NLRP3 inflammasome inhibitor and application thereof

Abstract

The invention belongs to the technical field of medicines, and relates to an NLRP3 inflammasome inhibitor and application thereof. Specifically, the invention relates to a compound represented by a general formula (A) or a pharmaceutically acceptable salt, a stereoisomer and a tautomer thereof, and the definitions of all groups are as defined in the specification. Researches show that the compound represented by the general formula (A) or pharmaceutically acceptable salts, stereoisomers and tautomers thereof have relatively high biological activity on NLRP3 inflammasomes, and have important clinical development value for treating NLRP3 related diseases. And Y-W-R3 (A).

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to NLRP3 inflammasome inhibitors and applications thereof. Background Art

[0002] 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).

[0003] 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.

[0004] 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.

[0005] 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. Summary of the Invention

[0006] The present invention studies the following compounds or their pharmaceutically acceptable salts, stereoisomers, and tautomers. The study found that the compounds or their pharmaceutically acceptable salts, stereoisomers, and tautomers have high biological activity against the NLRP3 inflammasome and have important clinical development value for the treatment of NLRP3-related diseases.

[0007] To achieve the above object, the present invention provides the following solutions:

[0008] The compound represented by general formula (A) or its pharmaceutically acceptable salt, stereoisomer, or tautomer:

[0009] YW-R3

[0010] (A)

[0011] Wherein, W is selected from

[0012] X1 and X2 are independently selected from C or N;

[0013] R1 is selected from hydrogen, hydroxy, amino, carboxyl, cyano, nitro, halogen, carbonyl, 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, aryl, 5-7 membered heteroaryl, -N(C 1-6Alkyl)2, -SC 1-6 Alkyl group or not present;

[0014] R2 is selected from hydrogen, hydroxy, amino, carboxyl, cyano, nitro, halogen, carbonyl, 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, aryl, 5-7 membered heteroaryl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl group or not present;

[0015] R1 and R2 are each optionally replaced by 1-3 groups selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl substituents;

[0016] or

[0017] 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, 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;

[0018] R3 is selected from -(C 1-6 alkylene) 0-2 -NR4R5、-(C 1-6 alkylene) 0-2 -NR4-COR5, -(C 1-6 alkylene) 0-2 -CO-NR4-R5、-(C 1-6 alkylene) 0-2 -NR4-C 1-6 Alkylene-R5;

[0019] R4 is selected from hydrogen or C 1-6 alkyl;

[0020] R5 is selected from 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl; said R5 is optionally substituted by 1-4 members selected from halogen, cyano, amino, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C 2-6 Alkenylcarbonyl, sulfonyl, C 1-6 Substitution of alkylcarbonyl groups by substituents;

[0021] When R5 is replaced,

[0022] Substituent on R5: C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, sulfonyl, optionally substituted by 1-3 groups selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, carboxyl, C 1-6 Substitution of the alkylsulfonyl group by substituents;

[0023] Y is selected from aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclyl, 3-12 membered cycloalkyl;

[0024] (1) When X1 and X2 are each selected from C,

[0025] The Y is C 2-6 Alkenyl, C 2-6 Alkynyl is substituted, and optionally substituted by 1-2 groups selected from halogen, cyano, amino, hydroxy, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C 1-6 Alkylamino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, sulfonyl substituents;

[0026] (2) When any one or both of X1 and X2 are selected from N,

[0027] The Y is optionally substituted by 1-3 selected from C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C 1-6 Alkylamino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, sulfonyl, -N(C 1-6 Alkyl)2, -SC 1-6 Substitution of alkyl groups;

[0028] In the above (1) and (2), when Y is substituted,

[0029] Substituent on Y: C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, sulfonyl, optionally substituted by 1-3 groups selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 Alkyl, 3-6 membered cycloalkyl substituents;

[0030] Substituent on Y: C 2-6 Alkenyl, C 2-6 Alkynyl, optionally substituted by 1-3 groups selected from halogen, cyano, amino, hydroxy, carbonyl, unsubstituted or substituted C 1-6 Alkyl, unsubstituted or hydroxy-substituted 3-6 membered cycloalkyl, halogenated C 1-6 The alkyl group is substituted with a substituent.

[0031] In some embodiments, the present invention further provides a compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

[0032]

[0033] in,

[0034] R1 is selected from hydrogen, hydroxy, amino, carboxyl, cyano, nitro, halogen, 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, aryl, 5-7 membered heteroaryl;

[0035] R2 is selected from hydrogen, hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl;

[0036] R1 and R2 are each optionally replaced by 1-3 groups selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl substituents;

[0037] or

[0038] R1, R2 and the carbon atoms 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, 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;

[0039] R3 is selected from -(C 1-6 alkylene) 0-2 -NR4R5、-(C 1-6 alkylene) 0-2 -NR4-COR5, -(C 1-6 alkylene) 0-2 -CO-NR4-R5、-(C 1-6 alkylene) 0-2 -NR4-C 1-6 Alkylene-R5;

[0040] R4 is selected from hydrogen or C 1-6 alkyl;

[0041] R5 is selected from 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl; said R5 is optionally substituted by 1-4 members selected from halogen, cyano, amino, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C 2-6 Alkenylcarbonyl, sulfonyl, C 1-6 Substitution of alkylcarbonyl groups by substituents;

[0042] Y is selected from aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic group, 3-12 membered cycloalkyl, and the Y is C 2-6 Alkenyl, C 2-6 Alkynyl is substituted, and optionally substituted by 1-2 groups selected from halogen, cyano, amino, hydroxy, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C 1-6 Alkylamino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, sulfonyl substituents;

[0043] When R5 is replaced,

[0044] Substituent on R5: C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, sulfonyl, optionally substituted by 1-3 groups selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 Alkyl, 3-6 membered cycloalkyl, C 1-6 Substitution of the alkylsulfonyl group by substituents;

[0045] When Y is replaced,

[0046] Substituent on Y: C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, sulfonyl, optionally substituted by 1-3 groups selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 Alkyl, 3-6 membered cycloalkyl substituents;

[0047] Substituent on Y: C 2-6 Alkenyl, C 2-6 Alkynyl, optionally substituted by 1-3 groups selected from halogen, cyano, amino, hydroxy, carbonyl, C 1-6 Alkyl, 3-6 membered cycloalkyl, halogenated C 1-6 The alkyl group is substituted with a substituent.

[0048] In some embodiments, the present invention provides a compound represented by the general formula (I) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

[0049]

[0050] in,

[0051] R1 is selected from hydrogen, hydroxy, amino, carboxyl, cyano, nitro, halogen, 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, aryl, 5-7 membered heteroaryl;

[0052] R2 is selected from hydrogen, hydroxy, amino, carboxyl, cyano, nitro, halogen, 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, aryl, 5-7 membered heteroaryl;

[0053] R1 and R2 are each optionally replaced by 1-3 groups selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl substituents;

[0054] or

[0055] R1, R2 and the carbon atoms 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, 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;

[0056] R3 is selected from -(C 1-6 alkylene) 0-2 -NR4R5、-(C 1-6 alkylene) 0-2 -NR4-COR5, -(C 1-6 alkylene) 0-2 -CO-NR4-R5;

[0057] R4 is selected from hydrogen or C 1-6 alkyl;

[0058] R5 is selected from 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl; said R5 is optionally substituted by 1-4 members selected from halogen, cyano, amino, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C 2-6 Alkenylcarbonyl, sulfonyl, C 1-6 Substitution of alkylcarbonyl groups by substituents;

[0059] Y is selected from aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic group, 3-12 membered cycloalkyl, and the Y is C 2-6 Alkenyl, C 2-6 Alkynyl is substituted, and optionally substituted by 1-2 groups selected from halogen, cyano, amino, hydroxy, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C 1-6 Alkylamino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, sulfonyl substituents;

[0060] When R5 is replaced,

[0061] Substituent on R5: C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, sulfonyl, optionally substituted by 1-3 groups selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 Alkyl, 3-6 membered cycloalkyl substituents;

[0062] When Y is replaced,

[0063] Substituent on Y: C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, sulfonyl, optionally substituted by 1-3 groups selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 Alkyl, 3-6 membered cycloalkyl substituents;

[0064] Substituent on Y: C 2-6 Alkenyl, C 2-6 Alkynyl groups are not substituted.

[0065] In some embodiments, the compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

[0066]

[0067] in,

[0068] R1 is selected from hydrogen, hydroxy, amino, carboxyl, cyano, nitro, halogen, 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, aryl, 5-7 membered heteroaryl;

[0069] R2 is selected from hydrogen, hydroxy, amino, carboxyl, cyano, nitro, halogen, 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, aryl, 5-7 membered heteroaryl;

[0070] R1 and R2 are each optionally replaced by 1-3 groups selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl substituents;

[0071] or

[0072] R1, R2 and the carbon atoms 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, 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 1-6alkyl)2 is substituted with a substituent;

[0073] R3 is selected from -(C 1-6 alkylene) 0-2 -NR4R5、-(C 1-6 alkylene) 0-2 -NR4-COR5, -(C 1-6 alkylene) 0-2 -CO-NR4-R5; R4 is selected from hydrogen or C 1-6 Alkyl; R5 is selected from 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl; said R5 is optionally substituted by 1-4 members selected from halogen, cyano, amino, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C 2-6 Alkenylcarbonyl, sulfonyl, C 1-6 Substitution of alkylcarbonyl groups by substituents;

[0074] Y is selected from aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclyl, 3-12 membered cycloalkyl, and Y is optionally substituted by 1-3 groups selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C 1-6 Alkylamino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, C 2-6 Alkenyl, C 2-6 Substitution of alkynyl and sulfonyl groups;

[0075] Substituents of R5 and Y: C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, sulfonyl, optionally substituted by 1-3 groups selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 The substituents are substituted by alkyl or 3-6 membered cycloalkyl.

[0076] In some embodiments, the present invention further provides the compound or its pharmaceutically acceptable salt, stereoisomer, or tautomer, having a structure represented by general formula (B):

[0077]

[0078] R1 is selected from hydrogen, hydroxy, amino, carboxyl, cyano, nitro, halogen, carbonyl, 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, aryl, 5-7 membered heteroaryl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl group or not present;

[0079] R2 is selected from hydrogen, hydroxy, amino, carboxyl, cyano, nitro, halogen, carbonyl, 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, aryl, 5-7 membered heteroaryl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl group or not present;

[0080] R1 and R2 are each optionally replaced by 1-3 groups selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl substituents;

[0081] Any one or both of X1 and X2 are selected from N;

[0082] Y is substituted with hydroxy and optionally substituted with 1-2 groups selected from C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group, C 1-6 Alkylamino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, sulfonyl, -N(C 1-6 Alkyl)2, -SC 1-6 The alkyl group is substituted with a substituent.

[0083] In some embodiments, Y is selected from phenyl, 5-7 membered heteroaryl, 3-8 membered heterocyclyl, 3-7 membered cycloalkyl; Y is C 2-6 Alkenyl, C 2-6 Alkynyl is substituted and optionally substituted by 1-2 groups selected from halogen, cyano, amino, hydroxy, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group, C 1-6 Alkylamino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, sulfonyl substituents;

[0084] When Y is substituted, the substituent on Y: C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, sulfonyl, optionally substituted by 1-3 groups selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 Substitution of alkyl groups;

[0085] R3 is selected from -NH-R5, R5 is 1-2 selected from C 1-6 The substituent of the alkyl group is a 3- to 7-membered heterocyclic group substituted with a substituent.

[0086] In some embodiments, Ring A is selected from 5-12 membered cycloalkyl, 5-12 membered cycloalkenyl, 5-12 membered heterocyclyl, aryl, 5-12 membered heteroaryl.

[0087] In some embodiments, Ring A is selected from 5-8 membered cycloalkyl, 5-8 membered cycloalkenyl, 5-8 membered heterocyclyl, phenyl, 5-8 membered heteroaryl.

[0088] In some embodiments, the present invention provides a compound having a structure represented by general formula (II) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof,

[0089]

[0090] in,

[0091] 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 hydroxy, 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 1-6Alkoxy, 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.

[0092] In some embodiments, ring A is selected from phenyl, 5-7 membered heteroaryl; ring A is optionally substituted by 1-4 groups selected from hydroxy, 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.

[0093] In some embodiments, ring A is selected from phenyl, a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from O, S, and N, and a 5-6 membered saturated ring.

[0094] In some embodiments, Ring A is optionally substituted by 1-4 groups selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, carbonyl, 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.

[0095] In some embodiments, Ring A is unsubstituted.

[0096] In some embodiments, Ring A is substituted by 1-4 groups selected from hydroxy, 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.

[0097] In some embodiments, Ring A is replaced by 1-2 groups selected from cyano, C 1-6 Alkoxy, C 1-6 Alkyl, halogenated C 1-6Alkyl, C 1-6 Alkylsulfonyl, -N(C 1-6 alkyl)2 is substituted with a substituent.

[0098] In some embodiments, Ring A is replaced by 1 selected from cyano, C 1-6 Alkoxy, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkylsulfonyl, -N(C 1-6 alkyl)2 is substituted with a substituent.

[0099] In some embodiments, ring A is selected from phenyl, 5-6 membered heteroaryl containing 1-2 heteroatoms selected from O, S, N, 5-6 membered saturated ring, and ring A is not substituted or replaced by 1 selected from cyano, C 1-6 Alkoxy, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkylsulfonyl, -N(C 1-6 alkyl)2 is substituted with a substituent.

[0100] In some embodiments, Ring A is selected from Ring A is optionally substituted by 1-4 groups selected from hydroxy, 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.

[0101] In some embodiments, Ring A is selected from

[0102] Ring A is optionally substituted by 1-2 groups selected from cyano, nitro, halogen, 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.

[0103] In some embodiments, Ring A is

[0104] In some embodiments, R3 is selected from -(C1-6 alkylene) 0-2 -NR4R5、-(C 1-6 alkylene) 0-2 -NR4-COR5, -(C 1-6 alkylene) 0-2 -CO-NR4-R5、-(C 1-6 alkylene) 0-2 -NR4-C 1-6 Alkylene-R5; R4 is selected from hydrogen or C 1-6 Alkyl; R5 is selected from 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl.

[0105] In some embodiments, R4 is selected from hydrogen.

[0106] In some embodiments, R4 is selected from C 1-6 alkyl.

[0107] In some embodiments, R4 is selected from methyl, ethyl.

[0108] In some embodiments, R3 is selected from -NR4R5, -NR4-C 1-6 Alkylene-R5, R4 is selected from hydrogen, R5 is selected from 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl.

[0109] In some embodiments, R3 is selected from -NR4R5, -NR4-C 1-6 Alkylene -R5, R4 is selected from hydrogen, R5 is selected from 3-7 membered cycloalkyl, 3-7 membered heterocyclyl; preferably, R3 is selected from -NHR5, R5 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclyl.

[0110] In some embodiments, R5 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclyl containing 1 heteroatom selected from O, N, S.

[0111] In some embodiments, R5 is optionally replaced by 1-4 groups selected from halogen, cyano, amino, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C 2-6 Alkenylcarbonyl, sulfonyl, C 1-6 Substituents of the alkylcarbonyl group; when R5 is substituted, the substituents on R5: C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, sulfonyl, optionally substituted by 1-3 groups selected from halogen, cyano, amino, hydroxyl, carbonyl, C1-6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, carboxyl, C 1-6 The substituent of the alkylsulfonyl group is substituted.

[0112] In some embodiments, R5 is unsubstituted.

[0113] In some embodiments, R5 is replaced by 1-2 groups selected from halogen, cyano, amino, hydroxy, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C 2-6 Alkenylcarbonyl, sulfonyl, C 1-6 Substitution of alkylcarbonyl groups by substituents;

[0114] In some embodiments, when R5 is substituted, the substituent on R5: C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, and sulfonyl are unsubstituted.

[0115] In some embodiments, when R5 is substituted, the substituent on R5: C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, sulfonyl, 1-3 selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, carboxyl, C 1-6 The substituent of the alkylsulfonyl group is substituted.

[0116] In some embodiments, R5 is selected from

[0117] Preferably, R5 is selected from

[0118] In some embodiments, Y is selected from aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclyl, 3-12 membered cycloalkyl, and said Y is C 2-6 Alkenyl, C 2-6 Alkynyl is substituted, and optionally substituted by 1-2 groups selected from halogen, cyano, amino, hydroxy, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C1-6 Alkylamino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonyl, aminocarbonyl, C 1-6 The substituents of the alkylaminocarbonyl group and the sulfonyl group are substituted.

[0119] In some embodiments, Y is selected from phenyl, 5-7 membered heteroaryl, 3-8 membered heterocyclyl, 3-7 membered cycloalkyl; Y is C 2-6 Alkenyl, C 2-6 Alkynyl is substituted and optionally substituted by 1-2 groups selected from halogen, cyano, amino, hydroxy, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group, C 1-6 Alkylamino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonyl, aminocarbonyl, C 1-6 The substituents of the alkylaminocarbonyl group and the sulfonyl group are substituted.

[0120] In some embodiments, Y is selected from phenyl, 5-8 membered heteroaryl, 3-8 membered heterocyclyl, 3-7 membered cycloalkyl.

[0121] In some embodiments, Y is selected from phenyl, 5-6 membered heteroaryl.

[0122] In some embodiments, Y is selected from phenyl, 5-6 membered heteroaryl containing 1-2 N heteroatoms.

[0123] In some embodiments, Y is optionally replaced by 1-3 selected from C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C 1-6 Alkylamino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, sulfonyl, -N(C 1-6 Alkyl)2, -SC 1-6 The alkyl group is substituted with a substituent.

[0124] In some embodiments, Y is replaced by 1 selected from C 2-6 Alkenyl, C 2-6 The substituents of the alkynyl group are optionally substituted by 1-2 groups selected from halogen, cyano, amino, hydroxy, carbonyl, C 1-6 Alkyl, halogenated C1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group.

[0125] In some embodiments, Y is replaced by 1-2 selected from C 2-6 Alkenyl, C 2-6 The substituents of the alkynyl group are substituted.

[0126] In some embodiments, Y is replaced by 1 selected from C 2-6 Alkenyl, C 2-6 In some embodiments, Y is optionally substituted with 1-3 substituents selected from halogen, cyano, amino, hydroxy, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group.

[0127] In some embodiments, Y is optionally replaced by 1-2 groups selected from halogen, cyano, amino, hydroxy, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group.

[0128] In some embodiments, Y is replaced by 1-2 selected from C 2-6 Alkenyl, C 2-6 The substituents of the alkynyl group are optionally substituted by 1 to 3 groups selected from halogen, cyano, amino, hydroxy, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group.

[0129] In some embodiments, Y is replaced by 1 selected from C 2-6 Alkenyl, C 2-6 The substituents of the alkynyl group are substituted and Y is optionally substituted with one selected from halogen, cyano, amino, hydroxy, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 In some embodiments, Y is substituted by C 2-6 Alkenyl, C 2-6 Alkynyl is substituted and optionally substituted by 1-2 groups selected from halogen, cyano, amino, hydroxy, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C 1-6 Alkylamino, C 1-6Alkylcarbonylamino, C 1-6 Alkylsulfonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, sulfonyl, -N(C 1-6 Alkyl)2, -SC 1-6 The alkyl group is substituted with a substituent.

[0130] In some embodiments, Y is replaced by 1 selected from C 2-6 Alkenyl, C 2-6 Alkynyl is substituted with a substituent and Y is substituted with a hydroxyl group; said C 2-6 Alkenyl, C 2-6 Alkynyl is unsubstituted or substituted by 1-3 groups selected from halogen, cyano, amino, hydroxy, carbonyl, unsubstituted or substituted C 1-6 Alkyl, unsubstituted or hydroxy-substituted 3-6 membered cycloalkyl, halogenated C 1-6 The alkyl group is substituted with a substituent.

[0131] In some embodiments, when Y is substituted, the substituents on Y are: C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, sulfonyl, optionally substituted by 1-3 groups selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 The substituents are substituted by alkyl or 3-6 membered cycloalkyl.

[0132] In some embodiments, the substituents on Y: C 2-6 Alkenyl, C 2-6 Alkynyl is substituted by 1 to 3 groups selected from halogen, cyano, amino, hydroxy, carbonyl, unsubstituted or hydroxy-substituted C 1-6 Alkyl, unsubstituted or hydroxy-substituted 3-6 membered cycloalkyl, halogenated C 1-6 The alkyl group is substituted with a substituent.

[0133] In some embodiments, the substituents on Y: C 2-6 Alkenyl, C 2-6 Alkynyl groups are not substituted.

[0134] In some embodiments, Y is selected from phenyl, 5-7 membered heteroaryl, 3-8 membered heterocyclyl, 3-7 membered cycloalkyl; Y is C 2-6 Alkenyl, C 2-6 Alkynyl is substituted and optionally substituted by 1-2 groups selected from halogen, cyano, amino, hydroxy, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group, C 1-6 Alkylamino, C 1-6Alkylcarbonylamino, C 1-6 Alkylsulfonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, sulfonyl substituents;

[0135] When Y is substituted, the substituent on Y: C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, sulfonyl, optionally substituted by 1-3 groups selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 The alkyl group is substituted with a substituent.

[0136] In some embodiments, Y is selected from phenyl, 5-6 membered heteroaryl, said Y being C 2-6 Alkenyl, C 2-6 Alkynyl is substituted and optionally substituted by 1-2 groups selected from halogen, cyano, amino, hydroxy, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group; the C 2-6 Alkenyl, C 2-6 Alkynyl is substituted by 1-3 groups selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 Alkyl, 3-6 membered cycloalkyl, halogenated C 1-6 The alkyl group is substituted with a substituent.

[0137] In some embodiments, Y is selected from

[0138] In some embodiments, when Y is substituted, the substituents on Y are selected from: hydroxyl,

[0139] The present invention also provides the compound or its pharmaceutically acceptable salt, stereoisomer, or tautomer, having a structure represented by general formula (C):

[0140] The selection of R1, R2, R3, and Y is as described above.

[0141] In one embodiment of the present invention, the compounds represented by the aforementioned formula (A), (B), (C), (I) or (II), their pharmaceutically acceptable salts, or their stereoisomers and tautomers are shown in Table 1:

[0142] Table 1

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161] In one embodiment of the present invention, a pharmaceutical composition is provided, comprising any one of the above-mentioned compounds or pharmaceutically acceptable salts, stereoisomers, or tautomers thereof, and a pharmaceutically acceptable carrier.

[0162] In one embodiment of the present invention, the pharmaceutical composition may comprise one or more pharmaceutically acceptable carriers and may be administered to a patient or subject requiring such treatment via oral, parenteral, rectal, or transpulmonary administration. For oral administration, the pharmaceutical composition may be formulated into conventional solid preparations, such as tablets, capsules, pills, granules, or oral liquid preparations, such as oral solutions, oral suspensions, and syrups. Suitable fillers, binders, disintegrants, lubricants, and the like may be added to oral preparations. For parenteral administration, the pharmaceutical composition may be formulated into injectable preparations, including injection solutions, sterile powders for injection, and concentrated solutions for injection. Injectable preparations may be produced using conventional methods in the pharmaceutical field. Additives may be omitted or added depending on the properties of the drug. For rectal administration, the pharmaceutical composition may be formulated into suppositories. For transpulmonary administration, the pharmaceutical composition may be formulated into inhalers or sprays.

[0163] The present invention also provides the use of the compounds represented by the above-mentioned general formula (A), (B), (C), (I) or general formula (II) or their pharmaceutically acceptable salts, stereoisomers, tautomers, or the above-mentioned pharmaceutical compositions in the preparation of drugs for preventing and / or treating diseases related to NLRP3 inflammasome.

[0164] The present invention also provides the use of the above-mentioned compound or its pharmaceutically acceptable salt, stereoisomer, tautomer, or the above-mentioned pharmaceutical composition in the preparation of a drug for preventing and / or treating inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases or autoinflammatory diseases. Detailed Description of the Invention

[0166] The "halogen" described in the present invention refers to fluorine, chlorine, bromine and iodine.

[0167] The "hydroxyl group" described in the present invention refers to an -OH group.

[0168] The "cyano group" described in the present invention refers to a -CN group.

[0169] The "amino group" described in the present invention refers to the -NH2 group.

[0170] The "carboxyl group" described in the present invention refers to a -COOH group.

[0171] The "nitro" described in the present invention refers to a -NO2 group.

[0172] 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.

[0173] 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.

[0174] The "halogenated C 1-6 "Alkyl" refers to a C1-C6 alkyl group substituted by one or more halogen groups as defined above. 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.

[0175] 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.

[0176] 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.

[0177] 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.

[0178] 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.

[0179] The "C 1-6 Alkylamino", "C 1-6 Alkylcarbonylamino", "C 1-6 Alkylsulfonyl" and "aminocarbonyl" refer to C 1-6 Alkyl-NH-, C 1-6 Alkyl-C(O)-NH-, C 1-6 Groups formed in the form of alkyl-S(O)2-, NH2-C(O)-.

[0180] It can be understood that in the present invention, When R1 and R2 form a ring with the C or N atom to which they are connected, X1 and X2 form a double bond or a single bond according to the chemical bonding rules.

[0181] 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.

[0182] 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.

[0183] 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. The "3- to 7-membered cycloalkyl" may 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.

[0184] "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 5-8 membered cycloalkenyl, a 5-7 membered cycloalkenyl, a 4-6 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.

[0185] 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.

[0186] The "3-14 membered heterocyclic group" of the present invention refers to a monovalent group or (as needed) a 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, preferably containing 1-3 heteroatoms, and in which the ring atoms, including carbon atoms, nitrogen atoms, and sulfur atoms, are oxidized. "3-14 membered heterocyclic groups" (e.g., 5-14 membered heterocyclic groups, 5-12 membered heterocyclic groups) include monocyclic heterocyclic groups, bicyclic heterocyclic groups, or polycyclic heterocyclic groups, in which one or more rings may be saturated or partially saturated, but do not include aromatic rings. Unless otherwise specified, a certain-membered heterocyclic group (e.g., a 3- to 8-membered heterocyclic group, a 3- to 7-membered heterocyclic group, a 5- to 8-membered heterocyclic group, a 5- to 7-membered heterocyclic group, a 5- to 6-membered heterocyclic group, a 4- to 6-membered heterocyclic group, a 6-membered heterocyclic group) includes all possible monocyclic, fused (including fused in the form of bis-, spiro-, or bridged) and saturated and partially saturated rings.

[0187] 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 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.

[0188] 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.

[0189] 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.

[0190] 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:

[0191] 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:

[0192] 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.

[0193] 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.

[0194] 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.

[0195] The heterocyclic ring and heteroaryl group of the present invention include the case where ring atoms including carbon atoms, nitrogen atoms and sulfur atoms are substituted with oxo.

[0196] 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.

[0197] 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.

[0198] 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.

[0199] "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.

[0200] 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 interconvert. For example, tautomers can occur in the presence of ketones or oximes. Representative examples include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, and imine-enamine tautomers.

[0201] All enantiomers, diastereomers, racemates, cis-trans isomers, tautomers, geometric isomers, epimers and mixtures thereof of the compounds are included within the scope of the present invention.

[0202] 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 the point of attachment to the parent molecule.

[0203] Beneficial effects of the present invention

[0204] Studies have found that the compounds provided by the present invention or their pharmaceutically acceptable salts, stereoisomers, and tautomers have good inhibitory activity against the NLRP3 inflammasome. Therefore, the compounds of the present invention can be used to prevent and / or treat diseases related to the NLRP3 inflammasome. DETAILED DESCRIPTION

[0205] 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.

[0206] The abbreviations and English expressions used in this invention have the following meanings:

[0207] “THF” refers to tetrahydrofuran; “DMF” refers to N,N-dimethylformamide; “MeOH” refers to methanol; “EA” refers to ethyl acetate; “DCM” refers to dichloromethane; “DMAC” and “DMA” refer to N,N-dimethylacetamide; “MTBE” refers to methyl tert-butyl ether; “EtOH” refers to ethanol; “PE” refers to petroleum ether; “n-BuLi” refers to n-butyllithium; “NMP” refers to N-methylpyrrolidone; “DBDMH” and “DBH” refer to dibromohydantoin; “mCPBA” refers to m-chloroperbenzoic acid; “BINAP” refers to 1,1′-binaphthyl-2,2′-bis(diphenylphosphine); “TMSOTf” refers to trimethylsilyl trifluoromethanesulfonate; “TBAF” refers to tetrabutylammonium fluoride; “DIPEA” refers to N,N-diisopropylethylamine; “LDA” refers to lithium diisopropylamide; and “B2Pin2” refers to diboronic acid pinacol ester.

[0208] “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.

[0209] Example 1 Synthesis of (R)-5-ethynyl-2-(4-((1-methylpiperidin-3-yl)amino)-5,6,7,8-tetrahydrophthalazin-1-yl)phenol (Compound 1)

[0210]

[0211] Step 1: Synthesis of (R)-3-(ethoxymethoxy)-4-(4-((1-methylpiperidin-3-yl)amino)-5,6,7,8-tetrahydrophthalazin-1-yl)benzaldehyde

[0212]

[0213] 3-(Ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (393 mg, 1.28 mmol, 1.2 eq), (R)-4-chloro-N-(1-methylpiperidin-3-yl)-5,6,7,8-tetrahydrophthalazin-1-amine (300 mg, 1.07 mmol, 1.0 eq), Pd(dppf)Cl2 (78.3 mg, 0.107 mmol, 0.1 eq) and NaHCO3 (180 mg, 2.14 mmol, 2.0 eq) were added to 1,4-dioxane (6 mL) and water (3 mL) in sequence, heated to 110 ° C under nitrogen protection, and reacted for 2 hours. The mixture was cooled to room temperature, quenched by the addition of water (30 mL), extracted with EA (30 mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (DCM:MeOH=50:1-10:1) to obtain the product (320 mg, yield: 70.6%).

[0214] Step 2: Synthesis of (R)-4-(2-(ethoxymethoxy)-4-ethynylphenyl)-N-(1-methylpiperidin-3-yl)-5,6,7,8-tetrahydrophthalazin-1-amine

[0215]

[0216] (R)-3-(Ethoxymethoxy)-4-(4-((1-methylpiperidin-3-yl)amino)-5,6,7,8-tetrahydrophthalazin-1-yl)benzaldehyde (320 mg, 0.754 mmol, 1.0 eq) was dissolved in MeOH (5 mL), and KCO (209 mg, 1.51 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (217 mg, 1.13 mmol, 1.5 eq) were added. The mixture was stirred at room temperature for 5 hours. The mixture was concentrated, dissolved in water, and extracted with DCM (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (DCM:MeOH = 50:1 to 20:1) to obtain the product (275 mg, yield: 86.8%).

[0217] Step 3: Synthesis of (R)-5-ethynyl-2-(4-((1-methylpiperidin-3-yl)amino)-5,6,7,8-tetrahydrophthalazin-1-yl)phenol

[0218]

[0219] (R)-4-(2-(Ethoxymethoxy)-4-ethynylphenyl)-N-(1-methylpiperidin-3-yl)-5,6,7,8-tetrahydrophthalazin-1-amine (275 mg, 0.654 mmol, 1.0 eq) was dissolved in DCM (5 mL), followed by the dropwise addition of a solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 0.82 mL, 3.27 mmol, 5.0 eq). The mixture was stirred at room temperature for 2 hours. The pH was adjusted to 9 with saturated aqueous Na2CO3, and the mixture was extracted with DCM (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (DCM:MeOH = 50:1 to 10:1) to afford the product (198 mg, 83.5% yield).

[0220] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.11 (s, 1H), 7.11 (d, J = 7.6Hz, 1H), 7.04 (s, 1H), 6.99-6.97 (m, 1H), 6.07 (s, 1H), 4.55 (s, 1 H),4.20(s,1H),3.20(s,1H),2.70(s,5H),2.44(s,2H),2.34-2.32(m,2H),1.94(s,2H),1.76(s,4H),1.61(d,J=5.6Hz,3H).

[0221] Molecular formula: C 22 H 26 N4O exact molecular weight: 362.21 LC-MS (Pos, m / z) = 363.14 [M+H] + .

[0222] Example 2 Synthesis of (R)-5-ethynyl-2-(4-((tetrahydro-2H-pyran-3-yl)amino)phthalazin-1-yl)phenol (Compound 2)

[0223]

[0224] Step 1: Synthesis of 4-(4-chlorophthalazin-1-yl)-3-(ethoxymethoxy)benzaldehyde

[0225]

[0226] 3-(Ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (462 mg, 1.51 mmol, 1.0 eq), 1,4-dichlorophthalazine (300 mg, 1.51 mmol, 1.0 eq), Pd(dppf)Cl2 (110 mg, 0.151 mmol, 0.1 eq) and NaHCO3 (254 mg, 3.02 mmol, 2.0 eq) were added to 1,4-dioxane (5 mL) and water (2.5 mL) in sequence, heated to 110 ° C under nitrogen protection, and reacted for 2 hours. The mixture was cooled to room temperature, quenched by the addition of water (30 mL), extracted with EA (30 mL × 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (DCM:MeOH=100:1) to obtain the product (290 mg, yield: 56.1%).

[0227] Step 2: Synthesis of (R)-3-(ethoxymethoxy)-4-(4-((tetrahydro-2H-pyran-3-yl)amino)phthalazin-1-yl)benzaldehyde

[0228]

[0229] 4-(4-Chlorophthalazin-1-yl)-3-(ethoxymethoxy)benzaldehyde (240 mg, 0.700 mmol, 1.0 eq), (R)-3-aminotetrahydropyran hydrochloride (144 mg, 1.05 mmol, 1.5 eq), Pd2(dba)3 (64.1 mg, 0.0700 mmol, 0.1 eq), BINAP (87.1 mg, 0.140 mmol, 0.2 eq) and Cs2CO3 (456 mg, 1.40 mmol, 2.0 eq) were added to 1,4-dioxane (10 mL) in sequence, heated to 90 ° C under nitrogen protection, and reacted for 2 hours. The mixture was cooled to room temperature, quenched with water (30 mL), extracted with EA (20 mL × 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (DCM:MeOH=100:1-20:1) to obtain the product (212 mg, yield: 74.3%).

[0230] Step 3: Synthesis of (R)-4-(2-(ethoxymethoxy)-4-ethynylphenyl)-N-(tetrahydro-2H-pyran-3-yl)phthalazin-1-amine

[0231]

[0232] (R)-3-(Ethoxymethoxy)-4-(4-((tetrahydro-2H-pyran-3-yl)amino)phthalazin-1-yl)benzaldehyde (210 mg, 0.515 mmol, 1.0 eq) was dissolved in MeOH (4 mL), and KCO (142 mg, 1.03 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (119 mg, 0.618 mmol, 1.2 eq) were added. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated, dissolved in water, and extracted with DCM (20 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 isolated by silica gel column chromatography (DCM:MeOH = 100:1 to 20:1) to obtain the product (122 mg, yield: 58.7%).

[0233] Step 4: Synthesis of (R)-5-ethynyl-2-(4-((tetrahydro-2H-pyran-3-yl)amino)phthalazin-1-yl)phenol

[0234]

[0235] (R)-4-(2-(Ethoxymethoxy)-4-ethynylphenyl)-N-(tetrahydro-2H-pyran-3-yl)phthalazin-1-amine (120 mg, 0.297 mmol, 1.0 eq) was dissolved in DCM (4 mL), and a solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 0.22 mL, 0.891 mmol, 3.0 eq) was added dropwise. The mixture was stirred at room temperature for 1 hour. The pH was adjusted to 8 with saturated aqueous NaHCO₃, and the mixture was extracted with DCM (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by preparative thin-layer chromatography (DCM:MeOH = 20:1) to afford the product (62.0 mg, 60.4% yield).

[0236] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.02 (s, 1H), 8.41 (d, J = 8.4Hz, 1H), 7.88-7.84 (m, 1 H),7.81-7.77(m,1H),7.47(d,J=8.0Hz,1H),7.30(d,J=7.6Hz,1H),7.17(d,J=7.6Hz ,1H),7.09-7.06(m,2H),4.41-4.39(m,1H),4.24(s,1H),4.10-4.07(m,1H),3.84(d, J=11.2Hz,1H),3.36(s,1H),3.28-3.23(m,1H),2.12-2.11(m,1H),1.80-1.68(m,3H).

[0237] Molecular formula: C 21 H 19 N3O2 exact molecular weight: 345.15 LC-MS (Pos, m / z) = 346.03 [M+H] + .

[0238] Example 3: Synthesis of 5-ethynyl-2-(4-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)phthalazin-1-yl)phenol (Compound 3)

[0239]

[0240] Step 1: Synthesis of 3-(ethoxymethoxy)-4-(4-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)phthalazin-1-yl)benzaldehyde

[0241]

[0242] (cis)-3-((4-chlorophthalazin-1-yl)amino)-1-methylcyclobutane-1-ol (290.0 mg, 1.09 mmol, 1.0 eq.), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (505.0 mg, 1.64 mmol, 1.5 eq.), sodium bicarbonate (184.6 mg, 2.19 mmol, 2.0 eq.), water (5.0 mL) and Pd(dppf)Cl2 (40.2 mg, 0.05 mmol, 0.05 eq.) was added to 1,4-dioxane (10.0 mL). The reaction was carried out at 110°C for 3 hours under nitrogen protection. The reaction was complete as monitored by TLC. The system was cooled to room temperature, and water (50.0 mL) was added. The extraction was carried out 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 (silica gel specification: 100-200 mesh, dichloromethane:methanol = 100:1-40:1) to obtain the product (240.0 mg, yield: 53.5%).

[0243] Step 2: Synthesis of (cis)-3-((4-(2-(ethoxymethoxy)-4-ethynylphenyl)phthalazin-1-yl)amino)-1-methylcyclobutan-1-ol

[0244]

[0245] 3-(Ethoxymethoxy)-4-(4-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)phthalazin-1-yl)benzaldehyde (240 mg, 0.58 mmol, 1.0 eq), sodium carbonate (162.8 mg, 1.17 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (169.7 mg, 0.88 mmol, 1.5 eq) were added to methanol (10.0 mL) and stirred at room temperature for 2 hours. The reaction was completed as monitored by LC-MS. 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 preparative thin layer chromatography (dichloromethane:methanol = 10:1) to give the product (130.0 mg, yield: 54.7%).

[0246] Step 3: Synthesis of 5-ethynyl-2-(4-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)phthalazin-1-yl)phenol

[0247]

[0248] (cis)-3-((4-(2-(ethoxymethoxy)-4-ethynylphenyl)phthalazin-1-yl)amino)-1-methylcyclobutan-1-ol (130.0 mg, 0.32 mmol, 1.0 eq.) was added to dichloromethane (2.0 mL), and a hydrogen chloride-1,4-dioxane solution (4.0 mol / L, 4.0 mL) was added dropwise. The reaction was allowed to react at room temperature for 2 hours. The reaction was complete after monitoring by TLC. The pH of the system was adjusted to 7-8 with saturated sodium bicarbonate, 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 to obtain the product (50.0 mg, yield: 44.9%). 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.01 (s, 1H), 8.42-8.40 (d, J = 8Hz, 1H), 7.84 (t, J = 8Hz, 1H), 7.77 (t, J = 8Hz, 1H), 7.58-7.57 (d, J = 4Hz, 1H), 7.47-7 .45(d,J=8Hz,1H),7.30-7.28(d,J=8Hz,1H),7.07-7.05(m,2H),5.01(s,1 H),4.27-4.22(m,2H),2.50-2.47(m,2H),2.20-2.15(m,2H),1.34(s,3H).

[0249] Molecular formula: C 21 H 19 N3O2 exact molecular weight: 345.15 LC-MS (Pos, m / z) = 346.07 [M+H+ ].

[0250] Example 4: Synthesis of 5-ethynyl-2-(4-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-5,6,7,8-tetrahydrophthalazin-1-yl)phenol (Compound 4)

[0251]

[0252] Step 1: Synthesis of 3-(ethoxymethoxy)-4-(4-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-5,6,7,8-tetrahydrophthalazin-1-yl)benzaldehyde

[0253]

[0254] (cis)-3-((4-chloro-5,6,7,8-tetrahydrophthalazin-1-yl)amino)-1-methylcyclobutan-1-ol (390.0 mg, 1.45 mmol, 1.0 eq.), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (624.3 mg, 2.03 mmol, 1.4 eq.), sodium bicarbonate (244.6 mg, 2.91 mmol, 2.0 eq.), water (6.0 mL) and Pd(dppf)Cl 2 (53.2 mg, 0.07 mmol, 0.05 eq.) was added to 1,4-dioxane (12.0 mL) and reacted at 110°C under nitrogen for 4 hours. The reaction was completed as monitored by TLC. The system was cooled to room temperature, and water (50.0 mL) was added and extracted with ethyl acetate (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica gel specification: 100-200 mesh, dichloromethane:methanol = 80:1-30:1) to obtain the product (143.0 mg, yield: 23.8%).

[0255] Step 2: Synthesis of (cis)-3-((4-(2-(ethoxymethoxy)-4-ethynylphenyl)-5,6,7,8-tetrahydrophthalazin-1-yl)amino)-1-methylcyclobutan-1-ol

[0256]

[0257] 3-(Ethoxymethoxy)-4-(4-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)-5,6,7,8-tetrahydrophthalazin-1-yl)benzaldehyde (143.0 mg, 0.34 mmol, 1.0 eq), sodium carbonate (95.9 mg, 0.69 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (100.1 mg, 0.52 mmol, 1.5 eq) were added to methanol (6.0 mL) and stirred at room temperature for 14 hours. The reaction was completed as monitored by LC-MS. 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 preparative thin layer chromatography (dichloromethane:methanol = 10:1) to give the product (120.0 mg, yield: 84.8%). Step 3: Synthesis of 5-ethynyl-2-(4-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-5,6,7,8-tetrahydrophthalazin-1-yl)phenol

[0258]

[0259] (cis)-3-((4-(2-(ethoxymethoxy)-4-ethynylphenyl)-5,6,7,8-tetrahydrophthalazin-1-yl)amino)-1-methylcyclobutan-1-ol (120.0 mg, 0.29 mmol, 1.0 eq.) was added to dichloromethane (2.0 mL), and a hydrogen chloride-1,4-dioxane solution (4.0 mol / L, 4.0 mL) was added dropwise. The reaction was allowed to react at room temperature for 2 hours. The reaction was complete after monitoring by TLC. The pH of the system was adjusted to 7-8 with saturated sodium bicarbonate, 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 to obtain the product (80.0 mg, yield: 77.8%).

[0260] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 9.99 (s, 1H), 7.13-7.11 (d, J = 8Hz, 1H), 6.99-6.96 (m, 2H), 6.08-6.06 (d, J = 8Hz, 1H), 4.91 (s, 1H), 4.17 (s,1H),4.11-4.06(m,1H),2.42-2.37(m,4H),2.33-2.30(m,2H),2.09-2.04(m,2H),1.76-1.73(m,2H),1.60-1.58(m,2H),1.30(s,3H).

[0261] Molecular formula: C 21 H 23N3O2 exact molecular weight: 349.18 LC-MS (Pos, m / z) = 350.14 [M+H + ].

[0262] Example 5 Synthesis of (R)-2-(4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)-5-vinylphenol (Compound 99)

[0263]

[0264] Step 1: Synthesis of (R)-2-(4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)-5-vinylphenol

[0265]

[0266] (R)-5-Ethynyl-2-(4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)phenol (300 mg, 0.837 mmol, 1.0 eq) was dissolved in MeOH (10 mL), and Lindlar catalyst (30 mg, 10%) was added. The H₂ atmosphere was replaced, and the reaction was allowed to proceed at room temperature for 1 hour. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The crude product was isolated by preparative thin-layer chromatography (DCM:MeOH = 10:1) to afford the product (240 mg, 79.6% yield).

[0267] 1 HNMR(400MHz,DMSO-d6)δ(ppm):9.88(s,1H),8.51(s,1H),7.88-7.77(m,2H),7 .54(d,J=8.4Hz,1H),7.42(s,1H),7.28(d,J=7.6Hz,1H),7.10-7.07(m,2H),6. 79-6.72(m,1H),5.82(d,J=17.6Hz,1H),5.31(d,J=11.2Hz,1H),4.63(s,1H),3 .39(d,J=9.2Hz,1H),3.02(s,1H),2.55(s,5H),1.92(s,2H),1.77-1.71(m,2H).

[0268] Molecular formula: C 22 H 24 N4O exact molecular weight: 360.20 LC-MS (Pos, m / z) = 361.09 [M+H] + .

[0269] Example 6 Synthesis of (R)-5-ethynyl-2-(4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)phenol (Compound 100)

[0270]

[0271] Step 1: Synthesis of 4-bromo-3-hydroxybenzaldehyde

[0272]

[0273] 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 and quenched with water. 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 isolated by silica gel column chromatography (PE:EA = 50:1 to 5:1) to obtain the product (7.80 g, yield: 83.4%).

[0274] Step 2: Synthesis of 4-bromo-3-(ethoxymethoxy)benzaldehyde

[0275]

[0276] 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 isolated by silica gel column chromatography (PE:EA = 50:1 to 5:1) to obtain the product (7.60 g, yield: 75.6%).

[0277] Step 3: Synthesis of 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde

[0278]

[0279] 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. The mixture was cooled to room temperature, quenched with water (50 mL), 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 isolated by silica gel column chromatography (PE:EA = 20:1 to 5:1) to obtain the product (5.20 g, yield: 88.0%).

[0280] Step 4: Synthesis of (R)-3-(ethoxymethoxy)-4-(4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)benzaldehyde

[0281]

[0282] 3-(Ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (1.66 g, 5.42 mmol, 1.5 eq), (R)-4-chloro-N-(1-methylpiperidin-3-yl)phthalazin-1-amine (1.00 g, 3.61 mmol, 1.0 eq), Pd(dppf)Cl2 (264 mg, 0.361 mmol, 0.1 eq) and NaHCO3 (607 mg, 7.22 mmol, 2.0 eq) were added to 1,4-dioxane (10 mL) and water (5 mL) in sequence, heated to 110 ° C under nitrogen protection, and reacted for 3 hours. The mixture was cooled to room temperature, quenched by addition of water (30 mL), extracted with EA (30 mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (DCM:MeOH=50:1-10:1) to obtain the product (1.22 g, yield: 53.5%).

[0283] Step 5: Synthesis of (R)-4-(2-(ethoxymethoxy)-4-ethynylphenyl)-N-(1-methylpiperidin-3-yl)phthalazin-1-amine

[0284]

[0285] (R)-3-(Ethoxymethoxy)-4-(4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)benzaldehyde (1.20 g, 2.85 mmol, 1.0 eq) was dissolved in MeOH (15 mL), and KCO (788 mg, 5.70 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (657 mg, 3.42 mmol, 1.2 eq) were added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated, dissolved in water, and extracted with DCM (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (DCM:MeOH = 50:1 to 10:1) to obtain the product (1.08 g, yield: 90.9%).

[0286] Step 6: Synthesis of (R)-5-ethynyl-2-(4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)phenol

[0287]

[0288] (R)-4-(2-(ethoxymethoxy)-4-ethynylphenyl)-N-(1-methylpiperidin-3-yl)phthalazin-1-amine (1.08 g, 2.95 mmol, 1.0 eq) was dissolved in DCM (10 mL). A solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 3.24 mL, 12.9 mmol, 5.0 eq) was then added dropwise. The mixture was stirred at room temperature for 4 hours. The pH was adjusted to 8 with saturated aqueous NaHCO₃. The mixture was then extracted with DCM (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (DCM:MeOH = 50:1 to 10:1) to obtain the product (760 mg, yield: 81.8%).

[0289] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.10 (s, 1H), 8.53 (s, 1H), 7.88-7.78 (m, 2H), 7.49-7.47 (m, 2H), 7.29 (d, J = 7.6Hz, 1H), 7.13 (s, 1H) ,7.08-7.06(m,1H),4.66(s,1H),4.25(s,1H),3.43(d,J=9.6Hz,1H),3.06(s,1H),2.59(s,5H),1.99-1.92(m,2H),1.79-1.74(m,2H).

[0290] Molecular formula: C 22 H 22N4O exact molecular weight: 358.18 LC-MS (Pos, m / z) = 359.10 [M+H] + .

[0291] Example 7 Synthesis of (R)-5-ethynyl-2-(4-((1-methylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 5)

[0292]

[0293] Step 1: Synthesis of pyrido[3,4-d]pyridazine-1,4-diol

[0294]

[0295] Pyridine-3,4-dicarboxylic anhydride (16.0 g, 0.11 mol, 1.0 eq) was dissolved in EtOH (450 mL), and hydrazine hydrate (27.0 g, 0.54 mol, 5.0 eq) was added. The mixture was heated to 80°C and allowed to react for 7 hours, resulting in the precipitation of a large amount of solid. The mixture was cooled to room temperature and filtered. The filter cake was washed with EtOH and dried to obtain the product (15.0 g, 85.0% yield).

[0296] Step 2: Synthesis of 1,4-dichloropyrido[3,4-d]pyridazine

[0297]

[0298] Pyrido[3,4-d]pyridazine-1,4-diol (1.0 g, 6.13 mmol, 1.0 eq) was added to POCl (4.70 g, 30.7 mmol, 5.0 eq), followed by DIPEA (785 mg, 6.13 mmol, 1.0 eq). The mixture was heated to 100°C and allowed to react for 2 hours. The mixture was concentrated under reduced pressure, diluted with EA, and the pH was adjusted to alkaline with aqueous NaHCO. The organic phase was extracted with DCM, and concentrated under reduced pressure. The product (150 mg, 12.5% ​​yield) was isolated by silica gel column chromatography (PE:EA = 5:1).

[0299] Step 3: Synthesis of 4-chloropyrido[3,4-d]pyridazin-1-ol

[0300]

[0301] 1,4-Dichloropyrido[3,4-d]pyridazine (5.0 g, 25.0 mmol, 1.0 eq) was added to 1% dilute hydrochloric acid (150 mL), heated to 110°C, and reacted for 2 hours. Cooled to room temperature, filtered, and the filter cake was recrystallized from acetic acid to obtain the product (1.50 g, yield: 33.0%). Step 4: Synthesis of tert-butyl (R)-3-((1-hydroxypyrido[3,4-d]pyridazin-4-yl)amino)piperidine-1-carboxylate

[0302]

[0303] 4-Chloropyrido[3,4-d]pyridazin-1-ol (1.40 g, 7.73 mmol, 1.0 eq), (R)-tert-butyl 3-aminopiperidine-1-carboxylate (1.86 g, 9.28 mmol, 1.2 eq), Pd2(dba)3 (708 mg, 0.773 mmol, 0.1 eq), RuPhos (721 mg, 1.55 mmol, 0.2 eq), and tBuOK (2.20 g, 19.3 mmol, 2.5 eq) were added sequentially to NMP (30 mL). Under nitrogen, the mixture was heated to 110°C for 2.5 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the product (1.0 g, 37.5% yield) was isolated by silica gel column chromatography (DCM:MeOH = 100:1 to 30:1).

[0304] Step 5: Synthesis of (R)-1-chloro-N-(piperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0305]

[0306] (R)-tert-Butyl 3-((1-hydroxypyrido[3,4-d]pyridazin-4-yl)amino)piperidine-1-carboxylate (582 mg, 1.60 mmol, 1.0 eq) was added to ACN (10 mL), followed by POCl3 (736 mg, 4.80 mmol, 3.0 eq), heated to 90°C, and reacted for 4 hours. The mixture was cooled to room temperature, and the pH was adjusted to 8 by adding saturated aqueous NaHCO3. The mixture was extracted with DCM (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product (262 mg, 62.1% yield) was isolated by silica gel column chromatography (DCM:MeOH = 50:1 to 10:1).

[0307] Step 6: Synthesis of (R)-1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0308]

[0309] (R)-1-chloro-N-(piperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine (262 mg, 0.993 mmol, 1.0 eq) was dissolved in MeOH (5 mL), and aqueous formaldehyde (37%, 121 mg, 1.49 mmol, 1.5 eq) was added. The mixture was stirred at room temperature for 20 minutes. NaBH3CN (93.6 mg, 1.49 mmol, 1.5 eq) was then added and allowed to react for 1 hour. The mixture was quenched with saturated aqueous NaHCO3 and extracted with DCM (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product (215 mg, 77.9% yield) was isolated by preparative thin-layer chromatography (DCM:MeOH = 10:1).

[0310] Step 7: Synthesis of (R)-3-(ethoxymethoxy)-4-(4-((1-methylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)benzaldehyde

[0311]

[0312] 3-(Ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (284 mg, 0.929 mmol, 1.2 eq), (R)-1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine (215 mg, 0.774 mmol, 1.0 eq), Pd(dppf)Cl2 (56.6 mg, 0.0774 mmol, 0.1 eq) and NaHCO3 (130 mg, 1.55 mmol, 2.0 eq) were added to 1,4-dioxane (4 mL) in sequence, and H2O (2 mL) was added. Under nitrogen protection, the mixture was heated to 110°C and reacted for 3 hours. The mixture was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with EA (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product (40.0 mg, yield: 12.3%) was isolated by silica gel column chromatography (DCM:MeOH=100:1-10:1).

[0313] Step 8: Synthesis of (R)-1-(2-(ethoxymethoxy)-4-ethynylphenyl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0314]

[0315] (R)-3-(Ethoxymethoxy)-4-(4-((1-methylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)benzaldehyde (40.0 mg, 0.0949 mmol, 1.0 eq) was dissolved in MeOH (2 mL), and KCO (26.3 mg, 0.190 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (27.3 mg, 0.142 mmol, 1.5 eq) were added. The mixture was stirred at room temperature for 3 hours. The mixture was concentrated, dissolved in water, and extracted with DCM (5 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product (22.0 mg, 55.5% yield) was isolated by preparative thin-layer chromatography (DCM:MeOH = 10:1).

[0316] Step 9: Synthesis of (R)-5-ethynyl-2-(4-((1-methylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol

[0317]

[0318] (R)-1-(2-(Ethoxymethoxy)-4-ethynylphenyl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine (122 mg, 0.0527 mmol, 1.0 eq) was dissolved in DCM (2 mL), and then a solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 0.06 mL, 0.264 mmol, 5.0 eq) was added dropwise. The mixture was stirred at room temperature for 1 hour. The pH value was adjusted to 8 with saturated NaHCO3 aqueous solution, and the mixture was extracted with a mixed solvent of DCM:MeOH=10:1 (5 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product (12.0 mg, yield: 63.4%) was isolated by preparative thin layer chromatography (DCM:MeOH=10:1).

[0319] 1 HNMR (400MHz, CD3OD) δ (ppm): 9.72 (s, 1H), 8.86 (d, J = 8.0Hz, 1H), 7.53-7.51 (m, 1H),7.37(d,J=8.0Hz,1H),7.16-7.14(m,1H),7.12(d,J=1.2Hz,1H),4.71-4.65 (m,1H),3.60(s,1H),3.43(d,J=8.7Hz,1H),3.02(d,J=10.0Hz,1H),2.67(d,J=8 .9Hz,2H),2.60(s,3H),2.16-2.14(m,1H),2.06-2.01(m,1H),1.88-1.78(m,2H).

[0320] Molecular formula: C 21 H 21 N5O exact molecular weight: 359.17 LC-MS (Pos, m / z) = 360.13 [M+H] + .

[0321] Example 8 Synthesis of (R)-5-ethynyl-2-(5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)phenol (Compound 177)

[0322]

[0323] Step 1: Synthesis of 6-aza-2-thiouracil

[0324]

[0325] Thiosemicarbazide (100 g, 1.10 mol, 1.0 eq) was dissolved in water (300 mL), and 50% glyoxylic acid (162.89 g, 1.1 mol, 1.0 eq) was added dropwise. The mixture was reacted at 100°C for 1.5 h. A large amount of solid precipitated. The mixture was cooled to room temperature and filtered. The filter cake was added portionwise to a solution of NaOH (44 g, 1.10 mol, 1.0 eq) in water (300 mL). The reaction was continued at 100°C for 1 h. The mixture was cooled to room temperature. The pH of the aqueous phase was adjusted to 1 with hydrochloric acid. A large amount of solid precipitated. The mixture was filtered and the filter cake was dried to obtain the product (90 g, yield: 63.4%).

[0326] Step 2: Synthesis of 3-(methylthio)-1,2,4-triazin-5(4H)-one

[0327]

[0328] 6-Aza-2-thiouracil (90 g, 696.91 mmol, 1.0 eq) was dissolved in EtOH (1 L). Sodium tert-butoxide (66.97 g, 696.91 mmol, 1.0 eq) was added portionwise and stirred for 10 min. Methyl iodide (98.93 g, 696.91 mmol, 1.0 eq) was slowly added dropwise and allowed to react for 50 min. The reaction was monitored for completion by TLC. The mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (MeOH:DCM = 1:15), then slurried with EA (100 mL), filtered, and the filter cake dried to afford the product (30 g, 30% yield).

[0329] Step 3: Synthesis of 5,6-dichloro-3-(methylthio)-1,2,4-triazine

[0330]

[0331] 3-(Methylthio)-1,2,4-triazine-5(4H)-one (8.50 g, 59.4 mmol, 1.0 eq) was added to SOCl2 (40 mL), and DMF (0.4 mL) was added. The mixture was heated to 80°C and reacted for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product (12.2 g).

[0332] Step 4: Synthesis of 6-chloro-5-methyl-3-(methylthio)-1,2,4-triazine

[0333]

[0334] 5,6-Dichloro-3-(methylthio)-1,2,4-triazine (12.2 g, 62.2 mmol, 1.0 eq) was dissolved in THF (50 mL), cooled to -60°C, and MeMgCl (20.7 mL, 62.2 mmol, 1.0 eq) was added dropwise. The reaction was allowed to react for 0.5 h. The mixture was quenched by addition of 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. The product (1.52 g, two-step yield: 20.0%) was isolated by silica gel column chromatography (PE:EA = 100:1 to 10:1).

[0335] Step 5: Synthesis of 6-chloro-5-methyl-3-(methylsulfonyl)-1,2,4-triazine

[0336]

[0337] Dissolve 6-chloro-5-methyl-3-(methylthio)-1,2,4-triazine (1.52 g, 8.65 mmol, 1.0 eq) in DCM (50 mL) and stir at room temperature. Add m-chloroperbenzoic acid (3.73 g, 21.6 mmol, 2.5 eq) and allow to react for 2 hours. Add saturated aqueous NaHCO₃ to adjust the pH to 8. Extract with DCM (30 mL x 2). Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the product (1.38 g, 76.8% yield).

[0338] Step 6: Synthesis of tert-butyl (R)-3-((6-chloro-5-methyl-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate

[0339]

[0340] Dissolve 6-chloro-5-methyl-3-(methylsulfonyl)-1,2,4-triazine (1.38 g, 6.65 mmol, 1.0 eq) in DCM (30 mL), add (R)-tert-butyl 3-aminopiperidine-1-carboxylate (2.00 g, 9.98 mmol, 1.5 eq), and react at room temperature for 3 hours. The mixture was concentrated under reduced pressure and isolated by silica gel column chromatography (PE:EA = 20:1 to 2:1) to obtain the product (540 mg, 24.8% yield).

[0341] Step 7: Synthesis of (R)-6-chloro-5-methyl-N-(piperidin-3-yl)-1,2,4-triazin-3-amine

[0342]

[0343] Dissolve (R)-tert-Butyl 3-((6-chloro-5-methyl-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate (540 mg, 1.65 mmol, 1.0 eq) in DCM (5 mL). Add a solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 1.24 mL, 4.95 mmol, 3.0 eq) dropwise and stir at room temperature for 1 hour. Adjust the pH to 8 with saturated aqueous NaHCO₃. Extract with DCM (20 mL x 3). Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Isolate the product (332 mg, 88.5% yield) via silica gel column chromatography (DCM:MeOH = 50:1 to 10:1).

[0344] Step 8: Synthesis of (R)-6-chloro-5-methyl-N-(1-methylpiperidin-3-yl)-1,2,4-triazin-3-amine

[0345]

[0346] (R)-6-Chloro-5-methyl-N-(piperidin-3-yl)-1,2,4-triazin-3-amine (330 mg, 1.45 mmol, 1.0 eq) was dissolved in MeOH (5 mL), and aqueous formaldehyde (37%, 183 mg, 2.18 mmol, 1.5 eq) was added. The mixture was stirred at room temperature for 20 minutes. NaBH3CN (137 mg, 2.18 mmol, 1.5 eq) was then added and allowed to react for 1 hour. The mixture was quenched with saturated aqueous NaHCO3 and extracted with DCM (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product (280 mg, 77.9% yield) was isolated by silica gel column chromatography (DCM:MeOH = 50:1 to 10:1).

[0347] Step 9: Synthesis of (R)-3-(ethoxymethoxy)-4-(5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)benzaldehyde

[0348]

[0349] 3-(Ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (380 mg, 1.24 mmol, 1.5 eq), (R)-6-chloro-5-methyl-N-(1-methylpiperidin-3-yl)-1,2,4-triazine-3-amine (200 mg, 0.827 mmol, 1.0 eq), Pd(dppf)Cl2 (60.5 mg, 0.0827 mmol, 0.1 eq) and NaHCO3 (139 mg, 1.65 mmol, 2.0 eq) were added to 1,4-dioxane (6 mL) in sequence, and H2O (3 mL) was added. Under nitrogen protection, the mixture was heated to 110°C and reacted for 1 hour. The mixture was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with EA (30 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product (180 mg, yield: 56.4%) was isolated by silica gel column chromatography (DCM:MeOH=100:1-10:1).

[0350] Step 10: Synthesis of (R)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-N-(1-methylpiperidin-3-yl)-1,2,4-triazin-3-amine

[0351]

[0352] (R)-3-(Ethoxymethoxy)-4-(5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)benzaldehyde (180 mg, 0.467 mmol, 1.0 eq) was dissolved in MeOH (5 mL), and KCO (129 mg, 0.934 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (135 mg, 0.701 mmol, 1.5 eq) were added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated, dissolved in water, and extracted with EA (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product (152 mg, yield: 85.3%) was isolated by silica gel column chromatography (DCM:MeOH = 50:1 to 10:1).

[0353] Step 11: Synthesis of (R)-5-ethynyl-2-(5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)phenol

[0354]

[0355] (R)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-N-(1-methylpiperidin-3-yl)-1,2,4-triazin-3-amine (152 mg, 0.398 mmol, 1.0 eq) was dissolved in DCM (3 mL). A solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 0.3 mL, 1.19 mmol, 3.0 eq) was added dropwise and stirred at room temperature for 2 hours. The pH was adjusted to 8 with saturated aqueous NaHCO₃. The mixture was extracted with DCM (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product (82.0 mg, 63.6% yield) was isolated by silica gel column chromatography (DCM:MeOH = 50:1 to 10:1).

[0356] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.10 (s, 1H), 7.45 (s, 1H), 7.27-7.25 (m, 1H), 7.04-7.03 (m, 2H), 4.21 (s, 1H), 3.99 (s, 1H), 2.89 (d, J= 7.0Hz,1H),2.64(d,J=8Hz,1H),2.19(s,3H),2.18(s,3H),1.90-1.85(m,3H),1.72-1.68(m,1H),1.57-1.49(m,1H),1.36-1.30(m,1H).

[0357] Molecular formula: C 18 H 21 N5O exact molecular weight: 323.17 LC-MS (Pos, m / z) = 324.11 [M+H] + .

[0358] Example 9 Synthesis of (R)-2-(5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol (Compound 188)

[0359]

[0360] Step 1: Synthesis of (R)-6-(2-(ethoxymethoxy)-4-(trifluoromethyl)phenyl)-5-methyl-N-(1-methylpiperidin-3-yl)-1,2,4-triazin-3-amine

[0361]

[0362] (2-(Ethoxymethoxy)-4-(trifluoromethyl)phenyl)boric acid (131 mg, 0.496 mmol, 1.5 eq), (R)-6-chloro-5-methyl-N-(1-methylpiperidin-3-yl)-1,2,4-triazine-3-amine (80 mg, 0.331 mmol, 1.0 eq), Pd(dppf)Cl2 (24.2 mg, 0.0331 mmol, 0.1 eq) and NaHCO3 (55.6 mg, 0.662 mmol, 2.0 eq) were added to 1,4-dioxane (5 mL) in sequence, and H2O (2.5 mL) was added. Under nitrogen protection, the mixture was heated to 110°C and reacted for 1 hour. The mixture was cooled to room temperature, and water (10 mL) was added. The mixture was extracted with EA (15 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography (DCM:MeOH = 100:1 to 10:1) to give the product (83.0 mg, yield: 58.9%).

[0363] Step 2: Synthesis of (R)-2-(5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol

[0364]

[0365] (R)-6-(2-(ethoxymethoxy)-4-(trifluoromethyl)phenyl)-5-methyl-N-(1-methylpiperidin-3-yl)-1,2,4-triazin-3-amine (83 mg, 0.195 mmol, 1.0 eq) was dissolved in DCM (3 mL), followed by the dropwise addition of a solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 0.15 mL, 0.585 mmol, 3.0 eq). The mixture was stirred at room temperature for 2 hours. The pH was adjusted to 8 with saturated aqueous NaHCO₃, and the mixture was extracted with DCM (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product (47.0 mg, 65.6% yield) was isolated by silica gel column chromatography (DCM:MeOH = 50:1 to 10:1).

[0366] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.56 (s, 1H), 7.49 (d, J = 8Hz, 2H), 7.28-7.25 (m, 2H), 4.02 (s, 1H), 2.92 (s, 1H), 2.67 (d ,J=10.6Hz,1H),2.22(s,3H),2.19(s,3H),1.95-1.89(m,3H),1.71-1.69(m,1H),1.60-1.51(m,1H),1.35-1.32(m,1H).

[0367] Molecular formula: C 17 H 20 N5O exact molecular weight: 367.16 LC-MS (Pos, m / z) = 368.11 [M+H] + .

[0368] Example 10: Synthesis of (R)-5-ethynyl-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol (Compound 54)

[0369]

[0370] Step 1: Synthesis of (R)-3-(ethoxymethoxy)-4-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)benzaldehyde

[0371]

[0372] (R)-6-chloro-5-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine (300.0 mg, 1.24 mmol, 1.0 eq.), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)benzaldehyde (572.3 mg, 1.869 mmol, 1.5 eq.), sodium bicarbonate (209.3 mg, 2.49 mmol. 2.0 eq.) and Pd(dppf)Cl2 (45.5 mg, 0.06 mmol, 0. 0.5 eq.) was added to a mixed solution of 1,4-dioxane (12.0 mL) and water (4.0 mL). The reaction was carried out at 110°C under nitrogen protection for 4 hours. The reaction was completed as monitored by TLC. The system was cooled to room temperature, water (50.0 mL) was added, and extraction was carried out with ethyl acetate (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica gel specification: 100-200 mesh, dichloromethane:methanol = 50:1-10:1) to obtain the product (283.0 mg, yield: 59.0%).

[0373] Step 2: Synthesis of (R)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine

[0374]

[0375] (R)-3-(ethoxymethoxy)-4-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)benzaldehyde (283.0 mg, 0.73 mmol, 1.0 eq), anhydrous potassium carbonate (203.4 mg, 1.17 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (212.1 mg, 1.10 mmol, 1.5 eq.) were added to the The reaction mixture was added to methanol (10.0 mL) and reacted at room temperature for 12 hours. The reaction was completed as monitored by TLC. Saturated aqueous sodium chloride solution (50.0 mL) was added and 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 (silica gel specification: 100-200 mesh, dichloromethane:methanol = 50:1-10:1) to give the product (190.0 mg, yield: 67.8%).

[0376] Step 3: Synthesis of (R)-5-ethynyl-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol

[0377]

[0378] (R)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine (190.0 mg, 0.49 mmol, 1.0 eq) was added to dichloromethane (2.0 mL). A solution of hydrogen chloride in 1,4-dioxane (4.0 mol / L, 4.0 mL) was added dropwise. The reaction was allowed to react at room temperature for 1 hour. TLC monitored the reaction for completion. The pH was adjusted to 7-8 with saturated aqueous sodium bicarbonate. 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 product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to afford the product (110.0 mg, 68.7% yield).

[0379] 1 HNMR(400MHz,DMSO-d6)δ(ppm):10.09(s,1H),7.18-7.16(m,1H),7.00-6.98( m,2H),6.68(s,1H),6.60-6.58(d,J=8Hz,1H),4.17(s,1H),4.04-4.01(m,1H) ,2.86-2.84(d,J=8Hz,1H),2.51-2.50(m,1H),2.17(s,3H),1.99-2.02(m,4H) ,1.89-1.81(m,2H),1.73-1.69(m,1H),1.55-1.52(m,1H),1.30-1.24(m,1H).

[0380] Molecular formula: C 19 H 22 N4O exact molecular weight: 322.18 LC-MS (Pos, m / z) = 323.11 [M+H] + .

[0381] Example 11: Synthesis of (R)-5-ethynyl-2-(6-fluoro-4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)phenol (Compound 172)

[0382]

[0383] Step 1: Synthesis of methyl 2-(4-bromo-2-methoxybenzoyl)-5-fluorobenzoate

[0384]

[0385] Methyl 5-fluoro-2-iodobenzoate (10.0 g, 35.71 mmol, 1.0 eq.) was dissolved in THF (200 mL). Under nitrogen, the temperature was lowered to -30°C. A solution of isopropylmagnesium chloride and lithium chloride in tetrahydrofuran (1.3 mol / L, 30.2 mL, 39.28 mmol, 1.1 eq.) was added and stirred for 20 min. CuCN (3.2 g, 35.71 mmol, 1.0 eq.) was added and stirred for 20 min. 4-bromo-2-methoxybenzoyl chloride (10.7 g, 42.85 mmol, 1.0 eq.) was added and reacted for 20 min. The reaction was monitored by TLC to be complete. The reaction solution was poured into water (100 mL), stirred for 10 min, filtered, and the filtrate was separated. The aqueous phase was extracted with EA (100 mL × 2), and the EA phase was washed with aqueous potassium carbonate solution (100 mL × 2). The organic phases were combined, dried, and concentrated to obtain a crude product (13.13 g, yield: 100%).

[0386] Step 2: Synthesis of 4-(4-bromo-2-methoxyphenyl)-7-fluorophthalazin-1-ol

[0387]

[0388] Methyl 2-(4-bromo-2-methoxybenzoyl)-5-fluorobenzoate (13.13 g, 35.71 mmol, 1.0 eq.) and 85% hydrazine hydrate (4.20 g, 71.42 mmol, 2.0 eq.) were dissolved in ethanol (200 mL) and reacted at room temperature for 40 min. The reaction was completed after monitoring by TLC. The reaction was cooled to room temperature, filtered, and the filter cake was dried to obtain the product (6.5 g, yield: 52.1%).

[0389] Step 3: Synthesis of 1-(4-bromo-2-methoxyphenyl)-4-chloro-6-fluorophthalazine

[0390]

[0391] 4-(4-Bromo-2-methoxyphenyl)-7-fluorophthalazin-1-ol (6.5 g, 18.61 mmol, 1.0 eq.) and phosphorus oxychloride (5.71 g, 37.22 mmol, 2.0 eq.) were dissolved in acetonitrile (130 mL) and reacted at 90°C for 2 h. The reaction was completed as monitored by TLC. The reaction solution was concentrated under reduced pressure, water (100 mL) was added, and the pH was adjusted to 10 with sodium carbonate. The product was extracted with EA (100 mL × 3), and the organic phase was dried and concentrated. The product was purified by silica gel column chromatography (DCM:PE = 1:1) to obtain the product (5.5 g, yield: 80.4%).

[0392] Step 4: Synthesis of 1-(4-bromo-2-methoxyphenyl)-4,6-difluorophthalazine

[0393]

[0394] 1-(4-Bromo-2-methoxyphenyl)-4-chloro-6-fluorophthalazine (2.0 g, 5.44 mmol, 1.0 eq.) and tetramethylammonium fluoride (760 mg, 8.16 mmol, 1.5 eq.) were dissolved in DMF (20 mL) and reacted at 100°C for 1 h. The reaction was completed after monitoring by LC-MS. The reaction solution was poured into water (20 mL) and extracted with MTBE (20 mL × 2). The organic phases were combined, dried, concentrated, and purified by silica gel column chromatography (PE:EA=5:1) to obtain the product (0.9 g, yield: 47.1%).

[0395] Step 5: Synthesis of tert-butyl (R)-3-((4-(4-bromo-2-methoxyphenyl)-7-fluorophthalazin-1-yl)amino)piperidine-1-carboxylate

[0396]

[0397] 1-(4-Bromo-2-methoxyphenyl)-4,6-difluorophthalazine (0.9 g, 2.56 mmol, 1.0 eq.), tert-butyl (R)-3-aminopiperidine-1-carboxylate (566 mg, 2.82 mmol, 1.1 eq.), and TEA (777 mg, 7.68 mmol, 3.0 eq.) were dissolved in 1,4-dioxane (10 mL) and reacted at 80°C for 20 h. LC-MS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was slurried with a 10:1 mixture of PE and EA (20 mL), filtered, and the filter cake was dried to yield 1.0 g (yield: 73.5%).

[0398] Step 6: Synthesis of tert-butyl (R)-3-((7-fluoro-4-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)phthalazin-1-yl)amino)piperidine-1-carboxylate

[0399]

[0400] Tert-butyl (R)-3-((4-(4-bromo-2-methoxyphenyl)-7-fluorophthalazin-1-yl)amino)piperidine-1-carboxylate (1.0 mg, 1.88 mmol, 1.0 eq.), PdCl2(dppf)2 (133 mg, 0.19 mmol, 0.1 eq.), and CuI (107 mg, 0.26 mmol, 0.3 eq.) were dissolved in diisopropylamine (10 mL). Under nitrogen, trimethylsilylacetylene (1.85 mg, 18.80 mmol, 10 eq.) was added and the mixture was allowed to react at 60°C for 16 h. The reaction was complete by TLC. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 2:1) to obtain the product (510 mg, 49.5% yield).

[0401] Step 7: Synthesis of (R)-5-ethynyl-2-(6-fluoro-4-(piperidin-3-ylamino)phthalazin-1-yl)phenol

[0402]

[0403] Tert-butyl (R)-3-((7-fluoro-4-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)phthalazin-1-yl)amino)piperidine-1-carboxylate (0.5 g, 0.91 mmol, 1.0 eq.) was dissolved in DCM (10 mL), and boron tribromide (456 mg, 1.82 mmol, 2.0 eq.) was added. The reaction was carried out at 0°C for 3 h. The reaction was completed by TLC. The reaction solution was poured into water (20 mL), and the pH was adjusted to 9 with NaHCO3. The product was extracted with DCM (15 mL × 3). The organic phases were combined, dried, and concentrated to obtain the product (300 mg, yield: 90.9%).

[0404] Step 8: Synthesis of (R)-5-ethynyl-2-(6-fluoro-4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)phenol

[0405]

[0406] (R)-5-Ethynyl-2-(6-fluoro-4-(piperidin-3-ylamino)phthalazin-1-yl)phenol (300 mg, 0.82 mmol, 1.0 eq.) and 37% aqueous formaldehyde (67 mg, 0.82 mmol, 1.0 eq.) were dissolved in methanol (5 mL) and stirred at room temperature for 5 min. Sodium cyanoborohydride (52 mg, 0.82 mmol, 1.0 eq.) was added and allowed to react at room temperature for 5 min. LC-MS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, water (10 mL) was added, and the mixture was extracted with DCM (10 mL x 3). The organic phases were combined, dried, and concentrated. The crude product was purified by preparative thin-layer chromatography (DCM:MeOH = 10:1) to afford the product (108 mg, 35.1% yield).

[0407] 1 HNMR(400MHz,DMSO-d6)δ(ppm):10.01(s,1H),8.32-8.29(d,1H),7.71-7.6 6(t,1H),7.57-7.53(m,1H),7.31-7.29(d,1H),7.13-7.07(m,3H),4.43(s,1 H),4.23(s,1H),3.17-3.14(d,1H),2.80-2.78(d,1H),2.28(s,3H),2.02(s ,2H),1.81-1.78(d,1H),1.68-1.59(m,1H),1.49-1.46(d,1H),1.24(s,1H).

[0408] Molecular formula: C 22 H 21 FN4O exact molecular weight: 376.17 LC-MS (Pos, m / z) = 377.11 [M+H] + .

[0409] Example 12: Synthesis of (R)-3-hydroxy-4-(5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)benzonitrile (Compound 190)

[0410]

[0411] Step 1: Synthesis of 5-methyl-3-(methylsulfonyl)-1,2,4-triazine

[0412]

[0413] Dissolve 5-methyl-3-(methylthio)-1,2,4-triazine (1.5 g, 10.62 mmol, 1.0 eq) in DCM (50 mL) and add m-chloroperbenzoic acid (4.53 g, 22.30 mmol, 2.1 eq). React at room temperature for 0.5 h. Pour the reaction solution into water (20 mL), adjust the pH to 9 with NaHCO₃, and extract with DCM (20 mL x 2). The organic phase is dried and concentrated to obtain the product (1.84 g, 100% yield).

[0414] Step 2: Synthesis of tert-butyl (R)-3-((5-methyl-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate

[0415]

[0416] 5-Methyl-3-(methylsulfonyl)-1,2,4-triazine (1.84 g, 10.62 mmol, 1.0 eq), (R)-tert-butyl 3-aminopiperidine-1-carboxylate (2.13 g, 10.62 mmol, 1.5 eq), and TEA (1.61 g, 15.93 mmol, 1.5 eq) were dissolved in 1,4-dioxane (20 mL) and reacted at 100°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 2:1) to obtain the product (700 mg, 22.4% yield).

[0417] Step 3: Synthesis of tert-butyl (R)-3-((6-bromo-5-methyl-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate

[0418]

[0419] (R)-tert-Butyl 3-((5-methyl-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate (0.7 g, 2.38 mmol, 1.0 eq) and NBS (466 mg, 2.62 mmol, 1.1 eq) were dissolved in DMF (7 mL) and reacted at room temperature for 19 hours. The reaction solution was poured into water (20 mL) and extracted with MTBE (15 mL x 3). The organic phases were combined, dried, and concentrated. The crude product was purified by silica gel column chromatography (PE:EA = 5:1) to obtain the product (300 mg, 33.9% yield).

[0420] Step 4: Synthesis of tert-butyl (R)-3-((6-(4-cyano-2-(ethoxymethoxy)phenyl)-5-methyl-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate

[0421]

[0422] (R)-tert-Butyl 3-((6-bromo-5-methyl-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate (300 mg, 0.8 mmol, 1.5 eq), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (364 mg, 1.2 mmol, 1.5 eq), Pd(dppf)Cl2 (58 mg, 0.08 mmol, 0.1 eq) and NaHCO3 (134 mg, 1.6 mmol, 2.0 eq) were added to 1,4-dioxane (6 mL) and H2O (2 mL), heated to 110 ° C under nitrogen protection, and reacted for 1 hour. The reaction solution was poured into water (10 mL) and extracted with EA (20 mL×2). The organic phases were combined, dried, and concentrated. The crude product was purified by silica gel column chromatography (PE:EA=2:1) ​​to obtain the product (280 mg, yield: 74.7%).

[0423] Step 5: Synthesis of (R)-3-hydroxy-4-(5-methyl-3-(piperidin-3-ylamino)-1,2,4-triazin-6-yl)benzonitrile

[0424]

[0425] Tert-butyl (R)-3-((6-(4-cyano-2-(ethoxymethoxy)phenyl)-5-methyl-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate (280 mg, 0.6 mmol, 1.0 eq) was dissolved in DCM (3 mL), and a solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 1 mL) was added dropwise. The reaction was allowed to react at room temperature for 1.5 h. LC-MS monitored the reaction completion. The reaction solution was poured into water (10 mL) and back-extracted with DCM (10 mL × 3). The aqueous phase was adjusted to pH 10 with aqueous NaHCO₃ and extracted with DCM (10 mL × 4). The organic phases were combined, dried, and concentrated to afford the product (150 mg, 80.6% yield).

[0426] Step 6: Synthesis of (R)-3-hydroxy-4-(5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)benzonitrile

[0427]

[0428] (R)-3-Hydroxy-4-(5-methyl-3-(piperidin-3-ylamino)-1,2,4-triazin-6-yl)benzonitrile (150 mg, 0.48 mmol, 1.0 eq.) and 37% aqueous formaldehyde (39 mg, 0.48 mmol, 1.0 eq.) were dissolved in methanol (3 mL) and stirred at room temperature for 5 min. Sodium cyanoborohydride (30 mg, 0.48 mmol, 1.0 eq.) was added and allowed to react at room temperature for 5 min. The reaction was monitored for completion by TLC. The reaction solution was poured into water (10 mL) and extracted with DCM (30 mL x 3). The organic phases were combined, dried, and concentrated. The crude product was purified by preparative thin-layer chromatography (DCM:MeOH = 10:1) to obtain the product (65 mg, 41.9% yield).

[0429] 1 HNMR(400MHz,DMSO-d6)δ(ppm):10.71(s,1H),7.48-7.46(d,1H),7.40-7.38(t,1H),7.33-7.31(d,1H),4.06-4.01(m,1H),2.96(s,1 H),2.71(s,1H),2.25(s,3H),2.18(s,3H),1.99(s,2H),1.88-1.86(d,1H),1.75-1.71(t,1H),1.61-1.52(m,1H),1.40-1.30(m,1H).

[0430] Molecular formula: C 17 H 20 N6O exact molecular weight: 324.17 LC-MS (Pos, m / z) = 325.14 [M+H] + .

[0431] Example 13: Synthesis of (R)-3,5-dimethyl-2-(3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)phenol (Compound 202)

[0432]

[0433] Step 1: Synthesis of 6-bromo-3-(methylthio)-1,2,4-triazine

[0434]

[0435] 6-Bromo-1,2,4-triazine-3-amine (3.0 g, 17.14 mmol, 1.0 eq) and 1,2-dimethyl disulfide (2.4 g, 25.71 mmol, 1.5 eq) were added to acetonitrile (20 mL), and tert-butyl nitrite (3.5 g, 34.28 mmol, 2.0 eq) was added dropwise. The reaction was allowed to react at room temperature for 2 hours. The reaction was complete as monitored by TLC. The product was quenched with methanol (20.0 mL) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica gel specification: 100-200 mesh, petroleum ether:ethyl acetate = 5:1) to obtain the product (1.5 g, yield: 42.4%).

[0436] Step 2: Synthesis of 6-(2-(ethoxymethoxy)-4,6-dimethylphenyl)-3-(methylthio)-1,2,4-triazine

[0437]

[0438] 6-Bromo-3-(methylthio)-1,2,4-triazine (230.0 mg, 1.11 mmol, 1.0 eq.), (2-(ethoxymethoxy)-4,6-dimethylphenyl)boronic acid (250.0 mg, 1.11 mmol, 1.0 eq.), sodium bicarbonate (187.5 mg, 2.22 mmol. 2.0 eq.) and Pd(dppf)Cl2 (40.8 mg, 0.05 mmol, 0.05 eq.) were added to 1,4- The reaction mixture was stirred for 3 hours at 110° C. under nitrogen protection in a mixed solution of dioxane (12.0 mL) and water (6.0 mL). The reaction was completed by TLC monitoring. The system was cooled to room temperature, and water (50.0 mL) was added. The organic phase was extracted with ethyl acetate (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica gel specification: 100-200 mesh, petroleum ether:ethyl acetate = 10:1) to obtain the product (167.0 mg, yield: 49.0%).

[0439] Step 3: Synthesis of 6-(2-(ethoxymethoxy)-4,6-dimethylphenyl)-3-(methylsulfonyl)-1,2,4-triazine

[0440]

[0441] 6-(2-(Ethoxymethoxy)-4,6-dimethylphenyl)-3-(methylthio)-1,2,4-triazine (167.0 mg, 0.54 mmol, 1.0 eq) was dissolved in dichloromethane (10.0 mL), and m-chloroperbenzoic acid (85%) (222.0 mg, 1.08 mmol, 2.0 eq) was added. The mixture was reacted at room temperature for 1 hour. The reaction was completed as monitored by TLC. Saturated aqueous sodium bicarbonate solution (50.0 mL) was added and 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 (silica gel specification: 100-200 mesh, petroleum ether:ethyl acetate = 5:1-2:1) to obtain the product (137.0 mg, yield: 74.4%).

[0442] Step 4: Synthesis of tert-butyl (R)-3-((6-(2-(ethoxymethoxy)-4,6-dimethylphenyl)-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate

[0443]

[0444] 6-(2-(Ethoxymethoxy)-4,6-dimethylphenyl)-3-(methylsulfonyl)-1,2,4-triazine (108.0 mg, 0.32 mmol, 1.0 eq) and tert-butyl (R)-3-aminopiperidine-1-carboxylate (128.2 mg, 0.64 mmol, 2.0 eq) were added to N,N-dimethylacetamide (4.0 mL) and reacted at 108°C for 16 hours. The reaction was complete as monitored by TLC. The system was cooled to room temperature, water (50.0 mL) was added, and the mixture was extracted with ethyl acetate (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the product (60.0 mg, yield: 41.0%).

[0445] Step 5: Synthesis of (R)-3,5-dimethyl-2-(3-(piperidin-3-ylamino)-1,2,4-triazin-6-yl)phenol

[0446]

[0447] tert-Butyl (R)-3-((6-(2-(ethoxymethoxy)-4,6-dimethylphenyl)-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate (60.0 mg, 0.13 mmol, 1.0 eq.) was added to dichloromethane (2.0 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 1 hour. TLC monitored the reaction for completion. The pH of the reaction was adjusted to 7-8 with saturated aqueous sodium bicarbonate. 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 to afford the product (39.0 mg, 99.4% yield).

[0448] Step 6: Synthesis of (R)-3,5-dimethyl-2-(3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)phenol

[0449]

[0450] (R)-3,5-Dimethyl-2-(3-(piperidin-3-ylamino)-1,2,4-triazin-6-yl)phenol (39.0 mg, 0.13 mmol, 1.0 eq.) and formaldehyde aqueous solution (37%) (13.7 mg, 0.16 mmol, 1.3 eq.) were added to methanol (5.0 mL). After reacting at room temperature for 0.5 hour, sodium cyanoborohydride (12.2 mg, 0.19 mmol, 1.5 eq.) was added and the reaction was continued for 1 hour. After the reaction was completed as monitored by TLC, saturated aqueous sodium bicarbonate solution (20.0 mL) was added and 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 (dichloromethane:methanol = 10:1) to give the product (15.0 mg, yield: 50.0%). 1 HNMR(400MHz,DMSO-d6)δ(ppm):9.43(s,1H),8.22(s,1H),7.59(s,1H),6.60(s,2H),4.02(s,1H),3.02(s,1H),2.76(s, 1H),2.31(s,3H),2.23(s,3H),2.06(s,4H),1.91-1.88(m,1H),1.78-1.74(m,1H),1.59-1.53(m,1H),1.40-1.34(m,2H).

[0451] Molecular formula: C 17 H 23 N5O exact molecular weight: 313.19 LC-MS (Pos, m / z) = 314.15 [M+H] + .

[0452] Example 14: Synthesis of (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(prop-1-yn-1-yl)phenol (Compound 174):

[0453]

[0454] Step 1: Synthesis of 1-bromo-2-(ethoxymethoxy)-4-ethynylbenzene:

[0455]

[0456] 4-Bromo-3-(ethoxymethoxy)benzaldehyde (8 g, 30.88 mmol, 1.0 eq), dimethyl (1-diazo-2-oxopropyl)phosphonate (8.9 g, 46.32 mmol, 1.5 eq), and anhydrous potassium carbonate (8.5 g, 61.76 mmol, 2.0 eq) were added to methanol (150 mL) and reacted at room temperature for 3 h. TLC confirmed the absence of starting material. The mixture was concentrated under reduced pressure, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE = 1:150) to obtain the product (3 g, yield: 38.5%).

[0457] Step 2: Synthesis of 1-bromo-2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)benzene

[0458]

[0459] 1-Bromo-2-(ethoxymethoxy)-4-ethynylbenzene (500 mg, 1.96 mmol, 1.0 eq) was dissolved in anhydrous THF (10 mL), cooled to -70°C, and a 1.6 mol / L n-butyllithium solution in THF (1.35 mL, 1.1 eq) was added dropwise. The reaction was allowed to proceed at -75°C to -70°C for 1 h. Methyl iodide (834.6 mg, 5.88 mmol, 3.0 eq) was then added dropwise. The temperature was allowed to warm to room temperature and the reaction was allowed to proceed for 16 h. LC-MS analysis indicated that 20% of the starting material remained. Saturated aqueous ammonium chloride (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE = 1:100) to afford the product (485 mg, 91.9% yield).

[0460] Step 3: Synthesis of 2-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0461]

[0462] Dissolve 1-bromo-2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)benzene (485 mg, 1.8 mmol, 1.0 eq) in anhydrous THF (10 mL), cool to -70°C, add dropwise 1.6 mol / L n-butyllithium in THF solution (1.5 mL, 1.3 eq), and react at -70°C for 1 h. Add dropwise 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (502.4 mg, 2.7 mmol, 1.5 eq), and naturally warm to room temperature for 24 h. LC-MS detection showed no starting material, and saturated aqueous ammonium chloride solution (30 mL) was added, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE = 1:100 ~ EA = 100%) to give the product (383 mg, yield: 67.3%).

[0463] Step 4: Synthesis of (R)-6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine

[0464]

[0465] Bistriphenylphosphine palladium dichloride (70.2 mg, 0.1 mmol, 0.1 eq) and anhydrous sodium carbonate (530 mg, 5 mmol, 5.0 eq) were added to 1,4-dioxane (10 mL), and 2-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (379.4 mg, 1.2 mmol, 1.2 eq), (R)-6-chloro-5-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine (240.7 mg, 1 mmol, 1.0 eq) and water (2 mL) were added under nitrogen protection, and the reaction was heated to 100 ° C under nitrogen protection for 48 h. Water (30 mL) was added, and the mixture was extracted with DCM (30 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (MeOH:DCM=1:10) to give the product (150 mg, yield: 38%).

[0466] Step 5: Synthesis of (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(prop-1-yn-1-yl)phenol

[0467]

[0468] (R)-6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine (150 mg, 0.38 mmol, 1.0 eq) was added to DCM (5 mL), and a 4 mol / L solution of hydrogen chloride in dioxane (3 mL) was added dropwise. The reaction was allowed to proceed at room temperature for 1 h. TLC analysis indicated the absence of starting material. Water (30 mL) was added, and the mixture was back-extracted with DCM (30 mL x 2). The aqueous phase was adjusted to pH 8 with sodium carbonate, and extracted with DCM (30 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford the product (100 mg, 78.2% yield).

[0469] 1 HNMR(400MHz,DMSO-d6)δ(ppm):10.00(s,0.95H),7.14-7.12(d,1H),6.9 1-6.89(d,2H),6.68(s,1H),6.61-6.59(d,1H),4.05-4.03(m,1H),2.89-2 .87(m,1H),2.56(m,1H),2.22(s,3H),2.05-2.02(m,7H),1.92(m,1H),1. 85-1.82(m,1H),1.73-1.70(m,1H),1.56-1.54(m,1H),1.33-1.29(m,1H).

[0470] Molecular formula: C 20 H 24 N4O exact mass: 336.20 LC-MS (Pos, m / z) = 337.30 [M+H] + .

[0471] Example 15: Synthesis of (R)-2-(5-cyclopropyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)-5-ethynylphenol (Compound 179):

[0472]

[0473] Step 1: Synthesis of 2-cyclopropyl-2-oxoacetaldehyde

[0474]

[0475] Add selenium dioxide (18.5 g, 166.43 mmol, 1.4 eq), acetic acid (5 g, 83.22 mmol, 0.7 eq), and water (3.3 g, 184.26 mmol, 1.55 eq) to 1,4-dioxane (75 mL) and heat to reflux for 2 h. Add 1-cyclopropylethanone (10 g, 118.88 mmol, 1.0 eq) and heat to reflux for 22 h. Cool to room temperature, filter, rinse the filter cake with 1,4-dioxane, and use the theoretical amount of the filtrate in the next step.

[0476] Step 2: Synthesis of 5-cyclopropyl-3-(methylthio)-1,2,4-triazine

[0477]

[0478] To a solution of 2-cyclopropyl-2-oxoacetaldehyde (118.88 mmol, 1.0 eq) in dioxane, water (150 mL) was added, and sodium bicarbonate (20 g, 237.76 mmol, 2.0 eq) was slowly added. The temperature was lowered to -5 to 0°C, and an aqueous solution (100 mL) of S-methylisothiocarbazide hydroiodide (30.5 g, 130.77 mmol, 1.1 eq) was added dropwise. The temperature was naturally warmed to room temperature and the reaction was carried out for 48 h. TLC monitoring showed that there was no starting material. The mixture was extracted with ethyl acetate (200 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE = 1:30 to 1:10) to give the product (12.6 g, two-step yield: 63.3%).

[0479] Step 3: Synthesis of 5-cyclopropyl-3-(methylsulfonyl)-1,2,4-triazine

[0480]

[0481] 5-Cyclopropyl-3-(methylthio)-1,2,4-triazine (2 g, 11.96 mmol, 1.0 eq) was dissolved in DCM (40 mL), and 85% mass fraction of m-chloroperbenzoic acid (6 g, 29.9 mmol, 2.5 eq) was added in batches. The reaction was carried out at room temperature for 1 h. TCL monitoring showed that no starting material remained. Saturated aqueous sodium carbonate solution (50 mL) was added, stirred for 2 min, and extracted with DCM (50 mL × 3). The organic phases were combined and washed with 10% aqueous sodium thiosulfate solution (50 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product (2.1 g, yield: 88.2%).

[0482] Step 4: Synthesis of tert-butyl (R)-3-((5-cyclopropyl-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate

[0483]

[0484] 5-Cyclopropyl-3-(methylsulfonyl)-1,2,4-triazine (2.1 g, 10.54 mmol, 1.0 eq) was added to 1,4-dioxane (30 mL), followed by tert-butyl (R)-3-aminopiperidine-1-carboxylate (4.2 g, 21.08 mmol, 2.0 eq) and DIPEA (4.1 g, 31.62 mmol, 3.0 eq). The mixture was heated to 80°C for 20 h. TLC confirmed the absence of residual starting material. The mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE = 1:10 to 1:2) to afford the product (2.5 g, yield: 73.5%).

[0485] Step 5: Synthesis of tert-butyl (R)-3-((6-bromo-5-cyclopropyl-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate:

[0486]

[0487] Tert-butyl (R)-3-((5-cyclopropyl-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate (2.5 g, 7.83 mmol, 1.0 eq), tetrabutylammonium chloride (2.2 g, 7.83 mmol, 1.0 eq), anhydrous potassium carbonate (2.2 g, 15.66 mmol, 2.0 eq) and dibromohydantoin (1.3 g, 4.7 mmol, 0.6 eq) were added to acetonitrile (50 mL) and reacted at room temperature for 48 h. Water (50 mL) was added and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE=1:10 to 1:5) to obtain the product (1.5 g, yield: 48.4%).

[0488] Step 6: Synthesis of (R)-6-bromo-5-cyclopropyl-N-(piperidin-3-yl)-1,2,4-triazine-3-amine:

[0489]

[0490] Tert-butyl (R)-3-((6-bromo-5-cyclopropyl-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate (1.5 g, 3.76 mmol, 1.0 eq) was dissolved in DCM (20 mL), 2,6-lutidine (2.4 g, 22.56 mmol, 6.0 eq) was added, and the mixture was cooled in an ice-water bath. Trimethylsilyl trifluoromethanesulfonate (2.5 g, 11.28 mmol, 3.0 eq) was added dropwise. The reaction was allowed to proceed for 0.5 h. TLC monitoring showed that no starting material remained. Water (50 mL) was added, and the pH was adjusted to about 8 with sodium carbonate. The mixture was extracted with DCM (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (MeOH:DCM=1:100 to 1:20) to obtain the product (1.1 g, yield: 100%).

[0491] Step 7: Synthesis of (R)-6-bromo-5-cyclopropyl-N-(1-methylpiperidin-3-yl)-1,2,4-triazine-3-amine:

[0492]

[0493] (R)-6-Bromo-5-cyclopropyl-N-(piperidin-3-yl)-1,2,4-triazin-3-amine (1.1 g, 3.76 mmol, 1.0 eq), acetic acid (225.6 mg, 3.76 mmol, 1.0 eq) and 37% formaldehyde (305.2 mg, 3.76 mmol, 1.0 eq) were added to methanol (7 mL) and reacted at room temperature for 1 h. Sodium cyanoborohydride (472.5 mg, 7.52 mmol, 2.0 eq) was added. TLC monitoring showed that no starting material remained. Saturated aqueous sodium carbonate solution (30 mL) was added and extracted with DCM (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (MeOH:DCM=1:100 to 1:20) to give the product (776 mg, yield: 66.3%).

[0494] Step 8: Synthesis of (R)-4-(5-cyclopropyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)-3-(ethoxymethoxy)benzaldehyde:

[0495]

[0496] (R)-6-Bromo-5-cyclopropyl-N-(1-methylpiperidin-3-yl)-1,2,4-triazin-3-amine (776 mg, 2.47 mmol, 1.0 eq), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (1.1 g, 3.71 mmol, 1.5 eq), sodium bicarbonate (622.4 mg, 7.41 mmol, 1.0 eq) and PdCl2(dppf) (182. 9 mg, 0.25 mmol, 0.1 eq) was dissolved in a mixed solution of 1,4-dioxane (20 mL) and water (5 mL). Under nitrogen protection, the mixture was heated to 110°C for 2 h. TLC monitoring showed that no starting material remained. The mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with DCM (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (MeOH:DCM = 1:100 to 1:20) to obtain the product (1.1 g, yield: 100%).

[0497] Step 9: Synthesis of (R)-5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-N-(1-methylpiperidin-3-yl)-1,2,4-triazine-3-amine:

[0498]

[0499] (R)-4-(5-cyclopropyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)-3-(ethoxymethoxy)benzaldehyde (1 g, 2.43 mmol, 1.0 eq) was added to methanol (10 mL), and anhydrous potassium carbonate (671.7 mg, 4.86 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (699.2 mg, 3.64 mmol, 1.5 eq) were added. The reaction was carried out at room temperature for 1 h. LC-MS monitoring showed that no starting material remained. The mixture was concentrated under reduced pressure, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product (940 mg, yield: 94.9%).

[0500] Step 10: Synthesis of (R)-2-(5-cyclopropyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)-5-ethynylphenol:

[0501]

[0502] (R)-5-Cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-N-(1-methylpiperidin-3-yl)-1,2,4-triazine-3-amine (324 mg, 0.79 mmol, 1.0 eq) was added to DCM (9 mL), and trifluoroacetic acid (1 mL) was added dropwise. The reaction was carried out at room temperature for 3 h. TLC monitoring showed that there was no starting material. Water (30 mL) was added, and sodium carbonate was added to adjust the pH to about 8. The mixture was extracted with DCM (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (MeOH:DCM=1:7) to give the product (130 mg, yield: 47.1%).

[0503] 1 HNMR(400MHz,DMSO-d6)δ(ppm):10.1(s,1H),7.74-7.44(d,1H),7.30-7.28(d,1H),7.04(d,2H),4.22(s,1H),3.93-3.87(m,1H),2.87( m,1H),2.64-2.62(m,1H),2.20(s,3H),1.91-1.84(m,3H),1.71-1.64(m,2H),1.54-1.52(m,1H),1.35-1.30(m,1H),1.02-0.97(m,4H).

[0504] Molecular formula: C 20 H 23 N5O exact mass: 249.19 LC-MS (Pos, m / z) = 350.28 [M+H] + .

[0505] Example 16 Synthesis of (R)-5-alkynyl-2-(8-((1-methylpiperidin-3-yl)amino)pyrido[2,3-d]pyridazin-5-yl)phenol (Compound 203):

[0506]

[0507] Step 1: Synthesis of intermediate 6,7-dihydropyrido[2,3-d]pyridazine-5,8-dione:

[0508]

[0509] Dissolve 2,3-pyridinedicarboxylic anhydride (10.0 g, 67.06 mmol, 1.0 eq) in ethanol (150 mL) and add 85% hydrazine hydrate (19.74 g, 335.3 mmol, 5.0 eq). The mixture is allowed to react at 90°C for 16 h. LC-MS confirms the reaction is complete. The reaction mixture is cooled and filtered, and the filter cake is dissolved in water (100 mL). The pH is adjusted to acidic with acetic acid, resulting in the precipitation of a large amount of solid. The solid is then filtered and the filter cake is dried to afford the product (7.95 g, 72.6% yield).

[0510] Step 2: Synthesis of intermediate 5,8-dichloropyrido[2,3-d]pyridazine

[0511]

[0512] Phosphorus oxychloride (70 mL) and N,N-dimethylaniline (7 mL) were added to 6,7-dihydropyrido[2,3-d]pyridazine-5,8-dione (7.16 g, 43.89 mmol, 1.0 eq). The mixture was heated to 100°C for 1 h. TLC confirmed the reaction was complete. The reaction solution was concentrated and poured into ice water. A large amount of solid precipitated, which was filtered. The filter cake was dissolved in dichloromethane (100 mL), dried over anhydrous magnesium sulfate, and concentrated to yield the product (6.0 g, 68.3% yield).

[0513] Step 3: Synthesis of intermediate 5-chloropyrido[2,3-d]pyridazin-8-ol

[0514]

[0515] 5,8-Dichloropyrido[2,3-d]pyridazine (6 g, 30 mmol, 1.0 eq) was dissolved in 1% aqueous hydrochloric acid (75 mL) and reacted at 100°C for 1 h. The reaction was complete by TLC. The reaction solution was concentrated and purified by silica gel column chromatography to obtain a crude product. The crude product was dissolved in 1% aqueous NaOH (40 mL) and reacted at 100°C for 1 h. The mixture was cooled and filtered to obtain the product (3.6 g, 66% yield) as a filter cake.

[0516] Step 4: Synthesis of intermediate 4-(8-hydroxypyrido[2,3-d]pyridazin-5-yl)-3-methoxybenzaldehyde

[0517]

[0518] 5-Chloropyrido[2,3-d]pyridazin-8-ol (1.5 g, 8.26 mmol, 1.0 eq) was dissolved in 1,4-dioxane (20 mL), and 3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (4.33 g, 16.52 mmol, 2.0 eq), sodium bicarbonate (1.39 g, 16.52 mmol, 2.0 eq), PdCl2(dppf) (604 mg, 0.826 mmol, 0.1 eq) and water (5 mL) were added. Under nitrogen protection, the temperature was raised to 100 ° C for 2 h. The reaction was completed by TLC detection. The reaction solution was filtered through celite, water (10 mL) was added to the filtrate, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1, dichloromethane:methanol = 100:1-30:1) to obtain the product (1.03 g, yield: 44.4%).

[0519] Step 5: Synthesis of the intermediate 5-(4-alkynyl-2-methoxy)pyrido[2,3-d]pyridazine-8-phenol

[0520]

[0521] Dissolve 4-(8-hydroxypyrido[2,3-d]pyridazin-5-yl)-3-methoxybenzaldehyde (1.03 g, 3.66 mmol, 1.0 eq) in methanol (10 mL), add potassium carbonate (1.01 g, 7.32 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (1.05 g, 5.49 mmol, 1.5 eq) in sequence, and react at 25°C for 2 h. TLC shows that the reaction is almost complete. Add water (20 mL) to the reaction solution, extract with dichloromethane (20 mL × 3), combine the organic phases, dry over anhydrous magnesium sulfate, concentrate, and use the crude product directly in the next step. Step 6: Synthesis of Intermediate 8-Chloro-5-(4-alkynyl-2-methoxy)pyrido[2,3-d]pyridazine

[0522]

[0523] 5-(4-Alkynyl-2-methoxy)pyrido[2,3-d]pyridazine-8-phenol (3.66 mmol, 1.0 eq) was dissolved in acetonitrile (10 mL), and phosphorus oxychloride (1.12 g, 7.32 mmol, 2.0 eq) was added. The mixture was reacted at 100°C for 2 h. TLC confirmed the reaction was complete. The reaction solution was concentrated, poured into ice water (10 mL), and extracted with MTBE (20 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 (PE:EA = 5:1) to obtain the product (300 mg, two-step yield: 27.8%).

[0524] Step 7: Synthesis of intermediate 2-(8-chloropyrido[2,3-d]pyridazin-5-yl)-5-ethynylphenol

[0525]

[0526] 8-Chloro-5-(4-alkynyl-2-methoxy)pyrido[2,3-d]pyridazine (300 mg, 1.01 mmol, 1.0 eq) was dissolved in dichloromethane (3 mL). Boron tribromide (759 mg, 3.03 mmol, 3.0 eq) was added dropwise. The mixture was allowed to react at 25°C for 30 min. TLC indicated that the reaction was nearly complete. The reaction solution was poured into saturated aqueous sodium bicarbonate (10 mL) and extracted with MTBE (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was directly used in the next step.

[0527] Step 8: Synthesis of compound (R)-tert-butyl 3-((5-(4-ethynyl-2-hydroxyphenyl)pyrido[2,3-d]pyridazin-8-yl)amino)piperidine-1-carboxylate

[0528]

[0529] 2-(8-chloropyrido[2,3-d]pyridazin-5-yl)-5-ethynylphenol (230 mg, 0.816 mmol, 1.0 eq) was dissolved in DMAc (3 mL). (R)-1-tert-Butoxycarbonyl-3-aminopiperidine (327 mg, 1.632 mmol, 2.0 eq) was added and reacted at 100°C for 24 h. LC-MS analysis showed that the reaction was nearly complete. The reaction solution was poured into water (10 mL) and filtered. The filter cake was dissolved in dichloromethane (10 mL), dried over anhydrous magnesium sulfate, and concentrated. The crude product was directly used in the next step.

[0530] Step 9: Synthesis of intermediate (R)-5-alkynyl-2-(8-((piperidin-3-yl)amino)pyrido[2,3-d]pyridazin-5-yl)phenol

[0531]

[0532] Tert-butyl (R)-3-((5-(4-ethynyl-2-hydroxyphenyl)pyrido[2,3-d]pyridazin-8-yl)amino)piperidine-1-carboxylate (300 mg, 0.673 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL) and added dropwise to a solution of hydrogen chloride in 1,4-dioxane (2 mL, 4 mol / L). The mixture was allowed to react at 25°C for 5 min. TLC confirmed the reaction was complete. Water (10 mL) was added to the reaction solution, which was then back-extracted with dichloromethane (10 mL x 2). The aqueous phase was adjusted to a basic pH with saturated sodium bicarbonate. The mixture was concentrated, and the crude product was dissolved in a dichloromethane / methanol mixture, dried over anhydrous magnesium sulfate, filtered, and concentrated to yield the product (232 mg, three-step yield: 66.5%).

[0533] Step 10: Synthesis of compound (R)-5-alkynyl-2-(8-((1-methylpiperidin-3-yl)amino)pyrido[2,3-d]pyridazin-5-yl)phenol

[0534]

[0535] (R)-5-Alkynyl-2-(8-((piperidin-3-yl)amino)pyrido[2,3-d]pyridazin-5-yl)phenol (232 mg, 0.671 mmol, 1.0 eq) was dissolved in methanol (3 mL). 37% aqueous formaldehyde (55 mg, 0.671 mmol, 1.0 eq) and sodium cyanoborohydride (46 mg, 0.738 mmol, 1.1 eq) were added. The mixture was allowed to react at room temperature for 5 min. TLC confirmed the reaction was complete. The reaction solution was concentrated, saturated brine (5 mL) was added, and the mixture was extracted with a 7 / 1 dichloromethane / methanol mixture (20 mL x 3). The organic phases were combined, dried, and concentrated. The crude product was purified by preparative thin-layer chromatography (dichloromethane:ammonia / methanol solution (7 mol / L) = 14:1) to obtain the product (40 mg, yield: 16.6%).

[0536] 1 H-NMR(400MHz,DMSO-d6)δ(ppm):10.07(s,1H),9.12-9.11(d,1H),7.93-7.91(m,1H),7.88-7.85(m,1H),7.38(s,1H),7.36(s,1H) ,7.10(s,1H),7.09(s,1H),4.45(s,1H),4.25(s,1H),2.78-2.66(m,1H),2.40-2.34(m,3H),2.27(s,3H),1.76(s,3H),1.59(m,1H).

[0537] Molecular formula: C 21 H21 N5O exact molecular weight: 359.17 LC-MS (m / z): 360.08 [M+H] +

[0538] Example 17 Synthesis of (R)-2-(4-cyclopropyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-ethynylphenol (Compound 173):

[0539]

[0540] Step 1: Synthesis of intermediate 3,6-dichloro-4-cyclopropylpyridazine

[0541]

[0542] 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 to the reaction mixture 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. The reaction is complete by TLC. The reaction solution was adjusted to pH 8 with 1 mol / L aqueous sodium hydroxide solution, extracted with ethyl acetate (400 mL × 2), the organic phases were combined, dried, and concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50:1) to obtain a mixed product (18 g). After standing overnight, a large amount of solid precipitated, which was filtered, and the filter cake was slurried with a petroleum ether / ethyl acetate mixed solvent to obtain the product (17 g, yield: 67.1%).

[0543] Step 2: Synthesis of tert-butyl (R)-3-((6-chloro-5-cyclopropylpyridazin-3-yl)amino)piperidine-1-carboxylate

[0544]

[0545] 3,6-Dichloro-4-cyclopropylpyridazine (5.0 g, 26.45 mmol, 1.0 eq) was dissolved in DMAc (50 mL), and (R)-1-tert-butoxycarbonyl-3-aminopiperidine (26.5 g, 132.25 mmol, 5.0 eq) and N,N-diisopropylethylamine (10.26 g, 79.35 mmol, 3.0 eq) were added thereto. The mixture was reacted at 120°C for 24 h. The reaction solution was poured into water (100 mL) and extracted with MTBE (50 mL×3). The organic phases were combined, dried, and concentrated. The crude product was purified by silica gel column chromatography (PE:EA=10:1 to 4:1) to obtain the product (2.5 g, yield: 26.8%).

[0546] Step 3: Synthesis of intermediate (R)-tert-butyl 3-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-formaldehydephenyl)pyridazin-3-yl)amino)piperidine-1-carboxylate

[0547]

[0548] Tert-butyl (R)-3-((6-chloro-5-cyclopropylpyridazin-3-yl)amino)piperidine-1-carboxylate (1.0 g, 3.95 mmol, 1.0 eq) was dissolved in 1,4-dioxane (10 mL), and 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (1.45 g, 4.74 mmol, 1.2 eq), sodium bicarbonate (664 mg, 7.9 mmol, 2.0 eq), PdCl2(dppf) (289 mg, 0.395 mmol, 0.1 eq) and water (2.5 mL) were added. Under nitrogen protection, the temperature was raised to 110°C for 1 h. The reaction was completed by TLC. The reaction solution was filtered through celite, water (20 mL) was added to the filtrate, and the mixture was extracted with MTBE (20 mL × 3). The organic phases were combined, dried, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 2:1) to obtain the product (760 mg, yield: 38.8%).

[0549] Step 4: Synthesis of intermediate (R)-tert-butyl 3-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-yl)amino)piperidine-1-carboxylate

[0550]

[0551] Tert-butyl (R)-3-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-formaldehydephenyl)pyridazin-3-yl)amino)piperidine-1-carboxylate (760 mg, 1.53 mmol, 1.0 eq) was dissolved in methanol (8 mL). Potassium carbonate (423 mg, 3.06 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (422 mg, 2.3 mmol, 1.5 eq) were added sequentially. The mixture was reacted at 25°C for 5 min. TLC confirmed the reaction was complete. Water (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 to 2:1) to obtain the product (340 mg, yield: 45.2%). Step 5: Synthesis of intermediate (R)-2-(4-cyclopropyl-6-(piperidin-3-ylamino)pyridazin-3-yl)-5-ethynylphenol

[0552]

[0553] Tert-butyl (R)-3-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-yl)amino)piperidine-1-carboxylate (340 mg, 0.69 mmol, 1.0 eq) was dissolved in dichloromethane (1.5 mL) and added dropwise to a solution of hydrogen chloride in 1,4-dioxane (1.5 mL, 4 mol / L). The mixture was allowed to react at 25°C for 5 min. TLC confirmed the reaction was complete. The reaction solution was concentrated and dissolved in dichloromethane (5 mL). The resulting solution was slowly added dropwise to a saturated aqueous sodium bicarbonate solution (20 mL). The mixture was extracted with a 10:1 dichloromethane:methanol ratio (20 mL x 3). The organic phases were combined, dried, and concentrated to afford the product (90 mg, 39.1% yield).

[0554] Step 6: Synthesis of compound (R)-2-(4-cyclopropyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-ethynylphenol

[0555]

[0556] (R)-2-(4-cyclopropyl-6-(piperidin-3-ylamino)pyridazin-3-yl)-5-ethynylphenol (90 mg, 0.269 mmol, 1.0 eq) was dissolved in methanol (1 mL). 37% aqueous formaldehyde solution (22 mg, 0.269 mmol, 1.0 eq) and sodium cyanoborohydride (19 mg, 0.296 mmol, 1.1 eq) were added. The mixture was allowed to react at 25°C for 5 min. TLC confirmed the reaction was complete. The reaction solution was concentrated, saturated brine (2 mL) was added, and extraction was performed with a 10:1 dichloromethane:methanol mixture (10 mL x 3). The organic phases were combined and dried. The crude product was purified by preparative thin-layer chromatography (7:1 dichloromethane:methanol) to obtain the product (31 mg, 33.3% yield).

[0557] 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 10.09 (s, 1H), 7.24-7.20 (m, 1H), 7.01-6. 99(m,2H),6.59-6.58(d,1H),6.34(s,1H),4.18(s,1H),4.11(s,1H),3.01(m ,1H),2.76-2.68(m,1H),2.30(s,3H),1.82-1.76(m,2H),1.62-1.53(m,2H), 1.36-1.30(m,1H),1.26-1.21(m,2H),0.88-0.85(m,2H),0.63-0.59(m,2H).

[0558] Molecular formula: C 21 H 24 N4O exact molecular weight: 348.20 LC-MS (m / z): 349.11 [M+H] +

[0559] Example 18 Synthesis of (R)-2-(4,5-dicyclopropyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-ethynylphenol (Compound 221):

[0560]

[0561] Step 1: Synthesis of intermediate 3,6-dichloro-4,5-dicyclopropylpyridazine:

[0562]

[0563] 3,6-Dichloropyridazine (8.83 g, 59.24 mmol, 1.0 eq) was dissolved in water (200 mL), and cyclopropylcarboxylic acid (12.75 g, 148.1 mmol, 2.5 eq) and silver nitrate (25.16 g, 148.1 mmol, 2.5 eq) were added thereto. Concentrated sulfuric acid (24 mL, 444.3 mmol, 7.5 eq) was added dropwise to the reaction solution at 50°C. After the addition was complete, the temperature was raised to 60°C, and an aqueous solution (200 mL) of ammonium persulfate (101 g, 444.3 mmol, 7.5 eq) was added dropwise to the reaction solution. After the addition was complete, the reaction was detected by TLC to ensure completion. The reaction solution was adjusted to pH 8 with 1 mol / L aqueous sodium hydroxide solution and extracted with ethyl acetate (200 mL × 2). The organic phases were combined, dried, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1) to obtain the product (5.69 g, yield: 41.9%).

[0564] Step 2: Synthesis of the intermediate 4-(6-chloro-4,5-dicyclopropylpyridazin-3-yl)-3-(ethoxymethoxy)benzaldehyde

[0565]

[0566] 3,6-Dichloro-4,5-dicyclopropylpyridazine (2.0 g, 8.73 mmol, 1.0 eq) was dissolved in 1,4-dioxane (20 mL), and 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (2.67 g, 8.73 mmol, 1.0 eq), sodium bicarbonate (1.47 g, 17.46 mmol, 2.0 eq), PdCl2(dppf) (639 mg, 0.873 mmol, 0.1 eq) and water (5 mL) were added. Under nitrogen protection, the temperature was raised to 100 ° C for 3 h. The reaction was completed by TLC detection. The reaction solution was filtered through celite, water (20 mL) was added to the filtrate, and the mixture was extracted with MTBE (20 mL × 3). The organic phases were combined, dried, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1 to 10:1) to obtain the product (1.19 g, yield: 36.6%).

[0567] Step 3: Synthesis of tert-butyl (R)-3-((4,5-dicyclopropyl-6-(2-(ethoxymethoxy)-4-formaldehydephenyl)pyridazin-3-yl)amino)piperidine-1-carboxylate

[0568]

[0569] 4-(6-chloro-4,5-dicyclopropylpyridazin-3-yl)-3-(ethoxymethoxy)benzaldehyde (1.19 g, 3.19 mmol, 1.0 eq) was dissolved in 1,4-dioxane (12 mL), and (R)-1-tert-butyloxycarbonyl-3-aminopiperidine (639 mg, 3.19 mmol, 1.0 eq), BINAP (199 mg, 0.319 mmol, 0.1 eq), cesium carbonate (3.12 g, 9.57 mmol, 3.0 eq) and Pd2(dba)3 (292 mg, 0.319 mmol, 0.1 eq) were added. The reaction was carried out at 90 ° C under nitrogen protection for 16 h. The reaction was basically complete when detected by TLC. The reaction solution was filtered through celite, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography (PE:EA=10:1 to 1:1) to obtain the product (1.14 g, yield: 66.7%).

[0570] Step 4: Synthesis of intermediate (R)-tert-butyl 3-((4,5-dicyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-yl)amino)piperidine-1-carboxylate

[0571]

[0572] Tert-butyl (R)-3-((4,5-dicyclopropyl-6-(2-(ethoxymethoxy)-4-formaldehydephenyl)pyridazin-3-yl)amino)piperidine-1-carboxylate (1.14 g, 2.12 mmol, 1.0 eq) was dissolved in methanol (10 mL). Potassium carbonate (586 mg, 4.24 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (611 mg, 3.18 mmol, 1.5 eq) were added sequentially. The mixture was reacted at 25°C for 30 min. TLC confirmed the reaction was complete. Water (20 mL) was added to the reaction solution, and the mixture was extracted with MTBE (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 3:1) to obtain the product (340 mg, yield: 30.1%). Step 5: Synthesis of intermediate (R)-2-(4,5-dicyclopropyl-6-(piperidin-3-ylamino)pyridazin-3-yl)-5-ethynylphenol

[0573]

[0574] Tert-butyl (R)-3-((4,5-dicyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-yl)amino)piperidine-1-carboxylate (340 mg, 0.638 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL) and added dropwise to a solution of hydrogen chloride in 1,4-dioxane (2 mL, 4 mol / L). The mixture was allowed to react at 25°C for 30 min. TLC confirmed the reaction was complete. The reaction solution was concentrated and dissolved in dichloromethane (5 mL). The resulting concentrate was slowly added dropwise to a saturated sodium bicarbonate solution (10 mL). The mixture was extracted with a 10:1 dichloromethane:methanol ratio (20 mL x 3). The organic phases were combined, dried, and concentrated to afford the product (120 mg, 50.2% yield).

[0575] Step 6: Synthesis of compound (R)-2-(4,5-dicyclopropyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-ethynylphenol

[0576]

[0577] (R)-2-(4,5-dicyclopropyl-6-(piperidin-3-ylamino)pyridazin-3-yl)-5-ethynylphenol (120 mg, 0.32 mmol, 1.0 eq) was dissolved in methanol (1 mL). 37% aqueous formaldehyde solution (26 mg, 0.32 mmol, 1.0 eq) and sodium cyanoborohydride (22 mg, 0.35 mmol, 1.1 eq) were added. The mixture was reacted at 25°C for 5 min. TLC confirmed the reaction was complete. The reaction solution was concentrated, saturated brine (2 mL) was added, and extraction was performed with a 10:1 dichloromethane:methanol mixture (10 mL x 3). The organic phases were combined and dried. The crude product was purified by preparative thin-layer chromatography (8:1 dichloromethane:methanol) to obtain the product (30 mg, yield: 24.2%).

[0578] 1 H-NMR(400MHz,DMSO-d6)δ(ppm):10.14(s,1H),7.25-7.23(m,1H),6.98-6.96(m ,2H),5.82(s,1H),4.38-4.36(m,1H),4.17(s,1H),3.09-3.00(m,1H),2.75-2.68 (m,1H),2.43(s,3H),2.34-2.33(m,1H),2.01-1.94(m,1H),1.81(m,2H),1.63(m, 3H),1.26-1.24(m,1H),1.16-1.14(m,2H),0.63-0.60(m,4H),0.25-0.20(m,2H).

[0579] Molecular formula: C24 H 28 N4O exact molecular weight: 388.23 LC-MS (m / z): 389.15 [M+H] +

[0580] Example 19: Synthesis of (R)-5-ethynyl-2-(4-((1-(2-hydroxyethyl)piperidin-3-yl)amino)phthalazin-1-yl)phenol (Compound 76)

[0581]

[0582] Step 1: Synthesis of (R)-2-(3-((4-chlorophthalazin-1-yl)amino)piperidin-1-yl)ethan-1-ol

[0583]

[0584] (R)-4-Chloro-N-(piperidin-3-yl)phthalazin-1-amine (1.5 g, 5.70 mmol, 1.0 eq.), 2-bromo-1-ol (1.0 g, 8.56 mmol, 1.5 eq.), and triethylamine (1.15 g, 11.41 mmol, 2.0 eq.) were added to dichloromethane (15.0 mL) and stirred at 50°C for 12 hours. The reaction was monitored for completion by TLC. Saturated aqueous ammonium chloride (100.0 mL) was added, 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 = 50:1 to 20:1) to obtain the product (1.2 g, yield: 68.5%).

[0585] Step 2: Synthesis of (R)-3-(ethoxymethoxy)-4-(4-((1-(2-hydroxyethyl)piperidin-3-yl)amino)phthalazin-1-yl)benzaldehyde

[0586]

[0587] (R)-2-(3-((4-chlorophthalazin-1-yl)amino)piperidin-1-yl)ethan-1-ol (500.0 mg, 1.62 mmol, 1.0 eq.), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (598.7 mg, 1.94 mmol, 1.2 eq.), sodium bicarbonate (273.8 mg, 3.25 mmol, 2.0 eq.) and Pd(dppf)Cl2 (59. 6 mg, 0.08 mmol, 0.05 eq.) was added to a mixed solution of 1,4-dioxane (10.0 mL) and water (5.0 mL), the atmosphere was replaced with nitrogen for 2 minutes, and the reaction was carried out at 110°C for 3 hours. The reaction was completed by TLC monitoring. Water (50.0 mL) was added and extracted with ethyl acetate (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 80:1 to 10:1) to obtain the product (400.0 mg, yield: 54.4%). Step 3: Synthesis of (R)-2-(3-((4-(2-(ethoxymethoxy)-4-ethynylphenyl)phthalazin-1-yl)amino)piperidin-1-yl)ethan-1-ol

[0588]

[0589] (R)-3-(Ethoxymethoxy)-4-(4-((1-(2-hydroxyethyl)piperidin-3-yl)amino)phthalazin-1-yl)benzaldehyde (395.0 mg, 0.87 mmol, 1.0 eq.), dimethyl (1-diazo-2-oxopropyl)phosphonate (252.6 mg, 1.31 mmol, 1.3 eq.), and anhydrous potassium carbonate (242.1 mg, 1.75 mmol, 2.0 eq.) were added to methanol (10.0 mL) and allowed to react at room temperature for 2 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 = 50:1 to 10:1) to obtain the product (293.0 mg, 74.9% yield).

[0590] Step 4: Synthesis of (R)-5-ethynyl-2-(4-((1-(2-hydroxyethyl)piperidin-3-yl)amino)phthalazin-1-yl)phenol

[0591]

[0592] (R)-2-(3-((4-(2-(ethoxymethoxy)-4-ethynylphenyl)phthalazin-1-yl)amino)piperidin-1-yl)ethan-1-ol (293.0 mg, 0.65 mmol, 1.0 eq.) was added to dichloromethane (4.0 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 2 hours. TLC monitored the reaction for completion. The pH of the reaction was adjusted to 8-9 with saturated aqueous sodium carbonate solution. The mixture was extracted with dichloromethane (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford the product (100.0 mg, 39.3% yield).

[0593] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.00 (s, 1H), 8.40-8.38 (d, J = 8Hz, 1H), 7.8 7-7.77(m,2H),7.47-7.45(d,J=8Hz,1H),7.30-7.28(d,J=8Hz,1H),7.18(s, 1H),7.08-7.06(m,2H),4.48(s,2H),4.24(s,1H),3.58(s,2H),3.38-3.36(m ,2H),2.94(s,1H),2.67-2.61(m,1H),2.33-1.99(m,3H),1.79-1.52(m,3H).

[0594] Molecular formula: C 23 H 24 N4O2 exact molecular weight: 388.19 LC-MS (Pos, m / z) = 389.14 [M+H] + .

[0595] Example 20: Synthesis of (R)-2-(3-((4-(4-ethynyl-2-hydroxyphenyl)phthalazin-1-yl)amino)piperidin-1-yl)acetic acid hydrochloride (hydrochloride salt of compound 257)

[0596]

[0597] Step 1: Synthesis of (R)-4-chloro-N-(piperidin-3-yl)phthalazin-1-amine

[0598]

[0599] Tert-butyl (R)-3-((4-chlorophthalazin-1-yl)amino)piperidine-1-carboxylate (5.0 g, 13.78 mmol, 1.0 eq.) was added to dichloromethane (50.0 mL), and a solution of hydrogen chloride in 1,4-dioxane (4.0 mol / L) (10.0 mL) was added dropwise. The mixture was reacted at room temperature for 2 hours. The reaction was complete after monitoring by TLC. 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 to obtain the product (3.5 g, yield: 96.6%).

[0600] Step 2: Synthesis of (R)-ethyl 2-(3-((4-chlorophthalazin-1-yl)amino)piperidin-1-yl)acetate

[0601]

[0602] (R)-4-Chloro-N-(piperidin-3-yl)phthalazin-1-amine (2.0 g, 7.61 mmol, 1.0 eq.), ethyl bromoacetate (2.0 g, 12.18 mmol, 1.6 eq.), and triethylamine (1.54 g, 15.22 mmol, 2.0 eq.) were added to dichloromethane (20.0 mL) and stirred at room temperature for 12 hours. The reaction was monitored for completion by TLC. Saturated aqueous ammonium chloride (100.0 mL) was added, 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 (heptane:ethyl acetate = 5:1 to 1:1) to obtain the product (2.4 g, yield: 90.5%).

[0603] Step 3: Synthesis of (R)-ethyl 2-(3-((4-(2-(ethoxymethoxy)-4-formylphenyl)phthalazin-1-yl)amino)piperidin-1-yl)acetate

[0604]

[0605] Ethyl (R)-2-(3-((4-chlorophthalazin-1-yl)amino)piperidin-1-yl)acetate (1.2 g, 3.44 mmol, 1.0 eq.), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (1.36 g, 4.47 mmol, 1.3 eq.), sodium bicarbonate (577.9 mg, 6.88 mmol, 2.0 eq.) and Pd(dppf)Cl2 (125. 8 mg, 0.17 mmol, 0.05 eq.) was added to a mixed solution of 1,4-dioxane (12.0 mL) and water (6.0 mL), and the atmosphere was replaced with nitrogen for 2 minutes. The reaction was carried out at 110°C for 3 hours. The reaction was completed after TLC monitoring. Water (50.0 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 = 80:1 to 40:1) to obtain the product (1.1 g, yield: 65%).

[0606] Step 4: Synthesis of (R)-ethyl 2-(3-((4-(2-(ethoxymethoxy)-4-ethynylphenyl)phthalazin-1-yl)amino)piperidin-1-yl)acetate

[0607]

[0608] Ethyl (R)-2-(3-((4-(2-(ethoxymethoxy)-4-formylphenyl)phthalazin-1-yl)amino)piperidin-1-yl)acetate (1.1 g, 2.23 mmol, 1.0 eq.), dimethyl (1-diazo-2-oxopropyl)phosphonate (557.6 mg, 2.90 mmol, 1.3 eq.), and anhydrous potassium carbonate (617.2 mg, 4.46 mmol, 2.0 eq.) were added to methanol (15.0 mL) and reacted at room temperature for 2 hours. The reaction was complete as monitored by TLC. The system was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 80:1 to 50:1) to obtain the product (550.0 mg, yield: 51.9%).

[0609] Step 5: Synthesis of (R)-ethyl 2-(3-((4-(4-ethynyl-2-hydroxyphenyl)phthalazin-1-yl)amino)piperidin-1-yl)acetate

[0610]

[0611] Ethyl (R)-2-(3-((4-(2-(ethoxymethoxy)-4-ethynylphenyl)phthalazin-1-yl)amino)piperidin-1-yl)acetate (528.0 mg, 1.11 mmol, 1.0 eq.) was added to dichloromethane (5.0 mL). A solution of hydrogen chloride in 1,4-dioxane (4.0 mol / L, 5.0 mL) was added dropwise. The mixture was allowed to react at room temperature for 2 hours. TLC monitored the reaction for completion. The pH of the reaction was adjusted to 8-9 with saturated aqueous sodium carbonate solution. 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 = 80:1) to obtain the product (370.0 mg, yield: 79.9%).

[0612] Step 6: Synthesis of (R)-2-(3-((4-(4-ethynyl-2-hydroxyphenyl)phthalazin-1-yl)amino)piperidin-1-yl)acetic acid hydrochloride

[0613]

[0614] Ethyl (R)-2-(3-((4-(4-ethynyl-2-hydroxyphenyl)phthalazin-1-yl)amino)piperidin-1-yl)acetate (370.0 mg, 0.88 mmol, 1.0 eq.) was added to methanol (10.0 mL), and an aqueous solution (5.0 mL) of lithium hydroxide monohydrate (111.8 mg, 2.66 mmol, 3.0 eq.) was added dropwise. The reaction was allowed to react at room temperature for 2 hours. The reaction was complete as monitored by TLC. Hydrochloric acid (2.0 mol / L) was added dropwise to the system to adjust the pH to 2. A white solid precipitated, which was filtered and the filter cake was dried to obtain the product (365.0 mg, yield: 93.8%).

[0615] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.72 (s, 1H), 9.46 (s, 1H), 9.08 (s, 1H), 8.16-8.04 (m, 2H), 7.70-7.68 (d, J = 8Hz, 1H), 7.41-7.39 (d, J = 8Hz, 1H) ,7.27(s,1H),7.15-7.12(m,1H),4.80(s,1H),4.36(s,1H),4.24-4.14( m,2H),3.72-3.70(d,J=8Hz,1H),3.46-3.20(m,3H),2.08-1.88(m,4H).

[0616] Molecular formula: C 23 H 23 ClN4O3 free base exact molecular weight: 402.17 LC-MS (Pos, m / z) = 403.11 [M+H]+ .

[0617] Example 21: Synthesis of 5-ethynyl-2-(4-((3-hydroxybenzyl)amino)phthalazin-1-yl)phenol (Compound 268)

[0618]

[0619] Step 1: Synthesis of 3-(((4-chlorophthalazin-1-yl)amino)methyl)phenol

[0620]

[0621] 1,4-Dichlorophthalazine (1.0 g, 5.02 mmol, 1.0 eq.), 3-(aminomethyl)phenol (618.8 mg, 5.02 mmol, 1.0 eq.), and N,N-diisopropylethylamine (1.29 g, 10.04 mmol, 2.0 eq.) were added to N,N-dimethylacetamide (10.0 mL) and stirred at 120°C for 4 hours. The reaction was monitored for completion by TLC. Water (100.0 mL) was added, followed by extraction with ethyl acetate (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 80:1 to 30:1) to obtain the product (714.0 mg, 49.7% yield).

[0622] Step 2: Synthesis of 3-(ethoxymethoxy)-4-(4-((3-hydroxybenzyl)amino)phthalazin-1-yl)benzaldehyde

[0623]

[0624] 3-(((4-Chlorophthalazin-1-yl)amino)methyl)phenol (388.8 mg, 1.36 mmol, 1.0 eq.), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (500.0 mg, 1.63 mmol, 1.2 eq.), sodium bicarbonate (228.6 mg, 2.72 mmol, 2.0 eq.) and Pd(dppf)Cl2 (49.7 mg, 0.0 6mmol, 0.05eq.) was added to a mixed solution of 1,4-dioxane (10.0mL) and water (5.0mL), and the atmosphere was replaced with nitrogen for 2 minutes. The reaction was carried out at 110°C for 3 hours. The reaction was completed after monitoring by TLC. Water (50.0mL) was added and extracted with ethyl acetate (100.0mL). 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 = 80:1 to 50:1) to obtain the product (180.0mg, yield: 30.8%).

[0625] Step 3: Synthesis of 3-((4-(2-(ethoxymethoxy)-4-ethynylphenyl)phthalazin-1-yl)amino)methyl)phenol

[0626]

[0627] 3-(Ethoxymethoxy)-4-(4-((3-hydroxybenzyl)amino)phthalazin-1-yl)benzaldehyde (174.0 mg, 0.40 mmol, 1.0 eq.), dimethyl (1-diazo-2-oxopropyl)phosphonate (116.7 mg, 0.60 mmol, 1.5 eq.), and anhydrous potassium carbonate (140.0 mg, 1.01 mmol, 2.5 eq.) were added to methanol (10.0 mL) and allowed to react at room temperature for 2 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 = 80:1 to 60:1) to obtain the product (158.0 mg, 91.8% yield).

[0628] Step 4: Synthesis of 5-ethynyl-2-(4-((3-hydroxybenzyl)amino)phthalazin-1-yl)phenol

[0629]

[0630] 3-((4-(2-(ethoxymethoxy)-4-ethynylphenyl)phthalazin-1-yl)amino)methyl)phenol (158.0 mg, 0.37 mmol, 1.0 eq.) was added to dichloromethane (4.0 mL). A solution of hydrogen chloride in 1,4-dioxane (4.0 mol / L, 2.0 mL) was added dropwise. The mixture was allowed to react at room temperature for 1 hour. TLC monitored the reaction for completion. The pH of the mixture was adjusted to 8-9 with saturated aqueous sodium carbonate solution. 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 = 80:1 to 50:1) to obtain the product (100.0 mg, yield: 73.5%).

[0631] 1HNMR(400MHz,DMSO-d6)δ(ppm):9.97(s,1H),9.27(s,1H),8.41-8.39(d,J =8Hz,1H),8.13-8.10(m,1H),7.90-7.86(m,1H),7.82-7.78(m,1H),7.50-7 .48(d,J=8Hz,1H),7.30-7.28(d,J=8Hz,1H),7.13-7.05(m,3H),6.86-6.8 4(d,J=8Hz,2H),6.63-6.60(m,1H),4.78-4.77(d,J=4Hz,2H),4.23(s,1H).

[0632] Molecular formula: C 23 H 17 N3O2 exact molecular weight: 367.13 LC-MS (Pos, m / z) = 368.11 [M+H] + .

[0633] Example 22: Synthesis of (R)-2-(3-((4-(2-hydroxy-4-(propyn-1-yl)phenyl)phthalazin-1-yl)amino)piperidin-1-yl)acetic acid (Compound 265)

[0634]

[0635] Step 1: Synthesis of (R)-ethyl 2-(3-((4-(2-(ethoxymethoxy)-4-(propyn-1-yl)phenyl)phthalazin-1-yl)amino)piperidin-1-yl)acetate

[0636]

[0637] Ethyl (R)-2-(3-((4-chlorophthalazin-1-yl)amino)piperidin-1-yl)acetate (279.5 mg, 1.20 mmol, 1.0 eq), 2-(2-(ethoxymethoxy)-4-(propyn-1-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (380 mg, 0.80 mmol, 1.5 eq), PdCl2(dppf) (58.6 mg, 0.08 mmol, 0.1 eq) and sodium bicarbonate (134.6 mg, 1.60 mmol, 2.0 eq) were added to a mixed solvent of 1,4-dioxane (4 mL) and water (1 mL) and heated to 100 °C under nitrogen protection for 4 h. The reaction was complete as monitored by LC-MS, and the mixture was cooled to room temperature. Water (5 mL) was added and extracted with a mixed solvent (DCM:MeOH=10:1, 5 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by preparative thin-layer chromatography (DCM:MeOH=10:1) to give the product (310.2 mg, yield: 77.0%).

[0638] Step 2: Synthesis of (R)-ethyl 2-(3-((4-(2-hydroxy-4-(propyn-1-yl)phenyl)phthalazin-1-yl)amino)piperidin-1-yl)acetate

[0639]

[0640] Ethyl (R)-2-(3-((4-(2-(ethoxymethoxy)-4-(propyn-1-yl)phenyl)phthalazin-1-yl)amino)piperidin-1-yl)acetate (310.2 mg, 0.62 mmol, 1.0 eq) was added to DCM (2.5 mL), and a 4 mol / L solution of hydrogen chloride in 1,4-dioxane (2.5 mL) was added dropwise. The mixture was allowed to react at room temperature for 1 h. LC-MS confirmed the reaction was complete. Water (5 mL) was added, and the pH was adjusted to approximately 8 with sodium bicarbonate. The mixture was extracted with a mixed solvent (DCM:MeOH = 10:1, 5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (DCM:MeOH = 10:1) to obtain the product (240 mg, 87.5% yield).

[0641] Step 3: Synthesis of (R)-2-(3-((4-(2-hydroxy-4-(propyn-1-yl)phenyl)phthalazin-1-yl)amino)piperidin-1-yl)acetic acid

[0642]

[0643] Ethyl (R)-2-(3-((4-(2-hydroxy-4-(propyn-1-yl)phenyl)phthalazin-1-yl)amino)piperidin-1-yl)acetate (240 mg, 0.54 mmol, 1.0 eq) was added to MeOH (4 mL), followed by water (2 mL) and LiOH·H₂O (68.0 mg, 1.62 mmol, 3.0 eq). The mixture was allowed to react at room temperature for 2 h. LC-MS monitored the reaction completion. The product was concentrated under reduced pressure, and the crude product was added with water (5 mL). The pH was adjusted to approximately 2 with 2N HCl to precipitate a solid. DMAc (3 mL) was added for dissolution, and the product was purified by reverse-phase column chromatography (C18 column, MeCN:H₂O = 0-4:1, 30 min) to obtain the product (129.6 mg, 57.6% yield).

[0644] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 8.43 (d, J = 8.4Hz, 1H), 7.90-7.80 (m, 2H), 7.5 1-7.49(m,2H),7.25(d,J=7.6Hz,1H),7.03(m,1H),6.98-6.96(m,1H),4.61(s ,1H),3.52(s,2H),3.43(d,J=8.0Hz,1H),3.13-3.10(m,1H),2.73-2.68(m,2H ),2.08-2.02(m,5H),1.88-1.85(m,1H),1.78-1.75(m,1H),1.64-1.61(m,1H).

[0645] Molecular formula: C 24 H 24 N4O3 exact molecular weight: 416.18 LC-MS (Pos, m / z) = 417.11 [M+H] + .

[0646] Example 23: Synthesis of (R)-2-(4-((1-(2-(methylsulfonyl)ethyl)piperidin-3-yl)amino)phthalazin-1-yl)-5-(propyn-1-yl)phenol (Compound 266)

[0647]

[0648] Step 1: Synthesis of (R)-4-chloro-N-(piperidin-3-yl)phthalazin-1-amine:

[0649]

[0650] Dissolve (R)-tert-Butyl 3-((4-chlorophthalazin-1-yl)amino)piperidine-1-carboxylate (4.965 g, 13.68 mmol, 1.0 eq) in DCM (25 mL). Add 4 mol / L hydrogen chloride in 1,4-dioxane (15.0 mL) dropwise and allow to react at room temperature for 2 h. LC-MS monitoring confirmed the reaction was complete. Water (25 mL) was added, and the pH was adjusted to approximately 8 with sodium bicarbonate. The mixture was extracted with a mixed solvent (DCM:MeOH = 10:1, 25 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to obtain the product (3.376 g, 93.9% yield).

[0651] Step 2: Synthesis of (R)-4-(2-(ethoxymethoxy)-4-(propyn-1-yl)phenyl)-N-(piperidin-3-yl)phthalazin-1-amine

[0652]

[0653] (R)-4-chloro-N-(piperidin-3-yl)phthalazin-1-amine (210.5 mg, 1.20 mmol, 1.0 eq), 2-(2-(ethoxymethoxy)-4-(propyn-1-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (380 mg, 0.80 mmol, 1.5 eq), PdCl2(dppf) (58.6 mg, 0.08 mmol, 0.1 eq) and sodium bicarbonate (134.6 mg, 1.60 mmol, 2.0 eq) were added to a mixed solvent of 1,4-dioxane (4 mL) and water (1 mL) and heated to 100 ° C under nitrogen protection for 4 h. The reaction was complete after LC-MS monitoring. The mixture was cooled to room temperature, and water (5 mL) was added. The mixture was extracted with a mixed solvent (DCM:MeOH = 10:1, 5 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by preparative thin-layer chromatography (DCM:MeOH = 10:1) to obtain the product (245.8 mg, yield: 73.6%).

[0654] Step 3: Synthesis of (R)-4-(2-(ethoxymethoxy)-4-(propyn-1-yl)phenyl)-N-(1-(2-(methylsulfonyl)ethyl)piperidin-3-yl)phthalazin-1-amine

[0655]

[0656] (R)-4-(2-(ethoxymethoxy)-4-(propyn-1-yl)phenyl)-N-(piperidin-3-yl)phthalazin-1-amine (245.8 mg, 0.59 mmol, 1.0 eq) was dissolved in DCM (3 mL), and (methylsulfonyl)ethylene (162.2 mg, 1.53 mmol, 2.6 eq) was added dropwise. The mixture was allowed to react at room temperature for 48 h. LC-MS monitored the reaction completion, and the mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography (DCM:MeOH = 10:1) to give the product (154.4 mg, 50.0% yield).

[0657] Step 4: Synthesis of (R)-2-(4-((1-(2-(methylsulfonyl)ethyl)piperidin-3-yl)amino)phthalazin-1-yl)-5-(propyn-1-yl)phenol

[0658]

[0659] (R)-4-(2-(ethoxymethoxy)-4-(propyn-1-yl)phenyl)-N-(1-(2-(methylsulfonyl)ethyl)piperidin-3-yl)phthalazin-1-amine (2.8 g, 9.48 mmol, 1.0 eq) was dissolved in DCM (1.5 mL). A 4 mol / L solution of hydrogen chloride in 1,4-dioxane (1.5 mL) was added dropwise and allowed to react at room temperature for 2 h. LC-MS monitored the reaction completion. Water (1.5 mL) was added and the pH was adjusted to approximately 8 with sodium bicarbonate. The product was extracted with a mixed solvent (DCM:MeOH = 10:1, 1.5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by preparative thin-layer chromatography (DCM:MeOH = 10:1) afforded the product (57.6 mg, 42.0% yield).

[0660] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 9.90 (s, 1H), 8.38 (d, J = 8.4Hz, 1H), 7.87-7.77 (m, 2 H),7.48(d,J=8Hz,1H),7.25(d,J=7.6Hz,1H),7.14-7.12(m,1H),6.99-6.96(m,2H) ,4.43-4.42(m,1H),3.35-3.33(m,2H),3.18-3.16(m,1H),3.07(s,3H),2.86-2.77( m,3H),2.12-2.08(m,5H),2.00-1.98(m,1H),1.80-1.77(m,1H),1.61-1.52(m,2H).

[0661] Molecular formula: C 25 H 28N4O3S exact molecular weight: 464.19 LC-MS (Pos, m / z) = 465.09 [M+H] + .

[0662] Example 24: Synthesis of (R)-2-(5-methyl-3-(1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)-5-(prop-1-yn-1yl)phenol (Compound 195)

[0663]

[0664] Step 1: Synthesis of (R)-6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methyl-N-(1-methylpiperidin-3-yl)-1,2,4-triazin-3-amine

[0665]

[0666] (R)-6-Bromo-5-methyl-N-(1-methylpiperidin-3-yl)-1,2,4-triazine-3-amine (200 mg, 0.7 mmol, 1.0 eq), 2-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (332 mg, 1.05 mmol, 1.5 eq), PdCl2(dppf) (51.2 mg, 0.07 mmol, 0.1 eq) and sodium bicarbonate (176.4 mg, 2.1 mmol, 3.0 eq) were added to a mixed solvent of 1,4-dioxane (5 mL) and water (1 mL), and the mixture was heated to 100 ° C under nitrogen protection for 3 h. LC-MS monitoring showed no starting material, and the mixture was cooled to room temperature. Water (30 mL) was added and extracted with DCM (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (MeOH:DCM=1:10) to give the product (217 mg, yield: 78.4%).

[0667] Step 2: Synthesis of (R)-2-(5-methyl-3-(1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)-5-(prop-1-yn-1yl)phenol

[0668]

[0669] (R)-6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methyl-N-(1-methylpiperidin-3-yl)-1,2,4-triazin-3-amine (217 mg, 0.55 mmol, 1.0 eq) was added to DCM (10 mL), and a 4 mol / L solution of hydrogen chloride in 1,4-dioxane (4 mL) was added dropwise. The reaction was allowed to react at room temperature for 1 h. TLC confirmed the absence of starting material. Water (30 mL) was added, and the pH was adjusted to approximately 8 with sodium carbonate. The mixture was extracted with DCM (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was slurried with tert-butyl methyl ether (4 mL), filtered, and the filter cake was dried to obtain the product (130 mg, 70% yield).

[0670] 1 HNMR(400MHz,DMSO-d6)δ(ppm):9.97(s,1.0H),7.44-7.42(d,1H),7.22-7.20(s,1H),6.94-6.93(d,2H),3.99(m,1H),2.89-2. 88(m,1H),2.65-2.62(m,1H),2.18(s,6H),2.06(s,3H),1.86(m,3H),1.72-1.68(m,1H),1.55-1.52(m,1H),1.33-1.29(m,1H).

[0671] Molecular formula: C 19 H 23 N5O exact molecular weight: 337.19 LC-MS (Pos, m / z) = 338.33 [M+H] + .

[0672] Example 25: Synthesis of (R)-5-(cyclopropylethynyl)-2-(5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)phenol (Compound 197)

[0673]

[0674] step:

[0675]

[0676] Step 1: Synthesis of 2-bromo-5-iodophenol

[0677]

[0678] Dissolve 2-bromo-5-iodoanisole (3.8 g, 12.14 mmol, 1.0 eq) in DCM (40 mL), cool to -10°C, and add boron tribromide (6.1 g, 24.28 mmol, 2.0 eq) dropwise. After completion of the addition, warm the mixture to room temperature and react for 17 hours. TLC analysis indicated the absence of starting material. Methanol (10 mL) was added dropwise, stirred for 10 minutes, and water (30 mL) was added. The mixture was extracted with DCM (30 mL x 2). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to obtain the product (3.6 g, 100% yield).

[0679] Step 2: Synthesis of 1-bromo-2-(ethoxymethoxy)-4-iodobenzene

[0680]

[0681] 2-Bromo-5-iodophenol (3.6 g, 12.14 mmol, 1.0 eq) was dissolved in anhydrous THF (40 mL). 60% sodium hydride (728.4 mg, 18.21 mmol, 1.5 eq) was slowly added and allowed to react at room temperature for 0.5 h. Chloromethyl ethyl ether (1.7 g, 18.21 mmol, 1.5 eq) was then added dropwise and allowed to react at room temperature for 1 h. LC-MS analysis indicated the absence of starting material. Saturated ammonium chloride solution (40 mL) was added and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE = 1:10) to afford the product (4.3 g, 100% yield).

[0682] Step 3: Synthesis of 1-bromo-4-(cyclopropylethynyl)-2-(ethoxymethoxy)benzene

[0683]

[0684] 1-Bromo-2-(ethoxymethoxy)-4-iodobenzene (3.6 g, 10.08 mmol, 1.0 eq), bis(triphenylphosphine)palladium dichloride (701.9 mg, 1 mmol, 0.1 eq), cuprous iodide (380.9 mg, 2 mmol, 0.2 eq), and DIPEA (1.9 g, 15.12 mmol, 1.5 eq) were dissolved in anhydrous THF (40 mL) and stirred under nitrogen for 10 min. Cyclopropylacetylene (733 mg, 11.09 mmol, 1.1 eq) was added and allowed to react at room temperature for 16 h. TLC confirmed the absence of starting material. Water (100 mL) was added and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE = 1:200 to 1:100) to afford the product (2.8 g, 93.3% yield).

[0685] Step 4: Synthesis of 2-(4-(cyclopropylethynyl)-2-(ethoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0686]

[0687] Dissolve 1-bromo-4-(cyclopropylethynyl)-2-(ethoxymethoxy)benzene (2.8 g, 9.48 mmol, 1.0 eq) in anhydrous THF (30 mL), cool to -75 ° C, add 1.6 mol / L n-butyllithium THF solution (7.7 mL, 12.32 mmol, 1.3 eq) dropwise, and keep at -70 ° C for 1 h. Add 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.6 g, 14.22 mmol, 1.5 eq) dropwise, and keep at -70 ° C for 1 h. Then naturally warm to room temperature and react for 15 h. TLC detection showed that there was no starting material. Saturated aqueous ammonium chloride solution (30 mL) was added and stirred for 5 min. The mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE=1:100~EA=100%) to obtain the product (2.3 g, yield: 71.9%).

[0688] Step 5: Synthesis of (R)-6-(4-(cyclopropylethynyl)-2-(ethoxymethoxy)phenyl)-5-methyl-N-(1-methylpiperidin-3-yl)-1,2,4-triazin-3-amine

[0689]

[0690] (R)-6-Bromo-5-methyl-N-(1-methylpiperidin-3-yl)-1,2,4-triazine-3-amine (286.2 mg, 1 mmol, 1.0 eq), 2-(4-(cyclopropylethynyl)-2-(ethoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (684.5 mg, 2 mmol, 2.0 eq), sodium bicarbonate (252 mg, 3 mmol, 3.0 eq) and PdCl2(dppf) (73.2 mg, 0.1 mmol, 0.1 eq) were added to a mixed solution of 1,4-dioxane (10 mL) and water (2 mL), and the mixture was heated to 100 ° C under nitrogen protection for 3 h. LC-MS monitoring showed no starting material, and the mixture was cooled to room temperature. Water (50 mL) was added and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (MeOH:DCM = 1:100 to 1:20) to give the product (412 mg, yield: 97.7%).

[0691] Step 6: Synthesis of (R)-5-(cyclopropylethynyl)-2-(5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)phenol

[0692]

[0693] (R)-6-(4-(cyclopropylethynyl)-2-(ethoxymethoxy)phenyl)-5-methyl-N-(1-methylpiperidin-3-yl)-1,2,4-triazin-3-amine (410 mg, 0.97 mmol, 1.0 eq) was added to DCM (5 mL), cooled to approximately 0°C with ice water, and a solution of TFA (0.5 mL) in DCM (5 mL) was added dropwise. The mixture was allowed to react at room temperature for 8 h. LC-MS analysis indicated approximately 5% of the starting material remained. Saturated aqueous sodium bicarbonate (30 mL) was added, and the mixture was extracted with DCM (30 mL x 5). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (MeOH:DCM = 1:10) to afford the product (125 mg, 35.4% yield).

[0694] 1 HNMR(400MHz,DMSO-d6)δ(ppm):9.98(s,1H),7.40(d,1H),7.20-7.18(d,1H),6.92-6.90(d,2H),3.98(m,1H),2.88(m,1H),2.65-2.63(m, 1H),2.18-2.17(s,6H),1.86-1.84(m,3H),1.71-1.68(m,1H),1.58-1 .52(m,2H),1.34-1.28(m,1H),0.91-0.88(m,2H),0.75-0.74(m,2H).

[0695] Molecular formula: C 21 H 25 N5O exact molecular weight: 363.21 LC-MS (Pos, m / z) = 364.30 [M+H] + .

[0696] Example 26: Synthesis of (R)-5-(cyclopropylethynyl)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol (Compound 254)

[0697]

[0698] Step 1: Synthesis of (R)-6-(4-(cyclopropylethynyl)-2-(ethoxymethoxy)phenyl)-5-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine

[0699]

[0700] (R)-6-Chloro-5-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine (142.6 mg, 0.59 mmol, 1.0 eq), 2-(4-(cyclopropylethynyl)-2-(ethoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (403.8 mg, 1.18 mmol, 2.0 eq), sodium bicarbonate (147.8 mg, 1.77 mmol, 3.0 eq) and PdCl2(dppf) (43.9 mg, 0.06 mmol, 0.1 eq) were added to a mixed solution of 1,4-dioxane (10 mL) and water (2 mL), and the mixture was heated to 100 ° C under nitrogen protection for 3 h. LC-MS monitoring showed no starting material, and the mixture was cooled to room temperature. Water (30 mL) was added and extracted with DCM (30 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (MeOH:DCM = 1:100 to 1:20) to obtain the product (183 mg, yield: 73.7%).

[0701] Step 2: Synthesis of (R)-5-(cyclopropylethynyl)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol

[0702]

[0703] (R)-6-(4-(cyclopropylethynyl)-2-(ethoxymethoxy)phenyl)-5-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine (183 mg, 0.43 mmol, 1.0 eq) was added to DCM (5 mL), cooled with ice water, and a solution of TFA (0.5 mL) in DCM (5 mL) was added dropwise. The reaction was allowed to react at room temperature for 8 h. LC-MS analysis indicated that approximately 5% of the starting material remained. Saturated aqueous sodium bicarbonate (30 mL) was added, stirred for 5 min, and extracted with DCM (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (MeOH:DCM = 1:10) to afford the product (78 mg, 50% yield).

[0704] 1HNMR(400MHz,DMSO-d6)δ(ppm):10.01(s,1H),7.12-7.10(d,1H),6.88-6.86 (d,2H),6.67(s,1H),6.62-6.60(d,1H),4.04-4.00(m,1H),2.87-2.85(m,1H) ,2.51(m,1H),2.18(s,3H),2.00(m,4H),1.89-1.82(m,2H),1.72-1.69(m,1H) ,1.57-1.52(m,2H),1.29-1.27(m,1H),0.91-0.88(m,2H),0.75-0.73(m,2H).

[0705] Molecular formula: C 22 H 26 N4O exact molecular weight: 362.21 LC-MS (Pos, m / z) = 363.07 [M+H] + .

[0706] Example 27: Synthesis of (R)-2-(4-((1-(2-hydroxyethyl)piperidin-3-yl)amino)phthalazin-1-yl)-5-(prop-1-yn-1-yl)phenol (Compound 270)

[0707]

[0708] Step 1: Synthesis of (R)-2-(3-((4-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)phthalazin-1-yl)amino)piperidin-1-yl)ethan-1-ol

[0709]

[0710] (R)-2-(3-((4-chlorophthalazin-1-yl)amino)piperidin-1-yl)ethan-1-ol (200 mg, 0.65 mmol, 1.0 eq), 2-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (306.7 mg, 0.97 mmol, 1.5 eq), sodium bicarbonate (163.8 mg, 1.95 mmol, 3.0 eq) and PdCl2(dppf) (43.9 mg, 0.06 mmol, 0.1 eq) were added to a mixed solution of 1,4-dioxane (10 mL) and water (2 mL), and the mixture was heated to 100 ° C under nitrogen protection for 18 h. LC-MS monitoring showed no starting material. The mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with DCM (30 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (MeOH:DCM = 1:100 to 1:10) to obtain the product (166 mg, yield: 55.4%).

[0711] Step 2: Synthesis of (R)-2-(4-((1-(2-hydroxyethyl)piperidin-3-yl)amino)phthalazin-1-yl)-5-(prop-1-yn-1-yl)phenol

[0712]

[0713] (R)-2-(3-((4-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)phthalazin-1-yl)amino)piperidin-1-yl)ethan-1-ol (166 mg, 0.36 mmol, 1.0 eq) was added to DCM (5 mL), and a 4 mol / L solution of hydrogen chloride in 1,4-dioxane (3 mL) was added dropwise. The mixture was allowed to react at room temperature for 1 h. LC-MS analysis indicated the absence of starting material. Water (30 mL) was added, and the pH was adjusted to approximately 7 with sodium bicarbonate. The mixture was extracted with DCM (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (MeOH:DCM = 1:10) to afford the product (72 mg, 49.7% yield).

[0714] 1HNMR(400MHz,DMSO-d6)δ(ppm):9.88(s,1H),8.38-8.36(d,1H),7.86-7.76(d ,2H),7.48-7.46(d,1H),7.26-7.24(d,1H),7.09-7.07(d,1H),6.98-6.96(d,1 H),4.44(m,2H),3.53-3.52(m,2H),3.16-3.14(m,1H),2.83-2.81(m,1H),2.47 -2.44(m,2H),2.08(m,5H),1.97(m,1H),1.76-1.73(m,1H),1.61-1.49(m,2H).

[0715] Molecular formula: C 24 H 26 N4O2 exact molecular weight: 402.21 LC-MS (Pos, m / z) = 403.35 [M+H] + .

[0716] Example 28: Synthesis of (R)-5-bromoethynyl-2-(4-methyl-6-(1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol (Compound 259)

[0717]

[0718] step:

[0719]

[0720] Step 1: Synthesis of (R)-3-(ethoxymethoxy)-4-(4-methyl-6-(1-methylpiperidin-3-yl)amino)pyridazin-3-yl)benzaldehyde

[0721]

[0722] (R)-6-Chloro-5-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine (650 mg, 2.70 mmol, 1.0 eq) was dissolved in 1,4-dioxane (7 mL) and water (3 mL). 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (1.16 g, 3.78 mmol, 1.4 eq), sodium bicarbonate (454 mg, 5.40 mmol, 2.0 eq), and Pd(dppf)Cl2 (198 mg, 0.27 mmol, 0.1 eq) were added sequentially. The mixture was stirred at 90°C for 2 h under nitrogen. The reaction was complete by LC-MS. The reaction solution was concentrated, water (5 mL) was added, and the mixture was extracted with dichloromethane (5 mL×3). The organic phase was dried and filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=20:1-10:1) to obtain the product (520 mg, yield: 50.0%).

[0723] Step 2: Synthesis of (R)-6-(4-(2,2-dibromovinyl)-2-(ethoxymethoxy)phenyl)-5-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine

[0724]

[0725] The (R)-3-(ethoxymethoxy)-4-(4-methyl-6-(1-methylpiperidin-3-yl)amino)pyridazin-3-yl)benzaldehyde (400 mg, 1.04 mmol, 1.0 eq) obtained in the previous step was dissolved in dichloromethane (5 mL), and carbon tetrabromide (2.07 g, 6.24 mmol, 6.0 eq) was added. A dichloromethane solution (12 mL) of triphenylphosphine (3.27 g, 12.5 mmol, 12.0 eq) was added dropwise under an ice-water bath. After the addition was complete, the mixture was stirred for 30 min, the ice-water bath was removed, and stirring was continued for 1 h. The reaction was determined to be complete by TLC. The reaction solution was diluted with dichloromethane, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 40:1 to 20:1) to obtain a crude product (900 mg).

[0726] Step 3: Synthesis of (R)-5-(2,2-dibromovinyl)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol

[0727]

[0728] Crude (R)-6-(4-(2,2-dibromovinyl)-2-(ethoxymethoxy)phenyl)-5-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine (700 mg) was dissolved in dichloromethane (7 mL). A 4 mol / L solution of hydrogen chloride in 1,4-dioxane (1 mL) was added and stirred at room temperature for 1 hour. LC-MS confirmed the reaction was complete. The reaction mixture was poured into water, and the pH was adjusted to approximately 8 with sodium bicarbonate. The layers were separated and extracted with dichloromethane (5 mL x 2). The mixture was dried, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 40:1 to 20:1) to obtain the product (390 mg, two-step yield: 99.9%).

[0729] Step 4: Synthesis of (R)-5-bromoethynyl-2-(4-methyl-6-(1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol

[0730]

[0731] (R)-5-(2,2-dibromovinyl)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol (200 mg, 0.41 mmol, 1.0 eq) obtained in the previous step was dissolved in tetrahydrofuran (3 mL). TBAF trihydrate (786 mg, 2.49 mmol, 6.0 eq) was added and stirred at 60°C for 4 h. The reaction was complete by TLC. The reaction solution was concentrated, and the crude product was purified by preparative thin-layer chromatography (dichloromethane:7% ammonia in methanol = 20:1) to obtain the product (100 mg, 60.8% yield).

[0732] 1 H-NMR(400MHz,DMSO-d6)δ(ppm):10.20(s,1H),7.17-7.15(m,1H),7.01(s,2H),6.83(s,1H),6.70(s,1H),4.15 (s,1H),3.18(s,2H),2.87(s,1H),2.44-2.24(m,4H),2.02(s,3H),1.87-1.81(m,2H),1.67(s,1H),1.40(s,1H).

[0733] Molecular formula: C 19 H 21 BrN4O exact molecular weight: 400.09 LC-MS (m / z): 401.07, 403.06 [M+H] +

[0734] Example 29: Synthesis of (R)-5-bromoethynyl-2-(4-cyclopropyl-6-(1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol (Compound 260)

[0735]

[0736] step:

[0737]

[0738] Step 1: Synthesis of (R)-5-cyclopropyl-(6-(4-(2,2-dibromovinyl)-2-(ethoxymethoxy)phenyl)-N-(1-methylpiperidin-3-yl)pyridazin-3-amine

[0739]

[0740] The (R)-4-(4-cyclopropyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-(ethoxymethoxy)benzaldehyde (300 mg, 0.73 mmol, 1.0 eq) obtained in the previous step was dissolved in dichloromethane (4 mL), and carbon tetrabromide (1.45 g, 4.38 mmol, 6.0 eq) was added. A dichloromethane solution (9 mL) of triphenylphosphine (2.30 g, 8.77 mmol, 12.0 eq) was added dropwise under an ice-water bath. After the addition was complete, the mixture was stirred for 30 min, the ice-water bath was removed, and stirring was continued for 30 min. The reaction was determined to be complete by LC-MS. The reaction solution was diluted with dichloromethane, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 50:1-10:1) to obtain a crude product containing the product (560 mg).

[0741] Step 2: Synthesis of (R)-2-(4-cyclopropyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(2,2-dibromovinyl)phenol

[0742]

[0743] The crude product (560 mg) of (R)-5-cyclopropyl-(6-(4-(2,2-dibromovinyl)-2-(ethoxymethoxy)phenyl)-N-(1-methylpiperidin-3-yl)pyridazin-3-amine was dissolved in dichloromethane (5 mL). A 4 mol / L solution of hydrogen chloride in 1,4-dioxane (0.5 mL) was added and stirred at room temperature for 1 h. The reaction was complete as determined by LC-MS. The reaction solution was poured into water and the pH was adjusted to approximately 8 with sodium bicarbonate. The layers were separated and extracted with dichloromethane (5 mL x 2). The organic phase was dried, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1-10:1) to obtain the product (300 mg, two-step yield: 80.8%).

[0744] Step 3: Synthesis of (R)-5-bromoethynyl-2-(4-cyclopropyl-6-(1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol

[0745]

[0746] (R)-2-(4-cyclopropyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(2,2-dibromovinyl)phenol (300 mg, 0.59 mmol, 1.0 eq) obtained in the previous step was dissolved in tetrahydrofuran (3 mL). TBAF trihydrate (931 mg, 2.95 mmol, 6.0 eq) was added and stirred at 70°C overnight. LC-MS confirmed the reaction was complete. The reaction solution was concentrated, and the crude product was purified by preparative thin-layer chromatography (dichloromethane:7% ammonia in methanol = 20:1) to obtain the product (90 mg, 35.7% yield).

[0747] 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 10.14 (s, 1H), 7.22 (d, J = 7.68Hz, 1H), 7.02-6.99 (m, 2H), 6.55 (d, J = 7.48Hz, 1H), 6.33 (s, 1H), 4.07 (s, 1H), 2.90 (s ,1H),2.61(s,1H),2.25(s,3H),2.16-2.01(m,2H),1.80-1.72(m,2H),1.5 8-1.51(m,2H),1.34-1.25(m,1H),0.88-0.85(m,2H),0.61-0.60(m,2H),.

[0748] Molecular formula: C 21 H 23 BrN4O exact molecular weight: 426.11 LC-MS (m / z): 427.10, 429.08 [M+H] +

[0749] Example 30: Synthesis of (R)-5-(3-hydroxyprop-1-yn-1-yl)-2-(4-methyl-6-((1-methylpiperidin-3-yl)aminopyridazin-3-yl)phenol (Compound 262)

[0750]

[0751] Step 1: Synthesis of 3-(4-bromo-3-(ethoxymethoxy)phenyl)prop-2-yn-1-yl acetate

[0752]

[0753] Disperse 1-bromo-2-(ethoxymethoxy)-4-iodobenzene (5.0 g, 14.00 mmol, 1.0 eq.), PdCl2(PPh3)2 (983 mg, 1.40 mmol, 0.1 eq.), CuI (267 mg, 1.40 mmol, 0.1 eq.), and DIPEA (5.43 g, 42.00 mmol, 3.0 eq.) in THF (50 mL). Under nitrogen, cool to 0-5°C and react for 20 min. Add propargyl acetate (1.65 mg, 16.8 mmol, 1.2 eq.) and react for 40 min. Completion is monitored by TLC. The reaction mixture is poured into water (100 mL) and extracted with EA (50 mL x 2). The organic phase is dried and concentrated to obtain the crude product (4.58 g, 100% yield).

[0754] Step 2: Synthesis of 3-(4-bromo-3-(ethoxymethoxy)phenyl)prop-2-yn-1-ol

[0755]

[0756] 3-(4-Bromo-3-(ethoxymethoxy)phenyl)prop-2-yn-1-yl acetate (4.58 g, 14.00 mmol, 1.0 eq.) and lithium hydroxide monohydrate (1.76 g, 42.00 mmol, 3.0 eq.) were dissolved in methanol (50 mL) and water (10 mL), and the reaction was carried out at 50° C. for 5 min. The reaction was completed after monitoring by TLC. The reaction solution was concentrated under reduced pressure, and the crude product was dispersed with water (30 mL). The product was extracted with EA (30 mL×2), the organic phase was dried, concentrated, and purified by silica gel column chromatography (EA:PE=1:4) to obtain the product (2.3 g, yield: 56.7%).

[0757] Step 3: Synthesis of 1-bromo-2-(ethoxymethoxy)-4-(3-(ethoxymethoxy)prop-1-yn-1-yl)benzene

[0758]

[0759] 3-(4-Bromo-3-(ethoxymethoxy)phenyl)prop-2-yn-1-ol (2.3 g, 8.07 mmol, 1.0 eq.) was dissolved in THF (25 mL) and 60% NaH (484 mg, 12.10 mmol, 1.5 eq.) was added. The mixture was allowed to react at room temperature for 0.5 h. Chloromethyl ethyl ether (1.14 g, 12.10 mmol, 1.5 eq.) was then added and allowed to react at room temperature for 1 h. TLC monitored the reaction until complete. The reaction solution was poured into water (50 mL) and extracted with EA (20 mL x 2). The organic phase was dried, concentrated, and purified by silica gel column chromatography (EA:PE = 70:1) to obtain the product (2.0 g, yield: 72.5%).

[0760] Step 4: Synthesis of 2-(2-(ethoxymethoxy)-4-(3-(ethoxymethoxy)prop-1-yn-1-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0761]

[0762] 1-Bromo-2-(ethoxymethoxy)-4-(3-(ethoxymethoxy)prop-1-yn-1-yl)benzene (2.0 g, 5.83 mmol, 1.0 eq.) was dissolved in THF (20 mL). Under nitrogen, the temperature was cooled to -65°C, and n-butyllithium (1.6 mol / L, 5.5 mL) was added dropwise. The mixture was stirred for 1 hour. Isopropyl pinacol borate (1.63 g, 8.74 mmol, 1.5 eq.) was added, and the reaction was continued at -65°C for 1.5 hours. The reaction was complete after TLC monitoring. The reaction solution was poured into water (20 mL) and extracted with EA (20 mL x 2). The organic phase was dried, concentrated, and purified by silica gel column chromatography (EA:PE = 10:1) to obtain the product (1.45 g, yield: 63.9%).

[0763] Step 5: Synthesis of (R)-6-(2-(ethoxymethoxy)-4-(3-(ethoxymethoxy)prop-1-yn-1-yl)phenyl)-5-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine

[0764]

[0765] (R)-6-Chloro-5-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine (130 mg, 0.54 mmol, 1.0 eq.), (R)-6-(2-(ethoxymethoxy)-4-(3-(ethoxymethoxy)prop-1-yn-1-yl)phenyl)-5-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine (316 mg, 0.81 mmol, 1.5 eq), Pd(dppf)Cl2 (40 mg, 0.054 mmol, 0.1 eq) and NaHCO3 (91 mg, 1.08 mmol, 2.0 eq) were added to 1,4-dioxane (5 mL) and H2O (1 mL), heated to 110°C under nitrogen protection, and reacted for 20 hours. The reaction solution was poured into water (10 mL), extracted with EA (20 mL×3), and the organic phase was dried and concentrated to obtain a crude product (253 mg, yield: 100%).

[0766] Step 6: Synthesis of (R)-5-(3-hydroxyprop-1-yn-1-yl)-2-(4-methyl-6-((1-methylpiperidin-3-yl)aminopyridazin-3-yl)phenol

[0767]

[0768] (R)-6-(2-(ethoxymethoxy)-4-(3-(ethoxymethoxy)prop-1-yn-1-yl)phenyl)-5-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine (253 mg, 0.54 mmol, 1.0 eq.) was dissolved in DCM (2 mL). A solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 5 mL) was added and allowed to react at room temperature for 10 min. The reaction solution was poured into water (10 mL) and extracted with DCM (10 mL x 2). The aqueous phase was retained and the pH was adjusted to approximately 9 with NaHCO₃. The resulting mixture was then extracted with DCM (15 mL x 4). The organic phase was dried and concentrated. The crude product was purified by preparative thin-layer chromatography (MeOH:DCM = 1:10) to afford the product (30 mg, yield: 15.8%).

[0769] 1 HNMR (400MHz, DMSO-d6, D2O exchange) δ (ppm): 7.15-7.13 (d, 1H), 6.97-6.95 (t, 2H), 6.73 (s, 1H), 4.29 (s, 2H), 4.26-4.20 (t, 1H), 3.65(s,1H),3.42-3.35(m,1H),2.87(s,1H),2.78(s,3H),2.68(s,1H),2.02(s,4H),1.79-1.77(d,2H),1.47-1.44(d,1H).

[0770] Molecular formula: C 20 H 24 N4O2 exact molecular weight: 352.19 LC-MS (Pos, m / z) = 353.18 [M+H] + .

[0771] Example 31: Synthesis of (R)-5-ethynyl-2-(4-methyl-6-(1-(2-(methylsulfonyl)ethyl)piperidin-3-amino)pyridazin-3-yl)phenol (Compound 263)

[0772]

[0773] step:

[0774]

[0775] Step 1: Synthesis of intermediate (R)-3-(ethoxymethoxy)-4-(4-methyl-6-(piperidin-3-ylamino)pyridazin-3-yl)benzaldehyde

[0776]

[0777] (R)-6-Chloro-5-methyl-N-(piperidin-3-yl)pyridazin-3-amine (200 mg, 0.88 mmol, 1.0 eq) was dissolved in 1,4-dioxane (2 mL), and 3-(ethoxymethoxy)-4-(4,4,5,5-trimethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (404 mg, 1.32 mmol, 1.5 eq), sodium bicarbonate (148 mg, 1.76 mmol, 2.0 eq), PdCl2(dppf) (64 mg, 0.088 mmol, 0.1 eq) and water (0.5 mL) were added. Under nitrogen protection, the temperature was raised to 100°C for 2 h. The reaction was completed by TLC. The reaction solution was filtered through celite, the filtrate was dried and concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol=100:1-7:1) to obtain the product (250 mg, yield: 76.7%).

[0778] Step 2: Synthesis of intermediate (R)-3-(ethoxymethoxy)-4-(4-methyl-6-(1-(2-(methylsulfonyl)ethyl)piperidin-3-amino)pyridazin-3-yl)benzaldehyde

[0779]

[0780] (R)-3-(Ethoxymethoxy)-4-(4-methyl-6-(piperidin-3-ylamino)pyridazin-3-yl)benzaldehyde (250 mg, 0.675 mmol, 1.0 eq) was dissolved in dichloromethane (3 mL). Methyl vinyl sulfone (72 mg, 0.675 mmol, 1.0 eq) was added and allowed to react at 25°C for 2 h. The reaction was complete by TLC. The reaction solution was concentrated to obtain the product (300 mg crude product, 93.5% yield), which was used directly in the next step.

[0781] Step 3: Synthesis of intermediate (R)-6-(2-ethoxymethoxy)-4-ethynylphenyl)-5-methyl-N-(1-(2-methylsulfonyl)ethyl)piperidin-3-yl)pyridazin-3-amine

[0782]

[0783] (R)-3-(Ethoxymethoxy)-4-(4-methyl-6-(1-(2-(methylsulfonyl)ethyl)piperidin-3-amino)pyridazin-3-yl)benzaldehyde (300 mg, 0.629 mmol, 1.0 eq) was dissolved in methanol (3 mL). Potassium carbonate (174 mg, 1.258 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (182 mg, 0.944 mmol, 1.5 eq) were added sequentially. The mixture was reacted at 25°C for 5 min. LC-MS confirmed the reaction was complete. Water (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 50:1) to obtain the product (148 mg, 49.8% yield). Step 4: Synthesis of compound (R)-5-ethynyl-2-(4-methyl-6-(1-(2-(methylsulfonyl)ethyl)piperidin-3-amino)pyridazin-3-yl)phenol

[0784]

[0785] (R)-6-(2-ethoxymethoxy)-4-ethynylphenyl)-5-methyl-N-(1-(2-methylsulfonyl)ethyl)piperidin-3-yl)pyridazin-3-amine (148 mg, 0.313 mmol) was dissolved in dichloromethane (1 mL) and added dropwise to a solution of hydrogen chloride in 1,4-dioxane (1 mL, 4 mol / L). The mixture was allowed to react at 25°C for 5 min. LC-MS confirmed the reaction was complete. The reaction solution was poured into saturated aqueous sodium bicarbonate (5 mL) and extracted with dichloromethane / methanol (10:1, 10 mL x 5). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 50:1 to 20:1) to obtain the product (59 mg, 45% yield).

[0786] 1 H-NMR(400MHz,DMSO-d6)δ(ppm):10.09(s,1H),7.19-7.17(d,1H),7.00-6.99(m,2 H),6.66-6.62(m,2H),4.20(s,1H),4.02-4.00(m,1H),3.33-3.24(m,2H),3.04(s, 3H),3.03-3.00(m,1H),2.76-2.72(m,3H),2.11-2.06(m,1H),2.02(s,3H),1.99(m ,1H),1.89-1.86(m,1H),1.74-1.71(m,1H),1.58-1.49(m,1H),1.33-1.24(m,1H).

[0787] Molecular formula: C 21 H 26 N4O3S exact molecular weight: 414.17 LC-MS (m / z): 415.16 [M+H] +

[0788] Example 32: Synthesis of (R)-2-(4-cyclopropyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(propyl-1-yn-1-yl)phenol (Compound 264)

[0789]

[0790] step:

[0791]

[0792] Step 1: Synthesis of intermediate (R)-6-chloro-5-cyclopropyl-N-(piperidin-3-yl)pyridazin-3-amine

[0793]

[0794] Dissolve (R)-tert-Butyl 3-((6-chloro-5-cyclopropylpyridazin-3-yl)amino)piperidine-1-carboxylate (4.0 g, 11.34 mmol) in dichloromethane (20 mL) and add dropwise to a solution of hydrogen chloride in 1,4-dioxane (40 mL, 4 mol / L). Allow to react at 25°C for 5 min. TLC confirms the reaction is complete. Pour the reaction solution into saturated aqueous sodium bicarbonate (50 mL) and extract with dichloromethane / methanol (10:1, 50 mL). The organic phases are combined, dried, and concentrated to afford the product (1.93 g, 67.2% yield).

[0795] Step 2: Synthesis of intermediate (R)-6-chloro-5-cyclopropyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine

[0796]

[0797] (R)-6-Chloro-5-cyclopropyl-N-(piperidin-3-yl)pyridazin-3-amine (1.93 g, 7.64 mmol, 1.0 eq) was dissolved in methanol (20 mL). 37% aqueous formaldehyde solution (620 mg, 7.64 mmol, 1.0 eq) and sodium cyanoborohydride (528 mg, 8.40 mmol, 1.1 eq) were added thereto. The mixture was reacted at 25°C for 5 min. The reaction was complete when detected by TLC. The reaction mixture was concentrated, saturated brine (15 mL) was added, and the mixture was extracted with dichloromethane / methanol (10:1, 20 mL×3). The organic phases were combined, dried, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=100:1-30:1) to give the product (645 mg, yield: 31.6%) and the by-product (R)-2-(3-(6-chloro-5-cyclopropyl-pyridazin-3-yl)amino)piperidin-1-yl)acetonitrile (110 mg, yield: 4.9%).

[0798] Step 3: Synthesis of intermediate (R)-5-cyclopropyl-6-(2-ethoxymethoxy)-4-(propyl-1-yn-1-yl)phenyl)-N-(1-methylpiperidin-3-yl)pyridazin-3-amine

[0799]

[0800] (R)-6-chloro-5-cyclopropyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine (125 mg, 0.469 mmol, 1.0 eq) was dissolved in 1,4-dioxane (2 mL), and 2-(2-(ethoxymethoxy)-4-(propyl-1-yn-1-ylphenyl)-4,4,5,5-trimethyl-1,3,2-dioxaborolane (223 mg, 0.704 mmol, 1.5 eq), carbonic acid, and 1,4-dioxane were added. Sodium hydroxide (79 mg, 0.938 mmol, 2.0 eq), PdCl2(dppf) (34 mg, 0.469 mmol, 0.1 eq), and water (0.5 mL) were heated to 100°C under nitrogen for 3 h. LC-MS confirmed the reaction was complete. The reaction solution was filtered through celite, dried, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 50:1 to 20:1) to obtain the product (110 mg, 55.8% yield).

[0801] Step 4: Synthesis of compound (R)-2-(4-cyclopropyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(propyl-1-yn-1-yl)phenol

[0802]

[0803] (R)-5-Cyclopropyl-6-(2-ethoxymethoxy)-4-(propyl-1-yn-1-yl)phenyl)-N-(1-methylpiperidin-3-yl)pyridazin-3-amine (110 mg, 0.262 mmol) was dissolved in dichloromethane (1 mL) and added dropwise to a solution of hydrogen chloride in 1,4-dioxane (1 mL, 4 mol / L). The mixture was allowed to react at 25°C for 5 min. LC-MS confirmed the reaction was complete. The reaction solution was poured into saturated aqueous sodium bicarbonate (5 mL) and extracted with dichloromethane / methanol (10:1, 10 mL x 5). The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 20:1) to obtain the product (123 mg, yield: 59.4%).

[0804] 1 H-NMR(400MHz,DMSO-d6)δ(ppm):10.00(s,1H),7.17-7.15(d,1H),6.94-6.90 (m,3H),6.33(s,1H),4.28(s,1H),3.18-3.16(m,1H),2.94-2.78(m,1H),2.72 (s,3H),2.05(s,3H),2.01-1.89(m,2H),1.80-1.77(m,1H),1.61-1.54(m,1H) ,1.46-1.42(m,1H),1.30-1.24(m,2H),0.93-0.84(m,2H),0.66-0.60(m,2H).

[0805] Molecular formula: C 22 H 26 N4O exact molecular weight: 362.21 LC-MS (m / z): 363.20 [M+H] +

[0806] Example 33: Synthesis of (R)-2-(3-((5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)amino)piperidin-1-yl)acetonitrile (Compound 267)

[0807]

[0808] Step 1: Synthesis of the intermediate (R)-2-(5-cyclopropyl-6-(2-ethoxymethoxy)-4-formylphenyl)pyridazin-3-yl)amino)piperidin-1-yl)acetonitrile

[0809]

[0810] (R)-2-(3-(6-chloro-5-cyclopropyl-pyridazin-3-yl)amino)piperidin-1-yl)acetonitrile (110 mg, 0.377 mmol, 1.0 eq) was dissolved in 1,4-dioxane (2 mL), and 3-(ethoxymethoxy)-4-(4,4,5,5-trimethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (173 mg, 0.566 mmol, 1.5 eq), sodium bicarbonate (64 mg, 0.754 mmol, 2.0 eq), PdCl2(dppf) (28 mg, 0.0377 mmol, 0.1 eq) and water (0.5 mL) were added. The temperature was raised to 100°C under nitrogen for 1 h. The reaction was completed by TLC. The reaction solution was filtered through celite and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=100:1-70:1) to obtain the product (90 mg, yield: 54.9%).

[0811] Step 2: Synthesis of the intermediate (R)-2-(5-cyclopropyl-6-(2-ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-yl)amino)piperidin-1-yl)acetonitrile

[0812]

[0813] (R)-2-(5-cyclopropyl-6-(2-ethoxymethoxy)-4-formylphenyl)pyridazin-3-yl)amino)piperidin-1-yl)acetonitrile (90 mg, 0.207 mmol, 1.0 eq) was dissolved in methanol (1 mL). Potassium carbonate (57 mg, 0.414 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (60 mg, 0.311 mmol, 1.5 eq) were added sequentially. The mixture was reacted at 25°C for 20 min. TLC confirmed the reaction was complete. The mixture was concentrated, water (10 mL) was added, and extraction with dichloromethane (10 mL x 3) was performed. The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1) to obtain the crude product, which was directly used in the next step.

[0814] Step 3: Synthesis of compound (R)-2-(3-((5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)amino)piperidin-1-yl)acetonitrile

[0815]

[0816] The crude product from the previous step, (R)-2-(5-cyclopropyl-6-(2-ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-yl)amino)piperidin-1-yl)acetonitrile, was dissolved in dichloromethane (1 mL) and added dropwise to a solution of hydrogen chloride in 1,4-dioxane (1 mL, 4 mol / L). The mixture was allowed to react at 25°C for 5 min. LC-MS confirmed the reaction was complete. The reaction solution was poured into saturated aqueous sodium bicarbonate (5 mL) and extracted with dichloromethane / methanol (10:1, 10 mL x 5). The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain the product (5 mg, two-step yield: 6.5%).

[0817] 1 H-NMR(400MHz,DMSO-d6)δ(ppm):10.07(s,1H),7.24-7.22(d,1H),7.02-6.99(m,2H),6.58-6.56(d,1H),6.31(s,1H),4.1 9(s,1H),4.09-4.07(m,1H),3.77(s,2H),2.97-2.95(m,1H),2.68-2.63(m,1H),2.28-2.23(m,1H),2.13-2.08(s,1H),1.86 -1.83(m,1H),1.78-1.75(m,1H),1.61-1.52(m,2H),1.34-1.28(m,1H),0.88-0.84(m,2H),0.63-0.60(m,2H).

[0818] Molecular formula: C 22 H 23 N5O exact molecular weight: 373.19 LC-MS (m / z): 374.11 [M+H] +

[0819] Example 34 Synthesis of (R)-5-ethynyl-2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-4-methylpyridazin-3-yl)phenol (Compound 253)

[0820]

[0821] Step 1: Synthesis of (R)-2-(3-((6-chloro-5-methylpyridazin-3-yl)amino)piperidin-1-yl)ethan-1-ol

[0822]

[0823] (R)-6-chloro-5-methyl-N-(piperidin-3-yl)pyridazin-3-amine (250 mg, 1.10 mmol, 1.0 eq) was dissolved in DCM (5 mL), and triethylamine (223 mg, 2.20 mmol, 2.0 eq) and 2-bromoethanol (275 mg, 2.20 mmol, 2.0 eq) were added. The mixture was stirred at room temperature for 22 hours. After concentration, the crude product was purified by silica gel column chromatography (DCM:MeOH = 50:1 to 15:1) to obtain the product (282 mg, yield: 94.4%). Step 2: Synthesis of (R)-3-(ethoxymethoxy)-4-(6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-4-methylpyridazin-3-yl)benzaldehyde

[0824]

[0825] 3-(Ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (382 mg, 1.25 mmol, 1.2 eq), (R)-2-(3-((6-chloro-5-methylpyridazin-3-yl)amino)piperidin-1-yl)ethan-1-ol (282 mg, 1.04 mmol, 1.0 eq), Pd(dppf)Cl2 (76.1 mg, 0.104 mmol, 0.1 eq) and NaHCO3 (175 mg, 2.08 mmol, 2.0 eq) were added to 1,4-dioxane (10 mL) in sequence, and H2O (5 mL) was added. The mixture was heated to 110°C under nitrogen protection for 2 hours. The mixture was cooled to room temperature, quenched by the addition of water (30 mL), extracted with EA (30 mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH=50:1-15:1) to give the product (314 mg, yield: 72.7%).

[0826] Step 3: Synthesis of (R)-2-(3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)ethan-1-ol

[0827]

[0828] (R)-3-(Ethoxymethoxy)-4-(6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-4-methylpyridazin-3-yl)benzaldehyde (314 mg, 0.758 mmol, 1.0 eq) was dissolved in MeOH (10 mL). KCO (210 mg, 1.52 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (218 mg, 1.14 mmol, 1.5 eq) were added, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated, and the crude product was purified by silica gel column chromatography (DCM:MeOH = 50:1 to 15:1) to obtain the product (253 mg, 81.4% yield).

[0829] Step 4: Synthesis of (R)-5-ethynyl-2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-4-methylpyridazin-3-yl)phenol

[0830]

[0831] (R)-2-(3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)ethan-1-ol (253 mg, 0.616 mmol, 1.0 eq) was dissolved in DCM (5 mL), and a solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 0.46 mL, 1.85 mmol, 3.0 eq) was added dropwise. The mixture was stirred at room temperature for 2 hours. The pH was adjusted to 8 with saturated aqueous NaHCO₃ solution, and the mixture was extracted with DCM (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (DCM:MeOH = 8:1) to afford the product (158 mg, 72.7% yield).

[0832] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.15 (s, 1H), 7.17 (d, J = 7.7Hz, 1H), 7.02-6.98 (m, 2H), 6.74 (s, 1H), 6.69 (s, 1H), 4.61 (s, 1H), 4.20 (s, 1H), 4.13 (s,1H),3.57(s,2H),3.11(s,1H),2.83(s,1H),2.60(s,2H),2.35-2.19( m,2H),2.02(s,3H),1.86(s,1H),1.74(s,1H),1.62(s,1H),1.38(s,1H).

[0833] Molecular formula: C 20 H 24N4O2 exact molecular weight: 352.19 LC-MS (Pos, m / z) = 353.17 [M+H] + .

[0834] Example 35 Synthesis of (R)-2-(3-((6-(4-ethynyl-2-hydroxyphenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)acetic acid (Compound 256)

[0835]

[0836] Step 1: Synthesis of (R)-ethyl 2-(3-((6-chloro-5-methylpyridazin-3-yl)amino)piperidin-1-yl)acetate

[0837]

[0838] (R)-6-chloro-5-methyl-N-(piperidin-3-yl)pyridazin-3-amine (250 mg, 1.10 mmol, 1.0 eq) was dissolved in DCM (5 mL), and triethylamine (223 mg, 2.20 mmol, 2.0 eq) and ethyl bromoacetate (367 mg, 2.20 mmol, 2.0 eq) were added. The mixture was stirred at room temperature for 20 hours. After concentration, the crude product was purified by silica gel column chromatography (DCM:MeOH = 50:1 to 15:1) to obtain the product (325 mg, yield: 94.2%). Step 2: Synthesis of (R)-ethyl 2-(3-((6-(2-(ethoxymethoxy)-4-formylphenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)acetate

[0839]

[0840] 3-(Ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (382 mg, 1.25 mmol, 1.2 eq), (R)-2-(3-((6-chloro-5-methylpyridazin-3-yl)amino)piperidin-1-yl)ethan-1-ol (282 mg, 1.04 mmol, 1.0 eq), Pd(dppf)Cl2 (76.1 mg, 0.104 mmol, 0.1 eq) and NaHCO3 (175 mg, 2.08 mmol, 2.0 eq) were added to 1,4-dioxane (10 mL) in sequence, and H2O (5 mL) was added. The mixture was heated at 110°C under nitrogen protection for 1 hour. The mixture was cooled to room temperature, quenched by addition of water (30 mL), extracted with EA (30 mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH=100:1-50:1) to give the product (402 mg, yield: 84.7%).

[0841] Step 3: Synthesis of (R)-methyl 2-(3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)acetate

[0842]

[0843] Ethyl (R)-2-(3-((6-(2-(ethoxymethoxy)-4-formylphenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)acetate (402 mg, 0.881 mmol, 1.0 eq) was dissolved in MeOH (10 mL). KCO (243 mg, 1.76 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (254 mg, 1.32 mmol, 1.5 eq) were added, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated, and the crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 50:1) to give the product (352 mg, 91.2% yield).

[0844] Step 4: Synthesis of (R)-2-(3-((6-(4-ethynyl-2-hydroxyphenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)acetic acid

[0845]

[0846] Methyl (R)-2-(3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)acetate (330 mg, 0.753 mmol, 1.0 eq) was dissolved in MeOH (2 mL). HO (2 mL) and lithium hydroxide monohydrate (63.2 mg, 1.51 mmol, 2.0 eq) were added, and the mixture was stirred at room temperature for 2 hours. The solution was concentrated, the pH was adjusted to 2 with dilute hydrochloric acid, and the mixture was stirred at room temperature for 1 hour. The product was purified by reverse phase column chromatography (ACN:HO = 20:80) to obtain the product (182 mg, 66.0% yield).

[0847] 1HNMR (400MHz, DMSO-d6) δ (ppm): 10.37 (s, 1H), 7.25 (s, 1H), 7.17 (d, J = 7.8Hz, 1H), 7.07 (d ,J=1.4Hz,1H),7.01-6.99(m,1H),6.80(s,1H),4.34-4.33(m,1H),4.21(s,1H),3.85(s,2 H),3.54(d,J=10.0Hz,1H),3.28(d,J=11.3Hz,1H),2.92-2.87(m,1H),2.82-2.76(m,1H), 2.04(s,3H),1.98-1.95(m,1H),1.90-1.86(m,1H),1.83-1.79(m,1H),1.52-1.44(m,1H).

[0848] Molecular formula: C 20 H 22 N4O3 exact molecular weight: 366.17 LC-MS (Pos, m / z) = 367.14 [M+H] + .

[0849] Example 36 Synthesis of 5-ethyl-2-(6-((3-hydroxybenzyl)amino)-4-methylpyridazin-3-yl)phenol (Compound 261)

[0850]

[0851] Step 1: Synthesis of 3-(((6-chloro-5-methylpyridazin-3-yl)amino)methyl)phenol

[0852]

[0853] 3,6-Dichloro-4-methylpyridazine (2.0 g, 12.3 mmol, 1.0 eq), 3-(aminomethyl)phenol (1.51 g, 12.3 mmol, 1.0 eq), and triethylamine (6.22 g, 61.5 mmol, 5.0 eq) were added to isopropanol (30 mL) and heated at 85°C for 24 hours. The mixture was concentrated, dissolved in EA (30 mL), and washed with water (20 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 (DCM:MeOH = 100:1 to 60:1) to obtain the product (300 mg, yield: 9.8%).

[0854] Step 2: Synthesis of 3-(ethoxymethoxy)-4-(6-((3-hydroxybenzyl)amino)-4-methylpyridazin-3-yl)benzaldehyde

[0855]

[0856] 3-(Ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (294 mg, 0.961 mmol, 1.2 eq), 3-(((6-chloro-5-methylpyridazin-3-yl)amino)methyl)phenol (200 mg, 0.801 mmol, 1.0 eq), Pd(dppf)Cl2 (58.6 mg, 0.0801 mmol, 0.1 eq) and NaHCO3 (135 mg, 1.60 mmol, 2.0 eq) were added to 1,4-dioxane (10 mL) in sequence, and H2O (5 mL) was added. The mixture was heated to 110°C under nitrogen protection and reacted for 1 hour. The mixture was cooled to room temperature, quenched by addition of water (30 mL), extracted with EA (20 mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH=100:1-50:1) to give the product (248 mg, yield: 78.7%).

[0857] Step 3: Synthesis of 3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylpyridazin-3-yl)amino)methyl)phenol

[0858]

[0859] 3-(Ethoxymethoxy)-4-(6-((3-hydroxybenzyl)amino)-4-methylpyridazin-3-yl)benzaldehyde (248 mg, 0.630 mmol, 1.0 eq) was dissolved in MeOH (10 mL). KCO (174 mg, 1.26 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (182 mg, 0.945 mmol, 1.5 eq) were added and stirred at room temperature for 2 hours. The mixture was concentrated and the crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 50:1) to afford the product (215 mg, 87.6% yield).

[0860] Step 4: Synthesis of 5-ethyl-2-(6-((3-hydroxybenzyl)amino)-4-methylpyridazin-3-yl)phenol

[0861]

[0862] 3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylpyridazin-3-yl)amino)methyl)phenol (215 mg, 0.552 mmol, 1.0 eq) was dissolved in DCM (5 mL), followed by the dropwise addition of a solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 0.42 mL, 1.66 mmol, 3.0 eq). The mixture was stirred at room temperature for 1 hour. The pH was adjusted to 8 with saturated aqueous NaHCO₃, and the mixture was extracted with DCM (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 20:1) to afford the product (116 mg, 63.4% yield).

[0863] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.10 (s, 1H), 9.34 (s, 1H), 7.31-7.28 (m, 1H), 7.18 (d, J = 8.1Hz, 1H), 7.14-7.10 (m, 1H), 6.99 (d,J=5.6Hz,2H),6.79(d,J=6.6Hz,2H),6.71(s,1H),6.63(d,J=8.3Hz,1H),4.51(d,J=5.7Hz,2H),4.19(s,1H),2.03(s,3H).

[0864] Molecular formula: C 20 H 17 N3O2 exact molecular weight: 331.13 LC-MS (Pos, m / z) = 332.10 [M+H] + .

[0865] Example 37: Synthesis of (R)-2-(5-(dimethylamino)-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)-5-ethynylphenol (Compound 181)

[0866]

[0867] Step 1: Synthesis of 6-chloro-N,N-dimethyl-3-(methylthio)-1,2,4-triazin-5-amine

[0868]

[0869] 5,6-Dichloro-3-(methylthio)-1,2,4-triazine (6.85 g, 34.92 mmol, 1.0 eq) was dispersed in THF (100 mL) and a solution of dimethylamine in tetrahydrofuran (2 mol / L, 30 mL). The mixture was allowed to react at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (EA:PE = 1:10) to obtain the product (1.2 g, 16.8% yield).

[0870] Step 2: Synthesis of 4-(5-(dimethylamino)-3-(methylthio)-1,2,4-triazin-6-yl)-3-(ethoxymethoxy)benzaldehyde

[0871]

[0872] 6-Chloro-N,N-dimethyl-3-(methylthio)-1,2,4-triazine-5-amine (1.2 g, 5.86 mmol, 1.0 eq), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (2.15 g, 7.03 mmol, 1.2 eq), Pd(dppf)Cl2 (432 mg, 0.59 mmol, 0.1 eq) and NaHCO3 (984 mg, 11.72 mmol, 2.0 eq) were dissolved in 1,4-dioxane (20 mL) and H2O (4 mL) and reacted at 110 °C under nitrogen protection for 3 hours. The reaction was complete as determined by TLC. The reaction solution was poured into water (30 mL) and extracted with EA (30 mL × 3). The organic phase was dried, concentrated, and purified by silica gel column chromatography (MeOH:DCM=1:100) to obtain the product (1.7 g, yield: 83.3%).

[0873] Step 3: Synthesis of 6-(2-(ethoxymethoxy)-4-ethynylphenyl)-N,N-dimethyl-3-(methylthio)-1,2,4-triazin-5-amine

[0874]

[0875] 4-(5-(dimethylamino)-3-(methylthio)-1,2,4-triazin-6-yl)-3-(ethoxymethoxy)benzaldehyde (1.7 g, 4.88 mmol, 1.0 eq) and potassium carbonate (1.01 g, 7.32 mmol, 1.5 eq) were dispersed in MeOH (30 mL). After 5 minutes, dimethyl (1-diazo-2-oxopropyl)phosphonate (1.41 g, 7.32 mmol, 1.5 eq) was added and allowed to react for 2 hours. TLC confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was dispersed in water (30 mL) and extracted with EA (20 mL x 2). The organic phase was dried and concentrated to give the product (1.5 g, 89.3% yield).

[0876] Step 4: Synthesis of 6-(2-(ethoxymethoxy)-4-ethynylphenyl)-N,N-dimethyl-3-(methylsulfinyl)-1,2,4-triazin-5-amine

[0877]

[0878] Dissolve 6-(2-(ethoxymethoxy)-4-ethynylphenyl)-N,N-dimethyl-3-(methylthio)-1,2,4-triazin-5-amine (1.5 g, 4.35 mmol, 1.0 eq.) in DCM (30 mL). Add 85% m-chloroperbenzoic acid (883 mg, 4.35 mmol, 1.0 eq.) and allow to react at room temperature for 30 min. TLC monitored the reaction until complete. The reaction solution was concentrated under reduced pressure to afford the crude product (1.57 g, 100% yield).

[0879] Step 5: Synthesis of tert-butyl (R)-3-((5-(dimethylamino)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate

[0880]

[0881] 6-(2-(Ethoxymethoxy)-4-ethynylphenyl)-N,N-dimethyl-3-(methylsulfinyl)-1,2,4-triazin-5-amine (1.57 mg, 4.35 mmol, 1.0 eq.), (R)-tert-butyl 3-aminopiperidine-1-carboxylate (1.30 g, 6.52 mmol, 1.5 eq.), and TEA (880 mg, 8.70 mmol, 2.0 eq.) were dissolved in dioxane (30 mL) and reacted at 100°C for 23 h. The reaction was monitored for completion by TLC. The reaction solution was concentrated, and the crude product was dispersed in water (20 mL) and extracted with EA (20 mL x 3). The organic phase was dried and concentrated to afford the product (1.5 g, 69.4% yield). Step 6: Synthesis of (R)-2-(5-(dimethylamino)-3-(piperidin-3-ylamino)-1,2,4-triazin-6-yl)-5-ethynylphenol

[0882]

[0883] Tert-butyl (R)-3-((5-(dimethylamino)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate (1.5 g, 3.02 mmol, 1.0 eq) was dissolved in DCM (30 mL), and a solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 6 mL) was added dropwise. The reaction was allowed to react at room temperature for 2 h. LC-MS confirmed the reaction was complete. The reaction solution was poured into water (30 mL) and separated. The aqueous phase was retained and the pH was adjusted to approximately 10 with aqueous NaHCO₃. The resulting mixture was then extracted with DCM (20 mL x 2). The organic phase was dried and concentrated, and the crude product was purified by silica gel column chromatography (MeOH:DCM = 1:15) to afford the product (600 mg, 58.8% yield).

[0884] Step 7: Synthesis of (R)-2-(5-(dimethylamino)-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)-5-ethynylphenol

[0885]

[0886] (R)-2-(5-(Dimethylamino)-3-(piperidin-3-ylamino)-1,2,4-triazin-6-yl)-5-ethynylphenol (600 mg, 1.77 mmol, 1.0 eq.) and 37% formaldehyde solution (144 mg, 1.77 mmol, 1.0 eq.) were dissolved in methanol (6 mL) and stirred at room temperature for 5 min. Sodium cyanoborohydride (111 mg, 1.77 mmol, 1.0 eq.) was added and allowed to react at room temperature for 5 min. TLC monitored the reaction completion. The reaction solution was concentrated under reduced pressure, and the crude product was dispersed in water (10 mL) and extracted with DCM (20 mL x 3). The organic phase was dried and concentrated. The crude product was purified by silica gel column chromatography (MeOH:DCM = 1:15) to obtain the product (200 mg, yield: 32.1%).

[0887] 1 HNMR(400MHz,DMSO-d6)δ(ppm):9.91(s,1H),7.29-7.27(d,1H),7.01-6.99(d,1H),6.95(s,1H),6.75(s,1H),4.18(s,1H),3.91(s,1H),2. 88-2.86(d,1H),2.82(s,6H),2.61-2.58(d,1H),2.18(s,3H),1.95-1 .79(m,3H),1.71-1.66(m,1H),1.57-1.47(m,1H),1.35-1.27(m,1H).

[0888] Molecular formula: C 19 H24 N6O exact molecular weight: 352.20 LC-MS (Pos, m / z) = 353.15 [M+H] + .

[0889] Example 38: Synthesis of (R)-5-ethynyl-2-(5-methoxy-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)phenol (Compound 182)

[0890]

[0891] Step 1: Synthesis of 6-chloro-5-methoxy-3-(methylthio)-1,2,4-triazine

[0892]

[0893] Disperse 5,6-dichloro-3-(methylthio)-1,2,4-triazine (6.85 g, 34.92 mmol, 1.0 eq) in MeOH (50 mL) and allow to react at room temperature for 10 min. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (EA:PE = 1:20) to obtain the product (1.5 g, yield: 22.4%). Step 2: Synthesis of 3-(ethoxymethoxy)-4-(5-methoxy-3-(methylthio)-1,2,4-triazin-6-yl)benzaldehyde

[0894]

[0895] 6-Chloro-5-methoxy-3-(methylthio)-1,2,4-triazine (1.5 g, 7.82 mmol, 1.0 eq), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (2.63 g, 8.60 mmol, 1.1 eq), Pd(dppf)Cl2 (571 mg, 0.78 mmol, 0.1 eq) and NaHCO3 (1.31 g, 15.64 mmol, 2.0 eq) were dissolved in 1,4-dioxane (20 mL) and H2O (4 mL) and reacted at 110 °C under nitrogen protection for 2 hours. The reaction was complete by TLC. The reaction solution was poured into water (20 mL) and extracted with EA (20 mL × 3). The organic phase was dried and concentrated. The crude product was purified by silica gel column chromatography (EA:PE = 1:20) to obtain the product (1.0 g, yield: 38.2%).

[0896] Step 3: Synthesis of 6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methoxy-3-(methylthio)-1,2,4-triazine

[0897]

[0898] 3-(Ethoxymethoxy)-4-(5-methoxy-3-(methylthio)-1,2,4-triazin-6-yl)benzaldehyde (1.0 g, 2.98 mmol, 1.0 eq), dimethyl (1-diazo-2-oxopropyl)phosphonate (859 mg, 4.47 mmol, 1.5 eq), and potassium carbonate (617 mg, 4.47 mmol, 1.5 eq) were dissolved in MeOH (20 mL) and allowed to react for 1 h. TLC confirmed the reaction was complete, and the reaction solution was concentrated under reduced pressure. The crude product was taken up in water (30 mL) and extracted with EA (20 mL x 2). The organic phase was dried and concentrated to afford the product (988 mg, 100% yield).

[0899] Step 4: Synthesis of 6-(2-(ethoxymethoxy)-4-ethynylphenyl)-N,N-dimethyl-3-(methylsulfinyl)-1,2,4-triazin-5-amine

[0900]

[0901] Dissolve 6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methoxy-3-(methylthio)-1,2,4-triazine (988 mg, 2.98 mmol, 1.0 eq.) in DCM (20 mL). Add 85% m-chloroperbenzoic acid (605 mg, 2.98 mmol, 1.0 eq.) and allow to react at room temperature for 20 min. TLC monitored the reaction completion. The reaction solution was poured into saturated aqueous sodium carbonate (20 mL) and extracted with DCM (20 mL x 2). The organic phase was dried and concentrated to afford the product (1.03 g, 100% yield).

[0902] Step 5: Synthesis of tert-butyl (R)-3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methoxy-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate

[0903]

[0904] 6-(2-(Ethoxymethoxy)-4-ethynylphenyl)-N,N-dimethyl-3-(methylsulfinyl)-1,2,4-triazin-5-amine (1.03 mg, 2.98 mmol, 1.0 eq.) and (R)-tert-butyl 3-aminopiperidine-1-carboxylate (1.20 g, 5.96 mmol, 2.0 eq.) were dissolved in 1,4-dioxane (20 mL) and reacted at 100°C for 1 h. LC-MS monitored the reaction completion. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (EA:PE = 1:1) to obtain the product (600 mg, 41.7% yield).

[0905] Step 6: Synthesis of (R)-5-ethynyl-2-(5-methoxy-3-(piperidin-3-ylamino)-1,2,4-triazin-6-yl)phenol

[0906]

[0907] Tert-butyl (R)-3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methoxy-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate (0.6 g, 1.03 mmol, 1.0 eq) was dissolved in DCM (10 mL), followed by the dropwise addition of a solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 1 mL). The reaction was allowed to react at room temperature for 2.5 h. LC-MS confirmed the reaction was complete. The reaction solution was washed with water (20 mL). The retained aqueous phase was adjusted to pH 9 with aqueous NaHCO₃. The product was extracted with DCM (20 mL x 2). The organic phase was dried and concentrated to afford the product (250 mg, 74.6% yield).

[0908] Step 7: Synthesis of (R)-5-ethynyl-2-(5-methoxy-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)phenol

[0909]

[0910] (R)-5-Ethynyl-2-(5-methoxy-3-(piperidin-3-ylamino)-1,2,4-triazin-6-yl)phenol (250 mg, 0.77 mmol, 1.0 eq.) and 37% aqueous formaldehyde (62 mg, 0.77 mmol, 1.0 eq.) were dissolved in methanol (5 mL) and stirred at room temperature for 5 min. Sodium cyanoborohydride (48 mg, 0.77 mmol, 1.0 eq.) was added and allowed to react at room temperature for 5 min. TLC monitored the reaction completion. The reaction solution was concentrated under reduced pressure, and the crude product was dispersed in water (15 mL) and extracted with DCM (20 mL x 2). The organic phase was dried, concentrated, and purified by preparative thin-layer chromatography (MeOH:DCM = 1:8) to afford the product (120 mg, 46.0% yield).

[0911] 1 HNMR(400MHz,DMSO-d6)δ(ppm):10.61(s,1H),7.94(s,1H),7.42-7.40(d,1H),7.00-6.98(d,1H), 4.22(s,2H),3.92(s,3H),3.00(s,1H),2.51(s,6H),1.91-1.83(d,2H),1.73(s,1H),1.49(s,1H).

[0912] Molecular formula: C18 H 21 N5O2 exact molecular weight: 339.17 LC-MS (Pos, m / z) = 340.19 [M+H] + .

[0913] Example 39: Synthesis of 5-ethynyl-2-(((tetrahydrofuran-2-yl)methyl)amino)phthalazin-1-yl)phenol (Compound 63)

[0914]

[0915] step:

[0916]

[0917] Step 1: Synthesis of intermediate 4-chloro-N-(tetrahydrofuran-2-yl)methyl)phthalazin-1-amine

[0918]

[0919] 1,4-Dichlorophthalazine (1.0 g, 5.0 mmol, 1.0 eq) was dissolved in NMP (10 mL), and 2-tetrahydrofurfurylamine (506 mg, 5.0 mmol, 1.2 eq) and DIPEA (2.26 g, 17.5 mmol, 3.5 eq) were added. The mixture was reacted at 80°C for 16 h. The reaction was complete by TLC. The reaction solution was poured into water (20 mL) and extracted with dichloromethane (20 mL x 2). The organic phases were combined, dried, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:1) to obtain the crude product, which was directly used in the next step.

[0920] Step 2: Synthesis of compound 3-(ethoxymethoxy)-4-(4-(((tetrahydrofuran-2-yl)methyl)amino)phthalazin-1-yl)benzaldehyde

[0921]

[0922] 4-Chloro-N-(tetrahydrofuran-2-yl)methyl)phthalazin-1-amine (500 mg, 1.89 mmol, 1.0 eq) was dissolved in 1,4-dioxane (5 mL), and 3-(ethoxymethoxy)-4-(4,4,5,5-trimethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (753 mg, 2.46 mmol, 1.3 eq), sodium bicarbonate (318 mg, 3.78 mmol, 2.0 eq), PdCl2(dppf) (69 mg, 0.095 mmol, 0.05 eq) and water (1 mL) were added. The atmosphere was replaced with nitrogen, and the temperature was raised to 100 ° C for 4 h. The reaction was completed by TLC. The reaction solution was filtered through celite, the filter cake was washed with dichloromethane (20 mL), the filtrate was dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to ethyl acetate) to give the product (377 mg, two-step yield: 52.4%).

[0923] Step 3: Synthesis of the intermediate 4-(2-ethoxymethoxy)-4-ethynylphenyl-N-(tetrahydrofuran-2-yl)methyl)phthalazin-1-amine

[0924]

[0925] 3-(Ethoxymethoxy)-4-(4-(((tetrahydrofuran-2-yl)methyl)amino)phthalazin-1-yl)benzaldehyde (377 mg, 0.925 mmol, 1.0 eq) was dissolved in methanol (4 mL). Potassium carbonate (256 mg, 1.85 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (267 mg, 1.388 mmol, 1.5 eq) were added sequentially. The mixture was reacted at 25°C for 1 h. TLC confirmed the reaction was complete. The reaction solution was concentrated, water (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated. The crude product was directly used in the next step.

[0926] Step 4: Synthesis of 5-ethynyl-2-(4-(((tetrahydrofuran-2-yl)methyl)amino)phthalazin-1-yl)phenol

[0927]

[0928] 4-(2-Ethoxymethoxy)-4-ethynylphenyl-N-(tetrahydrofuran-2-yl)methyl)phthalazin-1-amine (crude product, 0.925 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL) and added dropwise to a solution of hydrogen chloride in 1,4-dioxane (2 mL, 4 mol / L). The mixture was allowed to react at 25°C for 5 min. TLC confirmed the reaction was complete. The reaction solution was slowly poured into saturated aqueous sodium bicarbonate (10 mL) and extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1), then slurried with ethyl acetate (2 mL) and dried to obtain the product (101 mg, yield: 31.7%).

[0929] 1 H-NMR(400MHz,DMSO-d6)δ(ppm):9.97(s,1H),8.37-8.35(d,1H),7.87-7.83 (m,1H),7.80-7.76(m,1H),7.63-7.60(t,1H),7.49-7.47(d,1H),7.31-7.29( m,1H),7.08-7.06(m,2H),4.31-4.24(m,1H),4.22(s,1H),3.89-3.82(m,1H) ,3.70-3.64(m,3H),2.03-1.95(m,1H),1.94-1.79(m,2H),1.73-1.64(m,1H).

[0930] Molecular formula: C 21 H 19 N3O2 exact molecular weight: 345.15 LC-MS (m / z): 346.06 [M+H] +

[0931] Example 40: Synthesis of (R)-5-ethynyl-2-(4-((1-(2-(methylsulfonyl)ethyl)piperidin-3-yl)amino)phthalazin-1-yl)phenol (Compound 62)

[0932]

[0933] step:

[0934]

[0935] Step 1: Synthesis of intermediate (R)-3-(ethoxymethoxy)-4-(4-(piperidin-3-ylamino)phthalazin-1-yl)benzaldehyde

[0936]

[0937] (R)-6-Chloro-5-methyl-N-(piperidin-3-yl)pyridazin-3-amine (500 mg, 1.9 mmol, 1.0 eq) was dissolved in 1,4-dioxane (4 mL), and 3-(ethoxymethoxy)-4-(4,4,5,5-trimethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (873 mg, 2.85 mmol, 1.5 eq), sodium bicarbonate (319 mg, 3.8 mmol, 2.0 eq), PdCl2(dppf) (139 mg, 0.19 mmol, 0.1 eq) and water (1 mL) were added. The atmosphere was replaced with nitrogen, and the temperature was raised to 100°C for 1 h. The reaction was completed by TLC. The reaction solution was filtered through celite, and the filter cake was washed with dichloromethane (10 mL) and water (5 mL) in sequence. The liquids were separated, and the organic phase was dried and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 50:1 to 7:1) to give the product (560 mg, yield: 72.5%).

[0938] Step 2: Synthesis of intermediate (R)-3-(ethoxymethoxy)-4-(4-((1-(2-(methylsulfonyl)ethyl)piperidin-3-amino)phthalazin-1-yl)benzaldehyde

[0939]

[0940] Dissolve (R)-3-(ethoxymethoxy)-4-(4-(piperidin-3-ylamino)phthalazin-1-yl)benzaldehyde (200 mg, 0.492 mmol, 1.0 eq) in dichloromethane (2 mL). Add methyl vinyl sulfone (52 mg, 0.492 mmol, 1.0 eq). Incubate at 25°C for 5 h. TLC confirms the reaction is complete. The reaction solution is concentrated and directly used in the next step.

[0941] Step 3: Synthesis of the intermediate (R)-4-(2-ethoxymethoxy)-4-ethynylphenyl)-N-(1-(2-methylsulfonyl)ethyl)piperidin-3-yl)phthalazin-1-amine

[0942]

[0943] (R)-3-(Ethoxymethoxy)-4-(4-((1-(2-(methylsulfonyl)ethyl)piperidin-3-amino)phthalazin-1-yl)benzaldehyde (crude, 0.492 mmol, 1.0 eq) was dissolved in methanol (2 mL). Potassium carbonate (136 mg, 0.984 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (142 mg, 0.738 mmol, 1.5 eq) were added sequentially. The mixture was reacted at 25°C for 2.5 h. TLC confirmed the reaction was complete. The reaction solution was concentrated, water (5 mL) was added, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated. The crude product was directly used in the next step.

[0944] Step 4: Synthesis of (R)-5-ethynyl-2-(4-((1-(2-(methylsulfonyl)ethyl)piperidin-3-amino)phthalazin-1-yl)phenol

[0945]

[0946] (R)-4-(2-ethoxymethoxy)-4-ethynylphenyl)-N-(1-(2-methylsulfonyl)ethyl)piperidin-3-yl)phthalazin-1-amine (crude product, 0.492 mmol) was dissolved in dichloromethane (2 mL) and added dropwise to a solution of hydrogen chloride in 1,4-dioxane (2 mL, 4 mol / L). The reaction was allowed to react at 25°C for 5 min. LC-MS confirmed the reaction was complete. The reaction solution was poured into saturated aqueous sodium bicarbonate (15 mL) and extracted with dichloromethane:methanol (20:1) (20 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 50:1) to obtain the product (112 mg, three-step yield: 50.7%).

[0947] 1 H-NMR(400MHz,DMSO-d6)δ(ppm):10.00(s,1H),8.39-8.37(d,1H),7.89-7.83(m,1H) ,7.80-7.76(m,1H),7.49-7.47(d,1H),7.31-7.29(d,1H),7.11-7.06(m,3H),4.43-4. 42(m,1H),4.22(s,1H),3.35-3.28(m,2H),3.18-3.16(m,1H),3.07(s,3H),2.85-2.7 7(m,3H),2.14-2.09(m,2H),2.00-1.98(m,1H),1.79-1.76(m,1H),1.61-1.53(m,2H).

[0948] Molecular formula: C24 H 26 N4O3S exact molecular weight: 450.17 LC-MS (m / z): 451.12 [M+H] +

[0949] Example 41: Synthesis of (R)-3-ethynyl-2-fluoro-6-(4-((tetrahydrofuran-3-yl)amino)phthalazin-1-yl)phenol (Compound 46)

[0950]

[0951] step:

[0952]

[0953] Step 1: Synthesis of intermediate (R)-4-chloro-N-(tetrahydrofuran-3-yl)phthalazin-1-amine

[0954]

[0955] 1,4-Dichlorophthalazine (1 g, 5.02 mmol, 1.0 eq) was dissolved in dimethylacetamide (10 mL), and (R)-tetrahydrofuran-3-amine hydrochloride (683 mg, 5.53 mmol, 1.1 eq) and sodium bicarbonate (924 mg, 11.04 mmol, 2.2 eq) were added. The mixture was stirred at 120°C for 3 h. The reaction was complete by TLC. Water (50 mL) and dichloromethane (25 mL) were added to the reaction solution, and the layers were separated. The aqueous phase was extracted with dichloromethane (25 mL). The organic phases were combined and washed sequentially with water (15 mL × 2) and saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 40:1 to 20:1) to obtain the product (1.25 g, yield: 99.7%).

[0956] Step 2: Synthesis of intermediate (R)-3-(ethoxymethoxy)-2-fluoro-4-(4-((tetrahydrofuran-3-yl)amino)phthalazin-1-yl)benzaldehyde

[0957]

[0958] (R)-4-chloro-N-(tetrahydrofuran-3-yl)phthalazin-1-amine (400 mg, 1.60 mmol, 1.0 eq) obtained in the previous step was dissolved in 1,4-dioxane (4 mL) and water (2 mL). 3-(ethoxymethoxy)-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (675 mg, 2.08 mmol, 1.3 eq), sodium bicarbonate (269 mg, 3.20 mmol, 2.0 eq), and Pd(dppf)Cl2 (117 mg, 0.16 mmol, 0.1 eq) were added sequentially. The mixture was stirred at 90°C under nitrogen for 2 h. The reaction was complete as determined by LC-MS. The reaction solution was concentrated, water (5 mL) was added, and the mixture was extracted with dichloromethane (5 mL × 3). The organic phase was dried and filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 50:1 to 20:1) to obtain the product (420 mg, yield: 63.8%).

[0959] Step 3: Synthesis of intermediate (R)-4-(2-(ethoxymethoxy)-4-ethynyl-3-fluorophenyl)-N-(tetrahydrofuran-3-yl)phthalazin-1-amine

[0960]

[0961] (R)-3-(Ethoxymethoxy)-2-fluoro-4-(4-((tetrahydrofuran-3-yl)amino)phthalazin-1-yl)benzaldehyde (400 mg, 0.97 mmol, 1.0 eq) was dissolved in methanol (5 mL). Dimethyl (1-diazo-2-oxopropyl)phosphonate (224 mg, 1.17 mmol, 1.2 eq) and potassium carbonate (251 mg, 1.82 mmol, 2.0 eq) were added sequentially. The mixture was stirred at room temperature for 1 h. LC-MS confirmed the reaction was complete. The reaction solution was concentrated, water (5 mL) was added, and the mixture was extracted with dichloromethane (5 mL x 3). The organic phase was dried and concentrated to obtain the crude product (550 mg).

[0962] Step 4: Synthesis of (R)-3-ethynyl-2-fluoro-6-(4-((tetrahydrofuran-3-yl)amino)phthalazin-1-yl)phenol

[0963]

[0964] The crude product (R)-4-(2-(ethoxymethoxy)-4-ethynyl-3-fluorophenyl)-N-(tetrahydrofuran-3-yl)phthalazin-1-amine (550 mg) obtained in the previous step was dissolved in dichloromethane (10 mL). A 4 mol / L hydrogen chloride / 1,4-dioxane solution (1.25 mL) was added and stirred at room temperature for 30 min. The reaction was complete by LC-MS. The reaction solution was poured into water, and the pH was adjusted to approximately 8 with sodium bicarbonate. The layers were separated, and the aqueous phase was extracted with dichloromethane (5 mL x 2). The organic phase was dried, filtered, and concentrated. The crude product was purified by preparative thin-layer chromatography to obtain the product (130 mg, two-step yield: 38.3%).

[0965] 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 10.23 (s, 1H), 8.45 (d, J = 8.2Hz, 1H), 7.90-7.86 (m, 1H), 7.81-7.78 (m, 1H), 7.52-7.50 (m, 2H), 7.15-7.0 6(m,2H),4.82-4.76(m,1H),4.54(s,1H),4.07-4.03(m,1H),3.98-3.93(m,1H),3.82-3.74(m,2H),2.36-2.27(m,1H),2.16-2.08(m,1H).

[0966] Molecular formula: C 20 H 16 FN3O2 exact molecular weight: 349.12 LC-MS (m / z): 350.03 [M+H] +

[0967] Example 42: Synthesis of 2-fluoro-6-(4-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)phthalazin-1-yl)-3-vinylphenol (Compound 171)

[0968]

[0969] step:

[0970]

[0971] Step 1: Synthesis of the intermediate (cis)-3-((4-chlorophthalazin-1-yl)amino)-1-methylcyclobutane-1-ol

[0972]

[0973] 1,4-Dichlorophthalazine (2 g, 10.04 mmol, 1.0 eq) was dissolved in 1,4-dioxane (40 mL). (cis)-3-amino-1-methylcyclobutan-1-ol hydrochloride (683 mg, 5.53 mmol, 1.1 eq), BINAP (1.25 g, 2.01 mmol, 0.2 eq), Pd2(dba)3 (915 mg, 1.00 mmol, 0.1 eq), and cesium carbonate (9.78 g, 30.12 mmol, 3.0 eq) were added sequentially. Under nitrogen, the mixture was stirred at 90°C overnight. The reaction was complete as determined by TLC. The mixture was filtered through celite, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 50:1 to 10:1) to obtain the product (1.50 g, yield: 56.9%).

[0974] Step 2: Synthesis of the intermediate 3-(ethoxymethoxy)-2-fluoro-4-(4-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)phthalazin-1-yl)benzaldehyde

[0975]

[0976] (cis)-3-((4-chlorophthalazin-1-yl)amino)-1-methylcyclobutan-1-ol (600 mg, 2.28 mmol, 1.0 eq) obtained in the previous step was dissolved in 1,4-dioxane (6 mL) and water (2 mL). 3-(ethoxymethoxy)-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (958 mg, 2.96 mmol, 1.3 eq), sodium bicarbonate (383 mg, 4.56 mmol, 2.0 eq), and Pd(dppf)Cl2 (167 mg, 0.23 mmol, 0.1 eq) were added sequentially. The mixture was stirred at 90°C under nitrogen for 2 h. The reaction was complete as determined by LC-MS. The reaction solution was concentrated, water (5 mL) was added, and the mixture was extracted with dichloromethane (5 mL × 3). The organic phase was dried and filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 50:1 to 20:1) to obtain the product (700 mg, yield: 72.2%).

[0977] Step 3: Synthesis of the intermediate (cis)-3-((4-(2-(ethoxymethoxy)-4-ethynyl-3-fluorophenyl)phthalazin-1-yl)amino)-1-methylcyclobutane-1-ol

[0978]

[0979] 3-(Ethoxymethoxy)-2-fluoro-4-(4-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)phthalazin-1-yl)benzaldehyde (500 mg, 1.18 mmol, 1.0 eq) was dissolved in methanol (5 mL). Dimethyl (1-diazo-2-oxopropyl)phosphonate (271 mg, 1.41 mmol, 1.2 eq) and potassium carbonate (326 mg, 2.36 mmol, 2.0 eq) were added sequentially and stirred at room temperature for 2 h. LC-MS analysis indicated the reaction was complete. The reaction solution was concentrated, water (5 mL) was added, and extraction with dichloromethane (5 mL x 3) was performed. The organic phase was dried and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain the product (300 mg, yield: 60.3%).

[0980] Step 4: Synthesis of the intermediate 3-ethynyl-2-fluoro-6-(4-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)phthalazin-1-yl)phenol

[0981]

[0982] (cis)-3-((4-(2-(ethoxymethoxy)-4-ethynyl-3-fluorophenyl)phthalazin-1-yl)amino)-1-methylcyclobutane-1-ol (300 mg, 0.71 mmol, 1.0 eq) obtained in the previous step was dissolved in dichloromethane (3 mL). A 4 mol / L hydrogen chloride / 1,4-dioxane solution (0.9 mL) was added and stirred at room temperature for 30 min. LC-MS confirmed the reaction was complete. The reaction solution was poured into water, and the pH was adjusted to approximately 8 with sodium bicarbonate. The layers were separated, and the aqueous phase was extracted with dichloromethane (5 mL x 2). The organic phase was dried, filtered, and concentrated. The crude product was purified by preparative thin-layer chromatography to obtain the product (220 mg, 85.3% yield).

[0983] Step 5: Synthesis of 2-fluoro-6-(4-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)phthalazin-1-yl)-3-vinylphenol

[0984]

[0985] 3-Ethynyl-2-fluoro-6-(4-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)phthalazin-1-yl)phenol (120 mg, 0.33 mmol, 1.0 eq) obtained in the previous step was dissolved in methanol (4 mL). Lindlar catalyst (12 mg, 12 wt%) was added and stirred at room temperature for 1 hour. LC-MS analysis indicated a large amount of residual starting material. Additional Lindlar catalyst (12 mg, 12 wt%) was added and the reaction was allowed to proceed overnight. LC-MS analysis indicated the reaction was complete. The reaction was filtered through celite, the filtrate was concentrated, and the crude product was purified by preparative thin-layer chromatography to yield the product (25 mg, 20.7% yield).

[0986] 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 10.03 (s, 1H), 8.45 (d, J = 8.1Hz, 1H), 7.89-7.85 (m,1H),7.82-7.78(m,1H),7.68-7.67(m,1H),7.56-7.54(m,1H),7.24-7.20(m,1 H),7.15-7.13(m,1H),6.96-6.89(m,1H),6.01-5.96(m,1H),5.51-5.48(m,1H),5 .01(s,1H),4.30-4.21(m,1H),2.49-2.46(m,2H),2.22-2.17(m,2H),1.35(s,3H).

[0987] Molecular formula: C 21 H 20 FN3O2 exact molecular weight: 365.15 LC-MS (m / z): 366.10 [M+H] +

[0988] Example 43: Synthesis of 5-(bromoethynyl)-2-(4-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)phthalazin-1-yl)phenol (Compound 111)

[0989]

[0990] step:

[0991]

[0992] Step 1: Synthesis of the intermediate 3-(ethoxymethoxy)-4-(4-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)phthalazin-1-yl)benzaldehyde

[0993]

[0994] (cis)-3-((4-chlorophthalazin-1-yl)amino)-1-methylcyclobutan-1-ol (486 mg, 1.85 mmol, 1.0 eq) was dissolved in 1,4-dioxane (5 mL) and water (2 mL). 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (849 mg, 2.78 mmol, 1.5 eq), sodium bicarbonate (311 mg, 3.70 mmol, 2.0 eq), and Pd(dppf)Cl2 (135 mg, 0.19 mmol, 0.1 eq) were added sequentially. The mixture was stirred at 90°C under nitrogen for 2 h. The reaction was complete by LC-MS. The reaction solution was concentrated, water (5 mL) was added, and the mixture was extracted with dichloromethane (5 mL × 3). The organic phase was dried and filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 50:1 to 20:1) to obtain the product (450 mg, yield: 60.0%).

[0995] Step 2: Synthesis of the intermediate (cis)-3-((4-(2-(ethoxymethoxy)-4-ethynylphenyl)phthalazin-1-yl)amino)-1-methylcyclobutane-1-ol

[0996]

[0997] 3-(Ethoxymethoxy)-4-(4-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)phthalazin-1-yl)benzaldehyde (450 mg, 1.10 mmol, 1.0 eq) was dissolved in methanol (5 mL). Dimethyl (1-diazo-2-oxopropyl)phosphonate (254 mg, 1.33 mmol, 1.2 eq) and potassium carbonate (304 mg, 2.20 mmol, 2.0 eq) were added sequentially and stirred at room temperature for 1 h. LC-MS confirmed the reaction was complete. The reaction solution was concentrated, water (5 mL) was added, and the mixture was extracted with dichloromethane (5 mL x 3). The organic phase was dried and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain the product (430 mg, yield: 96.8%).

[0998] Step 3: Synthesis of the intermediate (cis)-3-((4-(4-(bromoethynyl)-2-(ethoxymethoxy)phenyl)phthalazin-1-yl)amino)-1-methylcyclobutane-1-ol

[0999]

[1000] (cis)-3-((4-(2-(ethoxymethoxy)-4-ethynylphenyl)phthalazin-1-yl)amino)-1-methylcyclobutan-1-ol (300 mg, 0.74 mmol, 1.0 eq) obtained in the previous step was dissolved in acetone (6 mL). NBS (158 mg, 0.89 mmol, 1.2 eq) and silver nitrate (13 mg, 0.074 mmol, 0.1 eq) were added and stirred at room temperature overnight. LC-MS confirmed the reaction was complete. The reaction solution was concentrated, water (5 mL) was added, and the mixture was extracted with dichloromethane (5 mL x 3). The organic phase was dried and concentrated to obtain the product (350 mg crude product).

[1001] Step 4: Synthesis of 5-(bromoethynyl)-2-(4-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)phthalazin-1-yl)phenol

[1002]

[1003] (cis)-3-((4-(4-(bromoethynyl)-2-(ethoxymethoxy)phenyl)phthalazin-1-yl)amino)-1-methylcyclobutan-1-ol (350 mg crude product) obtained in the previous step was dissolved in dichloromethane (6 mL). A 4 mol / L hydrogen chloride / 1,4-dioxane solution (0.9 mL) was added and stirred at room temperature for 30 min. LC-MS confirmed the reaction was complete. The reaction solution was poured into water, and the pH was adjusted to approximately 8 with sodium bicarbonate. The layers were separated, and the aqueous phase was extracted with dichloromethane (5 mL x 2). The organic phase was dried, filtered, and concentrated. The crude product was purified by preparative thin-layer chromatography to obtain the product (30 mg, two-step yield: 28.3%).

[1004] 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 9.90 (s, 1H), 8.42 (d, J = 8.2Hz, 1H), 7.87-7.76 (m, 2H), 7.60 (s, 1H), 7.47 (m, d, J = 8.2Hz, 1 H),7.30(d,J=8.0Hz,1H),7.08-7.06(m,2H),5.00(s,1H),4.23(s,1H),2.48-2.47(m,2H),2.21-2.16(m,2H),1.35(s,3H).

[1005] Molecular formula: C 21 H 18 BrN3O2 exact molecular weight: 423.06 LC-MS (m / z): 423.98, 425.98 [M+H] +

[1006] Example 44: Synthesis of (R)-3-ethynyl-2-fluoro-6-(4-((tetrahydro-2H-pyran-3-yl)amino)phthalazin-1-yl)phenol (Compound 45)

[1007]

[1008] step:

[1009]

[1010] The synthesis of this compound was carried out by referring to the steps of the aforementioned examples.

[1011] 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 10.16 (s, 1H), 8.43 (d, J = 8.2Hz, 1H), 7.90-7.79 (m, 2H), 7.50 (d, J = 8.2Hz, 1H), 7.23-7.10 (m, 3H ),4.57(s,1H),4.45-4.41(m,1H),4.10-4.06(m,1H),3.86-3.83(m,1H),3.39-3.24(m,2H),2.17-2.08(m,1H),1.80-1.66(m,3H).

[1012] Molecular formula: C 21 H 18 FN3O2 exact molecular weight: 363.14 LC-MS (m / z): 364.09 [M+H] +

[1013] Example 45: Synthesis of 5-ethynyl-2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazin-3-yl)phenol (Compound 55)

[1014]

[1015] Step 1: Synthesis of 3-(ethoxymethoxy)-4-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazin-3-yl)benzaldehyde

[1016]

[1017] (cis)-3-((6-chloro-5-methylpyridazin-3-yl)amino)-1-methylcyclobutan-1-ol (266.0 mg, 1.16 mmol, 1.0 eq.), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (536.4 mg, 1.75 mmol, 1.5 eq.), sodium bicarbonate (196.2 mg, 2.33 mmol, 2.0 eq.) and Pd(dppf)Cl2 (42.7 mg, 0.05 mmol, 0.05 eq.) were added to a mixed solution of 1,4-dioxane (12.0 mL) and water (4.0 mL). The reaction was carried out at 110 ° C. under nitrogen protection for 3 hours. The reaction was completed after monitoring by TLC. Water (50.0 mL) was added, and the mixture was extracted with ethyl acetate (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 80:1 to 20:1) to give the product (300.0 mg, yield: 69.2%).

[1018] Step 2: Synthesis of (cis)-3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylpyridazin-3-yl)amino)-1-methylcyclobutane-1-ol

[1019]

[1020] 3-(Ethoxymethoxy)-4-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazin-3-yl)benzaldehyde (300.0 mg, 0.80 mmol, 1.0 eq.), dimethyl (1-diazo-2-oxopropyl)phosphonate (232.7 mg, 1.21 mmol, 1.5 eq.), and anhydrous potassium carbonate (223.2 mg, 1.60 mmol, 2.0 eq.) were added to methanol (15.0 mL) and allowed to react at room temperature for 2 hours. TLC monitored the reaction for completion. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 60:1 to 20:1) to obtain the product (270.0 mg, 91.0% yield).

[1021] Step 3: Synthesis of 5-ethynyl-2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazin-3-yl)phenol

[1022]

[1023] (cis)-3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylpyridazin-3-yl)amino)-1-methylcyclobutane-1-ol (270.0 mg, 0.73 mmol, 1.0 eq.) was added to dichloromethane (2.0 mL), and a hydrogen chloride-1,4-dioxane solution (4.0 mol / L, 4.0 mL) was added dropwise. The reaction was allowed to react at room temperature for 1 hour. TLC monitored the reaction to be 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 = 50:1 to 20:1) to obtain the product (150.0 mg, yield: 66.0%).

[1024] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.09 (s, 1H), 7.18-7.16 (d, J = 8Hz, 1H), 6.99 (s, 3H), 6.61 (s, 1H), 4.98 (s,1H),4.17(s,1H),3.93-3.88(m,1H),2.43-2.39(m,2H),2.03(s,3H),1.97-1.92(m,2H),1.29(s,3H).

[1025] Molecular formula: C 18 H 19 N3O2 molecular weight: 309.15 LC-MS (Pos, m / z) = 310.11 [M+H] + .

[1026] Example 46: Synthesis of (R)-5-cyclopropyl-2-(5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)phenol (Compound 192)

[1027]

[1028] Step 1: Synthesis of methyl 4-bromo-2-methoxybenzoate

[1029]

[1030] 4-Bromo-2-methoxybenzoic acid (15.0 g, 64.92 mmol, 1.0 eq.), iodomethane (11.97 g, 84.40 mmol, 1.3 eq.), and anhydrous potassium carbonate (11.60 g, 84.40 mmol, 1.3 eq.) were added to a mixture of acetonitrile (50.0 mL) and N,N-dimethylformamide (50.0 mL). The mixture was allowed to react at room temperature for 12 hours. TLC confirmed the reaction was complete. Water (150.0 mL) was added, followed by extraction with ethyl acetate (200.0 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 (100-200 mesh, heptane:ethyl acetate = 20:1) to obtain the product (15.0 g, yield: 94.3%).

[1031] Step 2: Synthesis of methyl 4-cyclopropyl-2-methoxybenzoate

[1032]

[1033] Methyl 4-bromo-2-methoxybenzoate (6.0 g, 24.48 mmol, 1.0 eq.), cyclopropylboronic acid (4.2 g, 48.96 mmol, 2.0 eq.), potassium phosphate (15.6 g, 73.44 mmol, 3.0 eq.), palladium acetate (1.0 g, 4.89 mmol, 0.2 eq.) and tricyclohexylphosphine (2.7 g, 9.79 mmol, 0.4 eq.) were added to 1, A mixed solution of 4-dioxane (30.0 mL) and water (6.0 mL) was reacted at 100°C under nitrogen protection for 12 hours. The reaction was completed as monitored by TLC. Water (50.0 mL) was added and extracted with ethyl acetate (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (heptane:ethyl acetate = 100:1 to 40:1) to obtain the product (4.4 g, yield: 80.0%).

[1034] Step 3: Synthesis of 4-cyclopropyl-2-methoxybenzoic acid

[1035]

[1036] Methyl 4-cyclopropyl-2-methoxybenzoate (4.4 g, 21.33 mmol, 1.0 eq.) was added to methanol (20.0 mL), and an aqueous solution (10.0 mL) of lithium hydroxide monohydrate (4.4 g, 106.67 mmol, 5.0 eq.) was added dropwise. The reaction was allowed to react at room temperature for 12 hours. The reaction was monitored to be complete by TLC. Hydrochloric acid (2.0 mol / L) was added dropwise to adjust the pH to 2-3. A white solid precipitated, which was filtered and the filter cake was dried to obtain the product (3.8 g, yield: 92.6%).

[1037] Step 4: Synthesis of 1-bromo-4-cyclopropyl-2-methoxybenzene

[1038]

[1039] 4-Cyclopropyl-2-methoxybenzoic acid (3.8 g, 19.77 mmol, 1.0 eq.), potassium phosphate (4.2 g, 19.77 mmol, 1.0 eq.), and tetrabutylammonium tribromide (9.53 g, 19.77 mmol, 1.0 eq.) were added to acetonitrile (40.0 mL) and reacted at 100°C for 2 hours. TLC monitored the reaction for completion. Water (50.0 mL) was added, and the mixture was extracted with ethyl acetate (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (heptane:ethyl acetate = 200:1) to obtain the product (3.5 g, yield: 78.1%).

[1040] Step 5: Synthesis of 2-bromo-5-cyclopropylphenol

[1041]

[1042] 1-Bromo-4-cyclopropyl-2-methoxybenzene (3.5 g, 15.41 mmol, 1.0 eq.) was added to dichloromethane (20.0 mL), and boron tribromide (11.5 g, 46.23 mmol, 3.0 eq.) was added dropwise under an ice-water bath. The mixture was allowed to warm to room temperature and allowed to react for 1 hour. The reaction was monitored by TLC to be complete. The mixture was quenched with methanol (10.0 mL) under an ice-water bath and concentrated under reduced pressure. Dichloromethane (100.0 mL) was added and the mixture was back-extracted with water (50.0 mL). The aqueous phase was adjusted to pH 7-8 with saturated aqueous sodium bicarbonate solution 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 (heptane:ethyl acetate = 10:1) to obtain the product (2.6 g, yield: 79.2%). Step 6: Synthesis of 1-Bromo-4-cyclopropyl-2-(ethoxymethoxy)benzene

[1043]

[1044] 2-Bromo-5-cyclopropylphenol (2.1 g, 9.85 mmol, 1.0 eq.) was added to dry tetrahydrofuran (20.0 mL). The mixture was cooled to 0°C under nitrogen. Sodium hydride (60% by mass, 591.3 mg, 14.78 mmol, 1.5 eq.) was slowly added portionwise. The reaction was allowed to proceed for 0.5 h. Chloromethoxyethane (1.39 g, 14.78 mmol, 1.5 eq.) was then added. The mixture was allowed to warm to room temperature for 2 h. The reaction was complete after TLC monitoring. Water (20.0 mL) was added and extracted with ethyl acetate (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (100-200 mesh, heptane:ethyl acetate = 100:1) to obtain the product (2.5 g, 96.1% yield).

[1045] Step 7: Synthesis of (4-cyclopropyl-2-(ethoxymethoxy)phenyl)boronic acid

[1046]

[1047] 1-Bromo-4-cyclopropyl-2-(ethoxymethoxy)benzene (2.5 g, 9.21 mmol, 1.0 eq.) was added to dry tetrahydrofuran (20.0 mL). The mixture was cooled to -70°C under nitrogen. A solution of n-butyllithium in n-hexane (2.5 mol / L, 5.5 mL, 13.82 mmol, 1.5 eq.) was slowly added dropwise. The mixture was allowed to react for 1 hour. Triisopropyl borate (2.25 g, 11.98 mmol, 1.3 eq.) was added and the mixture was allowed to warm to room temperature for 3 hours. The reaction was complete after TLC monitoring. Saturated aqueous ammonium chloride (50.0 mL) was added and the mixture was extracted with ethyl acetate (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product (1.5 g, yield: 69.1%).

[1048] Step 8: Synthesis of (R)-6-(4-cyclopropyl-2-(ethoxymethoxy)phenyl)-5-methyl-N-(1-methylpiperidin-3-yl)-1,2,4-triazin-3-amine

[1049]

[1050] (R)-6-Bromo-5-methyl-N-(1-methylpiperidin-3-yl)-1,2,4-triazin-3-amine (311.0 mg, 1.08 mmol, 1.0 eq.), (4-cyclopropyl-2-(ethoxymethoxy)phenyl)boronic acid (384.8 mg, 1.63 mmol, 1.5 eq.), sodium bicarbonate (182.4 mg, 2.17 mmol, 2.0 eq.) and Pd(dppf)Cl2 (79.4 mg, 0.10 mm ol, 0.1 eq.) was added to a mixed solution of 1,4-dioxane (10.0 mL) and water (5.0 mL). The reaction was carried out at 110°C under nitrogen protection for 2 hours. The reaction was completed after monitoring by TLC. Water (50.0 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 = 80:1 to 40:1) to obtain the product (333.0 mg, yield: 77.2%).

[1051] Step 9: Synthesis of (R)-5-cyclopropyl-2-(5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)phenol

[1052]

[1053] (R)-6-(4-cyclopropyl-2-(ethoxymethoxy)phenyl)-5-methyl-N-(1-methylpiperidin-3-yl)-1,2,4-triazin-3-amine (300.0 mg, 0.75 mmol, 1.0 eq.) was added to dichloromethane (4.0 mL), and a solution of hydrogen chloride in 1,4-dioxane (4.0 mol / L, 4.0 mL) was added dropwise. The mixture was allowed to react at room temperature for 1 hour. TLC monitored the reaction for completion. 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 preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain the product (200.0 mg, yield: 78.1%).

[1054] 1HNMR (400MHz, DMSO-d6) δ (ppm): 9.61 (s, 1H), 7.36 (s, 1H), 7.11-7.09 (d, J = 8Hz, 1H), 6.64-6.62 (m, 2H), 3.97 (s, 1H), 2.88 (s, 1H), 2.65-2.62 (m,1H),2.18-2.17(m,6H),1.92-1.85(m,4H),1.72-1.68(m,1H),1.57 -1.47(m,1H),1.35-1.23(m,1H),0.99-0.92(m,2H),0.68-0.64(m,2H).

[1055] Molecular formula: C 19 H 25 N5O molecular weight: 339.21 LC-MS (Pos, m / z) = 340.15 [M+H] + .

[1056] Example 47: Synthesis of (R)-5-ethynyl-2-(5-methyl-3-(((tetrahydrofuran-2-yl)methyl)amino)-1,2,4-triazin-6-yl)phenol (Compound 250)

[1057]

[1058] Step 1: Synthesis of (R)-5-methyl-N-((tetrahydrofuran-2-yl)methyl)-1,2,4-triazin-3-amine

[1059]

[1060] 5-Methyl-3-(methylsulfinyl)-1,2,4-triazine (1.39 g, 8.85 mmol, 1.0 eq.), (R)-(tetrahydrofuran-2-yl)methanamine (1.34 g, 13.27 mmol, 1.5 eq.), and triethylamine (2.68 g, 26.55 mmol, 3.0 eq.) were added to 1,4-dioxane (20.0 mL) and stirred at 100°C for 1 hour. The reaction was complete after TLC monitoring. The mixture was concentrated under reduced pressure, and saturated aqueous ammonium chloride (100.0 mL) was added. 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 to 80:1) to obtain the product (1.27 g, yield: 73.8%).

[1061] Step 2: Synthesis of (R)-6-bromo-5-methyl-N-((tetrahydrofuran-2-yl)methyl)-1,2,4-triazin-3-amine

[1062]

[1063] (R)-5-Methyl-N-((tetrahydrofuran-2-yl)methyl)-1,2,4-triazin-3-amine (1.27 g, 6.53 mmol, 1.0 eq.) and N-bromosuccinimide (1.22 g, 6.86 mmol, 1.05 eq.) were added to N,N-dimethylformamide (10.0 mL) and allowed to react at room temperature for 2 hours. TLC confirmed the reaction was complete. Water (50.0 mL) was added, and the mixture was extracted with ethyl acetate (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (heptane:ethyl acetate = 10:1 to 6:1) to obtain the product (520.0 mg, yield: 29.1%).

[1064] Step 3: Synthesis of (R)-3-(ethoxymethoxy)-4-(5-methyl-3-(((tetrahydrofuran-2-yl)methyl)amino)-1,2,4-triazin-6-yl)benzaldehyde

[1065]

[1066] (R)-6-Bromo-5-methyl-N-((tetrahydrofuran-2-yl)methyl)-1,2,4-triazin-3-amine (520.0 mg, 1.90 mmol, 1.0 eq.), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (874.3 mg, 2.85 mmol, 1.5 eq.), sodium bicarbonate (319.7 mg, 3.80 mmol, 2.0 eq.) and Pd(dppf)Cl2 (69.6 mg, 0.09 mmol, 0.05 eq.) were added to a mixed solution of 1,4-dioxane (10.0 mL) and water (5.0 mL). The reaction was carried out at 110°C under nitrogen protection for 3 hours. The reaction was completed after monitoring by TLC. Water (50.0 mL) was added, extracted with ethyl acetate (100.0 mL), and 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 (630.0 mg, yield: 88.9%).

[1067] Step 4: Synthesis of (R)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-N-((tetrahydrofuran-2-yl)methyl)-1,2,4-triazin-3-amine

[1068]

[1069] (R)-3-(Ethoxymethoxy)-4-(5-methyl-3-(((tetrahydrofuran-2-yl)methyl)amino)-1,2,4-triazin-6-yl)benzaldehyde (315.0 mg, 0.84 mmol, 1.0 eq.), dimethyl (1-diazo-2-oxopropyl)phosphonate (243.7 mg, 1.26 mmol, 1.5 eq.), and anhydrous potassium carbonate (350.3 mg, 2.53 mmol, 3.0 eq.) were added to methanol (10.0 mL) and allowed to react at room temperature for 2 hours. TLC monitored the reaction for completion. The mixture 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 (290.0 mg, yield: 93.2%).

[1070] Step 5: Synthesis of (R)-5-ethynyl-2-(5-methyl-3-(((tetrahydrofuran-2-yl)methyl)amino)-1,2,4-triazin-6-yl)phenol

[1071]

[1072] (R)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-N-((tetrahydrofuran-2-yl)methyl)-1,2,4-triazin-3-amine (280.0 mg, 0.75 mmol, 1.0 eq.) was added to dichloromethane (3.0 mL), and 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 1 hour, and the reaction was complete after TLC monitoring. 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 preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to obtain the product (150.0 mg, yield: 63.6%).

[1073] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.11 (s, 1H), 7.63 (s, 1H), 7.27-7.25 (d, J = 8Hz, 1H), 7.04 (s, 1H), 7.01 (s, 1H), 4.23 (s, 1H), 4.06-4 .03(m,1H),3.81-3.76(m,1H),3.66-3.60(m,1H),3.50-3.46(m,1H),3.38(s,1H),2.18(s,3H),1.98-1.75(m,3H),1.66-1.58(m,1H).

[1074] Molecular formula: C 17 H 18N4O2 molecular weight: 310.14 LC-MS (Pos, m / z) = 311.10 [M+H] + .

[1075] Example 48: Synthesis of (R)-5-ethynyl-2-(5-methyl-3-((1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-3-yl)amino)-1,2,4-triazin-6-yl)phenol (Compound 255)

[1076]

[1077] Step 1: Synthesis of (R)-5-ethynyl-2-(5-methyl-3-((1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-3-yl)amino)-1,2,4-triazin-6-yl)phenol

[1078]

[1079] (R)-5-Ethynyl-2-(5-methyl-3-(piperidin-3-ylamino)-1,2,4-triazin-6-yl)phenol (211.7 mg, 0.68 mmol, 1.0 eq.) and aqueous formaldehyde (37% by mass, 117.1 mg, 1.02 mmol, 1.5 eq.) were added to methanol (10.0 mL) and allowed to react at room temperature for 0.5 hour. Sodium cyanoborohydride (64.5 mg, 1.02 mmol, 1.5 eq.) was then added and allowed to react at room temperature for another hour. TLC monitored the reaction for completion. Saturated aqueous sodium bicarbonate (50.0 mL) was added, and the mixture was stirred for 30 minutes. The mixture was extracted with dichloromethane (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to afford the product (80.0 mg, 28.7% yield).

[1080] 1 HNMR(400MHz,DMSO-d6)δ(ppm):10.11(s,1H),7.63(s,1H),7.27-7.25(d, J=8Hz,1H),7.04-7.01(m,2H),4.23(s,1H),3.98(s,1H),3.83-3.80(m,2H) ),3.29-3.23(m,3H),2.94-2.92(m,1H),2.70-2.68(m,1H),2.17(s,3H),2 .15-2.13(m,2H),1.93-1.85(m,5H),1.61-1.47(m,4H),1.40-1.33(m,1H).

[1081] Molecular formula: C 23H 29 N5O2 molecular weight: 407.23 LC-MS (Pos, m / z) = 408.18 [M+H] + .

[1082] Example 49 Synthesis of 5-ethynyl-2-(7-((cis-3-hydroxy-3-methylcyclobutyl)amino)thieno[2,3-d]pyridazin-4-yl)phenol (Compound 11)

[1083]

[1084] Step 1: Synthesis of cis-3-((4-chlorothienyl[2,3-d]pyridazin-7-yl)amino)-1-methylcyclobutan-1-ol

[1085]

[1086] 4,7-Dichlorothieno[2,3-d]pyridazine (1.00 g, 4.88 mmol, 1.0 eq), cis-3-amino-1-methylcyclobutanol hydrochloride (671 mg, 4.88 mmol, 1.1 eq), Pd2(dba)3 (447 mg, 4.88 mmol, 0.1 eq), BINAP (607 mg, 0.976 mmol, 0.2 eq) and Cs2CO3 (3.18 g, 9.76 mmol, 2.0 eq) were added to 1,4-dioxane (50 mL) in sequence, heated to 90 ° C under nitrogen protection, and reacted for 2 hours. The mixture was cooled to room temperature, quenched by addition of water (50 mL), extracted with EA (30 mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (DCM:MeOH=20:1) to give the product (240 mg, yield: 18.2%).

[1087] Step 2: Synthesis of 3-(ethoxymethoxy)-4-(7-((cis-3-hydroxy-3-methylcyclobutyl)amino)thienyl[2,3-d]pyridazin-4-yl)benzaldehyde

[1088]

[1089] 3-(Ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (409 mg, 1.34 mmol, 1.5 eq), cis-3-((4-chlorothienyl[2,3-d]pyridazin-7-yl)amino)-1-methylcyclobutane-1-ol (240 mg, 0.890 mmol, 1.0 eq), Pd(dppf)Cl2 (65.1 mg, 0.0890 mmol, 0.1 eq) and NaHCO3 (150 mg, 1.78 mmol, 2.0 eq) were added to 1,4-dioxane (6 mL) in sequence, and H2O (3 mL) was added. Under nitrogen protection, the mixture was heated to 100°C and reacted for 2 hours. The mixture was cooled to room temperature, quenched with water (20 mL), extracted with EA (30 mL × 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 20:1) to obtain the product (214 mg, yield: 58.2%). Step 3: Synthesis of cis-3-((4-(2-(ethoxymethoxy)-4-ethynylphenyl)thieno[2,3-d]pyridazin-7-yl)amino)-1-methylcyclobutane-1-ol

[1090]

[1091] 3-(Ethoxymethoxy)-4-(7-((cis-3-hydroxy-3-methylcyclobutyl)amino)thiopheno[2,3-d]pyridazin-4-yl)benzaldehyde (214 mg, 0.518 mmol, 1.0 eq) was dissolved in MeOH (4 mL), and KCO (144 mg, 1.04 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (149 mg, 0.777 mmol, 1.5 eq) were added. The mixture was stirred at room temperature for 2 hours. Water (10 mL) was added to quench the mixture, and the mixture was extracted with EA (10 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 (DCM:MeOH = 100:1 to 30:1) to obtain the product (192 mg, yield: 90.6%).

[1092] Step 4: Synthesis of 5-ethynyl-2-(7-((cis-3-hydroxy-3-methylcyclobutyl)amino)thieno[2,3-d]pyridazin-4-yl)phenol

[1093]

[1094] cis-3-((4-(2-(ethoxymethoxy)-4-ethynylphenyl)thieno[2,3-d]pyridazin-7-yl)amino)-1-methylcyclobutan-1-ol (192 mg, 0.469 mmol, 1.0 eq) was dissolved in DCM (3 mL). A solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 0.59 mL, 2.35 mmol, 5.0 eq) was then added dropwise. The mixture was stirred at room temperature for 1 hour. The pH was adjusted to 8 with saturated aqueous NaHCO₃ solution, and the mixture was extracted with a 10:1 DCM:MeOH mixture (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 50:1 to 20:1) to obtain the product (142 mg, yield: 86.2%).

[1095] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 11.52 (s, 1H), 8.12 (d, J = 5.3Hz, 1H), 7.63-7.59 (m, 2H), 7.50 (d, J = 5.3Hz, 1H ),7.07(d,J=6.9Hz,2H),4.99(s,1H),4.29-4.20(m,2H),2.47-2.45(m,2H),2.19-2.14(m,2H),1.34(s,3H).

[1096] Molecular formula: C 19 H 17 N3O2S exact molecular weight: 351.10 LC-MS (Pos, m / z) = 352.05 [M+H] + .

[1097] Example 50 Synthesis of 5-(1-hydroxy-2-yn-1-yl)-2-(4-methyl-6-(((R)-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol (Compound 175)

[1098]

[1099] Step 1: Synthesis of 1-(3-(ethoxymethoxy)-4-(4-methyl-6-(((R)-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenyl)prop-2-yn-1-ol

[1100]

[1101] (R)-3-(Ethoxymethoxy)-4-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)benzaldehyde (160 mg, 0.416 mmol, 1.0 eq) was dissolved in THF (3 mL). Under nitrogen, a 0.5 mol / L solution of ethynylmagnesium bromide in tetrahydrofuran (2.50 mL, 1.25 mmol, 3.0 eq) was added dropwise at room temperature. The mixture was allowed to react for 3 hours. Saturated aqueous ammonium chloride was added to quench the reaction, and the mixture was extracted with DCM (15 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 (DCM:MeOH = 50:1 to 10:1) to afford the product (112 mg, 65.6% yield).

[1102] Step 2: Synthesis of 5-(1-hydroxy-2-yn-1-yl)-2-(4-methyl-6-(((R)-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol

[1103]

[1104] 1-(3-(Ethoxymethoxy)-4-(4-methyl-6-(((R)-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenyl)prop-2-yn-1-ol (90 mg, 0.219 mmol, 1.0 eq) was dissolved in DCM (2 mL), and then a solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 0.16 mL, 0.675 mmol, 3.0 eq) was added dropwise. The mixture was stirred at room temperature for 1 hour. The pH value was adjusted to 8 with saturated NaHCO3 aqueous solution, and then extracted with a mixed solvent (DCM:MeOH=10:1, 15 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (DCM:MeOH=8:1) to give the product (46.3 mg, yield: 59.9%).

[1105] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 9.89 (s, 1H), 7.14 (d, J = 7.7Hz, 1H), 7.09 (s, 1H) ,6.97(d,J=7.8Hz,1H),6.90(s,1H),6.72(s,1H),6.07(d,J=5.9Hz,1H),5.33(d ,J=3.8Hz,1H),4.25(s,1H),3.51(d,J=1.6Hz,1H),3.00(s,1H),2.55(s,3H),2. 05(s,3H),2.01-1.98(m,1H),1.90(s,2H),1.75-1.73(m,2H),1.48-1.40(m,2H).

[1106] Molecular formula: C 20 H 24 N4O2 exact molecular weight: 352.19 LC-MS (Pos, m / z) = 353.12 [M+H] + .

[1107] Example 51 Synthesis of (R)-2-(3-((6-(4-ethynyl-2-hydroxyphenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)acetonitrile (Compound 222)

[1108]

[1109] Step 1: Synthesis of (R)-2-(3-((6-(2-(ethoxymethoxy)-4-formylphenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)acetonitrile

[1110]

[1111] 3-(Ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (346 mg, 1.13 mmol, 1.5 eq), (R)-2-(3-((6-chloro-5-methylpyridazin-3-yl)amino)piperidin-1-yl)acetonitrile (200 mg, 0.753 mmol, 1.0 eq), Pd(dppf)Cl2 (55.1 mg, 0.0753 mmol, 0.1 eq) and NaHCO3 (127 mg, 1.51 mmol, 2.0 eq) were added to 1,4-dioxane (6 mL) in sequence, and H2O (3 mL) was added. Under nitrogen protection, the mixture was heated to 110°C and reacted for 2 hours. The mixture was cooled to room temperature, quenched by addition of water (20 mL), extracted with EA (20 mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH=100:1-20:1) to give the product (126 mg, yield: 40.9%).

[1112] Step 2: Synthesis of (R)-2-(3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)acetonitrile

[1113]

[1114] (R)-2-(3-((6-(2-(ethoxymethoxy)-4-formylphenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)acetonitrile (126 mg, 0.308 mmol, 1.0 eq) was dissolved in MeOH (4 mL), and KCO (85.1 mg, 0.616 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (88.7 mg, 0.462 mmol, 1.5 eq) were added. The mixture was stirred at room temperature for 2 hours. Water (20 mL) was added to quench the mixture, and the mixture was extracted with EA (20 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 (DCM:MeOH = 100:1 to 50:1) to obtain the product (72.0 mg, yield: 57.7%).

[1115] Step 3: Synthesis of (R)-2-(3-((6-(4-ethynyl-2-hydroxyphenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)acetonitrile

[1116]

[1117] (R)-2-(3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)acetonitrile (72.0 mg, 0.178 mmol, 1.0 eq) was dissolved in DCM (2 mL), and a solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 0.13 mL, 0.534 mmol, 3.0 eq) was added dropwise. The mixture was stirred at room temperature for 1 hour. The pH was adjusted to 8 with saturated aqueous NaHCO₃, and the mixture was extracted with DCM (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 50:1) to obtain the product (26.0 mg, 42.1% yield).

[1118] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.12 (s, 1H), 7.17 (d, J = 7.6Hz, 1H), 7.01-6.98 (m,2H),6.72-6.69(m,2H),4.18(s,1H),4.09-4.07(m,1H),3.77(s,2H),2.99(d, J=87.3Hz,1H),2.68-2.66(m,1H),2.26-2.21(m,1H),2.14-2.09(m,1H),2.03(s, 3H),1.91-1.87(m,1H),1.80-1.76(m,1H),1.62-1.54(m,1H),1.34-1.30(m,1H).

[1119] Molecular formula: C 20 H 21 N5O2 exact molecular weight: 347.17 LC-MS (Pos, m / z) = 348.14 [M+H] + .

[1120] Example 52 Synthesis of (R)-2-(5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)-5-vinylphenol (Compound 189)

[1121]

[1122] Step 1: Synthesis of (R)-2-(5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)-5-vinylphenol

[1123]

[1124] (R)-5-Ethynyl-2-(5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)phenol (80.0 mg, 0.247 mmol, 1.0 eq) was dissolved in MeOH (5 mL) and Lindlar catalyst (8 mg, 10%) was added. The hydrogen atmosphere was replaced and the reaction was allowed to proceed at room temperature for 1 hour. The mixture was filtered through Celite, concentrated under reduced pressure, and slurried in a 5:1 PE:EA mixture to obtain the product (65.0 mg, 80.7% yield).

[1125] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 9.96 (s, 1H), 7.61 (s, 1H), 7.23 (d, J = 7.8Hz, 1H), 7.05(d,J=7.5Hz,2H),5.75-6.68(m,1H),5.79(d,J=17.6Hz,1H),5.29(d,J=11.0 Hz,1H),4.15(s,1H),3.17(s,1H),2.91(s,1H),2.44(s,3H),2.33(s,2H),2.21(s ,3H),1.92-1.90(m,1H),1.82-1.79(m,1H),1.72-1.66(m,1H),1.44-1.40(m,1H).

[1126] Molecular formula: C 18 H 23 N5O exact molecular weight: 325.19 LC-MS (Pos, m / z) = 326.12 [M+H] + .

[1127] Example 53 Synthesis of 5-ethynyl-2-(3-((cis-3-hydroxy-3-methylcyclobutyl)amino)-5-methyl-1,2,4-triazin-6-yl)phenol (Compound 59)

[1128]

[1129] Step 1: Synthesis of 1-amino-S-methylisothiourea hydroiodide

[1130]

[1131] Thiosemicarbazide (100 g, 1.10 mol, 1.0 eq) and iodomethane (187 g, 1.32 mol, 1.2 eq) were added to ethanol (400 mL) and heated to 80°C for 16 hours. After cooling to room temperature, a solid precipitated, which was filtered and dried to obtain the product (233 g, 91.1% yield).

[1132] Step 2: Synthesis of 5-methyl-3-(methylthio)-1,2,4-triazine

[1133]

[1134] A 40% aqueous solution of methylglyoxal (180 g, 1.00 mol, 1.0 eq) was dissolved in H2O (500 mL) and cooled to 0°C in an ice-water bath. NaHCO3 (84.0 g, 1.00 mol, 1.0 eq) was then added. 1-Amino-S-methylisothiourea hydroiodide (233 g, 1.00 mol, 1.0 eq) was then dissolved in water and added dropwise to the aqueous solution of methylglyoxal at 0°C. The mixture was allowed to react for 6 hours. The mixture was extracted with DCM (300 mL x 4), 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 10:1) to obtain the crude product, which was then recrystallized from a PE:EA = 20:1 mixed solvent to obtain the product (85.0 g, yield: 60.2%).

[1135] Step 3: Synthesis of 5-methyl-3-(methylsulfinyl)-1,2,4-triazine

[1136]

[1137] Dissolve 5-methyl-3-(methylthio)-1,2,4-triazine (2.00 g, 0.0142 mol, 1.0 eq) in DCM (20 mL) and stir at room temperature. Add m-chloroperbenzoic acid (2.88 g, 0.0142 mol, 1.0 eq) portionwise and stir at room temperature for 1 hour. Filter and concentrate the filtrate under reduced pressure and use directly in the next step.

[1138] Step 4: Synthesis of cis-1-methyl-3-((5-methyl-1,2,4-triazin-3-yl)amino)cyclobutan-1-ol

[1139]

[1140] 5-Methyl-3-(methylsulfinyl)-1,2,4-triazine was dissolved in 1,4-dioxane (30 mL), and triethylamine (2.87 g, 0.0284 mol, 2.0 eq) and cis-3-amino-1-methylcyclobutanol hydrochloride (1.95 g, 0.0142 mol, 1.0 eq) were added. The mixture was heated to 100°C for 1 hour. After cooling to room temperature, the mixture was quenched by the addition of water (100 mL) and extracted with EA (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 20:1) to obtain the product (2.10 g, two-step yield: 76.3%).

[1141] Step 5: Synthesis of cis-3-((6-bromo-5-methyl-1,2,4-triazin-3-yl)amino)-1-methylcyclobutane-1-ol

[1142]

[1143] Dissolve cis-1-methyl-3-((5-methyl-1,2,4-triazin-3-yl)amino)cyclobutan-1-ol (1.20 g, 6.18 mmol, 1.0 eq) in DCM (20 mL), add dibromohydantoin (3.53 g, 12.4 mmol, 2.0 eq), and allow to react at room temperature for 1 hour. Quench with saturated sodium thiosulfate solution, extract with DCM (50 mL x 2), dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product is purified by silica gel column chromatography (DCM:MeOH = 100:1 to 20:1) to afford the product (550 mg, 32.6% yield).

[1144] Step 6: Synthesis of 3-(ethoxymethoxy)-4-(3-((cis-3-hydroxy-3-methylcyclobutyl)amino)-5-methyl-1,2,4-triazin-6-yl)benzaldehyde

[1145]

[1146] 3-(Ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (840 mg, 2.75 mmol, 1.5 eq), cis-3-((6-bromo-5-methyl-1,2,4-triazin-3-yl)amino)-1-methylcyclobutane-1-ol (500 mg, 1.83 mmol, 1.0 eq), Pd(dppf)Cl2 (134 mg, 0.183 mmol, 0.1 eq) and NaHCO3 (307 mg, 3.66 mmol, 2.0 eq) were added to 1,4-dioxane (10 mL) in sequence, and H2O (5 mL) was added. Under nitrogen protection, the mixture was heated to 110°C and reacted for 2 hours. The mixture was cooled to room temperature, quenched by addition of water (30 mL), extracted with EA (30 mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH=100:1-20:1) to give the product (510 mg, yield: 74.8%).

[1147] Step 7: Synthesis of cis-3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-1,2,4-triazin-3-yl)amino)-1-methylcyclobutane-1-ol

[1148]

[1149] 3-(Ethoxymethoxy)-4-(3-((cis-3-hydroxy-3-methylcyclobutyl)amino)-5-methyl-1,2,4-triazin-6-yl)benzaldehyde (510 mg, 1.37 mmol, 1.0 eq) was dissolved in MeOH (10 mL). KCO (379 mg, 2.74 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (395 mg, 2.06 mmol, 1.5 eq) were added and stirred at room temperature for 2 hours. The mixture was concentrated and the crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 20:1) to obtain the product (495 mg, 98.1% yield).

[1150] Step 8: Synthesis of 5-ethynyl-2-(3-((cis-3-hydroxy-3-methylcyclobutyl)amino)-5-methyl-1,2,4-triazin-6-yl)phenol

[1151]

[1152] cis-3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-1,2,4-triazin-3-yl)amino)-1-methylcyclobutan-1-ol (490 mg, 1.33 mmol, 1.0 eq) was dissolved in DCM (10 mL). A solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 1.0 mL, 3.99 mmol, 3.0 eq) was added dropwise and stirred at room temperature for 1 hour. The pH was adjusted to 8 with saturated aqueous NaHCO₃ solution, and the mixture was extracted with DCM (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 20:1) to obtain the product (310 mg, yield: 75.1%).

[1153] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.09 (s, 1H), 7.85 (s, 1H), 7.26 (d, J = 7.6Hz, 1H), 7.04-7.02 (m, 2H), 4 .99(s,1H),4.21(s,1H),3.95(s,1H),2.39-2.35(m,2H),2.18(s,3H),2.08-2.03(m,2H),1.28(s,3H).

[1154] Molecular formula: C 17 H 18 N4O2 exact molecular weight: 310.14 LC-MS (Pos, m / z) = 311.11 [M+H] + .

[1155] Example 54: Synthesis of (R)-6-(4-ethynyl-2-hydroxyphenyl)-5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazine-2-oxide (Compound 249)

[1156]

[1157] Step 1: Synthesis of (R)-6-bromo-3-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-5-methyl-1,2,4-triazine-2-oxide

[1158]

[1159] Dissolve (R)-tert-Butyl 3-((6-bromo-5-methyl-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate (1.00 g, 2.69 mmol, 1.0 eq) in DCM (10 mL) and stir at room temperature. Add m-chloroperbenzoic acid (464 mg, 2.69 mmol, 1.0 eq) and stir at room temperature for 4 hours. Quench with saturated aqueous NaHCO₃ solution and extract with DCM (20 mL x 2). The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The crude product is purified by silica gel column chromatography (PE:EA = 10:1 to 2:1) to obtain the product (945 mg, 90.6% yield).

[1160] Step 2: Synthesis of (R)-3-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-6-(2-(ethoxymethoxy)-4-formylphenyl)-5-methyl-1,2,4-triazine-2-oxide

[1161]

[1162] 3-(Ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (712 mg, 2.33 mmol, 1.5 eq), (R)-6-bromo-3-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-5-methyl-1,2,4-triazine-2-oxide (600 mg, 1.55 mmol, 1.0 eq), Pd(dppf)Cl2 (113 mg, 0.155 mmol, 0.1 eq) and NaHCO3 (260 mg, 3.10 mmol, 2.0 eq) were added to 1,4-dioxane (20 mL) in sequence, and H2O (5 mL) was added. Under nitrogen protection, the mixture was heated to 110°C and reacted for 1 hour. The mixture was cooled to room temperature, quenched by addition of water (50 mL), extracted with EA (30 mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH=100:1-20:1) to give the product (650 mg, yield: 86.3%).

[1163] Step 3: Synthesis of (R)-3-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-1,2,4-triazine-2-oxide

[1164]

[1165] (R)-3-((1-(tert-Butoxycarbonyl)piperidin-3-yl)amino)-6-(2-(ethoxymethoxy)-4-formylphenyl)-5-methyl-1,2,4-triazine-2-oxide (650 mg, 1.33 mmol, 1.0 eq) was dissolved in MeOH (15 mL). KCO (368 mg, 2.66 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (384 mg, 2.00 mmol, 1.5 eq) were added, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated, and the crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 20:1) to obtain the product (582 mg, 90.3% yield).

[1166] Step 4: Synthesis of (R)-6-(4-ethynyl-2-hydroxyphenyl)-5-methyl-3-(piperidin-3-ylamino)-1,2,4-triazine-2-oxide

[1167]

[1168] (R)-3-((1-(tert-Butoxycarbonyl)piperidin-3-yl)amino)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-1,2,4-triazine-2-oxide (580 mg, 1.20 mmol, 1.0 eq) was dissolved in DCM (10 mL). A solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 1.2 mL, 4.80 mmol, 4.0 eq) was added dropwise and stirred at room temperature for 2 hours. The pH was adjusted to 8 with saturated aqueous NaHCO₃ solution, and the mixture was extracted with DCM (30 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 (DCM:MeOH = 50:1 to 10:1) to obtain the product (348 mg, yield: 89.2%).

[1169] Step 5: Synthesis of (R)-6-(4-ethynyl-2-hydroxyphenyl)-5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazine-2-oxide

[1170]

[1171] (R)-6-(4-ethynyl-2-hydroxyphenyl)-5-methyl-3-(piperidin-3-ylamino)-1,2,4-triazine-2-oxide (345 mg, 1.06 mmol, 1.0 eq) was dissolved in MeOH (30 mL). Aqueous formaldehyde (37% by mass, 103 mg, 1.27 mmol, 1.2 eq) was added and stirred at room temperature for 20 minutes. NaBH3CN (80.0 mg, 1.27 mmol, 1.2 eq) was then added and allowed to react for 1 hour. The mixture was concentrated, dissolved in DCM (30 mL), and washed with saturated aqueous NaHCO3. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 50:1) to obtain the product (312 mg, yield: 86.7%). 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.12 (s, 1H), 7.90 (d, J = 8.3Hz, 1H), 7.24-7.22 (m, 1H), 7.03-7.01 (m, 2H), 4.25 (s, 1H), 4.04-4.02 (m, 1 H),2.66(d,J=9.1Hz,1H),2.45(s,1H),2.20(s,3H),2.19(s,3H),2.12(s,1H),1.69-1.65(m,2H),1.61-1.52(m,2H),1.28-1.26(m,1H).

[1172] Molecular formula: C 18 H 21 N5O2 exact molecular weight: 339.17 LC-MS (Pos, m / z) = 340.15 [M+H] + .

[1173] Example 55 Synthesis of Compound 5-ethynyl-2-(4-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)phenol (Compound 8)

[1174]

[1175] Synthesis route

[1176]

[1177] The synthesis of this compound was carried out by referring to the steps of the aforementioned examples.

[1178] 1HNMR (400MHz, DMSO-d6) δ (ppm): 13.65 (s, 1H), 7.58-7.56 (d, J = 8Hz, 1H), 7.00-6.97 (m, 2H), 6.84-6.82 (d, J = 8Hz, 1H), 4.95 (s, 1H),4.21(s,1H),4.14-4.09(m,1H),3.15-3.11(m,2H),2.78(t,J=8Hz,2H),2.44-2.40(m,2H),2.11-2.03(m,4H),1.31(s,3H).

[1179] Molecular formula: C 20 H 21 N3O2 exact molecular weight: 335.16 LC-MS (Pos, m / z) = 336.09 [M+H] +

[1180] Example 56 Synthesis of (cis)-3-((4-(4-ethynyl-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1-yl)amino)-1-methylcyclobutane-1-ol (Compound 49)

[1181]

[1182] Synthesis route

[1183]

[1184] The synthesis of this compound was carried out by referring to the steps of the aforementioned examples.

[1185] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 7.43 (s, 1H), 7.36-7.34 (m, 1H), 7.14-7.12 (d, J = 8Hz, 1H), 6.11-6.10 (d, J = 4Hz, 1H), 4.90 (s, 1H), 4. 19(s,1H),4.14-4.09(m,1H),2.42-2.37(m,4H),2.10-2.08(m,4H),1.99(s,3H),1.74-1.73(m,2H),1.61-1.59(m,2H),1.30(s,3H).

[1186] Molecular formula: C 22 H 25 N3O exact molecular weight: 347.20 LC-MS (Pos, m / z) = 348.13 [M+H] +

[1187] Example 57 Synthesis of (cis)-3-((4-(4-ethynylphenyl)phthalazin-1-yl)amino)-1-methylcyclobutane-1-ol (Compound 148)

[1188]

[1189] Synthesis route

[1190]

[1191] The synthesis of this compound was carried out by referring to the steps of the aforementioned examples.

[1192] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 8.48-8.46 (d, J = 8Hz, 1H), 7.92-7.77 (m, 3H), 7.66-7.62 ( m,4H),4.99(s,1H),4.30-4.23(m,2H),2.51-2.47(m,2H),2.21-2.16(m,2H),1.34(s,3H).

[1193] Molecular formula: C 21 H 19 N3O exact molecular weight: 329.15 LC-MS (Pos, m / z) = 330.11 [M+H] +

[1194] Example 58 Synthesis of (cis)-3-((4-(4-ethynyl-2-fluorophenyl)phthalazin-1-yl)amino)-1-methylcyclobutane-1-ol (Compound 149)

[1195]

[1196] Synthesis route

[1197]

[1198] The synthesis of this compound was carried out by referring to the steps of the aforementioned examples.

[1199] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 8.48-8.46 (d, J = 8Hz, 1H), 7.92-7.72 (m, 3H), 7.59-7.46 ( m,4H),5.00(s,1H),4.29-4.24(m,1H),2.51-2.47(m,2H),2.21-2.16(m,2H),1.34(s,3H)

[1200] Molecular formula: C 21 H18 FN3O exact molecular weight: 347.14 LC-MS (Pos, m / z) = 348.08 [M+H] +

[1201] Example 59 Synthesis of (R)-5-ethynyl-2-(5-methyl-3-((1-(tetrahydro-2H-pyran-4-yl)piperidin-3-yl)amino)-1,2,4-triazin-6-yl)phenol (Compound 248)

[1202]

[1203] Synthesis route

[1204]

[1205] The synthesis of this compound was carried out by referring to the steps of the aforementioned examples.

[1206] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.11 (s, 1H), 7.49 (s, 1H), 7.27-7.25 (d, J = 8Hz, 1H), 7.04-7.02 (m, 2H), 4.23 (s, 1H), 3. 97-3.82(m,3H),3.26(t,J=12Hz,1H),3.04(s,1H),2.77(s,1H),2.05-2.18(m,5H),1.91-1.86(m,1H),1.65-1.33(m,7H).

[1207] Molecular formula: C 22 H 27 N5O2 exact molecular weight: 393.22 LC-MS (Pos, m / z) = 394.15 [M+H] +

[1208] Example 60 Synthesis of (S)-5-ethynyl-2-(5-methyl-3-(((tetrahydrofuran-2-yl)methyl)amino)-1,2,4-triazin-6-yl)phenol (Compound 251)

[1209]

[1210] Synthesis route

[1211]

[1212] The synthesis of this compound was carried out by referring to the steps of the aforementioned examples.

[1213] 1HNMR (400MHz, DMSO-d6) δ (ppm): 10.11 (s, 1H), 7.79 (s, 1H), 7.27-7.25 (d, J = 8Hz, 1H), 7.04-7.01 (m, 2H), 4.23 (s, 1H), 4.06-4.03 (m,1H),3.81-3.76(m,1H),3.66-3.60(m,1H),3.50-3.46(m,1H),3.38(s,1H),2.18(s,3H),1.98-1.75(m,3H),1.66-1.58(m,1H).

[1214] Molecular formula: C 17 H 18 N4O2 exact molecular weight: 310.14 LC-MS (Pos, m / z) = 311.08 [M+H] +

[1215] Example 61 Synthesis of (R)-2-(3-((6-(4-ethynyl-2-hydroxyphenyl)-5-methyl-1,2,4-triazin-3-yl)amino)piperidin-1-yl)acetic acid (Compound 258)

[1216]

[1217] Synthesis route

[1218]

[1219] The synthesis of this compound was carried out by referring to the steps of the aforementioned examples.

[1220] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.30 (s, 1H), 7.66 (s, 1H), 7.26-7.24 (d, J = 8Hz, 1H), 7.06-7.01 (m, 2H), 4.23-4.16 (m, 2H) ,3.51(s,2H),3.31-3.29(m,1H),3.06-3.03(m,1H),2.64-2.50(m,2H),2.19(s,3H),1.91-1.69(m,3H),1.51-1.43(m,1H).

[1221] Molecular formula: C 19 H 21 N5O3 exact molecular weight: 367.16 LC-MS (Pos, m / z) = 368.13 [M+H] +

[1222] Example 62 Synthesis of 2-(4-(((1S,3S)-3-aminocyclopentyl)amino)-5,6,7,8-tetrahydrophthalazin-1-yl)-5-ethynylphenol (Compound 53)

[1223]

[1224] Synthesis route:

[1225]

[1226] The synthesis of this compound was carried out by referring to the steps of the aforementioned examples.

[1227] 1 HNMR(400MHz, DMSO-d6)δ(ppm):7.13(d,J=8.2Hz,1H),6.98-6.96(m,2H),5.71(d,J=6.9Hz,1H),4.65-4.60(m,1H),4.16( s,1H),3.45-3.42(m,4H),2.38-2.31(m,4H),2.21-2.14(m,1H),1.99-1.91(m,1H),1.78-1.74(m,4H),1.61-1.51(m,3H).

[1228] Molecular formula: C 21 H 24 N4O exact molecular weight: 348.20 LC-MS (Pos, m / z) = 349.12 [M+H] + .

[1229] Example 63 Synthesis of 2-(4-((cis-3-aminocyclobutyl)amino)-5,6,7,8-tetrahydrophthalazin-1-yl)-5-ethynylphenol (Compound 51)

[1230]

[1231] Synthesis route:

[1232]

[1233] The synthesis of this compound was carried out by referring to the steps of the aforementioned examples.

[1234] 1HNMR (400MHz, DMSO-d6) δ (ppm): 7.11 (d, J = 7.7Hz, 1H), 7.05 (d, J = 1.3Hz, 1H), 6.97-6.95 (m, 1H), 6.09 (d, J = 6.7Hz, 1H), 4.17 (s, 1H), 4.15-4 .11(m,1H),3.39(s,2H),3.16-3.09(m,1H),2.69-2.62(m,2H),2.41- 2.38(m,2H),2.33-2.30(m,2H),1.84-1.74(m,4H),1.61-1.58(m,2H).

[1235] Molecular formula: C 20 H 22 N4O exact molecular weight: 334.18 LC-MS (Pos, m / z) = 335.11 [M+H] + .

[1236] Example 64 Synthesis of 2-(4-((trans-3-aminocyclobutyl)amino)-5,6,7,8-tetrahydrophthalazin-1-yl)-5-ethynylphenol (Compound 52)

[1237]

[1238] Synthesis route:

[1239]

[1240] The synthesis of this compound was carried out by referring to the steps of the aforementioned examples.

[1241] 1 HNMR (400MHz, DMSO-d6) δ (ppm): 8.38 (s, 1H), 7.11 (d, J = 7.7Hz, 1H), 7.07 (d, J = 1.4Hz, 1H), 6.98-6.96 (m, 1H), 6.34 (d, J = 6.3Hz, 1H), 4.81-4 .76(m,1H),4.17(s,1H),3.77-3.75(m,2H),2.47-2.41(m,6H),2.34- 2.31(m,2H),2.03-1.98(m,1H),1.76-1.75(m,2H),1.62-1.61(m,2H).

[1242] Molecular formula: C 20 H 22 N4O exact molecular weight: 334.18 LC-MS (Pos, m / z) = 335.13 [M+H] + .

[1243] Example 65 Synthesis of 5-ethynyl-2-(4-((cis-3-hydroxy-3-methylcyclobutyl)amino)-5,6,7,8-tetrahydro-5,8-ethylphthalazin-1-yl)phenol (Compound 12)

[1244]

[1245] Synthesis route:

[1246]

[1247] The synthesis of this compound was carried out by referring to the steps of the aforementioned examples.

[1248] 1 HNMR(400MHz,DMSO-d6)δ(ppm):10.40(s,1H),7.25-7.23(m,1H),7.02-7.00(m,2H),6.74(s,1H),4.94(s,1H),4.18(s,1H),4.10 -4.04(m,1H),3.44(s,1H),2.79(s,1H),2.45-2.40(m,2H),2.11-2.06(m,2H),1.75-1.67(m,4H),1.31(s,3H),1.27-1.20(m,4H).

[1249] Molecular formula: C 23 H 25 N3O2 exact molecular weight: 375.19 LC-MS (Pos, m / z) = 376.15 [M+H] + .

[1250] Example 66 Synthesis of 2-(4-((cis-3-hydroxy-3-methylcyclobutyl)amino)-5,6,7,8-tetrahydro-5,8-ethylphthalate-1-yl)-5-vinylphenol (Compound 21)

[1251]

[1252] Synthesis route:

[1253]

[1254] The synthesis of this compound was carried out by referring to the steps of the aforementioned examples.

[1255] 1HNMR(400MHz,DMSO-d6)δ(ppm):7.26-7.24(m,1H),7.06-7.05(m,2H),6.76-6.69(m,1H),5.81(d,J=17.6Hz,1H),5.81(d,J=11.2Hz,1H),5.02 (s,1H),4.06-4.00(m,1H),3.57(s,1H),2.89(s,1H),2.48-2.43(m,2H) ,2.17-2.12(m,2H),1.78-1.71(m,4H),1.31(s,3H),1.27-1.24(m,4H).

[1256] Molecular formula: C 23 H 27 N3O2 exact molecular weight: 377.21 LC-MS (Pos, m / z) = 378.15 [M+H] + .

[1257] Example 67 Synthesis of (R)-6-(5-ethylpyridin-2-yl)-5-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine (Compound 176)

[1258]

[1259] Syn...

Claims

1. A compound represented by general formula (A) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: YW-R3 (A) in, W is selected from X1 and X2 are independently selected from C or N; R1 is selected from hydrogen, hydroxy, amino, carboxyl, cyano, nitro, halogen, carbonyl, 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, aryl, 5-7 membered heteroaryl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl or absent; R2 is selected from hydrogen, hydroxy, amino, carboxyl, cyano, nitro, halogen, carbonyl, 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, aryl, 5-7 membered heteroaryl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl or absent; R1 and R2 are each optionally substituted by 1 to 3 groups selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl 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, 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 -(C 1-6 Alkylene) 0-2 -NR4R5、-(C 1-6 Alkylene) 0-2 -NR4-COR5, -(C 1-6 Alkylene) 0-2 -CO-NR4-R5, -(C 1-6 Alkylene) 0-2 -NR4-C 1-6 Alkylene-R5; R4 is selected from hydrogen or C 1-6 alkyl; R5 is selected from 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group, aryl group, 5-7 membered heteroaryl group; said R5 is optionally substituted by 1-4 members selected from halogen, cyano, amino, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group, aryl group, 5-7 membered heteroaryl group, C 2-6 Alkenylcarbonyl, sulfonyl, C 1-6 Substitution of alkylcarbonyl groups by substituents; When R5 is replaced, Substituent on R5: C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, sulfonyl, optionally substituted by 1-3 groups selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, carboxyl, C 1-6 Substitution of the alkylsulfonyl group by substituents; Y is selected from aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclyl, 3-12 membered cycloalkyl; (1) When X1 and X2 are selected from C, The Y is C 2-6 Alkenyl, C 2-6 Alkynyl is substituted, and optionally substituted by 1-2 groups selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group, aryl group, 5-7 membered heteroaryl group, C 1-6 Alkylamino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, sulfonyl substituent substitution; (2) When any one or both of X1 and X2 are selected from N, The Y is optionally 1-3 selected from C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group, aryl group, 5-7 membered heteroaryl group, C 1-6 Alkylamino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, sulfonyl, -N(C 1-6 Alkyl)2, -SC 1-6 Substitution of alkyl groups; In the above (1) and (2), when Y is substituted, Substituents on Y: C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, sulfonyl, optionally substituted by 1-3 groups selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 Alkyl, 3-6 membered cycloalkyl substituent substitution; Substituents on Y: C 2-6 Alkenyl, C 2-6 Alkynyl, optionally substituted with 1 to 3 groups selected from halogen, cyano, amino, hydroxy, carbonyl, unsubstituted or substituted with hydroxy 1-6 Alkyl, unsubstituted or hydroxy-substituted 3-6 membered cycloalkyl, halogenated C 1-6 The alkyl group is substituted with a substituent.

2. The compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, or tautomer, having the structure shown in general formula (I): in, R1 is selected from hydrogen, hydroxy, amino, carboxyl, cyano, nitro, halogen, 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, aryl, 5-7 membered heteroaryl; R2 is selected from hydrogen, hydroxy, amino, carboxyl, cyano, nitro, halogen, 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, aryl, 5-7 membered heteroaryl; R1 and R2 are each optionally substituted by 1 to 3 groups selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl substituents; or R1, R2 and the carbon atoms 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, 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 -(C 1-6 Alkylene) 0-2 -NR4R5、-(C 1-6 Alkylene) 0-2 -NR4-COR5, -(C 1-6 Alkylene) 0-2 -CO-NR4-R5, -(C 1-6 Alkylene) 0-2 -NR4-C 1-6 Alkylene-R5; R4 is selected from hydrogen or C 1-6 alkyl; R5 is selected from 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group, aryl group, 5-7 membered heteroaryl group; said R5 is optionally substituted by 1-4 members selected from halogen, cyano, amino, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group, aryl group, 5-7 membered heteroaryl group, C 2-6 Alkenylcarbonyl, sulfonyl, C 1-6 Substitution of alkylcarbonyl groups by substituents; Y is selected from aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclyl, 3-12 membered cycloalkyl, wherein Y is C 2-6 Alkenyl, C 2-6 Alkynyl is substituted, and optionally substituted by 1-2 groups selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group, aryl group, 5-7 membered heteroaryl group, C 1-6 Alkylamino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, sulfonyl substituent substitution; When R5 is replaced, Substituent on R5: C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, sulfonyl, optionally substituted by 1-3 groups selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 Alkyl, 3-6 membered cycloalkyl, C 1-6 Substitution of the alkylsulfonyl group by substituents; When Y is replaced, Substituents on Y: C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, sulfonyl, optionally substituted by 1-3 groups selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 Alkyl, 3-6 membered cycloalkyl substituent substitution; Substituents on Y: C 2-6 Alkenyl, C 2-6 Alkynyl, optionally substituted by 1 to 3 groups selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 Alkyl, 3-6 membered cycloalkyl, halogenated C 1-6 The alkyl group is substituted with a substituent.

3. The compound represented by the general formula (I) according to claim 2 or its pharmaceutically acceptable salt, stereoisomer, or tautomer: in, R1 is selected from hydrogen, hydroxy, amino, carboxyl, cyano, nitro, halogen, 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, aryl, 5-7 membered heteroaryl; R2 is selected from hydrogen, hydroxy, amino, carboxyl, cyano, nitro, halogen, 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, aryl, 5-7 membered heteroaryl; R1 and R2 are each optionally substituted by 1 to 3 groups selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl substituents; or R1, R2 and the carbon atoms 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, 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 -(C 1-6 Alkylene) 0-2 -NR4R5、-(C 1-6 Alkylene) 0-2 -NR4-COR5, -(C 1-6 Alkylene) 0-2 -CO-NR4-R5; R4 is selected from hydrogen or C 1-6 alkyl; R5 is selected from 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group, aryl group, 5-7 membered heteroaryl group; said R5 is optionally substituted by 1-4 members selected from halogen, cyano, amino, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group, aryl group, 5-7 membered heteroaryl group, C 2-6 Alkenylcarbonyl, sulfonyl, C 1-6 Substitution of alkylcarbonyl groups by substituents; Y is selected from aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclyl, 3-12 membered cycloalkyl, wherein Y is C 2-6 Alkenyl, C 2-6 Alkynyl is substituted, and optionally substituted by 1-2 groups selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group, aryl group, 5-7 membered heteroaryl group, C 1-6 Alkylamino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, sulfonyl substituent substitution; When R5 is replaced, Substituent on R5: C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, sulfonyl, optionally substituted by 1-3 groups selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 Alkyl, 3-6 membered cycloalkyl substituent substitution; When Y is replaced, Substituents on Y: C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, sulfonyl, optionally substituted by 1-3 groups selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 Alkyl, 3-6 membered cycloalkyl substituent substitution; Substituents on Y: C 2-6 Alkenyl, C 2-6 Alkynyl groups are not substituted.

4. The compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, or tautomer, having the structure shown in general formula (B): R1 is selected from hydrogen, hydroxy, amino, carboxyl, cyano, nitro, halogen, carbonyl, 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, aryl, 5-7 membered heteroaryl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl or absent; R2 is selected from hydrogen, hydroxy, amino, carboxyl, cyano, nitro, halogen, carbonyl, 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, aryl, 5-7 membered heteroaryl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl or absent; R1 and R2 are each optionally substituted by 1 to 3 groups selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl substituents; Any one or both of X1 and X2 are selected from N; Y is substituted with hydroxy and optionally substituted with 1-2 groups selected from C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group, C 1-6 Alkylamino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, sulfonyl, -N(C 1-6 Alkyl)2, -SC 1-6 The alkyl group is substituted with a substituent.

5. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, having a structure represented by general formula (II): in, 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 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, aryl group, 5-7 membered heteroaryl group, C 1-6 Alkylsulfonyl, -N(C 1-6 alkyl)2 is substituted with a substituent.

6. The compound according to claim 5 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, in, Ring A is selected from 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 group, C 1-6 Alkylsulfonyl, -N(C 1-6 alkyl)2 is substituted with a substituent.

7. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, in, Y is selected from phenyl, 5-7 membered heteroaryl, 3-8 membered heterocyclyl, 3-7 membered cycloalkyl; Y is C 2-6 Alkenyl, C 2-6 Alkynyl is substituted and optionally substituted by 1-2 groups selected from halogen, cyano, amino, hydroxy, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group, C 1-6 Alkylamino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, sulfonyl substituent substitution; When Y is substituted, the substituent on Y: C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, sulfonyl, optionally substituted by 1-3 groups selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 The alkyl group is substituted with a substituent.

8. The compound according to claim 6 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, in, Y is selected from phenyl, 5-7 membered heteroaryl, 3-8 membered heterocyclyl, 3-7 membered cycloalkyl; Y is C 2-6 Alkenyl, C 2-6 Alkynyl is substituted and optionally substituted by 1-2 groups selected from halogen, cyano, amino, hydroxy, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group, C 1-6 Alkylamino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, sulfonyl substituent substitution; When Y is substituted, the substituent on Y is: C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, sulfonyl, optionally substituted by 1-3 groups selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 Substitution of alkyl groups; R3 is selected from -NH-R5, R5 is 1-2 selected from C 1-6 The substituent of the alkyl group is a 3-7 membered heterocyclic group substituted with a alkyl group.

9. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, in, Ring A is selected from 5-12 membered cycloalkyl, 5-12 membered cycloalkenyl, 5-12 membered heterocyclyl, aryl, 5-12 membered heteroaryl; preferably, ring A is selected from 5-8 membered cycloalkyl, 5-8 membered cycloalkenyl, 5-8 membered heterocyclyl, phenyl, 5-8 membered heteroaryl.

10. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, in, R3 is selected from -NR4R5, -NR4-C 1-6 Alkylene -R5, R4 is selected from hydrogen, R5 is selected from 3-7 membered cycloalkyl, 3-7 membered heterocyclyl; preferably, R3 is selected from -NHR5, R5 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclyl.

11. The compound according to claim 10 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, Y is selected from phenyl, 5-6 membered heteroaryl, wherein Y is C 2-6 Alkenyl, C 2-6 Alkynyl is substituted and optionally substituted by 1-2 groups selected from halogen, cyano, amino, hydroxy, carbonyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-7 membered heterocyclic, 3-7 membered cycloalkyl substitution; the C 2-6 Alkenyl, C 2-6 Alkynyl is substituted by 1 to 3 groups selected from halogen, cyano, amino, hydroxyl, carbonyl, C 1-6 Alkyl, 3-6 membered cycloalkyl, halogenated C 1-6 The alkyl group is substituted with a substituent.

12. The compound according to claim 5 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, in, Ring A is selected from Ring A is optionally substituted by 1-4 groups selected from hydroxy, 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.

13. The compound according to claim 10 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, in, Ring A is selected from Ring A is optionally substituted by 1-2 groups selected from cyano, nitro, halogen, 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.

14. The compound according to claim 4 or 10, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, in, Y is selected from 15. The compound described below or its pharmaceutically acceptable salt, stereoisomer, tautomer: 16 . A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier.

17. Use of the compound according to any one of claims 1 to 15 or its pharmaceutically acceptable salt, stereoisomer, tautomer, or the pharmaceutical composition according to claim 16 in the preparation of a medicament for preventing and / or treating a disease associated with NLRP3 inflammasome.

18. Use of the compound according to any one of claims 1 to 15 or its pharmaceutically acceptable salt, stereoisomer, tautomer, or the pharmaceutical composition according to claim 16 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.

Images