: Synthesis of compound N-(6-(2-hydroxy-4-trifluoromethylphenyl)-5-methylpyridazin-3-yl)-2-(methylamino)acetamide

[0381] 2-Bromo-N-(6-(2-hydroxy-4-trifluoromethylphenyl)-5-methylpyridazin-3-yl)acetamide (200 mg, 0.513 mmol, 1.0 eq) was added to a mixture of acetonitrile and methanol (2 mL / 2 mL). N,N-diisopropylethylamine (199 mg, 1.539 mmol, 3.0 eq) and a 27% methylamine / methanol solution (177 mg, 1.539 mmol, 3.0 eq) were added to the suspension. The mixture was allowed to react at 25°C for 0.5 h. TLC indicated the reaction was complete. The reaction solution was poured into saturated aqueous ammonium chloride (10 mL) and extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated to obtain the crude product, which was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain the product (30 mg, yield: 17.1%).

[0382] 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 8.27 (s, 1H), 7.48-7.46 (d, 1H), 7.30-7.27 (m, 2H), 3.46 (s, 2H), 2.39 (s, 3H), 2.20 (s, 3H).

[0383] Molecular formula: C 15 H 15 F3N4O2 exact molecular weight: 340.11 LC-MS (m / z): 341.14 [M+H] + .

[0384] Example 21: Synthesis of N-(6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-isopropylpyridazin-3-yl)-2-(methylamino)acetamide (Compound 19)

[0385] Prepared by referring to the synthetic method of Example 19.

[0386] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 8.37 (s, 1H), 7.48-7.46 (d, J = 8Hz, 1H), 7.29-7.23 (m, 2H), 3.37 (s, 3H), 2.76-2.69 (m, 1H), 1.11-1.09 (d, J = 8Hz, 6H).

[0387] Molecular formula: C 17 H 19 F3N4O2 exact molecular weight: 368.15 LC-MS (m / z) = 369.17 [M+H] + .

[0388] Example 22: Synthesis of 2-amino-N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)acetamide (Compound 13)

[0389] Prepared by referring to the synthetic method of Example 14.

[0390] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 7.78 (s, 1H), 7.28-7.26 (d, J = 8Hz, 1H), 7.07-7.04 (m, 2H),4.23(s,1H),3.58(s,2H),1.70-1.66(m,1H),1.05-1.01(m,2H),0.72-0.69(m,2H)

[0391] Molecular formula: C 17 H 16 N4O2 exact molecular weight: 308.13 LC-MS (m / z) = 309.13 [M+H] + .

[0392] Example 23: Synthesis of (R)-N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)azetidine-2-carboxamide (Compound 42)

[0393] Prepared by referring to the synthetic method of Example 14.

[0394] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.49 (s, 1H), 7.83 (s, 1H), 7.28-7.26 (d, J = 8Hz, 1H), 7.07-7.04 (m, 2H), 4.37-4.33 (m, 1H), 4.22 (s, 1H) ),3.64-3.58(m,1H),3.30-3.25(m,1H),2.62-2.53(m,1H),2.36-2.28(m,1H),1.71-1.65(m,1H),1.04-0.99(m,1H),0.75-0.71(m,2H).

[0395] Molecular formula: C 19 H 18N4O2 exact molecular weight: 334.14 LC-MS (m / z) = 335.14 [M+H] + .

[0396] Example 24: Synthesis of (R)-N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)pyrrolidine-2-carboxamide (Compound 43)

[0397] Prepared by referring to the synthetic method of Example 14.

[0398] 1 HNMR(400MHz,DMSO-d6)δ(ppm):10.71(s,1H),10.21(s,1H),7.82(s,1H), 7.27-7.25(d,J=8Hz,1H),7.06-7.04(m,2H),4.22(s,1H),3.88-3.85(m,1H),2.99-2.88(m,2H) ,2.13-2.08(m,1H),1.87-1.80(m,1H),1.72-1.64(m,3H),1.03-0.98(m,2H),0.73-0.69(m,2H).

[0399] Molecular formula: C 20 H 20 N4O2 exact molecular weight: 348.16 LC-MS (m / z) = 349.15 [M+H] + .

[0400] Example 25: Synthesis of (R)-2-amino-N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)propionamide (Compound 44)

[0401] Prepared by referring to the synthetic method of Example 14.

[0402] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 7.83 (s, 1H), 7.27-7.25 (d, J = 8Hz, 1H), 7.06-7.04 (m, 2H), 4.22 (s, 1H),3.58-3.53(m,1H),1.69-1.64(m,1H),1.25-1.23(m,3H),1.03-0.98(m,2H),0.73-0.69(m,2H).

[0403] Molecular formula: C 18 H 18N4O2 exact molecular weight: 322.14 LC-MS (m / z) = 323.14 [M+H] + .

[0404] Example 26: Synthesis of (R)-N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)-3-methyl-2-(methylamino)butanamide (Compound 45)

[0405] Prepared by referring to the synthetic method of Example 14.

[0406] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.03 (s, 1H), 7.87 (s, 1H), 7.28-7.26 (d, J = 8Hz, 1H), 7.07-7.04 (m, 2H), 4.22 (s, 1H), 2.97-2.96 ( d,J=4Hz,1H),2.28(s,3H),1.92-1.87(m,1H),1.69-1.65(m,1H),1.03-0.98(m,2H),0.94-0.92(d,J=8Hz,6H),0.75-0.71(m,2H).

[0407] Molecular formula: C 21 H 24 N4O2 exact molecular weight: 364.19 LC-MS (m / z) = 365.20 [M+H] + .

[0408] Example 27: Synthesis of (R)-2-amino-N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)-3-methoxypropionamide (Compound 51)

[0409] Prepared by referring to the synthetic method of Example 14.

[0410] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.04 (s, 1H), 7.83 (s, 1H), 7.28-7.26 (d, J = 8Hz, 1H),7.07-7.04(m,2H),4.22(s,1H),3.69-3.66(m,1H),3.58-3.49(m,2H ),3.27(s,3H),1.70-1.64(m,1H),1.04-0.99(m,2H),0.73-0.69(m,2H).

[0411] Molecular formula: C 19 H20 N4O3 exact molecular weight: 352.12 LC-MS (m / z) = 353.15 [M+H] + .

[0412] Example 28: Synthesis of (R)-2-amino-N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)-3-phenylpropanamide (Compound 52)

[0413] Prepared by referring to the synthetic method of Example 14.

[0414] 1 HNMR(400MHz,DMSO-d6)δ(ppm):10.07(s,1H),7.81(s,1H),7.31-7.20(m,6H),7.06-7.04(m,2H),4.24(s,1H),3 .75-3.71(m,1H),3.08-3.03(m,1H),2.75-2.70(m,1H),1.69-1.65(m,1H),1.02-1.00(m,2H),0.71-0.70(m,2H).

[0415] Molecular formula: C 24 H 22 N4O2 exact molecular weight: 398.17 LC-MS (m / z) = 399.14 [M+H] + .

[0416] Example 29: Synthesis of (R)-2-amino-2-cyclopropyl-N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)acetamide (Compound 53)

[0417] Prepared by referring to the synthetic method of Example 14.

[0418] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.08 (s, 1H), 7.85 (s, 1H), 7.28-7.26 (d, J = 8Hz, 1H), 7.06-7.04 (m, 2H), 4.23 (s, 1H), 3.00-2.98 (d,J=8Hz,1H),1.68-1.65(m,1H),1.05-1.00(m,3H),0.73-0.71(m,2H),0.53-0.50(m,1H),0.42-0.40(m,2H),0.30-0.27(m,1H).

[0419] Molecular formula: C 20H 20 N4O2 exact molecular weight: 348.16 LC-MS (m / z) = 349.15 [M+H] + .

[0420] Example 30: Synthesis of (R)-2-amino-N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)-3-methylbutanamide (Compound 56)

[0421] Prepared by referring to the synthetic method of Example 14.

[0422] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.04 (s, 1H), 7.85 (s, 1H), 7.27-7.25 (d, J = 8Hz, 1H),7.06-7.04(m,2H),4.23(s,1H),3.29-3.28(m,1H),2.03-1.98(m,1H),1.68-1.6 5(m,1H),1.01-0.99(m,2H),0.95-0.94(m,3H),0.86-0.85(m,3H),0.72-0.71(m,2H).

[0423] Molecular formula: C 20 H 22 N4O2 exact molecular weight: 350.17 LC-MS (m / z) = 351.20 [M+H] + .

[0424] Example 31: Synthesis of Compound N-(6-(2-hydroxy-4-(1-propynyl)phenyl)-5-methylpyridazin-3-yl)-2-(methylamino)acetamide (Compound 46)

[0425] The intermediate (2-methoxy-4-(1-propynyl)phenyl)boronic acid and 3-amino-5-methyl-6-chloropyridazine were used as raw materials and prepared according to the synthetic method of Example 20.

[0426] 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 8.21 (s, 1H), 7.20-7.18 (d, 1H), 6.97-6.95 (m, 2H), 3.61 (s, 2H), 2.46 (s, 3H), 2.19 (s, 3H), 2.07 (s, 3H).

[0427] Molecular formula: C 17 H 18N4O2 exact molecular weight: 310.14 LC-MS (m / z): 311.13 [M+H] + .

[0428] Example 32: Synthesis of N-(5-cyclopropyl-6-(2-hydroxy-4-(prop-1-yn-1-yl)phenyl)pyridazin-3-yl)-2-(methylamino)acetamide (Compound 47)

[0429] The intermediate (2-methoxy-4-(1-propynyl)phenyl)boronic acid and 6-chloro-5-cyclopropylpyridazine-3-amine were used as raw materials and prepared according to the synthetic method of Example 20.

[0430] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 9.93 (s, 1H), 7.80 (s, 1H), 7.22-7.20 (d, J = 8Hz, 1H), 6.96-6.94 (m, 2 H),3.39(s,2H),2.35(s,3H),2.06(s,3H),1.71-1.66(m,1H),1.03-0.99(m,2H),0.73-0.69(m,2H).

[0431] Molecular formula: C 19 H 20 N4O2 exact molecular weight: 336.16 LC-MS (m / z) = 337.18 [M+H] + .

[0432] Example 33: Synthesis of N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)-2-hydroxyacetamide (Compound 15)

[0433] Step 1: Synthesis of 2-((tert-butyldimethylsilyl)oxy)acetic acid

[0434] 2-Hydroxyacetic acid (2.0 g, 26.29 mmol, 1.0 eq.), tert-butyldimethylsilyl chloride (5.1 g, 34.18 mmol, 1.3 eq.), and imidazole (2.7 g, 39.45 mmol, 1.5 eq.) were added to DMF (20.0 mL) and allowed to react at room temperature for 14 hours. TLC indicated the reaction was complete. Ethyl acetate (50.0 mL) was added, and the mixture was washed with water (50.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product (4.4 g, 88.0% yield).

[0435] Step 2: Synthesis of 2-((tert-butyldimethylsilyl)oxy)-N-(5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-yl)acetamide

[0436] The crude product was synthesized according to the method of step 3 of Example 5) and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1-3:1) to obtain the product (600.0 mg, yield: 76.1%).

[0437] Step 3: Synthesis of N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)-2-hydroxyacetamide

[0438] Referring to the preparation method of step 4 of Example 3, the crude product was purified by silica gel column chromatography (dichloromethane:methanol=80:1-50:1) to obtain the product (250.0 mg, yield: 71.0%).

[0439] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.32 (s, 1H), 10.05 (s, 1H), 7.79 (s, 1H), 7.28-7.26 (d, J = 8Hz, 1H), 7.07-7.04 (m,2H),5.70(s,1H),4.21(s,1H),4.11-4.10(m,2H),1.70-1.64(m,1H),1.04-0.99(m,2H),0.74-0.70(m,2H).

[0440] Molecular formula: C 17 H 15 N3O3 exact molecular weight: 309.11 LC-MS (m / z) = 310.11 [M+H] + .

[0441] Example 34: Synthesis of (R)-2-amino-N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)-3-hydroxypropionamide (Compound 55)

[0442] Prepared by referring to the synthetic method of Example 33.

[0443] 1HNMR (400MHz, DMSO-d6) δ (ppm): 7.84 (s, 1H), 7.27-7.25 (d, J = 8Hz, 1H), 7.05-7.03 (m, 2H), 4.91 (s, 1H), 4. 22(s,1H),3.62-3.59(m,2H),3.52-3.49(m,1H),1.69-1.67(m,1H),1.02-1.00(m,2H),0.71-0.70(m,2H).

[0444] Molecular formula: C 18 H 18 N4O3 exact molecular weight: 338.14 LC-MS (m / z) = 339.16 [M+H] + .

[0445] Example 35: Synthesis of (R)-2-amino-N-(5-cyclopropyl-6-(2-hydroxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)propionamide (Compound 50)

[0446] Step 1: Synthesis of tert-butyl (R)-(1-((6-chloro-5-cyclopropylpyridazin-3-yl)amino)-1-oxopropan-2-yl)carbamate

[0447] (tert-Butyloxycarbonyl)-D-alanine (669.0 mg, 3.54 mmol, 2.0 eq.), N,N-diisopropylethylamine (457.0 mg, 3.54 mmol, 2.0 eq.), and HATU (1.34 g, 3.54 mmol, 2.0 eq.) were added to DMF (10.0 mL), stirred for 1 hour, and then 6-chloro-5-cyclopropylpyridazin-3-amine (300.0 mg, 1.77 mmol, 1.0 eq.) was added. The reaction was allowed to react at room temperature for 12 hours. TLC showed that the reaction was complete. Ethyl acetate (50.0 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 = 100:1-80:1) to give the product (501.0 mg, yield: 83.2%).

[0448] Step 2: Synthesis of tert-butyl (R)-(1-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-1-oxopropan-2-yl)carbamate

[0449] Referring to the preparation method of step 2 of Example 3, the crude product was purified by silica gel column chromatography (dichloromethane:methanol=100:1-80:1) to obtain the product (250.0 mg, yield: 34.5%).

[0450] Step 3: Synthesis of (R)-2-amino-N-(5-cyclopropyl-6-(2-hydroxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)propionamide

[0451] Referring to the preparation method of step 4 of Example 3, the crude product was purified by preparative thin layer chromatography to obtain the product (30.0 mg, yield: 43.1%).

[0452] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 7.86 (s, 1H), 7.50-7.48 (d, J = 8Hz, 1H), 7.29-7.25 (m, 2H), 3. 57-3.56(m,1H),1.66-1.63(m,1H),1.26-1.24(m,4H),1.04-0.99(m,2H),0.75-0.71(m,2H).

[0453] Molecular formula: C 17 H 17 F3N4O2 exact molecular weight: 366.13 LC-MS (m / z) = 367.14 [M+H] + .

[0454] Example 36: Synthesis of (2R,3S)-2-amino-N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)-3-hydroxybutanamide (Compound 57)

[0455] Step 1: Synthesis of (9H-fluoren-9-yl)methyl[(2R,3S)-1-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-yl)amino)-3-hydroxy-1-oxobutan-2-yl]carbamate

[0456] Referring to the preparation method in step 3 of Example 6, the crude product was purified by silica gel column chromatography (dichloromethane:methanol=100:1-60:1) to obtain the product (300.0 mg, yield: 73.5%).

[0457] Step 2: Synthesis of (9H-fluoren-9-yl)methyl[(2R,3S)-1-((5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)amino)-3-hydroxy-1-oxobutan-2-yl]carbamate

[0458] The crude product was prepared according to the method of step 4 of Example 3, and purified by silica gel column chromatography (dichloromethane:methanol=100:1-40:1) to obtain the product (160.0 mg, yield: 58.8%).

[0459] Step 3: Synthesis of (2R,3S)-2-amino-N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)-3-hydroxybutanamide

[0460] (9H-fluoren-9-yl)methyl[(2R,3S)-1-((5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)amino)-3-hydroxy-1-oxobutan-2-yl]carbamate (150.0 mg, 0.26 mmol, 1.0 eq.) was added to methanol (30.0 mL), and piperidine (30.0 mL) was added dropwise. The reaction was allowed to react at room temperature for 18 hours. TLC indicated the reaction was complete. The mixture was concentrated under reduced pressure, and dichloromethane (50.0 mL) was added. 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 preparative thin-layer chromatography to obtain the product (80.0 mg, 86.9% yield).

[0461] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.04 (s, 1H), 7.85 (s, 1H), 7.27-7.25 (d, J = 8Hz, 1H), 7.06-7.04 (m, 2H), 4.79 (s, 1H), 4.23 (s,1H),4.07-4.05(m,1H),3.28(s,1H),1.69-1.65(m,1H),1.15-1.13(d,J=8Hz,3H),1.02-1.00(m,2H),0.71-0.70(m,2H).

[0462] Molecular formula: C 19 H 20 N4O3 exact molecular weight: 352.15 LC-MS (m / z) = 353.17 [M+H] + .

[0463] Example 37: Synthesis of (2R,3R)-2-amino-N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)-3-hydroxybutanamide (Compound 59)

[0464] Prepared by referring to the synthetic method of Example 36.

[0465] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.16 (s, 1H), 7.75 (s, 1H), 7.28-7.26 (d, J = 8Hz, 1H), 7.08-7.05 (m, 2H), 4.24 (s, 1H), 4.14 (s,1H),4.00-3.99(m,1H),3.38(s,1H),1.72-1.66(m,1H),1.19-1.17(d,J=8Hz,3H),1.04-1.02(m,2H),0.71-0.70(m,2H).

[0466] Molecular formula: C 19 H 20 N4O3 exact molecular weight: 352.15 LC-MS (m / z) = 353.16 [M+H] + .

[0467] Example 38: Synthesis of N-(5-cyclobutyl-6-(2-hydroxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)-2-(methylamino)acetamide (Compound 61)

[0468] The compound was prepared using N-(tert-butyloxycarbonyl)-N-methylglycine, the intermediate 6-chloro-5-cyclobutylpyridazin-3-amine and (2-(ethoxymethoxy)-4-(trifluoromethyl)phenyl)boric acid as raw materials and referring to the synthetic methods of steps 1, 2 and 4 of Example 3.

[0469] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 8.34 (s, 1H), 7.42-7.40 (d, J = 8Hz, 1H), 7.27-7. 24(m,2H),3.55-3.45(m,4H),2.38(s,3H),1.97-1.85(m,5H),1.72-1.68(m,1H).

[0470] Molecular formula: C 18 H 19 F3N4O2 exact molecular weight: 380.15 LC-MS (m / z) = 381.12 [M+H] + .

[0471] Example 39: Synthesis of N-(6-(4-ethynyl-2-hydroxyphenyl)-5-isopropylpyridazin-3-yl)-2-(methylamino)acetamide (Compound 16)

[0472] The compound was prepared using N-(tert-butyloxycarbonyl)-N-methylglycine, the intermediate 6-chloro-5-isopropylpyridazin-3-amine and 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde as raw materials and referring to the synthesis method of Example 3.

[0473] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.03 (s, 1H), 8.34 (s, 1H), 7.24-7.22 (d, J = 8Hz, 1H), 7.06-7. 03(m,2H),4.24(s,1H),3.36(s,3H),2.77-2.72(m,1H),2.34(s,3H),1.10-1.08(d,J=8Hz,6H).

[0474] Molecular formula: C 18 H 20 N4O2 exact molecular weight: 324.16 LC-MS (m / z) = 325.16 [M+H] + .

[0475] Example 40: Synthesis of N-(5-cyclobutyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)-2-(methylamino)acetamide (Compound 62)

[0476] The product was prepared using N-(tert-butyloxycarbonyl)-N-methylglycine, the intermediate 6-chloro-5-cyclobutylpyridazin-3-amine and 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde as raw materials and referring to the synthesis method of Example 3.

[0477] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 8.32 (s, 1H), 7.18-7.16 (d, J = 8Hz, 1H), 7.02-7.01 (m, 2H), 4. 23(s,1H),3.54-3.50(m,1H),3.37(s,3H),2.34(s,3H),1.96-1.82(m,5H),1.70-1.66(m,1H).

[0478] Molecular formula: C 19 H 20 N4O2 exact molecular weight: 336.16 LC-MS (m / z) = 337.17 [M+H] + .

[0479] Example 41: Synthesis of (R)-2-amino-N-(5-cyclobutyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)propionamide (Compound 65)

[0480] Prepared by referring to the synthetic method of Example 3.

[0481] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 8.34 (s, 1H), 7.18-7.16 (d, J = 8Hz, 1H), 7.02-7.00 ( m,2H),4.22(s,1H),3.61-3.50(m,2H),1.96-1.66(m,6H),1.27-1.25(d,J=8Hz,3H).

[0482] Molecular formula: C 19 H 20 N4O2 exact molecular weight: 336.16 LC-MS (m / z) = 337.10 [M+H] + .

[0483] Example 42: Synthesis of (R)-2-amino-N-(6-(4-ethynyl-2-hydroxyphenyl)-5-isopropylpyridazin-3-yl)propionamide (Compound 66)

[0484] Prepared by referring to the synthetic method of Example 3.

[0485] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 8.35 (s, 1H), 7.23-7.21 (d, J = 8Hz, 1H), 7.05-7.02 (m, 2H), 4.22 ( s,1H),3.60-3.55(m,1H),2.78-2.74(m,1H),1.27-1.25(d,J=8Hz,3H),1.10-1.08(d,J=8Hz,6H).

[0486] Molecular formula: C 18 H 20 N4O2 exact molecular weight: 324.16 LC-MS (m / z) = 325.14 [M+H] + .

[0487] Example 43: Synthesis of (R)-2-amino-N-(5-cyclobutyl-6-(2-hydroxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)propionamide (Compound 63)

[0488] The compound was prepared using (tert-butyloxycarbonyl)-D-alanine, the intermediate 6-chloro-5-cyclobutylpyridazin-3-amine and (2-(ethoxymethoxy)-4-(trifluoromethyl)phenyl)boric acid as raw materials and referring to the synthetic methods of steps 1, 2 and 4 of Example 3.

[0489] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 8.37 (s, 1H), 7.41-7.39 (d, J = 8Hz, 1H), 7.25-7.21 (m, 2 H),3.62-3.47(m,2H),1.97-1.82(m,5H),1.73-1.68(m,1H),1.27-1.26(d,J=4Hz,3H).

[0490] Molecular formula: C 18 H 19 F3N4O2 exact molecular weight: 380.15 LC-MS (m / z) = 381.12 [M+H] + .

[0491] Example 44: Synthesis of (R)-2-amino-N-(6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-isopropylpyridazin-3-yl)propionamide (Compound 64)

[0492] Prepared by referring to the synthetic method of step 1, step 2 and step 4 in Example 3.

[0493] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 8.38 (s, 1H), 7.47-7.45 (d, J = 8Hz, 1H), 7.28-7.22 (m,2H),3.62-3.56(m,1H),2.75-2.72(m,1H),1.27-1.25(d,J=8Hz,3H),1.11-1.09 (d,J=8Hz,6H).

[0494] Molecular formula: C 17 H 19 F3N4O2 exact molecular weight: 368.15 LC-MS (m / z) = 369.13 [M+H] + .

[0495] Example 45: Synthesis of N-(6-(4-chloro-2-hydroxyphenyl)-5-cyclopropylpyridazin-3-yl)-2-(methylamino)acetamide (Compound 67)

[0496] Prepared by referring to the synthetic method of step 1, step 2 and step 4 in Example 3.

[0497] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 7.82 (s, 1H), 7.29-7.27 (d, J = 8Hz, 1H), 6.99 (s, 2H) ,3.34(s,3H),2.33(s,3H),1.67-1.66(m,1H),1.02-1.00(m,2H),0.72-0.71(m,2H).

[0498] Molecular formula: C 16 H 17 ClN4O2 exact molecular weight: 332.10 LC-MS (m / z) = 333.06 [M+H] + .

[0499] Example 46: Synthesis of N-(5-cyclopropyl-6-(4-fluoro-2-hydroxyphenyl)pyridazin-3-yl)-2-(methylamino)acetamide (Compound 71)

[0500] Step 1: Synthesis of 5-cyclopropyl-6-(2-(ethoxymethoxy)-4-fluorophenyl)pyridazin-3-amine

[0501] 6-Chloro-5-cyclopropylpyridazin-3-amine (553.4 mg, 3.26 mmol, 1.0 eq.), (2-(ethoxymethoxy)-4-fluorophenyl)boronic acid (838.0 mg, 3.92 mmol, 1.2 eq.), sodium bicarbonate (411.1 mg, 4.89 mmol, 1.5 eq.) and Pd(dppf)Cl2 (119.3 mg, 0.16 mmol, 0.05 eq.) were added to the The reaction mixture was added to a mixed solution of 1,4-dioxane (8.0 mL) and water (4.0 mL) and reacted at 100°C under nitrogen for 12 hours. TLC showed that the reaction was complete. Ethyl acetate (50.0 mL) was added and washed with water (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 = 80:1-20:1) to obtain the product (700.0 mg, yield: 70.7%).

[0502] Step 2: Synthesis of tert-butyl (2-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-fluorophenyl)pyridazin-3-yl)amino)-2-oxoethyl)(methyl)carbamate

[0503] Referring to the synthesis method of step 3 of Example 6, the crude product was purified by silica gel column chromatography (dichloromethane:methanol=80:1-50:1) to obtain the product (440.0 mg, yield: 80.7%).

[0504] Step 3: Synthesis of N-(5-cyclopropyl-6-(4-fluoro-2-hydroxyphenyl)pyridazin-3-yl)-2-(methylamino)acetamide

[0505] The product was prepared according to the method of step 4 of Example 3, and the crude product was purified by preparative thin layer chromatography to obtain the product (80.0 mg, yield: 60.1%).

[0506] 1 HNMR(400MHz,DMSO-d6)δ(ppm):7.80(s,1H),7.31-7.27(m,1H),6.80-6.73(m,2H),3.38( s,2H),3.33(s,1H),2.35(s,3H),1.71-1.65(m,1H),1.02-1.00(m,2H),0.72-0.70(m,2H).

[0507] Molecular formula: C 16 H 17 FN4O2 exact molecular weight: 316.13 LC-MS (m / z) = 317.07 [M+H] + .

[0508] Example 47: Synthesis of (R)-2-amino-3-cyano-N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)propionamide (Compound 73)

[0509] Step 1: Synthesis of (9H-fluoren-9-yl)methyl (R)-(3-cyano-1-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-yl)amino)-1-oxopropan-2-yl)carbamate

[0510] Referring to the synthesis method of step 1 in Example 14, the crude product was purified by silica gel column chromatography (dichloromethane:methanol=80:1-60:1) to obtain the product (220.0 mg, yield: 36.2%).

[0511] Step 2: Synthesis of (9H-fluoren-9-yl)methyl (R)-(3-cyano-1-((5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)amino)-1-oxopropan-2-yl)carbamate

[0512] The crude product was prepared according to the method of step 4 of Example 3, and purified by silica gel column chromatography (dichloromethane:methanol=80:1-50:1) to obtain the product (167.0 mg, yield: 92.2%).

[0513] Step 3: Synthesis of (R)-2-amino-3-cyano-N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)propionamide

[0514] (9H-fluoren-9-yl)methyl (R)-(3-cyano-1-((5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)amino)-1-oxopropan-2-yl)carbamate (160.0 mg, 0.28 mmol, 1.0 eq.) was added to acetonitrile (3.0 mL), and diethylamine (3.0 mL) was added dropwise. The reaction was allowed to react at room temperature for 14 hours. TLC indicated the reaction was complete. The mixture was concentrated under reduced pressure, and dichloromethane (50.0 mL) was added. 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 preparative thin-layer chromatography to obtain the product (7.0 mg, 7.2% yield).

[0515] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.04 (s, 1H), 7.80 (s, 1H), 7.28-7.26 (d, J = 8Hz, 1H), 7.06-7.04 (m, 2H), 4 .22(s,1H),3.86-3.83(m,1H),2.91-2.72(m,2H),1.70-1.64(m,1H),1.03-1.01(m,2H),0.72-0.70(m,2H).

[0516] Molecular formula: C 19 H 17 N5O2 exact molecular weight: 347.14 LC-MS (m / z) = 348.08 [M+H] + .

[0517] Example 48: Synthesis of (R)-N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)-2-hydroxypropionamide (Compound 74)

[0518] Prepared by referring to the synthetic method of Example 33.

[0519] 1HNMR (400MHz, DMSO-d6) δ (ppm): 10.23 (s, 1H), 10.04 (s, 1H), 7.80 (s, 1H), 7.28-7.26 (d, J = 8Hz, 1H), 7.06-7.04 (m, 2H), 5.87-5.86 (d,J=4Hz,1H),4.32-4.25(m,1H),4.22(s,1H),1.69-1.64(m,1H),1.34-1.32(d,J=8Hz,3H),1.04-0.99(m,2H),0.75-0.71(m,2H).

[0520] Molecular formula: C 18 H 17 N3O3 exact molecular weight: 323.13 LC-MS (m / z) = 324.09 [M+H] + .

[0521] Example 49: Synthesis of 2-cyano-N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)acetamide (Compound 75)

[0522] Prepared by referring to the synthetic method of Example 14.

[0523] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 11.42 (s, 1H), 10.08 (s, 1H), 7.70 (s, 1H), 7.28-7.26 (d, J = 8Hz, 1H), 7 .06-7.04(m,2H),4.24(s,1H),4.06(s,2H),1.69-1.64(m,1H),1.03-1.01(m,2H),0.73-0.72(m,2H).

[0524] Molecular formula: C 18 H 14 N4O2 exact molecular weight: 318.11 LC-MS (m / z) = 319.03 [M+H] + .

[0525] Example 50: Synthesis of (R)-N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)-3-hydroxybutanamide (Compound 76)

[0526] Prepared by referring to the synthetic method of Example 33.

[0527] 1HNMR(400MHz,DMSO-d6)δ(ppm):10.96(s,1H),10.05(s,1H),7.81(s,1H), 7.27-7.25(d,J=8Hz,1H),7.06-7.03(m,2H),4.80-4.79(d,J=4Hz,1H),4.2 3(s,1H),4.13-4.07(m,1H),2.59-2.53(m,1H),2.48-2.44(m,1H),1.69-1. 62(m,1H),1.14-1.12(d,J=8Hz,3H),1.01-0.98(m,2H),0.71-0.68(m,2H).

[0528] Molecular formula: C 19 H 19 N3O3 exact molecular weight: 337.14 LC-MS (m / z) = 338.08 [M+H] + .

[0529] Example 51: Synthesis of (S)-N-(5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)-3-hydroxybutanamide (Compound 77)

[0530] Prepared by referring to the synthetic method of Example 33.

[0531] 1 HNMR(400MHz,DMSO-d6)δ(ppm):10.96(s,1H),10.04(s,1H),7.81(s,1H), 7.27-7.25(d,J=8Hz,1H),7.06-7.03(m,2H),4.80-4.79(d,J=4Hz,1H),4.2 3(s,1H),4.13-4.09(m,1H),2.59-2.53(m,1H),2.48-2.44(m,1H),1.69-1. 62(m,1H),1.14-1.13(d,J=4Hz,3H),1.01-0.98(m,2H),0.70-0.69(m,2H).

[0532] Molecular formula: C 19 H 19 N3O3 exact molecular weight: 337.14 LC-MS (m / z) = 338.09 [M+H] + .

[0533] Example 52: Synthesis of (R)-3-amino-4-((5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)amino)-4-oxobutanoic acid trifluoroacetate (Compound 79-TF)

[0534] Step 1: Synthesis of tert-butyl (R)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-yl)amino)-4-oxobutanoate

[0535] The crude product was prepared according to the method of step 3 of Example 6, and purified by silica gel column chromatography (dichloromethane:methanol=100:1-80:1) to obtain the product (740.0 mg, yield: 84.6%).

[0536] Step 2: Synthesis of tert-butyl (R)-3-amino-4-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-yl)amino)-4-oxobutanoate

[0537] The crude product was prepared according to the synthetic method of step 3 of Example 47, and purified by silica gel column chromatography (dichloromethane:methanol=100:1-30:1) to obtain the product (400.0 mg, yield: 79.0%).

[0538] Step 3: Synthesis of (R)-3-amino-4-((5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)amino)-4-oxobutanoic acid trifluoroacetate

[0539] Tert-butyl (R)-3-amino-4-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-yl)amino)-4-oxobutanoate (380.0 mg, 0.79 mmol, 1.0 eq.) was added to dichloromethane (4.0 mL), and trifluoroacetic acid (2.0 mL) was added dropwise. The mixture was allowed to react at room temperature for 3 hours. TLC indicated the reaction was complete. Dichloromethane (50.0 mL) was added, and water (50.0 mL) was added for back extraction. The aqueous phase was purified by reverse-phase preparative chromatography to obtain the product (110.0 mg, 37.9% yield).

[0540] 1HNMR (400MHz, DMSO-d6) δ (ppm): 11.58 (s, 1H), 10.13 (s, 1H), 8.39 (s, 2H), 7.17 (s, 1H), 7.28-7.26 (d, J = 8Hz, 1H), 7.0 7-7.06(m,2H),4.41(s,1H),4.23(s,1H),3.03-2.89(m,2H),1.71-1.68(m,1H),1.05-1.03(m,2H),0.70-0.68(m,2H).

[0541] Molecular formula: C 19 H 18 N4O4 free state exact molecular weight: 366.13 LC-MS (m / z) = 367.07 [M+H] + .

[0542] Example 53: Synthesis of N-(4-(4-ethynyl-2-hydroxyphenyl)-5,6,7,8-tetrahydrophthalazin-1-yl)-2-(methylamino)acetamide (Compound 24)

[0543] Step 1: Synthesis of 4-chloro-5,6,7,8-tetrahydrophthalazin-1-amine

[0544] The crude product was prepared according to the method of Step 2 of Intermediate Preparation Example 1, and purified by silica gel column chromatography (DCM:MeOH=100:1-20:1) to obtain the product (4.10 g, yield: 90.7%).

[0545] Step 2: Synthesis of 4-(4-amino-5,6,7,8-tetrahydrophthalazin-1-yl)-3-(ethoxymethoxy)benzaldehyde

[0546] The crude product was prepared according to the method of step 1 of Example 6, and purified by silica gel column chromatography (DCM:MeOH=100:1-20:1) to obtain the product (1.20 g, yield: 67.3%).

[0547] Step 3: Synthesis of 4-(2-(ethoxymethoxy)-4-ethynylphenyl)-5,6,7,8-tetrahydrophthalazin-1-amine

[0548] The crude product was prepared according to the method of step 2 of Example 6, and purified by silica gel column chromatography (DCM:MeOH=50:1-20:1) to obtain the product (1.10 g, yield: 92.8%).

[0549] Step 4: Synthesis of tert-butyl (2-(4-(2-(ethoxymethoxy)-4-ethynylphenyl)-5,6,7,8-tetrahydrophthalazin-1-yl)amino)-2-oxoethyl)(methyl)carbamate

[0550] Referring to the synthesis method of step 3 of Example 6, the crude product was purified by silica gel column chromatography (DCM:MeOH=100:1-50:1) to obtain the product (456 mg, yield: 74.5%).

[0551] Step 5: Synthesis of N-(4-(4-ethynyl-2-hydroxyphenyl)-5,6,7,8-tetrahydrophthalazin-1-yl)-2-(methylamino)acetamide

[0552] Referring to the synthesis method of step 4 of Example 6, the crude product was purified by silica gel column chromatography (DCM:MeOH=50:1-10:1) to obtain the product (110 mg, yield: 35.9%).

[0553] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 7.19 (d, J = 7.7Hz, 1H), 7.06-7.03 (m, 2H), 4.23 (s, 1H) ),3.48(s,3H),2.61-2.58(m,2H),2.49-2.46(m,2H),2.41(s,3H),1.72-1.37(m,4H).

[0554] Molecular formula: C 19 H 20 N4O2 exact molecular weight: 336.16 LC-MS (m / z) = 337.16 [M+H] + .

[0555] Example 54: Synthesis of N-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)phthalazin-1-yl)-2-(methylamino)acetamide (Compound 25)

[0556] Step 1: Synthesis of 4-chlorophthalazin-1-amine

[0557] 1,4-Dichlorophthalazine (8.00 g, 40.2 mmol, 1.0 eq) was added to an ammonia / isopropanol solution (50 mL) and heated to 100°C for 20 hours. The mixture was cooled to room temperature and filtered. The filter cake was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 20:1) to obtain the product (4.90 g, 67.9% yield).

[0558] Step 2: Synthesis of 4-(2-(ethoxymethoxy)-4-(trifluoromethyl)phenyl)phthalazin-1-amine

[0559] Prepared according to the method of step 1 of Example 6, the crude product was purified by silica gel column chromatography (DCM:MeOH=100:1-50:1) to obtain the product (660 mg, yield: 65.3%)

[0560] Step 3: Synthesis of tert-butyl (2-(4-(2-(ethoxymethoxy)-4-(trifluoromethyl)phenyl)phthalazin-1-yl)amino)-2-oxoethyl)(methyl)carbamate

[0561] The crude product was prepared according to the method of step 3 of Example 6, and purified by silica gel column chromatography (DCM:MeOH=100:1-50:1) to obtain the product (462 mg, yield: 78.5%).

[0562] Step 4: Synthesis of N-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)phthalazin-1-yl)-2-(methylamino)acetamide

[0563] The crude product was prepared according to the method of step 4 of Example 6, and purified by silica gel column chromatography (DCM:MeOH=50:1-10:1) to obtain the product (85.0 mg, yield: 26.2%).

[0564] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 8.42 (s, 1H), 8.07-7.99 (m, 2H), 7.67-7.60 (m, 2H), 7.45 (s, 1H), 7.37 (d, J = 7.8Hz, 1H), 4.23 (s, 2H), 2.67 (s, 3H).

[0565] Molecular formula: C 18 H 15 F3N4O2 exact molecular weight: 376.11 LC-MS (m / z) = 377.12 [M+H] + .

[0566] Example 55: Synthesis of N-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydrophthalazin-1-yl)-2-(methylamino)acetamide (Compound 26)

[0567] The intermediate 4-chloro-5,6,7,8-tetrahydrophthalazin-1-amine, (2-(ethoxymethoxy)-4-(trifluoromethyl)phenyl)boronic acid and tert-butyloxycarbonylsarcosine were used as raw materials and prepared by referring to the synthetic methods of steps 2, 3 and 4 of Example 54.

[0568] 1 HNMR(400MHz,DMSO-d6)δ(ppm):7.42(d,J=8.1Hz,1H),7.27(d,J=6.7Hz,2H), 3.40(s,2H),2.61-2.59(m,2H),2.48(s,2H),2.39(s,3H),1.71-1.69(m,4H).

[0569] Molecular formula: C 18 H 19 F3N4O2 exact molecular weight: 380.15 LC-MS (m / z) = 381.17 [M+H] + .

[0570] Example 56: Synthesis of N-(4-(4-ethynyl-2-hydroxyphenyl)phthalazin-1-yl)-2-(methylamino)acetamide (Compound 23)

[0571] It was prepared using 4-chlorophthalazin-1-amine, 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde and tert-butyloxycarbonylsarcosine as raw materials and referring to the synthetic method of Example 53.

[0572] 1 HNMR(400MHz,DMSO-d6)δ(ppm):8.38(s,1H),8.06-7.98(m,2H),7.68-7.66(m,1H),7.38(d,J =7.8Hz,1H),7.18(d,J=1.3Hz,1H),7.14-7.12(m,1H),4.31(s,1H),4.16(s,2H),2.66(s,3H).

[0573] Molecular formula: C 19 H 16 N4O2 exact molecular weight: 332.13 LC-MS (m / z) = 333.13 [M+H] + .

[0574] Example 57: Synthesis of N-(5-(tert-butyl)-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)-2-(methylamino)acetamide (Compound 68)

[0575] The product was prepared using 5-(tert-butyl)-6-chloropyridazin-3-amine, 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde and tert-butyloxycarbonylsarcosine as raw materials and referring to the synthetic method of Example 53.

[0576] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 8.52 (s, 1H), 7.16 (d, J = 7.6Hz, 1H), 7.02-7. 00(m,2H),4.21(s,1H),3.36(s,2H),3.17(s,1H),2.34(s,3H),1.17(s,9H).

[0577] Molecular formula: C 19 H 22 N4O2 exact molecular weight: 338.17 LC-MS (m / z) = 339.13 [M+H] + .

[0578] Example 58: Synthesis of N-(5-(tert-butyl)-6-(2-hydroxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)-2-(methylamino)acetamide (Compound 69)

[0579] Step 1: Synthesis of 2-(6-amino-4-(tert-butyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol

[0580] The crude product was prepared according to the method of step 1 of Example 6, and purified by silica gel column chromatography (DCM:MeOH=50:1-15:1) to obtain the product (504 mg, yield: 60.1%).

[0581] Step 2: Synthesis of 5-(tert-butyl)-6-(2-((tert-butyldimethylsilyl)oxy)-4-(trifluoromethyl)phenyl)pyridazin-3-amine

[0582] 2-(6-Amino-4-(tert-butyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol (450 mg, 1.45 mmol, 1.1 eq) was dissolved in DMF (10 mL), followed by the addition of imidazole (148 mg, 2.17 mmol, 1.5 eq) and TBSCl (262 mg, 1.74 mmol, 1.2 eq). The mixture was allowed to react at room temperature for 1 hour. Water (60 mL) was added, and the mixture was extracted with EA (30 mL). The organic phase was washed with water (20 mL x 2), 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 afford the product (480 mg, 78.0% yield).

[0583] Step 3: Synthesis of tert-butyl (2-((5-(tert-butyl)-6-(2-hydroxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-2-oxoethyl)(methyl)carbamate

[0584] The crude product was prepared according to the method of step 3 of Example 6, and purified by silica gel column chromatography (DCM:MeOH=50:1-20:1) to obtain the product (342 mg, yield: 62.8%).

[0585] Step 4: Synthesis of N-(5-(tert-butyl)-6-(2-hydroxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)-2-(methylamino)acetamide

[0586] The crude product was prepared according to the method of step 4 of Example 6, and purified by silica gel column chromatography (DCM:MeOH=20:1-8:1) to obtain the product (103 mg, yield: 39.1%).

[0587] 1 HNMR(400MHz,DMSO-d6)δ(ppm):11.75(s,1H),10.50(s,1H),9.18(s,1H),8.46(s,1 H),7.42(d,J=7.8Hz,1H),7.29-7.24(m,2H),4.07(s,2H),2.65(s,3H),1.18(s,9H).

[0588] Molecular formula: C 18 H 21 F3N4O2 exact molecular weight: 382.16 LC-MS (m / z) = 383.12 [M+H] + .

[0589] Example 59: Synthesis of (R)-2-amino-N-(5-(tert-butyl)-6-(2-hydroxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)propionamide (Compound 70)

[0590] Step 1: Synthesis of 2-(6-amino-4-(tert-butyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol

[0591] The crude product was prepared according to the method of step 1 of Example 6, and purified by silica gel column chromatography (DCM:MeOH=100:1-20:1) to obtain the product (135 mg, yield: 19.3%).

[0592] Step 2: Synthesis of tert-butyl (R)-(1-((5-(tert-butyl)-6-(2-methoxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-1-oxopropan-2-yl)carbamate

[0593] The crude product was prepared according to the method of step 3 of Example 6, and purified by silica gel column chromatography (DCM:MeOH=50:1) to obtain the product (36.0 mg, yield: 67.4%).

[0594] Step 3: Synthesis of (R)-2-amino-N-(5-(tert-butyl)-6-(2-hydroxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)propionamide

[0595] The crude product was prepared according to the method of step 3 of Example 20, and purified by preparative thin layer chromatography (DCM:MeOH=10:1) to obtain the product (13.0 mg, yield: 46.9%).

[0596] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.56 (s, 1H), 8.49 (s, 1H), 7.41 (d, J = 7.8Hz, 1H), 7.3 2(s,1H),7.25(d,J=8.0Hz,1H),4.21-4.17(m,1H),1.52(d,J=7.0Hz,3H),1.18(s,9H).

[0597] Molecular formula: C 18 H 21 F3N4O2 exact molecular weight: 382.16 LC-MS (m / z) = 383.09 [M+H] + .

[0598] Example 60: Synthesis of N-(6-(4-ethynyl-2-hydroxyphenyl)-5-methylpyridazin-3-yl)-2-(methylamino)acetamide (Compound 1)

[0599] The intermediate 6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylpyridazin-3-amine was used as the raw material and prepared according to the synthetic method of Example 7.

[0600] 1 H-NMR(400MHz,DMSO-d6)δ(ppm):10.19-10.18(d,1H),8.20(s,1H),7.25-7.23(d,1H),7.09-7.04 (m,2H),4.24(s,1H),3.78(s,2H),3.57-3.54(m,1H),3.08-3.06(d,1H),2.53(s,3H),2.20(s,3H).

[0601] Molecular formula: C 16 H 16 N4O2 exact molecular weight: 296.13 LC-MS (m / z): 297.17 [M+H] + .

[0602] Example 61: Synthesis of N-(6-(4-ethynyl-2-hydroxyphenyl)-5-methylpyridazin-3-yl)-2-(isopropylamino)acetamide (Compound 3)

[0603] Prepared by referring to the synthetic method of step 3 in Example 7.

[0604] 1 H-NMR(400MHz,DMSO-d6)δ(ppm):11.51(s,1H),10.24(s,1H),8.90(s,1H),8.17(s,1H),7.26-7.24(d ,1H),7.11-7.04(m,2H),4.24(s,1H),4.03(s,2H),3.38-3.36(m,1H),2.21(s,3H),1.27-1.25(d,6H).

[0605] Molecular formula: C 18 H 20 N4O2 exact molecular weight: 324.16 LC-MS (m / z): 325.19 [M+H] + .

[0606] Example 62: Synthesis of N-(6-(4-ethynyl-2-hydroxyphenyl)-5-methylpyridazin-3-yl)-2-(cyclopropylamino)acetamide (Compound 4)

[0607] Prepared by referring to the synthetic method of step 3 in Example 7.

[0608] 1 H-NMR(400MHz,DMSO-d6)δ(ppm):10.72(s,1H),10.12(s,1H),8.24(s,1H),7.24-7.23(d,1H),7.06-7.04(d,2H),4 .23(s,1H),3.47(s,2H),3.18-3.17(d,1H),2.23-2.21(m,1H),2.19(s,3H),0.42-0.38(m,2H),0.33-0.29(m,2H).

[0609] Molecular formula: C 18 H 18 N4O2 exact molecular weight: 324.16 LC-MS (m / z): 325.19 [M+H] + .

[0610] Example 63: Synthesis of Compound N-(6-(4-ethynyl-2-hydroxyphenyl)-5-methylpyridazin-3-yl)-2-(ethylamino)acetamide (Compound 2)

[0611] Prepared by referring to the synthetic method of step 3 in Example 7.

[0612] 1 H-NMR(400MHz,DMSO-d6)δ(ppm):11.56(s,1H),10.19(s,1H),9.02-8.98(s,1H),8.16(s ,1H),7.26-7.24(d,1H),7.08-7.05(d,2H),4.24(s,1H),4.07(s,2H),3.08-3.02(m,2H), 2.21(s,3H),1.25-1.22(t,3H).

[0613] Molecular formula: C 17 H 18 N4O2 exact molecular weight: 310.14 LC-MS (m / z): 311.19 [M+H] + .

[0614] Example 64: Synthesis of N-(6-(4-ethynyl-2-hydroxyphenyl)-5-methylpyridazin-3-yl)-2-(cyclobutylamino)acetamide (Compound 31)

[0615] Prepared by referring to the synthetic method of step 3 in Example 7.

[0616] 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 10.19 (s, 1H), 8.23 ​​(s, 1H), 7.24-7.22 (d, 1H), 7.08-7.03 (m, 2H), 4.23 (s, 1H) ),3.36-3.33(m,4H),3.28-3.22(m,1H),2.19(s,3H),2.14-2.07(m,2H),1.81-1.72(m,2H),1.68-1.52(m,2H).

[0617] Molecular formula: C 19 H 20 N4O2 exact molecular weight: 336.16 LC-MS (m / z): 337.19 [M+H] + .

[0618] Example 65: Synthesis of N-(6-(4-ethynyl-2-hydroxyphenyl)-5-methylpyridazin-3-yl)-2-(isobutylamino)acetamide (Compound 32)

[0619] Prepared by referring to the synthetic method of step 3 in Example 7.

[0620] 1 H-NMR(400MHz,DMSO-d6)δ(ppm):10.11(s,1H),8.26(s,1H),7.25-7.23(d,1H),7.06-7.04(m,2H),4.23(s,1H),4.12 -4.08(m,1H),3.39(s,2H),3.18-3.17(d,1H),2.39-2.38(d,2H),2.19(s,3H),1.74-1.67(m,1H),0.93-0.91(d,6H).

[0621] Molecular formula: C 19 H 22 N4O2 exact molecular weight: 338.17 LC-MS (m / z): 339.20 [M+H] + .

[0622] Example 66: Synthesis of N-(6-(4-ethynyl-2-hydroxyphenyl)-5-methylpyridazin-3-yl)-2-(cyclopropylmethylamino)acetamide (Compound 34)

[0623] Prepared by referring to the synthetic method of step 3 in Example 7.

[0624] 1 H-NMR(400MHz,DMSO-d6)δ(ppm):10.10(s,1H),8.25(s,1H),7.25-7.23(d,1H),7.06-7.04(m,2H),4.23(s, 1H),3.43(s,2H),2.47-2.45(d,2H),2.19(s,3H),0.96-0.86(m,1H),0.46-0.41(m,2H),0.16-0.12(m,2H).

[0625] Molecular formula: C 19 H 20 N4O2 exact molecular weight: 336.16 LC-MS (m / z): 337.19 [M+H] + .

[0626] Example 67: Synthesis of N-(6-(4-ethynyl-2-hydroxyphenyl)-5-methylpyridazin-3-yl)-2-((2-hydroxy-2-methylpropyl)amino)acetamide (Compound 35)

[0627] Prepared by referring to the synthetic method of step 3 in Example 7.

[0628] 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 10.11 (s, 1H), 8.26 (s, 1H), 7.25-7.23 (d, 1H), 7.06-7. 04(m,2H),4.39(s,1H),4.23(s,1H),3.44(s,2H),2.47(s,2H),2.19(s,3H),1.14(s,6H).

[0629] Molecular formula: C 19 H 22 N4O3 exact molecular weight: 354.17 LC-MS (m / z): 355.24 [M+H] + .

[0630] Example 68: Synthesis of N-(6-(4-ethynyl-2-hydroxyphenyl)-5-trifluoromethylpyridazin-3-yl)-2-(methylamino)acetamide (Compound 41)

[0631] Step 1: Synthesis of intermediate 6-chloro-5-trifluoromethylpyridazin-3-amine

[0632] 3,6-Dichloro-4-trifluoromethylpyridazine (3.0 g, 13.83 mmol, 1.0 eq) was dissolved in 3.5 mol / L ammonia / isopropanol solution (30 mL). The mixture was sealed and reacted at 100°C for 1 h. TLC indicated the reaction was complete. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1) to obtain the product (570 mg, 21.1% yield).

[0633] Step 2: Synthesis of intermediate 4-(6-amino-4-trifluoromethylpyridazin-3-yl)-3-(ethoxymethoxy)benzaldehyde

[0634] The crude product was prepared according to the method of step 1 of Example 6, and purified by silica gel column chromatography (dichloromethane:methanol=100:1-50:1) to obtain the product (790 mg, yield: 80.4%).

[0635] Step 3: Synthesis of intermediate 6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-trifluoromethylpyridazin-3-amine

[0636] The crude product was prepared according to the method of step 2 of Example 6, and purified by silica gel column chromatography (dichloromethane:methanol=100:1-20:1) to obtain the product (430 mg, yield: 55.1%).

[0637] Step 4: Synthesis of intermediate 2-bromo-N-(6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-trifluoromethylpyridazin-3-yl)acetamide

[0638] The crude product was prepared according to the method of step 1 of Example 7, and purified by preparative thin layer chromatography (petroleum ether:ethyl acetate=2:1) ​​to obtain the product (100 mg, yield: 36.8%).

[0639] Step 5: Synthesis of intermediate 2-bromo-N-(6-(4-ethynyl-2-hydroxyphenyl)-5-trifluoromethylpyridazin-3-yl)acetamide

[0640] The product was prepared according to the method of step 2 of Example 7, and the crude product was purified by preparative thin layer chromatography (dichloromethane:methanol=10:1) to obtain the product (30 mg, yield: 34.5%).

[0641] Step 6: Synthesis of compound N-(6-(4-ethynyl-2-hydroxyphenyl)-5-trifluoromethylpyridazin-3-yl)-2-(methylamino)acetamide

[0642] The product was prepared according to the method of step 3 of Example 7, and the crude product was purified by preparative thin layer chromatography (dichloromethane:methanol=7:1) to obtain the product (6 mg, yield: 23.1%).

[0643] 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 8.70 (s, 1H), 7.26-7.24 (d, 1H), 7.05-7.02 (m, 2H), 4.24 (s, 1H), 3.76 (s, 2H), 2.37 (s, 3H).

[0644] Molecular formula: C 16 H 13 F3N4O2 exact molecular weight: 350.10 LC-MS (m / z): 351.11 [M+H] + .

[0645] Example 69: Synthesis of N-(6-(5-cyano-3-hydroxypyridin-2-yl)-5-cyclopropylpyridazin-3-yl)-2-(methylamino)acetamide (Compound 78)

[0646] Step 1: Synthesis of 5-hydroxy-6-iodonicotinonitrile

[0647] 5-Hydroxynicotinonitrile (10.0 g, 83.26 mmol, 1.0 eq.) was added to water (100.0 mL), followed by potassium carbonate (23.0 g, 166.52 mmol, 2.0 eq.). After stirring for 2 minutes, iodine (19.0 g, 74.93 mmol, 0.9 eq.) was added. Stirring was continued for 18 hours, and sodium sulfite was added to quench the reaction. The pH was adjusted to approximately 3 with citric acid, and ethyl acetate (200 mL) was added. The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, slurried with methyl tert-butyl ether (50 mL), and filtered with suction. The filter cake was dried at 50°C to yield the product (8.65 g, 42.2% yield).

[0648] Step 2: Synthesis of 5-(ethoxymethoxy)-6-iodonicotinonitrile

[0649] 5-Hydroxy-6-iodonicotinonitrile (8.6 g, 34.96 mmol, 1.0 eq.) was added to tetrahydrofuran (100.0 mL). The temperature was maintained at approximately 10°C. Sodium hydride (2.1 g, 52.44 mmol, 1.5 eq.) was added and stirred for 0.5 h. Chloromethyl ether (5.0 g, 52.44 mmol, 1.5 eq.) was then added and stirred for another 1 h. TLC indicated the reaction was complete. Water (100.0 mL) and ethyl acetate (100.0 mL) were added and the mixture was allowed to stand for separation. 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 obtain the product (5.2 g, 49.0% yield).

[0650] Step 3: Synthesis of 5-(ethoxymethoxy)-6-(tributylstannyl)nicotinonitrile

[0651] 5-(Ethoxymethoxy)-6-iodonicotinonitrile (2.0 g, 6.58 mmol, 1.0 eq.) was added to tetrahydrofuran (20.0 mL). Under nitrogen, a solution of isopropylmagnesium chloride in tetrahydrofuran (3.9 mL, 7.90 mmol, 1.2 eq.) was added dropwise at -60°C. The mixture was stirred for 0.5 h. Tributyltin chloride (2.6 g, 7.90 mmol, 1.2 eq.) was added and stirred for 3 h. TLC indicated the reaction was complete. Aqueous potassium fluoride solution (50.0 mL) was added and stirred for 0.5 h. The mixture was extracted with ethyl acetate (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 (petroleum ether:ethyl acetate = 20:1) to obtain the product (0.6 g, yield: 19.4%).

[0652] Step 4: Synthesis of tert-butyl (2-((6-(5-cyano-3-hydroxypyridin-2-yl)-5-cyclopropylpyridazin-3-yl)amino)-2-oxoethyl)(methyl)carbamate

[0653] 5-(Ethoxymethoxy)-6-(tributylstannyl)nicotinonitrile (0.6 g, 1.28 mmol, 1.0 eq.) was added to N,N-dimethylformamide (5.0 mL). Tert-butyl (2-((6-chloro-5-cyclopropylpyridazin-3-yl)amino)-2-oxoethyl)(methyl)carbamate (0.3 g, 0.77 mmol, 0.6 eq.), tetrakis(triphenylphosphine)palladium (0.2 g, 0.13 mmol, 0.1 eq.), cesium fluoride (0.4 g, 2.56 mmol, 2.0 eq.), and cuprous iodide (24.7 mg, 0.13 mmol, 0.1 eq.) were also added. The reaction was carried out in a microwave oven at 150°C for 2 h under nitrogen protection. TLC indicated the reaction was complete. Water (20.0 mL) was added, extracted with ethyl acetate (20.0 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 (petroleum ether:ethyl acetate = 2:1) to give the product (90.0 mg, yield: 16.6%).

[0654] Step 5: Synthesis of N-(6-(5-cyano-3-hydroxypyridin-2-yl)-5-cyclopropylpyridazin-3-yl)-2-(methylamino)acetamide

[0655] Tert-butyl (2-((6-(5-cyano-3-hydroxypyridin-2-yl)-5-cyclopropylpyridazin-3-yl)amino)-2-oxoethyl)(methyl)carbamate (90.0 mg, 0.21 mmol, 1.0 eq.) was added to dichloromethane / methanol (1.0 mL / 1.0 mL). A solution of hydrogen chloride in ethyl acetate (2.0 mL) was added and stirred for 1 h. TLC indicated the reaction was complete. The pH was adjusted to approximately 8 with saturated aqueous sodium carbonate solution and the mixture was concentrated under reduced pressure. The residue was added to dichloromethane / methanol (20.0 mL / 2 mL), filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 7:1) to obtain the product (10.0 mg, yield: 14.7%).

[0656] 1 HNMR(400MHz,DMSO-d6)δ(ppm):8.60-8.59(d,1H),7.91(s,1H),7.75-7.74(d,1 H),3.43(s,2H),2.37(s,3H),1.73-1.66(m,1H),1.03-1.00(m,2H),0.75(s,2H).

[0657] Molecular formula: C 16 H 16 N6O2 exact molecular weight: 324.13 LC-MS (m / z) = 325.09 [M+H] + .

[0658] Example 70: Synthesis of Compound N-(6-(4-cyano-2-hydroxyphenyl)-5-cyclopropylpyridazin-3-yl)-2-(methylamino)acetamide (Compound 72)

[0659] Step 1: Synthesis of intermediate 4-bromo-3-(ethoxymethoxy)benzonitrile

[0660] The product (3.5 g, yield: 93.7%) was prepared by referring to the method of Step 1 of Intermediate Preparation Example 6.

[0661] Step 2: Synthesis of 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

[0662] The product (1.1 g, yield: 46.4%) was prepared by referring to the method of Step 3 of Intermediate Preparation Example 5.

[0663] Step 3: Synthesis of tert-butyl (2-((6-(4-cyano-2-(ethoxymethoxy)phenyl)-5-cyclopropylpyridazin-3-yl)amino)-2-oxoethyl)(methyl)carbamate

[0664] The product was prepared according to the method of Step 1 of Example 46, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol=50:1) to obtain the product (600 mg crude product).

[0665] Step 4: Synthesis of N-(6-(4-cyano-2-hydroxyphenyl)-5-cyclopropylpyridazin-3-yl)-2-(methylamino)acetamide

[0666] The product was prepared according to the method of Step 5 of Example 69, and the crude product was purified by preparative thin layer chromatography (dichloromethane:methanol=10:1) to obtain the product (80 mg, yield: 24.7%).

[0667] 1 H-NMR(400MHz,DMSO-d6)δ(ppm):7.82(s,1H),7.49-7.47(d,1H),7.42-7.40(d,1H),7. 34(s,1H),3.57(s,2H),2.43(s,2H),1.66-1.60(m,1H),1.04-0.99(m,2H),0.74(m,2H).

[0668] Molecular formula: C 17 H 17N5O2 exact molecular weight: 323.14 LC-MS (m / z): 324.09 [M+H] + .

[0669] Example 71: Synthesis of N-(6-(2-hydroxy-4-ethynylphenyl)-5-methyl-1,2,4-triazin-3-yl)-2-(methylamino)acetamide (Compound 21)

[0670] Step 1: Synthesis of 5-methyl-3-(methylthio)-1,2,4-triazine

[0671] S-Methylisothiosemicarbazide hydroiodide (30.92 g, 0.429 mol, 1.0 eq) was dissolved in water (300 mL). Under an ice-water bath, sodium bicarbonate (36.04 g, 0.429 mol, 1.0 eq) was added. A solution of 2-oxopropanal (100 g, 0.429 mol, 1.0 eq) in water (360 mL) was slowly added dropwise. The mixture was allowed to react at 25°C for 24 h. TLC indicated the reaction was complete. The reaction solution was extracted with dichloromethane (100 mL x 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 = 10:1 to 4:1) to obtain the product (24 g, yield: 39%).

[0672] Step 2: Synthesis of 5-methyl-3-(methylsulfinyl)-1,2,4-triazine

[0673] 5-Methyl-3-(methylthio)-1,2,4-triazine (20 g, 0.1416 mol, 1.0 eq) was dissolved in dichloromethane (200 mL). 85% m-chloroperbenzoic acid (31.63 g, 0.1833 mol, 1.1 eq) was slowly added to the mixture under an ice-water bath. The mixture was allowed to react for 40 minutes, and TLC indicated the reaction was complete. The filtrate was filtered, concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane) to obtain the product (17.5 g, 78.6% yield).

[0674] Step 3: Synthesis of 5-methyl-1,2,4-triazin-3-amine

[0675] 5-Methyl-3-(methylsulfinyl)-1,2,4-triazine (17.5 g, 0.1113 mol, 1.0 eq) was dissolved in tetrahydrofuran (25 mL) and slowly added dropwise to an ammonia solution in isopropanol (175 mL) under an ice-water bath. The mixture was allowed to react for 2.5 hours, with TLC indicating completion. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (methanol:ethyl acetate = 0-1:10) to obtain the product (4.16 g, 34% yield).

[0676] Step 4: Synthesis of intermediate 6-bromo-5-methyl-1,2,4-triazin-3-amine

[0677] 5-Methyl-1,2,4-triazine-3-amine (1 g, 9.1 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL). Dibromohydantoin (1.56 g, 5.4 mmol, 0.6 eq) was added at -10°C and allowed to react at 25°C for 1 hour. TLC indicated the reaction was complete. The reaction solution was poured into saturated aqueous sodium bicarbonate (10 mL) and extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the product (1.1 g, yield: 64.3%).

[0678] Step 5: Synthesis of 4-(3-amino-5-methyl-1,2,4-triazin-6-yl)-3-(ethoxymethoxy)benzaldehyde

[0679] 6-Bromo-5-methyl-1,2,4-triazine-3-amine (1.1 g, 5.8 mmol, 1.0 eq), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (3.86 g, 8.7 mmol, 1.5 eq), an aqueous solution (2 mL) of sodium bicarbonate (0.49 g, 5.8 mmol, 1.0 eq) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.426 g, 0.6 mmol, 0.1 eq) were added to 1,4-dioxane (8 mL) and reacted at 110 ° C for 3.5 hours under nitrogen protection. TLC showed that the reaction was complete. The reaction solution was filtered through celite, water (10 mL) was added to the filtrate, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain the product (0.8 g, yield: 50%).

[0680] Step 6: Synthesis of 6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-1,2,4-triazin-3-amine

[0681] The crude product was prepared according to the method of step 2 of Example 6, and purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to obtain the product (610 mg, yield: 77%).

[0682] Step 7: Synthesis of intermediate tert-butyl (2-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-1,2,4-triazin-3-yl)amino)-2-oxoethyl)(methyl)carbamate

[0683] The crude product was prepared according to the method of step 3 of Example 6, and the product (210 mg, yield: 87.5%) was obtained by silica gel column chromatography (petroleum ether:ethyl acetate=4:1 to ethyl acetate).

[0684] Step 8: Synthesis of compound N-(6-(2-hydroxy-4-ethynylphenyl)-5-methyl-1,2,4-triazin-3-yl)-2-(methylamino)acetamide

[0685] The crude product was purified by silica gel column chromatography according to the method of step 4 of Example 3 to obtain the product (13 mg, yield: 19.9%).

[0686] 1 H-NMR(400MHz,DMSO-d6)δ(ppm):7.49(s,1H),7.23-7.22(d,1H),7.05-7.03( d,2H),6.97-6.95(d,2H),4.26(s,2H),4.17(s,1H),3.20(s,3H),2.23(s,3H).

[0687] Molecular formula: C 15 H 15 N5O2 exact molecular weight: 297.12 LC-MS (m / z): 298.17 [M+H] + .

[0688] Example 72: Synthesis of N-(6-(2-hydroxy-4-ethynylphenyl)-5-cyclopropyl-1,2,4-triazin-3-yl)-2-(methylamino)acetamide (Compound 48)

[0689] Step 1: Synthesis of 2-cyclopropyl-2-oxoacetaldehyde

[0690] Selenium dioxide (18.47 g, 0.1664 mol, 1.4 eq), acetic acid (4.76 mL, 0.0832 mol, 0.7 eq), and water (3.32 g, 0.1842 mol, 1.55 eq) were added to 1,4-dioxane (75 mL) and refluxed for two hours. 1-Cyclopropylethane-1-one (10 g, 0.1189 mmol, 1.0 eq) was added and refluxed for 22 hours. TLC indicated the reaction was complete. The reaction mixture was filtered, the filter cake was washed with 1,4-dioxane, and the filtrate was concentrated. The crude product was directly used in the next step.

[0691] Step 2: Synthesis of intermediate 5-cyclopropyl-3-(methylthio)-1,2,4-triazine

[0692] S-Methylisothiosemicarbazide hydroiodide (35.58 g, 0.153 mol, 1.1 eq) was dissolved in water (100 mL). Sodium bicarbonate (28.31 g, 0.337 mol, 2.43 eq) was added under an ice-water bath. A mixture of the above solution of 2-cyclopropyl-2-oxoacetaldehyde and water (50 mL) was slowly added dropwise. The mixture was reacted at 25°C for 24 h. TLC showed that the reaction was complete. Dichloromethane (300 mL × 3) was added for extraction. 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 = 10:1 to 4:1) to obtain the product (11.02 g, two-step yield: 55.4%).

[0693] Step 3: Synthesis of intermediate 5-cyclopropyl-3-(methylsulfinyl)-1,2,4-triazine

[0694] The crude product was prepared according to the method of step 2 of Example 71, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the product (8.72 g, yield: 72.2%).

[0695] Step 4: Synthesis of intermediate 5-cyclopropyl-1,2,4-triazine-3-amine

[0696] Prepared according to the method of Step 3 of Example 71, the crude product was purified by silica gel column chromatography (ethyl acetate) to obtain the product (5.86 g, yield: 90.4%).

[0697] Step 5: Synthesis of intermediate 6-bromo-5-cyclopropyl-1,2,4-triazin-3-amine

[0698] The crude product was prepared according to the method of step 4 of Example 71, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain the product (4.8 g, yield: 58.6%).

[0699] Step 6: Synthesis of intermediate 4-(3-amino-5-cyclopropyl-1,2,4-triazin-6-yl)-3-(ethoxymethoxy)benzaldehyde

[0700] The crude product was prepared according to the method of Step 5 of Example 71, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain the product (980 mg, yield: 67.1%).

[0701] Step 7: Synthesis of compound 6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-cyclopropyl-1,2,4-triazin-3-amine

[0702] The crude product was prepared according to the method of step 2 of Example 6, and the product (860 mg, yield: 89.6%) was obtained by silica gel column chromatography (petroleum ether:ethyl acetate=2:1).

[0703] Step 8: Synthesis of intermediate tert-butyl (2-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-cyclopropyl-1,2,4-triazin-3-yl)amino)-2-oxoethyl)(methyl)carbamate

[0704] The crude product was prepared according to the method of step 3 of Example 6, and the product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to obtain the product (790 mg, yield: 59.4%).

[0705] Step 9: Synthesis of compound N-(6-(2-hydroxy-4-ethynylphenyl)-5-cyclopropyl-1,2,4-triazin-3-yl)-2-(methylamino)acetamide

[0706] The product was prepared according to the method of step 4 of Example 3, and the crude product was purified by preparative thin layer chromatography to obtain the product (8 mg, yield: 2.3%).

[0707] 1 H-NMR(400MHz,DMSO-d6)δ(ppm):10.11(s,1H),7.43(s,1H),7.29-7.27(d,1H) ,7.05-7.01(m,3H),4.21(m,3H),3.19(s,3H),1.69(s,1H),1.04-0.97(m,4H).

[0708] Molecular formula: C 17 H 17 N5O2 exact molecular weight: 323.14 LC-MS (m / z): 324.12 [M+H] + .

[0709] Example 73: Synthesis of (R)-2-amino-N-(6-(2-hydroxy-4-ethynylphenyl)-5-cyclopropyl-1,2,4-triazin-3-yl)propionamide (Compound 49)

[0710] Prepared by referring to the synthetic method of steps 8 and 9 of Example 72.

[0711] 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 10.05 (s, 1H), 7.55 (s, 1H), 7.29-7.27 (d, 2H), 7.04-7. 02(m,2H),6.94(s,1H),4.20(s,2H),1.67(s,1H),1.36-1.34(d,3H),1.05-0.95(m,4H).

[0712] Molecular formula: C 17 H 17 N5O2 exact molecular weight: 323.14 LC-MS (m / z): 324.14 [M+H] + .

[0713] Example 74: Synthesis of N-(5-cyclopropyl-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-1,2,4-triazin-3-yl)-2-(methylamino)acetamide (Compound 60)

[0714] Step 1: Synthesis of 5-cyclopropyl-6-(2-(ethoxymethoxy)-4-(trifluoromethyl)phenyl)-1,2,4-triazin-3-amine

[0715] The crude product was prepared according to the method of step 1 of Example 6, and purified by silica gel column chromatography (PE:EA=1:1) to obtain the product (1.47 g, yield: 91.8%).

[0716] Step 2: Synthesis of tert-butyl (2-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-(trifluoromethyl)phenyl)-1,2,4-triazin-3-yl)amino)-2-oxoethyl)(methyl)carbamate

[0717] The product (0.51 g, yield: 80.0%) was prepared by referring to the method of step 3 of Example 6.

[0718] Step 3: Synthesis of N-(5-cyclopropyl-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-1,2,4-triazin-3-yl)-2-(methylamino)acetamide

[0719] The product was prepared according to the method of step 4 of Example 3, and the crude product was purified by reverse phase column chromatography to obtain the product (21 mg).

[0720] 1 HNMR(400MHz,DMSO-d6)δ(ppm):11.64(s,1H),10.88(s,1H),8.88(s,2H),7.63-7.61(d,1H) ,7.36-7.34(d,1H),7.30(s,1H),4.29(s,2H),3.65(s,3H),1.86-1.80(m,1H),1.18(s,3H).

[0721] Molecular formula: C 16 H 16 F3N5O2 exact molecular weight: 368.26 LC-MS (m / z): 367.13 [M+H] + .

[0722] Example 75: Synthesis of N-(6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-1,2,4-triazin-3-yl)-2-(methylamino)acetamide (Compound 22)

[0723] Step 1: Synthesis of 6-(2-(ethoxymethoxy)-4-(trifluoromethyl)phenyl)-5-methyl-1,2,4-triazin-3-amine

[0724] The product (0.64 g, yield: 52.9%) was prepared by referring to the method of step 1 of Example 6.

[0725] Step 2: Synthesis of tert-butyl (2-((6-(2-(ethoxymethoxy)-4-(trifluoromethyl)phenyl)-5-methyl-1,2,4-triazin-3-yl)amino)-2-oxoethyl)(methyl)carbamate

[0726] Prepared by referring to the method of step 3 of Example 6 (0.36 g, yield: 69.6%).

[0727] Step 3: Synthesis of N-(6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-1,2,4-triazin-3-yl)-2-(methylamino)acetamide

[0728] The product was prepared according to the method of step 4 of Example 3, and the crude product was purified by reverse phase column chromatography to obtain the product (4.0 mg).

[0729] 1 HNMR(400MHz,DMSO-d6)δ(ppm):7.49(s,1H),7.46-7.44(d,1H),7.18(s,2H),7.07(s,1H),4.28(s,2H),3.22(s,3H),2.25(s,3H).

[0730] Molecular formula: C 14 H 14 F3N5O2 exact molecular weight: 341.11 LC-MS (m / z): 342.21 [M+H] + .

[0731] Experimental Example 1: Test of the Cellular NLRP3 Inflammasome Inhibitory Activity of the Compounds of the Invention

[0732] Test substance: Compound of the present invention, prepared according to the method of Example

[0733] THP-1 is an immortalized human macrophage cell line

[0734] Testing instrument: microplate reader (PE)

[0735] Test method:

[0736] 1. THP-1 cells were cultured in 1640 complete medium (500 ml 1640 + 56 ml FBS + 560 μl 1000× P / S + 2 μl mercaptoethanol) and used within 3-20 generations.

[0737] 2. Coated culture plate: Add 100 μl of poly-lysine solution to a 96-well cell culture plate and incubate at 37°C for 30 min. Discard the solution and wash twice with PBS for later use.

[0738] 3. Induction of THP-1 differentiation: THP-1 cells were resuspended in an appropriate amount of complete medium containing 10 ng / ml PMA to a cell suspension density of 5 × 10^ 5 cells / ml, added to a 96-well plate, 100ul cell suspension per well, and cultured overnight in a 37°C carbon dioxide cell culture incubator for 16 hours.

[0739] 4. THP-1 stimulation:

[0740] a. Add serum-free THP-1 culture medium containing LPS to a final concentration of 500 ng / ml and culture in a 37°C CO2 cell culture incubator for 3 h.

[0741] b. Prepare a gradient concentration of the test compound stock solution with DMSO, add it to the cells, mix well, and finally dilute it to 1:1000. Incubate the cells at 37°C in a CO2 cell culture incubator for 1 hour.

[0742] c. Add Nigericin to each well to a final concentration of 10 μg / ml and incubate at 37°C in a CO2 cell culture incubator for 30 min.

[0743] d. Transfer the culture medium in the wells to a new culture plate, then centrifuge at 3000 rpm for 5 minutes, and transfer the supernatant to a new 96-well plate.

[0744] e. Collect cell culture supernatant samples and test the content of human active caspase-1 using a commercial caspase-1glo kit according to the instructions.

[0745] The test results are shown in Table 2 below:

[0746] Table 2 Inhibitory activity of the compounds of the present invention on NLRP3 in THP-1 cells

[0747] As can be seen from the experimental results in Table 2, the compounds of the present invention have good inhibitory activity on NLRP3 inflammasome, and therefore the compounds of the present invention can be used to prevent and / or treat diseases related to NLRP3 inflammasome.

[0748] Experimental Example 2: Pharmacokinetics of Compounds in Mice

[0749] 1. Mouse strain: C57BL / 6J.

[0750] 2. Prepare a mixed solvent with 5% dimethyl sulfoxide, 20% PEG400 and 75% 20% polyoxyethylene hydrogenated castor oil, weigh an appropriate amount of the compound of the present invention and dissolve it in the mixed solvent for oral gavage and intravenous administration.

[0751] 3. Blood collection time: oral administration: 15min, 30min, 1h, 2h, 4h, 6h, 8h, 24h after administration; intravenous administration: 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 24h.

[0752] 4. Sample analysis method: Vortex the sample to be tested for 5 minutes, accurately pipette 10 μL of plasma samples from different individuals into 1.5 mL centrifuge tubes, then add the internal standard working solution (such as acetonitrile solution of tolbutamide), mix well, vortex for 5 minutes, centrifuge at 12000 rpm for 5 minutes, accurately pipette 50 μL of supernatant into a 96-well plate pre-added with 150 μL / well water, vortex to mix, and perform LC-MS / MS analysis.

[0753] 5. Data processing method: The test substance concentration was output using Analyst 1.6.3 from AB. The mean, standard deviation, coefficient of variation and other parameters were calculated using Microsoft Excel (no calculation was required for the direct output from Analyst 1.6.3). The PK parameters were calculated using WinNonlin Phenoix 8.2 software (NCA). max is the median).

[0754] Experimental Example 3: Experimental Protocol for Inhibition of hERG Potassium Channels by Compounds

[0755] 1. Cell Culture

[0756] 1.1 HEK-293 cells stably expressing hERG potassium channel were cultured in DMEM medium containing 10% fetal bovine serum and 0.8 mg / mL G418.

[0757] 1.2 Before patch clamp testing, cells were stained with TrypLE TM Express separation, 4×10 3 The cells were plated onto coverslips and cultured in 24-well plates.

[0758] 2. Preparation method of the compound of the present invention

[0759] Weigh the appropriate mass of compound and calculate the required volume of DMSO according to the formula: DMSO volume = actual amount × purity (content) / (molecular weight × theoretical concentration). Pipette the corresponding volume of DMSO, and then dissolve the weighed compound in the pried DMSO.

[0760] 3. Preparation method of the working solution of the compound of the present invention

[0761] The highest test concentration of the compound can be directly diluted with extracellular fluid to the stock solution concentration or the stock solution needs to be further diluted with DMSO. Other concentrations are first diluted with DMSO from high to low concentration to form dilutions, and then diluted with extracellular fluid to the working solution concentration.

[0762] 4. Patch clamp assay

[0763] After whole-cell seal formation, the cell membrane voltage was clamped at -80 mV. The clamping voltage was depolarized from -80 mV to -50 mV for 0.5 s (as a leak current measurement), then stepped to 30 mV for 2.5 s, and then quickly restored to -50 mV for 4 s to stimulate the hERG channel tail current. Data were collected repeatedly every 10 s to observe the effect of the compound on the hERG tail current. A 0.5 s stimulation at -50 mV was used as a leak current measurement. The experimental data were collected by an EPC 10 amplifier (HEKA) and stored in PatchMaster (HEKA) software.

[0764] 5. Data Analysis

[0765] IC 50 Calculations and curve fitting were performed using GraphPad Prism software.

[0766] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A compound represented by the general formula (I), or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: YW-R3 (I) in, W is selected from or is selected from a single bond or a double bond; R1 is independently selected from hydrogen, oxo, thio, hydroxy, amino, carboxyl, cyano, nitro, halogen, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl, aryl, 5-7 membered heteroaryl, sulfonyl, -N(C 1-6 Alkyl)2 or not present; R2 is independently selected from hydrogen, oxo, thio, hydroxy, amino, carboxyl, cyano, nitro, halogen, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl, aryl, 5-7 membered heteroaryl, sulfonyl, -N(C 1-6 Alkyl)2 or not present; The R1 and R2 are independently optionally substituted by 1-3 groups selected from hydroxyl, C 0-6 Alkylamino, carboxyl, cyano, nitro, halogen, C 0-6 Alkylcarbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl, aryl, 5-7 membered heteroaryl, C 0-6 Substitution of the alkylsulfonyl group by substituents; or R1, R2 and the C or N atom to which they are attached form a 5-12 membered ring A; The 5-12 membered ring A is optionally substituted by 1-4 groups selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen, carbonyl, oxo, C 1-6 Alkyl, -NH-C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group, aryl group, 5-7 membered heteroaryl group, C 1-6 Alkylsulfonyl, -N(C 1-6 Alkyl)2 is substituted by a substituent; R3 is selected from -(CH2) n -NR4-Z-(CH2) m -R5, -(CH2) n -NR4-Z-CR c R d -R5; n is an integer from 0 to 6; m is an integer from 0 to 3; R4 is selected from hydrogen or C 1-6 alkyl; Z is selected from C=O, C=S, S(O) or S(O)2; R5 is selected from 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl, aryl, 5-7 membered heteroaryl, NR a R b , OR b , C 1-6 alkyl; R a Selected from hydrogen or C 1-6 alkyl; R c Selected from hydrogen or C 1-6 alkyl; R b Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl, aryl, 5-7 membered heteroaryl, Sulfonyl, -N(C 1-6 Alkyl)2; The R b Optionally substituted by 1-2 groups selected from hydroxy, halogen, 3-7 membered cycloalkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy substituent substitution; R d Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl, aryl, 5-7 membered heteroaryl, sulfonyl, -N(C 1-6 Alkyl)2; The R d Optionally substituted by 1-2 groups selected from hydroxy, halogen, 3-7 membered cycloalkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, aryl, cyano, carboxyl substituents substitution; or R c , R d Together with the C atoms to which they are attached, they form a 3-7 membered cycloalkyl group; or When R5 is selected from NR a R b When R a Connected with R4 to form a 4-7 membered heterocyclic group with R3; The R5 is optionally substituted by 1-4 groups selected from oxo, thio, hydroxy, amino, carboxyl, cyano, nitro, halogen, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl, aryl, 5-7 membered heteroaryl, sulfonyl, ureido, hydrazine substituents; The substituents on R5 may be further optionally substituted by 1-3 groups selected from hydroxyl, C 0-6 Alkylamino, carboxyl, cyano, nitro, halogen, C 0-6 Alkylcarbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-6 membered heterocyclyl, 3-6 membered cycloalkyl, 5-6 membered cycloalkenyl, aryl, 5-7 membered heteroaryl, C 0-6 Alkylsulfonyl, urea, hydrazine substituents substitution; Y is selected from aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl; The Y is optionally substituted by 1-4 groups selected from oxo, thio, hydroxy, amino, carboxyl, cyano, nitro, halogen, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl, aryl, 5-7 membered heteroaryl, sulfonyl substituents; The substituents on Y may be further optionally substituted by 1 to 3 groups selected from hydroxyl, C 0-6 Alkylamino, carboxyl, cyano, nitro, halogen, C 0-6 Alkylcarbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-6 membered heterocyclyl, 3-7 membered cycloalkyl, 5-6 membered cycloalkenyl, aryl, 5-7 membered heteroaryl, C 0-6 The alkylsulfonyl substituent is substituted.

2. The compound according to claim 1, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in, W is selected from 3. The compound according to claim 1 or 2, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in, R1, R2 are independently selected from hydrogen, cyano, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-7 membered cycloalkyl, -N(C 1-6 Alkyl)2 or not present; Preferably, R1 and R2 are independently selected from hydrogen, cyano, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, cyclopropyl, cyclobutyl or absent.

4. The compound according to claim 1, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in, R3 is selected from -(CH2) n -NR4-Z-(CH2) m -R5, -(CH2) n -NR4-Z-CR c R d -R5; n is an integer from 0 to 2; m is an integer from 0 to 2; R4 is selected from hydrogen or C 1-6 alkyl; Z is selected from C=O; R5 is selected from 3-7 membered heterocyclic group, NR a R b , OR b , C 1-6 alkyl; R a Selected from hydrogen or C 1-6 alkyl; R c Selected from hydrogen or C 1-6 alkyl; R b Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, halogenated C 1-6 Alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl; The R b Optionally substituted by 1-2 groups selected from hydroxy, halogen, 3-7 membered cycloalkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy substituent substitution; R d Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, halogenated C 1-6 Alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl; The R d Optionally substituted by 1-2 groups selected from hydroxy, halogen, 3-7 membered cycloalkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, aryl, cyano, carboxyl substituents.

5. The compound according to claim 4, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: n is 0; m is 0; R5 is selected from 3-7 membered heterocyclic groups; The R5 is optionally substituted by 1-4 groups selected from hydroxyl, amino, carboxyl, cyano, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic, 3-7 membered cycloalkyl, aryl substituents; The substituents on R5 may be further optionally substituted by 1-3 groups selected from hydroxy, halogen, C 1-6 Alkyl substituent substitution; Preferably, R5 is a 4-6 membered heterocyclic group containing 1 N heteroatom.

6. The compound according to claim 4, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, n is 0; m is 0; R5 is selected from NR a R b ; R a Selected from hydrogen or C 1-6 alkyl; R c Selected from hydrogen or C 1-6 alkyl; R b Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, cyclopropyl, cyclobutyl; The R b Optionally, 1-2 selected from hydroxy, halogen, cyclopropyl, cyclobutyl, C 1-6 Alkoxy substituent substitution; R d Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, cyclopropyl, cyclobutyl; The R d Optionally substituted by 1-2 selected from hydroxy, halogen, cyclopropyl, cyclobutyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy and phenyl substituents.

7. The compound according to claim 1 or 2, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in, Y is selected from phenyl, 5-14 membered heteroaryl; The Y is optionally substituted by 1-4 groups selected from hydroxyl, amino, cyano, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, 3-7 membered cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl substitution; When the substituent on Y is selected from C 1-6 Alkyl, 3-7 membered cycloalkyl, C 2-6 Alkenyl, C 2-6 In the case of an alkynyl group, the substituent is further optionally substituted by 1 to 3 substituents selected from hydroxy, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, 3-7 membered cycloalkyl substituents; Preferably, Y is substituted with a hydroxyl group, and Y may be further optionally substituted with 1 to 3 groups selected from amino, cyano, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, cyclopropyl substituents, the substituents on Y may be further optionally substituted by 1-3 selected from halogen, C 1-6 Alkyl, cyclopropyl, trifluoromethyl, difluoromethyl substituents.

8. The compound described below, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

9. A pharmaceutical composition comprising a combination of the compound according to any one of claims 1 to 8, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

10. Use of the compound according to any one of claims 1 to 8, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9 in the preparation of a medicament for preventing and / or treating a disease associated with NLRP3 inflammasome.

11. Use of the compound according to any one of claims 1 to 8, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9 in the preparation 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.