NLRP3 inflammasome inhibitors and uses thereof

Abstract

The present invention belongs to the field of pharmaceutical technology and relates to an NLRP3 inflammasome inhibitor and its use. Specifically, the present invention relates to a compound represented by general formula (A) or its pharma- ceutically acceptable salt, stereoisomer, or tautomer. The inhibitor has biological activity against NLRP3 inflammasome and has important clinical development value for the treatment of NLRP3-related diseases.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to Chinese Patent Application No. 202210015181.X filed on January 7, 2022, Chinese Patent Application No. 202210015699.3 filed on January 7, 2022, Chinese Patent Application No. 202210563248.3 filed on May 20, 2022, Chinese Patent Application No. 202210895164.X filed on July 26, 2022, and Chinese Patent Application No. 202211093807.5 filed on September 8, 2022, the disclosures of which are incorporated herein by reference in their entireties.

[0002] <Technical field> The present invention relates to the field of pharmaceutical technology, and specifically to NLRP3 inflammasome inhibitors and their uses. [Background technology]

[0003] Nucleotide-binding oligomerization domain-like receptor protein 3 (NOD-like receptor protein 3, NLRP3) belongs to the nucleotide-binding oligomerization domain-like receptor (NOD-like receptors, NLRs) family and is also known as "pyrin structural domain protein 3." NLRP3 contains three modules: a pyrin structural domain (PYD), a nucleotide-binding site structural domain (NBD), and a leucine-rich repeat (LRR). Upon stimulation by sterile inflammatory danger signals, NLRP3 interacts with articulin apoptosis-associated speck-like protein (ASC) and caspase-1 (procaspase-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).

[0004] NLRP3 inflammasome activation generally involves two steps. The first step involves a trigger signal, in which Toll-like receptors recognize pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). This signal is then transmitted to cells, mediating activation of the NF-κB signaling pathway and upregulating the transcription levels of NLRP3 inflammasome-associated components, such as inactive NLRP3 and pro-IL-1β. The second step involves an activation signal, in which P2X7 receptors, upon stimulation by signals such as ATP and nigericin, oligomerize NLRP3 monomers to form NLRP3 oligomers, which then recruit ASC and pro-caspase 1 to form the NLRP3 inflammasome. This triggers the conversion of pro-caspase 1 to caspase 1 and the production and secretion of mature IL-1β and IL-18.

[0005] NLRP3 inflammasome activation has been implicated in a variety of diseases, including autoinflammatory fever syndromes such as cryopyrin-associated periodic fever syndromes (CAPS), sickle cell disease, systemic lupus erythematosus (SLE), chronic liver disease, nonalcoholic steatohepatitis (NASH), gout, pseudogout (chondrocalcinosis), type I and II diabetes and related complications (e.g., nephrosis, retinopathy), neuroinflammatory diseases (e.g., multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g., hypertension), hidradenitis suppurativa, wound healing, scarring, and cancer (e.g., colorectal cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), and myelofibrosis). Most treatments involve symptomatic treatment, therapies aimed at slowing disease / disability progression, and surgery as a last resort.

[0006] There are currently few types of NLRP3 inflammasome inhibitors under development, and there is a clinical need to develop NLRP3 inflammasome inhibitors with higher activity and excellent drug discovery potential. Summary of the Invention [Problem to be solved by the invention]

[0007] The present invention has investigated the following compound or its pharmaceutically acceptable salt, stereoisomer, or tautomer, and has found that the compound or its pharmaceutically acceptable salt, stereoisomer, or tautomer has high biological activity against NLRP3 inflammasome and is of great clinical value for the treatment of NLRP3-related diseases.

[0008] To achieve the above object, the present invention provides the following solutions: A compound represented by general formula (A) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: [ka] where: W is [ka] Selected from X1 and X2 are each independently selected from C or N; R1 is hydrogen, hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen, carbonyl group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkoxy group, C 1-6 Alkoxy group, halogen-substituted C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group, aryl group, 5-7 membered heteroaryl group, -N(C 1-6 Alkyl group)2, -SC 1-6 an alkyl group or absence; R2 is hydrogen, hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen, carbonyl group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkoxy group, C 1-6 Alkoxy group, halogen-substituted C 1-6 Alkoxy group, C 2-6 Alkenyl group, C2-6 Alkynyl group, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group, aryl group, 5-7 membered heteroaryl group, -N(C 1-6 Alkyl group)2, -SC 1-6 an alkyl group or absence; R1 and R2 are hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen, carbonyl group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen-substituted C 1-6 substituted by 1 to 3 substituents arbitrarily selected from an alkoxy group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group; or R1 and R2 together with the C or N atom to which they are attached form a 5-12 membered ring A, and the 5-12 membered ring A is selected from the group consisting of a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen atom, a carbonyl group, a C 1-6 Alkyl group, -NH-C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen-substituted C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylsulfonyl group, -N(C 1-6 substituted with 1 to 4 substituents arbitrarily selected from alkyl groups); R3 is -(C 1-6 alkylene group) 0-2 -NR4R5, -(C 1-6 alkylene group) 0-2 -NR4-COR5, -(C 1-6 alkylene group) 0-2 -CO-NR4-R5, -(C 1-6 alkylene group) 0-2 -NR4-C 1-6 an alkylene group -R5; R4 is hydrogen or C 1-6 selected from alkyl groups, R5 is selected from a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group, and R5 is selected from a halogen, a cyano group, an amino group, a hydroxy group, a C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 2-6 Alkenylcarbonyl group, sulfonyl group, C 1-6 substituted with 1 to 4 substituents arbitrarily selected from alkylcarbonyl groups; If R5 is replaced, C is a substituent in R5 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy groups, 3- to 7-membered heterocyclic groups, 3- to 7-membered cycloalkyl groups, aryl groups, 5- to 7-membered heteroaryl groups, sulfonyl groups, halogens, cyano groups, amino groups, hydroxy groups, carbonyl groups, C 1-6 Alkyl group, 3-6 membered cycloalkyl group, 3-6 membered heterocyclic group, carboxy group, C 1-6 substituted by 1 to 3 substituents arbitrarily selected from alkylsulfonyl groups; Y is selected from an aryl group, a 5- to 14-membered heteroaryl group, a 3- to 14-membered heterocyclic group, and a 3- to 12-membered cycloalkyl group; (1) When X1 and X2 are each selected from C, The Y is C 2-6 Alkenyl group, C 2-6 substituted with an alkynyl group, and halogen, cyano group, amino group, hydroxy group, carbonyl group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylamino group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkyl sulfonyl group, amino carbonyl group, C 1-6substituted with 1 to 2 substituents arbitrarily selected from an alkylaminocarbonyl group and a sulfonyl group; (2) When either X1 or X2 or both are selected from N, The Y is C 2-6 Alkenyl group, C 2-6 Alkynyl group, halogen, cyano group, amino group, hydroxy group, carbonyl group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylamino group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkyl sulfonyl group, amino carbonyl group, C 1-6 Alkylaminocarbonyl group, sulfonyl group, -N(C 1-6 Alkyl group)2, -SC 1-6 substituted with 1 to 3 substituents arbitrarily selected from alkyl groups; In the above (1) and (2), when Y is replaced, C is a substituent in Y 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy groups, 3- to 7-membered heterocyclic groups, 3- to 7-membered cycloalkyl groups, aryl groups, 5- to 7-membered heteroaryl groups, sulfonyl groups, halogens, cyano groups, amino groups, hydroxy groups, carbonyl groups, C 1-6 substituted by 1 to 3 substituents arbitrarily selected from an alkyl group and a 3- to 6-membered cycloalkyl group; C is a substituent in Y 2-6 Alkenyl group, C 2-6 Alkynyl groups are substituted with halogen, cyano, amino, hydroxy, carbonyl, unsubstituted or hydroxy groups. 1-6 Alkyl groups, unsubstituted or hydroxy-substituted 3-6 membered cycloalkyl groups, halogen-substituted C 1-6 It is substituted with 1 to 3 substituents arbitrarily selected from alkyl groups.

[0009] In some embodiments, the present invention further provides compounds represented by general formula (I) or pharmaceutically acceptable salts, stereoisomers, tautomers thereof: [ka] where: R1 is hydrogen, hydroxy group, amino group, carboxy group, cyano group, nitro group, halogen, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen-substituted C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 selected from an alkynyl group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group; R2 is hydrogen, hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen-substituted C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 selected from an alkynyl group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group; R1 and R2 are hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen, carbonyl group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen-substituted C 1-6 substituted by 1 to 3 substituents arbitrarily selected from an alkoxy group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group; or R1 and R2 together with the carbon atoms to which they are attached form a 5- to 12-membered ring A, and the 5- to 12-membered ring A is selected from the group consisting of a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen atom, a carbonyl group, a C 1-6Alkyl group, -NH-C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen-substituted C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylsulfonyl group, -N(C 1-6 substituted with 1 to 4 substituents arbitrarily selected from alkyl groups); R3 is -(C 1-6 alkylene group) 0-2 -NR4R5, -(C 1-6 alkylene group) 0-2 -NR4-COR5, -(C 1-6 alkylene group) 0-2 -CO-NR4-R5, -(C 1-6 alkylene group) 0-2 -NR4-C 1-6 an alkylene group -R5; R4 is hydrogen or C 1-6 selected from alkyl groups, R5 is selected from a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group, and R5 is selected from a halogen, a cyano group, an amino group, a hydroxy group, a C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 2-6 Alkenylcarbonyl group, sulfonyl group, C 1-6 substituted with 1 to 4 substituents arbitrarily selected from alkylcarbonyl groups; Y is selected from an aryl group, a 5- to 14-membered heteroaryl group, a 3- to 14-membered heterocyclic group, and a 3- to 12-membered cycloalkyl group, and said Y is C 2-6 Alkenyl group, C 2-6 substituted with an alkynyl group, and halogen, cyano group, amino group, hydroxy group, carbonyl group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylamino group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkyl sulfonyl group, amino carbonyl group, C 1-6 substituted with 1 to 2 substituents arbitrarily selected from an alkylaminocarbonyl group and a sulfonyl group; If R5 is replaced, C is a substituent in R5 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy groups, 3- to 7-membered heterocyclic groups, 3- to 7-membered cycloalkyl groups, aryl groups, 5- to 7-membered heteroaryl groups, sulfonyl groups, halogens, cyano groups, amino groups, hydroxy groups, carbonyl groups, C 1-6 Alkyl groups, 3-6 membered cycloalkyl groups, C 1-6 substituted by 1 to 3 substituents arbitrarily selected from alkylsulfonyl groups; When Y is replaced, C is a substituent in Y 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy groups, 3- to 7-membered heterocyclic groups, 3- to 7-membered cycloalkyl groups, aryl groups, 5- to 7-membered heteroaryl groups, sulfonyl groups, halogens, cyano groups, amino groups, hydroxy groups, carbonyl groups, C 1-6 substituted by 1 to 3 substituents arbitrarily selected from an alkyl group and a 3- to 6-membered cycloalkyl group; C is a substituent in Y 2-6 Alkenyl group, C 2-6 Alkynyl groups are substituted with halogens, cyano groups, amino groups, hydroxy groups, carbonyl groups, and C 1-6 Alkyl groups, 3-6 membered cycloalkyl groups, halogen-substituted C 1-6 It is substituted with 1 to 3 substituents arbitrarily selected from alkyl groups.

[0010] In some embodiments, the present invention provides a compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: [ka] where: R1 is hydrogen, hydroxy group, amino group, carboxy group, cyano group, nitro group, halogen, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen-substituted C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 selected from an alkynyl group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group; R2 is hydrogen, hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen-substituted C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 selected from an alkynyl group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group; R1 and R2 are hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen, carbonyl group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen-substituted C 1-6 substituted by 1 to 3 substituents arbitrarily selected from an alkoxy group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group; or R1 and R2 together with the carbon atoms to which they are attached form a 5- to 12-membered ring A, and the 5- to 12-membered ring A is selected from the group consisting of a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen atom, a carbonyl group, a C 1-6 Alkyl group, -NH-C 1-6 Alkyl group, halogen-substituted C1-6 Alkyl group, C 1-6 Alkoxy group, halogen-substituted C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylsulfonyl group, -N(C 1-6 substituted with 1 to 4 substituents arbitrarily selected from alkyl groups); R3 is -(C 1-6 alkylene group) 0-2 -NR4R5, -(C 1-6 alkylene group) 0-2 -NR4-COR5, -(C 1-6 alkylene group) 0-2 -CO-NR4-R5, R4 is hydrogen or C 1-6 selected from alkyl groups, R5 is selected from a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group, and R5 is selected from a halogen, a cyano group, an amino group, a hydroxy group, a C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 2-6 Alkenylcarbonyl group, sulfonyl group, C 1-6 substituted with 1 to 4 substituents arbitrarily selected from alkylcarbonyl groups; Y is selected from an aryl group, a 5- to 14-membered heteroaryl group, a 3- to 14-membered heterocyclic group, and a 3- to 12-membered cycloalkyl group, and said Y is C 2-6 Alkenyl group, C 2-6 substituted with an alkynyl group, and halogen, cyano group, amino group, hydroxy group, carbonyl group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylamino group, C 1-6 Alkylcarbonylamino group, C 1-6Alkyl sulfonyl group, amino carbonyl group, C 1-6 substituted with 1 to 2 substituents arbitrarily selected from an alkylaminocarbonyl group and a sulfonyl group; If R5 is replaced, C is a substituent in R5 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy groups, 3- to 7-membered heterocyclic groups, 3- to 7-membered cycloalkyl groups, aryl groups, 5- to 7-membered heteroaryl groups, sulfonyl groups, halogens, cyano groups, amino groups, hydroxy groups, carbonyl groups, C 1-6 substituted by 1 to 3 substituents arbitrarily selected from an alkyl group and a 3- to 6-membered cycloalkyl group; When Y is replaced, C is a substituent in Y 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy groups, 3- to 7-membered heterocyclic groups, 3- to 7-membered cycloalkyl groups, aryl groups, 5- to 7-membered heteroaryl groups, sulfonyl groups, halogens, cyano groups, amino groups, hydroxy groups, carbonyl groups, C 1-6 substituted by 1 to 3 substituents arbitrarily selected from an alkyl group and a 3- to 6-membered cycloalkyl group; C is a substituent in Y 2-6 Alkenyl group, C 2-6 The alkynyl group is unsubstituted.

[0011] In some embodiments, there is provided a compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: [ka] where: R1 is hydrogen, hydroxy group, amino group, carboxy group, cyano group, nitro group, halogen, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen-substituted C 1-6 Alkoxy group, C 2-6 Alkenyl group, C2-6 selected from an alkynyl group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group; R2 is hydrogen, hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen-substituted C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 selected from an alkynyl group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group; R1 and R2 are hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen, carbonyl group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen-substituted C 1-6 substituted by 1 to 3 substituents arbitrarily selected from an alkoxy group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group; or R1 and R2 together with the carbon atoms to which they are attached form a 5- to 12-membered ring A, and the 5- to 12-membered ring A is selected from the group consisting of a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen atom, a carbonyl group, a C 1-6 Alkyl group, -NH-C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen-substituted C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylsulfonyl group, -N(C 1-6 substituted with 1 to 4 substituents arbitrarily selected from alkyl groups); R3 is -(C 1-6 alkylene group) 0-2 -NR4R5, -(C 1-6 alkylene group) 0-2 -NR4-COR5, -(C 1-6alkylene group) 0-2 -CO-NR4-R5, where R4 is hydrogen or C 1-6 R5 is selected from a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group, and R5 is selected from a halogen, a cyano group, an amino group, a hydroxy group, a C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 2-6 Alkenylcarbonyl group, sulfonyl group, C 1-6 substituted with 1 to 4 substituents arbitrarily selected from alkylcarbonyl groups; Y is selected from an aryl group, a 5- to 14-membered heteroaryl group, a 3- to 14-membered heterocyclic group, and a 3- to 12-membered cycloalkyl group, and the Y is selected from a halogen, a cyano group, an amino group, a hydroxy group, a carbonyl group, a C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylamino group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkyl sulfonyl group, amino carbonyl group, C 1-6 Alkylaminocarbonyl group, C 2-6 Alkenyl group, C 2-6 substituted with 1 to 3 substituents arbitrarily selected from an alkynyl group and a sulfonyl group; R5, Y are substituted with C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy groups, 3- to 7-membered heterocyclic groups, 3- to 7-membered cycloalkyl groups, aryl groups, 5- to 7-membered heteroaryl groups, sulfonyl groups, halogens, cyano groups, amino groups, hydroxy groups, carbonyl groups, C 1-6 It is substituted with 1 to 3 substituents arbitrarily selected from an alkyl group and a 3- to 6-membered cycloalkyl group.

[0012] In some embodiments, the present invention provides the compound having the structure shown in general formula (B) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: [ka] where: R1 is hydrogen, hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen, carbonyl group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkoxy group, C 1-6 Alkoxy group, halogen-substituted C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group, aryl group, 5-7 membered heteroaryl group, -N(C 1-6 Alkyl group)2, -SC 1-6 an alkyl group or absence; R2 is hydrogen, hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen, carbonyl group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkoxy group, C 1-6 Alkoxy group, halogen-substituted C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group, aryl group, 5-7 membered heteroaryl group, -N(C 1-6 Alkyl group)2, -SC 1-6 an alkyl group or absence; R1 and R2 are hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen, carbonyl group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen-substituted C 1-6 substituted by 1 to 3 substituents arbitrarily selected from an alkoxy group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group; Either X1 or X2 or both are selected from N; Y is replaced with a hydroxy group, and C 2-6 Alkenyl group, C 2-6 Alkynyl group, halogen, cyano group, amino group, hydroxy group, carbonyl group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group, C 1-6 Alkylamino group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkyl sulfonyl group, amino carbonyl group, C 1-6 Alkylaminocarbonyl group, sulfonyl group, -N(C 1-6 Alkyl group)2, -SC 1-6 It is substituted with 1 to 2 substituents arbitrarily selected from alkyl groups.

[0013] In some embodiments, Y is selected from a phenyl group, a 5-7 membered heteroaryl group, a 3-8 membered heterocyclic group, a 3-7 membered cycloalkyl group, and Y is C 2-6 Alkenyl group, C 2-6 substituted with an alkynyl group, and halogen, cyano group, amino group, hydroxy group, carbonyl group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group, C 1-6 Alkylamino group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkyl sulfonyl group, amino carbonyl group, C 1-6 substituted with 1 to 2 substituents arbitrarily selected from an alkylaminocarbonyl group and a sulfonyl group; When Y is substituted, C is a substituent on Y. 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy groups, 3-7 membered heterocyclic groups, 3-7 membered cycloalkyl groups, sulfonyl groups, halogens, cyano groups, amino groups, hydroxy groups, carbonyl groups, C1-6 substituted with 1 to 3 substituents arbitrarily selected from alkyl groups; R3 is selected from -NH-R5, and R5 is C 1-6 It is a 3- to 7-membered heterocyclic group substituted with 1 to 2 substituents selected from alkyl groups.

[0014] In some embodiments, ring A is selected from a 5-12 membered cycloalkyl group, a 5-12 membered cycloalkenyl group, a 5-12 membered heterocyclic group, an aryl group, and a 5-12 membered heteroaryl group.

[0015] In some embodiments, ring A is selected from a 5-8 membered cycloalkyl group, a 5-8 membered cycloalkenyl group, a 5-8 membered heterocyclic group, a phenyl group, and a 5-8 membered heteroaryl group.

[0016] In some embodiments, the present invention provides a compound having the structure shown in general formula (II) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: [ka] where: Ring A is selected from a 5- to 7-membered cycloalkenyl group, a 5- to 7-membered cycloalkyl group, a 5- to 7-membered heterocyclic group, a phenyl group, and a 5- to 7-membered heteroaryl group, and Ring A is selected from a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen atom, a C 1-6 Alkyl group, -NH-C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen-substituted C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylsulfonyl group, -N(C 1-6 and substituted with 1 to 4 substituents arbitrarily selected from alkyl groups).

[0017] In some embodiments, Ring A is selected from a phenyl group, a 5-7 membered heteroaryl group, and Ring A is selected from a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen, a C 1-6 Alkyl group, -NH-C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen-substituted C 1-6 Alkoxy group, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group, C 1-6 Alkylsulfonyl group, -N(C 1-6 and substituted with 1 to 4 substituents arbitrarily selected from alkyl groups).

[0018] In some embodiments, ring A is selected from a phenyl group, a 5-6 membered heteroaryl group containing 1-2 heteroatoms selected from O, S, and N, and a 5-6 membered saturated ring.

[0019] In some embodiments, ring A is selected from the group consisting of a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen, a carbonyl group, C 1-6 Alkyl group, -NH-C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen-substituted C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylsulfonyl group, -N(C 1-6 and substituted with 1 to 4 substituents arbitrarily selected from alkyl groups).

[0020] In some embodiments, ring A is not replaced.

[0021] In some embodiments, ring A is a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen, C 1-6 Alkyl group, -NH-C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen-substituted C 1-6Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylsulfonyl group, -N(C 1-6 and substituted with 1 to 4 substituents selected from alkyl groups).

[0022] In some embodiments, ring A is a cyano group, C 1-6 Alkoxy group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkylsulfonyl group, -N(C 1-6 alkyl group)2.

[0023] In some embodiments, ring A is a cyano group, C 1-6 Alkoxy group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkylsulfonyl group, -N(C 1-6 alkyl group)2.

[0024] In some embodiments, Ring A is selected from a phenyl group, a 5-6 membered heteroaryl group containing 1-2 heteroatoms selected from O, S, and N, a 5-6 membered saturated ring, and Ring A is unsubstituted or is selected from a cyano group, C 1-6 Alkoxy group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkylsulfonyl group, -N(C 1-6 alkyl group)2.

[0025] In some embodiments, ring A is [ka] Ring A is selected from a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen, C 1-6 Alkyl group, -NH-C 1-6Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen-substituted C 1-6 Alkoxy group, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group, C 1-6 Alkylsulfonyl group, -N(C 1-6 and substituted with 1 to 4 substituents arbitrarily selected from alkyl groups).

[0026] In some embodiments, ring A is [ka] Ring A is selected from a cyano group, a nitro group, a halogen, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, 3-7 membered cycloalkyl group, 5-7 membered heteroaryl group, C 1-6 Alkylsulfonyl group, -N(C 1-6 and substituted with 1 to 2 substituents arbitrarily selected from alkyl groups).

[0027] In some embodiments, ring A is [ka] is.

[0028] In some embodiments, R3 is -(C 1-6 alkylene group) 0-2 -NR4R5, -(C 1-6 alkylene group) 0-2 -NR4-COR5, -(C 1-6 alkylene group) 0-2 -CO-NR4-R5, -(C 1-6 alkylene group) 0-2 -NR4-C 1-6 alkylene group -R5, R4 is selected from hydrogen or C 1-6 R5 is selected from a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group.

[0029] In some embodiments, R4 is selected from hydrogen.

[0030] In some embodiments, R4 is C 1-6 It is selected from alkyl groups.

[0031] In some embodiments, R4 is selected from a methyl group and an ethyl group.

[0032] In some embodiments, R3 is -NR4R5, -NR4-C 1-6 An alkylene group -R5 is selected from R4 is selected from hydrogen, and R5 is selected from a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group.

[0033] In some embodiments, R3 is -NR4R5, -NR4-C 1-6 R is selected from an alkylene group -R5, where R4 is selected from hydrogen, and R5 is selected from a 3- to 7-membered cycloalkyl group, a 3- to 7-membered heterocyclic group, preferably R3 is selected from -NHR5, and R5 is selected from a 4- to 6-membered cycloalkyl group, a 4- to 6-membered heterocyclic group.

[0034] In some embodiments, R5 is selected from a 4-6 membered cycloalkyl group, a 4-6 membered heterocyclic group containing one heteroatom selected from O, N, and S.

[0035] In some embodiments, R5 is a halogen, a cyano group, an amino group, a hydroxy group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 2-6 Alkenylcarbonyl group, sulfonyl group, C 1-6 alkylcarbonyl groups, and when R5 is substituted, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6Alkoxy groups, 3- to 7-membered heterocyclic groups, 3- to 7-membered cycloalkyl groups, aryl groups, 5- to 7-membered heteroaryl groups, sulfonyl groups, halogens, cyano groups, amino groups, hydroxy groups, carbonyl groups, C 1-6 Alkyl group, 3-6 membered cycloalkyl group, 3-6 membered heterocyclic group, carboxy group, C 1-6 It is substituted with 1 to 3 substituents arbitrarily selected from alkylsulfonyl groups.

[0036] In some embodiments, R5 is not replaced.

[0037] In some embodiments, R5 is a halogen, a cyano group, an amino group, a hydroxy group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 2-6 Alkenylcarbonyl group, sulfonyl group, C 1-6 It is substituted with 1 to 2 substituents arbitrarily selected from alkylcarbonyl groups.

[0038] In some embodiments, when R5 is replaced, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 An alkoxy group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, a 5- to 7-membered heteroaryl group, or a sulfonyl group cannot be replaced.

[0039] In some embodiments, when R5 is replaced, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy groups, 3- to 7-membered heterocyclic groups, 3- to 7-membered cycloalkyl groups, aryl groups, 5- to 7-membered heteroaryl groups, sulfonyl groups, halogens, cyano groups, amino groups, hydroxy groups, carbonyl groups, C 1-6 Alkyl group, 3-6 membered cycloalkyl group, 3-6 membered heterocyclic group, carboxy group, C 1-6It is substituted with 1 to 3 substituents selected from alkylsulfonyl groups.

[0040] In some embodiments, R5 is [ka] Selected from.

[0041] Preferably, R5 is [ka] Selected from.

[0042] In some embodiments, Y is selected from an aryl group, a 5-14 membered heteroaryl group, a 3-14 membered heterocyclic group, a 3-12 membered cycloalkyl group, and said Y is C 2-6 Alkenyl group, C 2-6 substituted with an alkynyl group, and halogen, cyano group, amino group, hydroxy group, carbonyl group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylamino group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkyl sulfonyl group, amino carbonyl group, C 1-6 It is substituted with 1 to 2 substituents arbitrarily selected from an alkylaminocarbonyl group and a sulfonyl group.

[0043] In some embodiments, Y is selected from a phenyl group, a 5-7 membered heteroaryl group, a 3-8 membered heterocyclic group, a 3-7 membered cycloalkyl group, and Y is C 2-6 Alkenyl group, C 2-6 substituted with an alkynyl group, and halogen, cyano group, amino group, hydroxy group, carbonyl group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6Alkoxy group, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group, C 1-6 Alkylamino group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkyl sulfonyl group, amino carbonyl group, C 1-6 It is substituted with 1 to 2 substituents arbitrarily selected from an alkylaminocarbonyl group and a sulfonyl group.

[0044] In some embodiments, Y is selected from a phenyl group, a 5-8 membered heteroaryl group, a 3-8 membered heterocyclic group, and a 3-7 membered cycloalkyl group.

[0045] In some embodiments, Y is selected from a phenyl group and a 5-6 membered heteroaryl group.

[0046] In some embodiments, Y is selected from a phenyl group, a 5-6 membered heteroaryl group containing 1-2 N heteroatoms.

[0047] In some embodiments, Y is C 2-6 Alkenyl group, C 2-6 Alkynyl group, halogen, cyano group, amino group, hydroxy group, carbonyl group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylamino group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkyl sulfonyl group, amino carbonyl group, C 1-6 Alkylaminocarbonyl group, sulfonyl group, -N(C 1-6 Alkyl group)2, -SC 1-6 It is substituted with 1 to 3 substituents arbitrarily selected from alkyl groups.

[0048] In some embodiments, Y is C 2-6 Alkenyl group, C 2-6and is substituted with one substituent selected from an alkynyl group, a halogen, a cyano group, an amino group, a hydroxy group, a carbonyl group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 It is substituted with 1 to 2 substituents arbitrarily selected from an alkoxy group, a 3- to 7-membered heterocyclic group, and a 3- to 7-membered cycloalkyl group.

[0049] In some embodiments, Y is C 2-6 Alkenyl group, C 2-6 It is substituted with 1 to 2 substituents selected from alkynyl groups.

[0050] In some embodiments, Y is C 2-6 Alkenyl group, C 2-6 In some embodiments, Y is substituted with one substituent selected from a halogen, a cyano group, an amino group, a hydroxy group, a carbonyl group, a C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 It is substituted with 1 to 3 substituents arbitrarily selected from an alkoxy group, a 3- to 7-membered heterocyclic group, and a 3- to 7-membered cycloalkyl group.

[0051] In some embodiments, Y is a halogen, a cyano group, an amino group, a hydroxy group, a carbonyl group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 It is substituted with 1 to 2 substituents arbitrarily selected from an alkoxy group, a 3- to 7-membered heterocyclic group, and a 3- to 7-membered cycloalkyl group.

[0052] In some embodiments, Y is C 2-6 Alkenyl group, C 2-6 alkynyl groups, and halogen, cyano group, amino group, hydroxy group, carbonyl group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6It is substituted with 1 to 3 substituents arbitrarily selected from an alkoxy group, a 3- to 7-membered heterocyclic group, and a 3- to 7-membered cycloalkyl group.

[0053] In some embodiments, Y is C 2-6 Alkenyl group, C 2-6 alkynyl group, and Y is a halogen atom, a cyano group, an amino group, a hydroxy group, a carbonyl group, or C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 In some embodiments, Y is substituted with one substituent selected from an alkoxy group, a 3- to 7-membered heterocyclic group, and a 3- to 7-membered cycloalkyl group. 2-6 Alkenyl group, C 2-6 substituted with an alkynyl group, and halogen, cyano group, amino group, hydroxy group, carbonyl group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylamino group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkyl sulfonyl group, amino carbonyl group, C 1-6 Alkylaminocarbonyl group, sulfonyl group, -N(C 1-6 Alkyl group)2, -SC 1-6 It is substituted with 1 to 2 substituents arbitrarily selected from alkyl groups.

[0054] In some embodiments, Y is C 2-6 Alkenyl group, C 2-6 and Y is replaced by one substituent selected from an alkynyl group and a hydroxy group; 2-6 Alkenyl group, C 2-6 Alkynyl groups are unsubstituted or substituted with halogen, cyano, amino, hydroxy, carbonyl, C 1-6Alkyl groups, unsubstituted or hydroxy-substituted 3-6 membered cycloalkyl groups, halogen-substituted C 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups.

[0055] In some embodiments, when Y is replaced, C is a substituent on Y. 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy groups, 3- to 7-membered heterocyclic groups, 3- to 7-membered cycloalkyl groups, aryl groups, 5- to 7-membered heteroaryl groups, sulfonyl groups, halogens, cyano groups, amino groups, hydroxy groups, carbonyl groups, C 1-6 It is substituted with 1 to 3 substituents arbitrarily selected from an alkyl group and a 3- to 6-membered cycloalkyl group.

[0056] In some embodiments, the substituent C on Y 2-6 Alkenyl group, C 2-6 Alkynyl groups are substituted with halogen, cyano, amino, hydroxy, carbonyl, unsubstituted or hydroxy groups. 1-6 Alkyl groups, unsubstituted or hydroxy-substituted 3-6 membered cycloalkyl groups, halogen-substituted C 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups.

[0057] In some embodiments, the substituent C on Y 2-6 Alkenyl group, C 2-6 The alkynyl group is unsubstituted.

[0058] In some embodiments, Y is selected from a phenyl group, a 5-7 membered heteroaryl group, a 3-8 membered heterocyclic group, a 3-7 membered cycloalkyl group, and Y is C 2-6 Alkenyl group, C 2-6 substituted with an alkynyl group, and halogen, cyano group, amino group, hydroxy group, carbonyl group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6Alkoxy group, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group, C 1-6 Alkylamino group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkyl sulfonyl group, amino carbonyl group, C 1-6 substituted with 1 to 2 substituents arbitrarily selected from an alkylaminocarbonyl group and a sulfonyl group; When Y is substituted, C is a substituent on Y. 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy groups, 3-7 membered heterocyclic groups, 3-7 membered cycloalkyl groups, sulfonyl groups, halogens, cyano groups, amino groups, hydroxy groups, carbonyl groups, C 1-6 It is substituted with 1 to 3 substituents arbitrarily selected from alkyl groups.

[0059] In some embodiments, Y is selected from a phenyl group, a 5-6 membered heteroaryl group, and said Y is C 2-6 Alkenyl group, C 2-6 substituted with an alkynyl group, and halogen, cyano group, amino group, hydroxy group, carbonyl group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 substituted with 1 to 2 substituents arbitrarily selected from an alkoxy group, a 3- to 7-membered heterocyclic group, and a 3- to 7-membered cycloalkyl group, 2-6 Alkenyl group, C 2-6 Alkynyl groups are substituted with halogens, cyano groups, amino groups, hydroxy groups, carbonyl groups, and C 1-6 Alkyl groups, 3-6 membered cycloalkyl groups, halogen-substituted C 1-6 It is substituted with 1 to 3 substituents arbitrarily selected from alkyl groups.

[0060] In some embodiments, Y is [ka] Selected from.

[0061] In some embodiments, when Y is substituted, the substituents on Y are hydroxy groups, [ka] Selected from.

[0062] The present invention also provides the compound having the structure shown in general formula (C) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: [ka] Here, the selection of R1, R2, R3, and Y is as described above.

[0063] In one embodiment of the present invention, the compounds of formula (A), (B), (C), (I) or (II), pharmaceutically acceptable salts thereof, or stereoisomers and tautomers thereof are shown in Table 1: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17]

[0064] In one embodiment of the present invention, there is provided a pharmaceutical composition comprising any one of the above compounds, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

[0065] In one embodiment of the present invention, the pharmaceutical composition may be administered to a patient or subject in need of such treatment via oral, parenteral, rectal, or pulmonary administration. When used for oral administration, the pharmaceutical composition may be in the form of a conventional solid formulation such as a tablet, capsule, pill, or granule, or an oral liquid formulation such as an oral solution, oral suspension, or syrup. When used for oral administration, appropriate fillers, adhesives, disintegrants, lubricants, etc. may be added. When used for parenteral administration, the pharmaceutical composition may be in the form of an injection, such as an injection solution, sterile powder for injection, or concentrated solution for injection. When used for injection, the injection can be prepared by conventional methods available in the pharmaceutical field, and the injection may contain no additives or appropriate additives depending on the nature of the drug. When used for rectal administration, the pharmaceutical composition may be in the form of a suppository, etc. When used for pulmonary administration, the pharmaceutical composition may be in the form of an inhalant, aerosol, etc.

[0066] The present invention further provides use of a compound represented by formula (A), (B), (C), (I) or (II), or a pharmaceutically acceptable salt, stereoisomer, tautomer, or pharmaceutical composition thereof, in the preparation of a pharmaceutical for the prevention and / or treatment of an NLRP3 inflammasome-associated disease.

[0067] The present invention further provides the use of the above-described compound, or a pharmaceutically acceptable salt, stereoisomer, reverse isomer thereof, or the above-described pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of an inflammasome-associated disease, an immune disease, an inflammatory disease, an autoimmune disease, or an autoinflammatory disease.

[0068] Detailed Description of the Invention For the purposes of the present invention, the term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0069] As used herein, the term "hydroxy group" refers to an --OH group.

[0070] As used herein, the term "cyano group" refers to a -CN group.

[0071] In the present invention, the term "amino group" refers to an -NH2 group.

[0072] In the present invention, the term "carboxy group" refers to a -COOH group.

[0073] As used herein, the term "nitro group" refers to the -NO2 group.

[0074] In the present invention, "C 1-6 The term "alkyl group" refers to a straight or branched chain alkyl group derived by removing one hydrogen atom from a hydrocarbon moiety containing from one to six carbon atoms, such as, for example, 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.

[0075] In the present invention, "C 1-6 The term "ene" in "alkylene group" refers to C 1-6 Refers to a divalent group derived by removing two hydrogen atoms from an alkyl group.

[0076] In the present invention, "halogen-substituted C 1-6 The term "alkyl group" refers to a C1-C6 alkyl group substituted with one or more halogens 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-dibromopropan-2-yl, 3-bromo-2-fluoropropyl, and 1,4,4-trifluorobutan-2-yl.

[0077] In the present invention, "C 1-6 The term "alkoxy group" refers to the "C" group defined above. 1-6 A group in which an alkyl group is attached to the parent molecule through an oxygen atom, i.e., a C 1-6 Alkyl-O- groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentyloxy, neopentyloxy, n-hexyloxy, and the like.

[0078] In the present invention, the "halogen-substituted C 1-6 The term "alkoxy group" refers to a C1-C6 alkoxy group substituted with one or more halogen groups as defined above, examples of which include, but are not limited to, fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy, and fluoropropoxy.

[0079] In the present invention, "C 2-6 The term "alkenyl group" refers to a straight or branched chain alkene derived by removing one hydrogen atom from an alkene moiety of 2 to 6 carbon atoms containing at least one carbon-carbon double bond, including vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butanedi-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, and the like. Preferably, "C 2-6 An "alkenyl group" contains one carbon-carbon double bond.

[0080] As used herein, the term "C2-6 alkynyl group" refers to a straight or branched chain alkyne derived by removing one hydrogen atom from an alkyne moiety of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, including ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Preferably, the "C2-6 alkynyl group" contains one carbon-carbon triple bond.

[0081] In the present invention, "C 1-6 alkylamino group," "C 1-6 alkylcarbonylamino group," "C 1-6 The terms "alkylsulfonyl group" and "aminocarbonyl group" refer to C 1-6 Alkyl-NH-, C 1-6 Alkyl-C(O)-NH-, C 1-6 Alkyl refers to a group formed in the manner of -S(O)2-, NH2-C(O)-.

[0082] In the present invention, [ka] When R1 and R2 in the formula (I) form a ring together with the C or N atom to which they are bonded, it can be understood that X1 and X2 form a double bond or a single bond according to the rules of chemical bonding.

[0083] In the present invention, the term "5- to 12-membered ring" includes carbocyclic or heterocyclic rings that can be chemically formed, and includes 5- to 12-membered cycloalkyl groups, 5- to 7-membered cycloalkyl groups, 5- to 12-membered cycloalkenyl groups, 5- to 7-membered cycloalkenyl groups, 6- to 12-membered fused cycloalkyl groups, 5- to 12-membered heterocyclic groups, 5- to 7-membered heterocyclic groups, 6- to 12-membered fused heterocyclic groups, aryl groups, 5- to 12-membered heteroaryl groups, 8- to 12-membered fused heteroaryl groups, and 5- to 7-membered heteroaryl groups.

[0084] As used herein, the term "3- to 12-membered cycloalkyl group" refers to a monovalent or (optionally) divalent group derived from a 3- to 12-membered cycloalkane (e.g., a 5- to 12-membered cycloalkyl group), which may be a monocyclic, bicyclic, or polycyclic cycloalkyl system. Unless otherwise specified, it includes all possible monocyclic and polycyclic (e.g., a 6- to 12-membered polycyclic alkyl group) rings, including fused, spiro, and bridged rings. Monocyclic ring systems are typically cyclic hydrocarbon groups containing 3 to 12 carbon atoms, e.g., 3 to 8 or 3 to 6 carbon atoms. Illustrative examples of cycloalkyl groups include, but are not limited to, cyclopropyl alkyl groups, cyclobutyl alkyl groups, cyclopentyl alkyl groups, cyclohexyl alkyl groups, cycloheptyl alkyl groups, cyclooctyl alkyl groups, cyclopentane-1,3-diyl, cyclohexane-1,4-diyl, cycloheptane-1,4-diyl, and the like. Polycyclic cycloalkyl groups include fused cycloalkyl groups, bridged cycloalkyl groups, and spirocycloalkyl groups. Fused cycloalkyl groups can be 6-11 membered fused cycloalkyl groups, for example, 7-10 membered fused cycloalkyl groups, typical examples of which include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane groups. Spirocycloalkyl groups can be 7-12 membered spirocycloalkyl groups, for example, 7-11 membered spirocycloalkyl groups, examples of which include: [ka] The bridged cycloalkyl group can be a 6-10 membered bridged cycloalkyl group, for example a 7-10 membered bridged cycloalkyl group, examples of which include: [ka] This includes, but is not limited to, groups.

[0085] As used herein, the term "3- to 7-membered cycloalkyl group" refers to a monovalent or (optionally) divalent group derived from a 3- to 7-membered cycloalkane. The "3- to 7-membered cycloalkyl group" can be a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group, and examples of 3- to 7-membered cycloalkyl groups include, but are not limited to, cyclopropylalkyl groups, cyclobutylalkyl groups, cyclopentylalkyl groups, and cyclohexylalkyl groups.

[0086] In the present invention, the term "cycloalkenyl group" refers to a group obtained by adding at least one double bond to the above-mentioned cycloalkyl group. For example, it may be a "3-12-membered cycloalkenyl group," i.e., it may have 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring-forming carbon atoms. Unless otherwise specified, a cycloalkenyl group includes all possible monocyclic and polycyclic (fused, spiro, bridged) situations. The cycloalkenyl group may be a 3-12-membered cycloalkenyl group, a 3-8-membered cycloalkenyl group, a 5-8-membered cycloalkenyl group, a 5-7-membered cycloalkenyl group, a 4-6-membered cycloalkenyl group, a 7-11-membered spirocycloalkenyl group, a 7-11-membered fused cycloalkenyl group, a 6-11-membered bridged cycloalkenyl group, etc. Illustrative examples of cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentene, cyclopentadiene, cyclohexene, 1,4-cyclohexadien-1-yl, cycloheptenyl, 1,4-cycloheptadien-1-yl, cyclooctenyl, 1,5-cyclooctadien-1-yl, and the like.

[0087] In the present invention, the term "5- to 7-membered cycloalkenyl group" refers to a group obtained by having at least one double bond in a 5- to 7-membered cycloalkyl group, and examples thereof include a cyclobutenyl group, a cyclopentene group, a cyclohexene group, and a cycloheptenyl group.

[0088] In the present invention, the term "3- to 14-membered heterocyclic group" refers to a monovalent or (optionally) divalent group derived from a 3- to 14-membered heterocyclic alkane, i.e., a non-aromatic cyclic group in which at least one ring carbon atom of a 3- to 14-membered heterocyclic group is replaced with a heteroatom selected from O, S, S(O), S(O)2, C(O), and N, preferably containing 1 to 3 heteroatoms, including situations in which ring-forming atoms including carbon, nitrogen, and sulfur atoms are replaced with oxygen. "3- to 14-membered heterocyclic group" (e.g., 5- to 14-membered heterocyclic group, 5- to 12-membered heterocyclic group) includes monocyclic, bicyclic, or polycyclic heterocyclic groups in which one or more rings may be saturated or partially saturated, but does not include aromatic rings. Unless otherwise specified, a reference to a 1-membered heterocyclic group (e.g., 3-8 membered heterocyclic group, 3-7 membered heterocyclic group, 5-8 membered heterocyclic group, 5-7 membered heterocyclic group, 5-6 membered heterocyclic group, 4-6 membered heterocyclic group, 6 membered heterocyclic group) includes all monocyclic, polycyclic (fused, spiro, bridged fused), saturated or partially saturated situations that may be formed.

[0089] The monocyclic heterocyclic group can be a 3- to 8-membered heterocyclic group, for example, a 5- to 7-membered heterocyclic group, a 3- to 7-membered heterocyclic group, a 4- to 7-membered heterocyclic group, or a 5- to 6-membered heterocyclic group; the 3- to 8-membered nitrogen-containing heterocyclic group can be, for example, a 4- to 7-membered nitrogen-containing heterocyclic group or a 5- to 6-membered nitrogen-containing heterocyclic group; and the 3- to 8-membered saturated heterocyclic group can be, for example, a 5- to 6-membered saturated heterocyclic group. Illustrative examples include aziridyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophene, 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-dihydrooxazoline, 2,5-dihydroisoxazolyl ... aryl, 2,3-dihydrooxazolyl, 3,4-dihydro-2H-pyrrole, 2,3-dihydro-1H-pyrrolyl, 2,5-dihydro-1H-imidazolyl, 4,5-dihydro-1H-imidazolyl, 4,5-dihydro-1H-pyrazolyl, 4,5-dihydro-3H-pyrazolyl, 4,5-dihydrothiazolyl, 2,5-dihydrothiazolyl, 2H-pyranyl, 4H-pyranyl, 2H-thiopyranyl, 4H-thiopyranyl, 2,3,4,5-tetrahydropyridyl, 1,2-isoxazinyl, 1,4-isoxazinyl or 6H-1,3-oxazinyl and the like.

[0090] Polycyclic heterocyclic groups (e.g., 6- to 12-membered polycyclic heterocyclic groups) include fused heterocyclic groups, spiro heterocyclic groups, and bridged heterocyclic groups, which may be saturated, partially saturated, or unsaturated, but are not aromatic. Polycyclic heterocyclic groups can be fused to a benzene ring, a 5- to 6-membered monocyclic cycloalkyl group, a 5- to 6-membered monocyclic cycloalkenyl group, a 5- to 6-membered monocyclic heterocyclic group, or a 5- to 6-membered monocyclic heteroaryl group.

[0091] The fused heterocyclic group may be a 6- to 12-membered fused heterocyclic group, for example, a 6- to 11-membered fused heterocyclic group or a 7- to 10-membered fused heterocyclic group, a 6- to 11-membered saturated fused heterocyclic group, or a 6- to 11-membered nitrogen-containing fused heterocyclic group, and representative examples thereof include 3-azabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.2.0]heptyl, 3,8-diazabicyclo[4.2.0]octyl, 3, including, but not limited to, 7-diazabicyclo[4.2.0]octyl, octahydropyrrolo[3,4-c]pyrrolidinyl, octahydropyrrolo[3,4-b]pyrrolidinyl, octahydropyrrolo[3,4-b][1,4]oxazinyl, octahydro-1H-pyrrolo[3,4-c]pyridinyl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, dihydroindol-1-yl, dihydroindol-2-yl, dihydroindol-3-yl, 2,3-dihydrobenzothiophen-2yl, octahydro-1H-indolyl, octahydrobenzofuranyl.

[0092] The spiroheterocyclic group may be a 6- to 12-membered spiroheterocyclic group, such as a 7- to 12-membered spiroheterocyclic group, a 7- to 12-membered saturated spiroheterocyclic group, or a 7- to 12-membered nitrogen-containing spiroheterocyclic group, examples of which include: [ka] Including, but not limited to:

[0093] The bridged heterocyclic group may be a 6- to 12-membered bridged heterocyclic group, for example, a 6- to 10-membered bridged heterocyclic group (for example, a 6- to 10-membered nitrogen-containing bridged heterocyclic group, particularly a 7-membered nitrogen-containing bridged heterocyclic group), or a 7- to 10-membered bridged heterocyclic group, examples of which include: [ka] Including, but not limited to:

[0094] As used herein, the term "aryl group" refers to a monovalent or optionally divalent cyclic aromatic group derived from an aromatic carbocyclic hydrocarbon containing from 6 to 14 carbon atoms, including benzene, naphthalene, phenanthrene, and the like.

[0095] In the present invention, the term "5-14-membered heteroaryl group" refers to an aromatic 5-14-membered cyclic group in which at least one ring carbon atom is replaced with a heteroatom selected from O, S, and N. The "5-14-membered heteroaryl group" can be a 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered heteroaryl group, preferably containing 1 to 3 heteroatoms, including situations in which carbon and sulfur atoms are replaced with oxygen and nitrogen, such as when a carbon atom is replaced with C(O) and a sulfur atom is replaced with S(O) or S(O)2. Heteroaryl groups include monocyclic and polycyclic heteroaryl groups, and unless otherwise specified, a 5-14-membered heteroaryl group includes all possible monocyclic, polycyclic, fully aromatic, and partially aromatic situations. The monocyclic heteroaryl group can be a 5- to 7-membered heteroaryl group, for example, a 5- to 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, tetrazole, thiadiazolyl, thienyl, triazolyl, and triazinyl.

[0096] In some embodiments, a polycyclic heteroaryl group refers to a group obtained by fusing a monocyclic heteroaryl ring to a phenyl group, a cycloalkenyl group, a heteroaryl group, a cycloalkyl group, or a heterocyclic group. In some embodiments, a polycyclic aryl group (e.g., an 8-14 membered polycyclic heteroaryl group) can be an 8-14 membered fused heteroaryl group, such as a 9-10 membered fused heteroaryl group, examples of which include benzimidazolyl, benzofuranyl, benzothienyl, benzoxadiazolyl, benzothiadiazolyl, benzothiazolyl, cinnolinyl, 5,6-dihydroquinolin-2-yl, 5,6-dihydroisoquinolin-1-yl, furopyridyl, indazolyl, indolyl, isoindolyl, isoquinolyl, diinyl, purinyl, quinolyl, including, but not limited to, 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, thienopyridyl, 4,5,6,7-tetrahydro[c][1,2,5]oxadiazolyl, and 6,7-dihydro[c][1,2,5]oxadiazol-4(5H)one.

[0097] In the present invention, heterocyclic, heteroaryl groups include situations in which ring-forming atoms, including carbon, nitrogen and sulfur atoms, are replaced with oxygen.

[0098] In the present invention, the term "pharmaceutically acceptable salts" refers to addition salts and solvates of pharmaceutically acceptable acids and bases. These pharmaceutically acceptable salts include salts of the following acids: 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, alkanoic acid (acetic acid, HOOC-(CH)-COOH (where n = 0 to 4)), and the like. These pharmaceutically acceptable salts also include salts of the following bases: sodium, potassium, calcium, ammonium, and the like. Various non-toxic pharmaceutically usable addition salts can be readily identified by those skilled in the art.

[0099] In the present invention, all ranges of values ​​are expressed to include the endpoints of the range, all integers within the range, and subranges formed from these integers. For example, "3-7 membered" includes 3, 4, 5, 6, and 7 members, "1-4" or "1-4" includes 1, 2, 3, and 4, and "1-3" or "1-3" includes 1, 2, and 3.

[0100] The term "optionally" or "optionally selected" refers to the situation described thereafter that may or may not occur, and the description includes the occurrence of the situation and the non-occurrence of the situation.

[0101] In the present invention, the "stereoisomer" of a compound refers to an isomer resulting from a difference in the spatial arrangement of atoms in the molecule. When a compound has an asymmetric carbon atom, it generates an enantiomer, and when a compound has a carbon-carbon double bond or a ring structure, it generates a cis-trans isomer.

[0102] The term "tautomer" refers to a special type of functional group isomer, where isomers with different functional groups exist in dynamic equilibrium and are readily interconvertible. For example, when a ketone or oxime is present, typical examples include ketone-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, and imine-enamine tautomers.

[0103] All enantiomers, diastereomers, racemic isomers, cis-trans isomers, tautomers, geometric isomers, epimers, and mixtures thereof of the compounds are included within the scope of the present invention.

[0104] In the chemical configuration of the compounds described in this invention, the bond [ka] indicates an unspecified configuration, i.e., if chiral isomers exist in the chemical structure, the bond [ka] teeth [ka] or [ka] or at the same time [ka] In the chemical structure of the compounds described in the present invention, [ka] indicates the point of attachment to the parent molecule. [Effects of the Invention]

[0105] The compounds provided by the present invention, or their pharmaceutically acceptable salts, stereoisomers, and tautomers, have been found to have favorable inhibitory activity against the NLRP3 inflammasome, and therefore the compounds of the present invention can be used for the prevention and / or treatment of diseases associated with the NLRP3 inflammasome. DETAILED DESCRIPTION OF THE INVENTION

[0106] In order to make the objectives, technical solutions and advantages of the present invention clearer and easier to understand, the present invention will be described in more detail below. Of course, the described embodiments are only a part of the embodiments of the present invention, but are not all of the embodiments. Based on the embodiments in the present invention, all other embodiments that can be obtained by those skilled in the art without creative efforts fall within the protection scope of the present invention.

[0107] The abbreviations and English expressions used in this invention have the following meanings: "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, and "DBDM "H" and "DBH" refer to dibromohydantoin, "mCPBA" refers to metachloroperbenzoic acid, "BINAP" refers to 1,1'-binaphthyl-2,2'-bis(diphenylphosphino), "TMSOTf" refers to trimethylsilyl trifluoromethanesulfonate, "TBAF" refers to tetra-n-butylammonium fluoride, "DIPEA" refers to N,N-diisopropylethylamine, "LDA" refers to lithium diisopropylamide, and "B2Pin2" refers to bis(pinacolato)diboron.

[0108] "FBS" refers to fetal bovine serum, "PBS" refers to phosphate buffered saline, "PMA" refers to phorbol ester, "LPS" refers to lipopolysaccharide, and "Nigericin" refers to nigericin.

[0109] Example 1 Synthesis of (R)-5-ethynyl-2-(4-((1-methylpiperidin-3-yl)amino)-5,6,7,8-tetrahydrophthalazin-1-yl)phenol (Compound 1) [ka]

[0110] Step 1: Synthesis of (R)-3-(ethoxymethoxy)-4-(4-((1-methylpiperidin-3-yl)amino)-5,6,7,8-tetrahydrophthalazin-1-yl)benzaldehyde [ka]

[0111] 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 sequentially to 1,4-dioxane (6 mL) and water (3 mL). The mixture was heated to 110 °C under nitrogen protection for 2 h. The reaction mixture was cooled to room temperature, quenched by the addition of water (30 mL), extracted with EA (30 mL × 2), the organic phase dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 50:1 to 10:1) to give the product (320 mg, yield: 70.6%).

[0112] Step 2: Synthesis of (R)-4-(2-(ethoxymethoxy)-4-ethynylphenyl)-N-(1-methylpiperidin-3-yl)-5,6,7,8-tetrahydrophthalazin-1-amine [ka]

[0113] (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). KCO (209 mg, 1.51 mmol, 2.0 eq) and (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (217 mg, 1.13 mmol, 1.5 eq) were added and stirred at room temperature for 5 h. 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 purified by silica gel column chromatography (DCM:MeOH = 50:1 to 20:1) to give the product (275 mg, yield: 86.8%).

[0114] Step 3: Synthesis of (R)-5-ethynyl-2-(4-((1-methylpiperidin-3-yl)amino)-5,6,7,8-tetrahydrophthalazin-1-yl)phenol [ka]

[0115] (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). A solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 0.82 mL, 3.27 mmol, 5.0 eq) was added dropwise and stirred at room temperature for 2 h. 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 purified by silica gel column chromatography (DCM:MeOH = 50:1 to 10:1) to give the product (198 mg, yield: 83.5%).

[0116] 1HNMR (400 MHz, DMSO-d6) δ(ppm):10.11 (s, 1H), 7.11 (d, J = 7.6 Hz, 1H), 7.04 (s, 1H), 6.99-6.97 (m, 1H), 6.07 (s, 1H), 4.55 (s, 1H), 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 = 5.6 Hz, 3H). Molecular formula:C 22 H 26 N4O exact mass:362.21 LC-MS(Pos, m / z)=363.14[M+H] + .

[0117] Example 2 Synthesis of (R)-5-ethynyl-2-(4-((tetrahydro-2H-pyran-3-yl)amino)phthalazin-1-yl)phenol (Compound 2) [ka]

[0118] Step 1: Synthesis of 4-(4-chlorophthalazin-1-yl)-3-(ethoxymethoxy)benzaldehyde [ka]

[0119] 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 sequentially to 1,4-dioxane (5 mL) and water (2.5 mL). The mixture was heated to 110 °C under nitrogen protection and reacted for 2 h. The reaction mixture was cooled to room temperature, quenched with water (30 mL), extracted with EA (30 mL × 2), 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 give the product (290 mg, yield: 56.1%).

[0120] Step 2: Synthesis of (R)-3-(ethoxymethoxy)-4-(4-((tetrahydro-2H-pyran-3-yl)amino)phthalazin-1-yl)benzaldehyde [ka]

[0121] 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 sequentially to 1,4-dioxane (10 mL) and heated to 90 °C under nitrogen protection for 2 h. The reaction mixture was cooled to room temperature, quenched with water (30 mL), extracted with EA (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 20:1) to give the product (212 mg, yield: 74.3%).

[0122] Step 3: Synthesis of (R)-4-(2-(ethoxymethoxy)-4-ethynylphenyl)-N-(tetrahydro-2H-pyran-3-yl)phthalazin-1-amine [ka]

[0123] (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). KCO (142 mg, 1.03 mmol, 2.0 eq) and (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (119 mg, 0.618 mmol, 1.2 eq) were added and stirred at room temperature for 16 h. The mixture was concentrated, dissolved in water, and 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 separated by silica gel column chromatography (DCM:MeOH = 100:1 to 20:1) to give the product (122 mg, yield: 58.7%).

[0124] Step 4: Synthesis of (R)-5-ethynyl-2-(4-((tetrahydro-2H-pyran-3-yl)amino)phthalazin-1-yl)phenol [ka]

[0125] (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). A solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 0.22 mL, 0.891 mmol, 3.0 eq) was added dropwise and stirred at room temperature for 1 h. The pH was adjusted to 8 with saturated aqueous NaHCO3, and the mixture was extracted with DCM (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 preparative thin-layer chromatography (DCM:MeOH = 20:1) to give the product (62.0 mg, yield: 60.4%).

[0126] 1 HNMR (400 MHz, DMSO-d6) δ(ppm):10.02 (s, 1H), 8.41 (d, J = 8.4 Hz, 1H), 7.88-7.84 (m, 1H), 7.81-7.77 (m, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.17 (d, J = 7.6 Hz, 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 = 11.2 Hz, 1H), 3.36 (s, 1H), 3.28-3.23 (m, 1H), 2.12-2.11 (m, 1H), 1.80-1.68 (m, 3H). Molecular formula:C 21 H 19 N3O2 exact mass: 345.15 LC-MS(Pos, m / z)=346.03[M+H] + .

[0127] Example 3: Synthesis of 5-ethynyl-2-(4-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)phthalazin-1-yl)phenol (Compound 3) [ka]

[0128] Step 1: Synthesis of 3-(ethoxymethoxy)-4-(4-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)phthalazin-1-yl)benzaldehyde [ka]

[0129] (cis)-3-((4-chlorophthalazin-1-yl)amino)-1-methylcyclobutan-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) were added to 1,4-dioxane (10.0 mL) and the reaction was carried out at 110 °C for 3 hours under nitrogen protection. After completion of the reaction, the reaction mixture was cooled to room temperature, water (50.0 mL) was added, and ethyl acetate (100.0 mL) was added. The mixture was extracted with 1 mL of HCl, 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 = 100:1-40:1) to give the product (240.0 mg, yield: 53.5%).

[0130] Step 2: Synthesis of (cis)-3-((4-(2-(ethoxymethoxy)-4-ethynylphenyl)phthalazin-1-yl)amino)-1-methylcyclobutan-1-ol [ka]

[0131] 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 (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (169.7 mg, 0.88 mmol, 1.5 eq) were added to methanol (10 mL) and stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was monitored by LC-MS. Water (50 mL) was added, and the mixture was extracted with dichloromethane (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give the product (130 mg, yield: 54.7%).

[0132] Step 3: Synthesis of 5-ethynyl-2-(4-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)phthalazin-1-yl)phenol [ka]

[0133] (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 hydrogen chloride-1,4-dioxane solution (4.0 mol / L, 4.0 mL) was added dropwise. The reaction was allowed to proceed at room temperature for 2 hours. After completion of the reaction was confirmed by TLC, the system was adjusted to pH 7-8 with saturated sodium bicarbonate 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 to give the product (50.0 mg, yield: 44.9%).

[0134] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 10.01 (s, 1H), 8.42-8.40 (d, J=8 Hz, 1H), 7.84 (t, J=8 Hz, 1H), 7.77 (t, J=8 Hz, 1H), 7.58-7.57 (d, J=4 Hz, 1H), 7.47-7.45 (d, J=8 Hz, 1H), 7.30-7.28 (d, J=8 Hz, 1H), 7.07-7.05 (m, 2H), 5.01 (s, 1H), 4.27-4.22 (m, 2H), 2.50-2.47 (m, 2H), 2.20-2.15 (m, 2H), 1.34 (s, 3H). Molecular formula:C 21 H 19 N3O2 exact mass: 345.15 LC-MS(Pos, m / z)=346.07[M+H + ].

[0135] Example 4: Synthesis of 5-ethynyl-2-(4-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-5,6,7,8-tetrahydrophthalazin-1-yl)phenol (Compound 4) [ka]

[0136] Step 1: Synthesis of 3-(ethoxymethoxy)-4-(4-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-5,6,7,8-tetrahydrophthalazin-1-yl)benzaldehyde [ka]

[0137] (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)Cl2 (53.2 mg, 0.07 mmol, 0.05 eq) were added to 1,4-dioxane (12.0 mL) and reacted at 110 °C for 4 h under nitrogen protection. Complete reaction was monitored by TLC. The system was cooled to room temperature and the reaction mixture was diluted with water (50.0 mL). The mixture was added to a 100 mL aliquot of 100% ethanol and extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica gel specification: 100-200 mesh, dichloromethane:methanol = 80:1-30:1) to give the product (143 mg, yield: 23.8%).

[0138] Step 2: Synthesis of (cis)-3-((4-(2-(ethoxymethoxy)-4-ethynylphenyl)-5,6,7,8-tetrahydrophthalazin-1-yl)amino)-1-methylcyclobutan-1-ol [ka]

[0139] 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 (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (100.1 mg, 0.52 mmol, 1.5 eq) were added to methanol (6.0 mL) and stirred at room temperature for 14 hours. Complete reaction was monitored by LC-MS. Water (50.0 mL) was added, and dichloromethane (100.0 mL) was added. mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol=10:1) to obtain the product (120.0 mg, yield: 84.8%).

[0140] Step 3: Synthesis of 5-ethynyl-2-(4-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-5,6,7,8-tetrahydrophthalazin-1-yl)phenol [ka]

[0141] (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 hydrogen chloride-1,4-dioxane solution (4.0 mol / L, 4.0 mL) was added dropwise. The reaction was allowed to proceed at room temperature for 2 hours. After completion of the reaction, the system was monitored 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 give the product (80.0 mg, yield: 77.8%).

[0142] 1HNMR (400 MHz, DMSO-d6) δ(ppm): 10.01 (s, 1H), 8.42-8.40 (d, J=8 Hz, 1H), 7.84 (t, J=8 Hz, 1H), 7.77 (t, J=8 Hz, 1H), 7.58-7.57 (d, J=4 Hz, 1H), 7.47-7.45 (d, J=8 Hz, 1H), 7.30-7.28 (d, J=8 Hz, 1H), 7.07-7.05 (m, 2H), 5.01 (s, 1H), 4.27-4.22 (m, 2H), 2.50-2.47 (m, 2H), 2.20-2.15 (m, 2H), 1.34 (s, 3H). Molecular formula:C 21 H 23 N3O2 exact mass: 349.18 LC-MS(Pos, m / z)=350.14[M+H + ].

[0143] Example 5 Synthesis of (R)-2-(4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)-5-vinylphenol (Compound 99) [ka]

[0144] Step 1: Synthesis of (R)-2-(4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)-5-vinylphenol [ka]

[0145] (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), Lindlar's catalyst (30 mg, 10%) was added, and the atmosphere was replaced with H. The reaction mixture was reacted at room temperature for 1 hour. The reaction mixture was filtered through diatomaceous earth with suction, and the filtrate was concentrated under reduced pressure. The crude product was separated by preparative thin-layer chromatography (DCM:MeOH=10:1) to give the product (240 mg, yield: 79.6%).

[0146] 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 = 8.4 Hz, 1H), 7.42 (s, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.10-7.07 (m, 2H), 6.79-6.72 (m, 1H), 5.82 (d, J = 17.6 Hz, 1H), 5.31 (d, J = 11.2 Hz, 1H), 4.63 (s, 1H), 3.39 (d, J = 9.2 Hz, 1H), 3.02 (s, 1H), 2.55 (s, 5H), 1.92 (s, 2H),1.77-1.71 (m, 2H). Molecular formula:C 22 H 24 N4O exact mass:360.20 LC-MS(Pos, m / z)=361.09[M+H] + .

[0147] Example 6 Synthesis of (R)-5-ethynyl-2-(4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)phenol (Compound 100) [ka]

[0148] Step 1: Synthesis of 4-bromo-3-hydroxybenzaldehyde [ka]

[0149] 4-Bromo-3-methoxybenzaldehyde (10.0 g, 46.5 mmol, 1.0 eq) was added to 40% aqueous HBr (60 mL) and heated to 100 °C for 20 h. The mixture was cooled to room temperature, quenched with water, and extracted with EA (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 50:1 to 5:1) to give the product (7.80 g, yield: 83.4%).

[0150] Step 2: Synthesis of 4-bromo-3-(ethoxymethoxy)benzaldehyde [ka]

[0151] 4-Bromo-3-hydroxybenzaldehyde (7.80 g, 38.8 mmol, 1.0 eq) was dissolved in THF (100 mL), cooled to 0 °C, and added in portions with 60% NaH (2.33 g, 58.2 mmol, 1.5 eq). The mixture was stirred for 20 min, and then chloromethyl ether (5.50 g, 86.2 mmol, 1.5 eq) was added and the reaction mixture was left for 2 h. The mixture was quenched with saturated aqueous NH4Cl, separated, and the aqueous phase was extracted with EA (30 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 50:1 to 5:1) to give the product (7.60 g, yield: 75.6%).

[0152] Step 3: Synthesis of 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde [ka]

[0153] 4-Bromo-3-(ethoxymethoxy)benzaldehyde (5.00 g, 19.3 mmol, 1.0 eq), bis(pinacolato)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 protection for 20 h. After cooling to room temperature, the mixture was quenched with water (50 mL). The mixture was extracted with EA (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 20:1 to 5:1) to give the product (5.20 g, yield: 88.0%).

[0154] Step 4: Synthesis of (R)-3-(ethoxymethoxy)-4-(4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)benzaldehyde [ka]

[0155] 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 sequentially to 1,4-dioxane (10 mL) and water (5 mL). The mixture was heated to 110 °C under nitrogen protection for 3 h. The reaction mixture was cooled to room temperature, quenched with water (30 mL), extracted with EA (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 50:1 to 10:1) to give the product (1.22 g, yield: 53.5%).

[0156] Step 5: Synthesis of (R)-4-(2-(ethoxymethoxy)-4-ethynylphenyl)-N-(1-methylpiperidin-3-yl)phthalazin-1-amine [ka]

[0157] (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). KCO (788 mg, 5.70 mmol, 2.0 eq) and (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (657 mg, 3.42 mmol, 1.2 eq) were added and stirred at room temperature for 2 h. 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 purified by silica gel column chromatography (DCM:MeOH = 50:1 to 10:1) to give the product (1.08 g, yield: 90.9%).

[0158] Step 6: Synthesis of (R)-5-ethynyl-2-(4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)phenol [ka]

[0159] (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 added dropwise and stirred at room temperature for 4 h. The pH was adjusted to 8 with saturated aqueous NaHCO3, and the mixture was 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 purified by silica gel column chromatography (DCM:MeOH = 50:1 to 10:1) to give the product (760 mg, yield: 81.8%).

[0160] 1 HNMR (400 MHz, 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 = 7.6 Hz, 1H), 7.13 (s, 1H), 7.08-7.06 (m, 1H), 4.66 (s, 1H), 4.25 (s, 1H), 3.43 (d, J = 9.6 Hz, 1H), 3.06 (s, 1H), 2.59 (s, 5H), 1.99-1.92 (m, 2H), 1.79-1.74 (m, 2H). Molecular formula:C 22 H 22 N4O exact mass:358.18 LC-MS(Pos, m / z)=359.10[M+H] + .

[0161] Example 7 Synthesis of (R)-5-ethynyl-2-(4-((1-methylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 5) [ka]

[0162] Step 1: Synthesis of pyrido[3,4-d]pyridazine-1,4-diol [ka]

[0163] 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 reacted for 7 hours, after which a large amount of solid precipitated. The mixture was cooled to room temperature, suction filtered, and the filter cake was washed with EtOH and dried to obtain the product (15.0 g, yield: 85.0%).

[0164] Step 2: Synthesis of 1,4-dichloropyrido[3,4-d]pyridazine [ka]

[0165] Pyrido[3,4-d]pyridazine-1,4-diol (1.0 g, 6.13 mmol, 1.0 eq) was added to POCl3 (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 reacted for 2 h. The mixture was concentrated under reduced pressure, diluted with EA, adjusted to alkaline pH with aqueous NaHCO3, extracted with DCM, and the organic phase was concentrated under reduced pressure. The product was separated by silica gel column chromatography (PE:EA = 5:1) to give the product (150 mg, yield: 12.5%).

[0166] Step 3: Synthesis of 4-chloropyrido[3,4-d]pyridazin-1-ol [ka]

[0167] 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. After cooling to room temperature, the mixture was suction filtered, and the filter cake was recrystallized with acetic acid to give the product (1.50 g, yield: 33.0%).

[0168] Step 4: Synthesis of (R)-3-((1-hydroxypyrido[3,4-d]pyridazin-4-yl)amino)piperidine-1-carboxylic acid tert-butyl ester [ka]

[0169] 4-Chloropyrido[3,4-d]pyridazin-1-ol (1.40 g, 7.73 mmol, 1.0 eq), (R)-3-aminopiperidine-1-carboxylic acid tert-butyl ester (1.86 g, 9.28 mmol, 1.2 eq), Pd(dba) (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). The mixture was heated to 110 °C under nitrogen protection for 2.5 h. The mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM:MeOH = 100:1 to 30:1) to give the product (1.0 g, 37.5% yield).

[0170] Step 5: Synthesis of (R)-1-chloro-N-(piperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine [ka]

[0171] (R)-3-((1-hydroxypyrido[3,4-d]pyridazin-4-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (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). The mixture was heated to 90 °C and incubated for 4 h. After cooling to room temperature, the pH was adjusted to 8 with saturated aqueous NaHCO3, and the mixture was extracted with DCM (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was separated by silica gel column chromatography (DCM:MeOH = 50:1 to 10:1) to give the product (262 mg, yield: 62.1%).

[0172] Step 6: Synthesis of (R)-1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine [ka]

[0173] (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 min. NaBH3CN (93.6 mg, 1.49 mmol, 1.5 eq) was then added and the mixture was stirred for 1 h. The reaction mixture was quenched with saturated aqueous NaHCO3, extracted with DCM (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product (215 mg, 77.9% yield) was obtained by preparative thin-layer chromatography (DCM:MeOH = 10:1).

[0174] Step 7: Synthesis of (R)-3-(ethoxymethoxy)-4-(4-((1-methylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)benzaldehyde [ka]

[0175] 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 sequentially to 1,4-dioxane (4 mL). HO (2 mL) was added and the mixture was heated to 110 °C under nitrogen protection for 3 h. After cooling to room temperature, water (20 mL) was added and 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 was separated by silica gel column chromatography (DCM:MeOH = 100:1 to 10:1) to give the product (40.0 mg, yield: 12.3%).

[0176] Step 8: Synthesis of (R)-1-(2-(ethoxymethoxy)-4-ethynylphenyl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine [ka]

[0177] (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). KCO (26.3 mg, 0.190 mmol, 2.0 eq) and (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (27.3 mg, 0.142 mmol, 1.5 eq) were added and stirred at room temperature for 3 h. 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, yield: 55.5%) was separated by preparative thin-layer chromatography (DCM:MeOH = 10:1) to give the product.

[0178] Step 9: Synthesis of (R)-5-ethynyl-2-(4-((1-methylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol [ka]

[0179] (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). A solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 0.06 mL, 0.264 mmol, 5.0 eq) was added dropwise and stirred at room temperature for 1 h. The pH was adjusted to 8 with saturated aqueous NaHCO3. The mixture was extracted with a 10:1 DCM:MeOH mixture (5 mL x 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 separated by preparative thin-layer chromatography (DCM:MeOH = 10:1).

[0180] 1HNMR (400 MHz, CD3OD) δ(ppm): 9.72 (s, 1H), 8.86 (d, J = 8.0 Hz, 1H), 7.53-7.51 (m, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.16-7.14 (m, 1H), 7.12 (d, J = 1.2 Hz, 1H), 4.71-4.65 (m, 1H), 3.60 (s, 1H), 3.43 (d, J = 8.7 Hz, 1H), 3.02 (d, J = 10.0 Hz, 1H), 2.67 (d, J = 8.9 Hz, 2H), 2.60 (s, 3H), 2.16-2.14 (m, 1H), 2.06-2.01 (m, 1H), 1.88-1.78 (m, 2H). Molecular formula:C 21 H 21 N5O exact mass:359.17 LC-MS(Pos, m / z)=360.13[M+H] + .

[0181] 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) [ka]

[0182] Step 1: Synthesis of 6-aza-2-thiouracil [ka]

[0183] 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 then reacted at 100 °C for 1.5 hours. A large amount of solid precipitated, and the mixture was cooled to room temperature and filtered. The filter cake was divided and added to an aqueous solution (300 mL) of NaOH (44 g, 1.10 mol, 1.0 eq). The mixture was reacted at 100 °C for 1 hour. The mixture was then cooled to room temperature, and the pH of the aqueous phase was adjusted to 1 with hydrochloric acid. A large amount of solid precipitated, and the mixture was suction filtered. The filter cake was dried to obtain the product (90 g, yield: 63.4%).

[0184] Step 2: Synthesis of 3-(methylthio)-1,2,4-triazin-5(4H)-one [ka]

[0185] 6-Aza-2-thiouracil (90 g, 696.91 mmol, 1.0 eq) was dissolved in EtOH (1 L) and added portionwise with sodium tert-butoxide (66.97 g, 696.91 mmol, 1.0 eq). The mixture was stirred for 10 min, and then iodomethane (98.93 g, 696.91 mmol, 1.0 eq) was added dropwise slowly and allowed to react for 50 min. The reaction was monitored for completeness by TLC, suction filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (MeOH:DCM = 1:15), slurried in EA (100 mL), suction filtered, and the filter cake was dried to give the product (30 g, 30% yield).

[0186] Step 3: Synthesis of 5,6-dichloro-3-(methylthio)-1,2,4-triazine [ka]

[0187] 3-(Methylthio)-1,2,4-triazin-5(4H)-one (8.50 g, 59.4 mmol, 1.0 eq) was added to SOCl (40 mL), DMF (0.4 mL) was added, and the mixture was heated to 80 °C and reacted for 2 h. The mixture was cooled to room temperature and concentrated under reduced pressure to give the crude product (12.2 g).

[0188] Step 4: Synthesis of 6-chloro-5-methyl-3-(methylthio)-1,2,4-triazine [ka]

[0189] 5,6-Dichloro-3-(methylthio)-1,2,4-triazine (12.2 g, 62.2 mmol, 1.0 eq) was dissolved in THF (50 mL) and cooled to -60 °C. MeMgCl (20.7 mL, 62.2 mmol, 1.0 eq) was added dropwise and the reaction mixture was allowed to react for 0.5 h. The mixture was quenched with saturated aqueous NH4Cl 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 was separated by silica gel column chromatography (PE:EA = 100:1 to 10:1) to give the product (1.52 g, 20.0% yield for two steps).

[0190] Step 5: Synthesis of 6-chloro-5-methyl-3-(methylsulfonyl)-1,2,4-triazine [ka]

[0191] 6-Chloro-5-methyl-3-(methylthio)-1,2,4-triazine (1.52 g, 8.65 mmol, 1.0 eq) was dissolved in DCM (50 mL) and stirred at room temperature. Metachloroperbenzoic acid (3.73 g, 21.6 mmol, 2.5 eq) was added and the mixture was allowed to react for 2 h. The pH was adjusted to 8 with saturated aqueous NaHCO3, and the mixture was extracted with DCM (30 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product (1.38 g, yield: 76.8%).

[0192] Step 6: Synthesis of (R)-3-((6-chloro-5-methyl-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester [ka]

[0193] 6-Chloro-5-methyl-3-(methylsulfonyl)-1,2,4-triazine (1.38 g, 6.65 mmol, 1.0 eq) was dissolved in DCM (30 mL), and (R)-3-aminopiperidine-1-carboxylic acid tert-butyl ester (2.00 g, 9.98 mmol, 1.5 eq) was added. The mixture was incubated at room temperature for 3 h. The mixture was concentrated under reduced pressure and separated by silica gel column chromatography (PE:EA = 20:1 to 2:1) to give the product (540 mg, yield: 24.8%).

[0194] Step 7: Synthesis of (R)-6-chloro-5-methyl-N-(piperidin-3-yl)-1,2,4-triazin-3-amine [ka]

[0195] (R)-3-((6-chloro-5-methyl-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (540 mg, 1.65 mmol, 1.0 eq) was dissolved in DCM (5 mL). A solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 1.24 mL, 4.95 mmol, 3.0 eq) was added dropwise and stirred at room temperature for 1 h. The pH was adjusted to 8 with saturated aqueous NaHCO3, and the mixture was extracted with DCM (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product (332 mg, yield: 88.5%) was separated by silica gel column chromatography (DCM:MeOH = 50:1 to 10:1).

[0196] Step 8: Synthesis of (R)-6-chloro-5-methyl-N-(1-methylpiperidin-3-yl)-1,2,4-triazin-3-amine [ka]

[0197] (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 min. NaBH3CN (137 mg, 2.18 mmol, 1.5 eq) was then added and the mixture was stirred for 1 h. The reaction mixture was quenched with saturated aqueous NaHCO3, extracted with DCM (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product (280 mg, yield: 77.9%) was obtained by silica gel column chromatography (DCM:MeOH = 50:1 to 10:1).

[0198] Step 9: Synthesis of (R)-3-(ethoxymethoxy)-4-(5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)benzaldehyde [ka]

[0199] 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-triazin-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 sequentially to 1,4-dioxane (6 mL). HO (3 mL) was added and the mixture was heated to 110 °C under nitrogen protection for 1 h. After cooling to room temperature, water (20 mL) was added and 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 was separated by silica gel column chromatography (DCM:MeOH = 100:1 to 10:1) to give the product (180 mg, yield: 56.4%).

[0200] Step 10: Synthesis of (R)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-N-(1-methylpiperidin-3-yl)-1,2,4-triazin-3-amine [ka]

[0201] (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). KCO (129 mg, 0.934 mmol, 2.0 eq) and (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (135 mg, 0.701 mmol, 1.5 eq) were added and stirred at room temperature for 2 h. The mixture was concentrated, dissolved in water, and extracted with EA (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product (152 mg, yield: 85.3%) was separated by silica gel column chromatography (DCM:MeOH = 50:1 to 10:1) to give the product.

[0202] Step 11: Synthesis of (R)-5-ethynyl-2-(5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)phenol [ka]

[0203] (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 h. The pH was adjusted to 8 with saturated aqueous NaHCO3, and the mixture was extracted with DCM (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product (82.0 mg, yield: 63.6%) was separated by silica gel column chromatography (DCM:MeOH = 50:1 to 10:1) to give the product.

[0204] 1HNMR(400 MHz, 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 = 7.0 Hz, 1H), 2.64 (d, J = 8 Hz, 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). Molecular formula:C 18 H 21 N5O exact mass:323.17 LC-MS(Pos, m / z)=324.11[M+H] + .

[0205] 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) [ka]

[0206] Step 1: Synthesis of (R)-6-(2-(ethoxymethoxy)-4-(trifluoromethyl)phenyl)-5-methyl-N-(1-methylpiperidin-3-yl)-1,2,4-triazin-3-amine [ka]

[0207] (2-(Ethoxymethoxy)-4-(trifluoromethyl)phenyl)boronic acid (131 mg, 0.496 mmol, 1.5 eq), (R)-6-chloro-5-methyl-N-(1-methylpiperidin-3-yl)-1,2,4-triazin-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 sequentially to 1,4-dioxane (5 mL). HO (2.5 mL) was added, and the mixture was heated to 110 °C under nitrogen protection for 1 h. After cooling to room temperature, water (10 mL) was added and extracted with EA (15 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (DCM:MeOH = 100:1 to 10:1) to give the product (83.0 mg, yield: 58.9%).

[0208] Step 2: Synthesis of (R)-2-(5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol [ka]

[0209] (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). A solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 0.15 mL, 0.585 mmol, 3.0 eq) was added dropwise and stirred at room temperature for 2 h. The pH was adjusted to 8 with saturated aqueous NaHCO3, and the mixture was extracted with DCM (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product (47.0 mg, yield: 65.6%) was separated by silica gel column chromatography (DCM:MeOH = 50:1 to 10:1).

[0210] 1 HNMR(400 MHz, DMSO-d6) δ(ppm): 10.56 (s, 1H), 7.49 (d, J = 8 Hz, 2H), 7.28-7.25 (m, 2H), 4.02 (s, 1H), 2.92 (s, 1H), 2.67 (d, J = 10.6 Hz, 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). Molecular formula:C 17 H 20 N5O exact mass:367.16 LC-MS(Pos, m / z)=368.11[M+H] + .

[0211] Example 10: Synthesis of (R)-5-ethynyl-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol (Compound 54) [ka]

[0212] Step 1: Synthesis of (R)-3-(ethoxymethoxy)-4-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)benzaldehyde [ka]

[0213] (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, 0.05 eq) were added to a mixture of 1,4-dioxane (12.0 mL) and water (4.0 mL). The mixture was reacted at 110 °C for 4 hours under nitrogen protection. After completion of the reaction, the mixture was cooled to room temperature, water (50.0 mL) was added, and ethyl acetate (100.0 mL) was added. The mixture was extracted with 1 mL of HCl, 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 (283.0 mg, yield: 59.0%).

[0214] Step 2: Synthesis of (R)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine [ka]

[0215] (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 (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (212.1 mg, 1.10 mmol, 1.5 eq) were added to methanol (10.0 mL) and reacted at room temperature for 12 hours. Complete reaction was monitored by TLC, and saturated aqueous sodium chloride solution (50.0 mL) was added, followed by dichloromethane (50.0 mL). The mixture was extracted with 1 mL of HCl, 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%).

[0216] Step 3: Synthesis of (R)-5-ethynyl-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol [ka]

[0217] (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), and a solution of hydrogen chloride in 1,4-dioxane (4.0 mol / L, 4.0 mL) was added dropwise. The reaction was allowed to proceed at room temperature for 1 hour. After completion of the reaction was monitored by TLC, the system was adjusted to pH 7-8 with saturated aqueous sodium bicarbonate 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 product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give the product (110.0 mg, yield: 68.7%).

[0218] 1 HNMR (400 MHz, 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=8 Hz, 1H), 4.17 (s, 1H), 4.04-4.01 (m, 1H), 2.86-2.84 (d, J=8 Hz, 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). Molecular formula:C 19 H 22 N4O exact mass:322.18 LC-MS(Pos, m / z)=323.11[M+H] + .

[0219] Example 11: Synthesis of (R)-5-ethynyl-2-(6-fluoro-4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)phenol (Compound 172) [ka]

[0220] Step 1: Synthesis of methyl 2-(4-bromo-2-methoxybenzoyl)-5-fluorobenzoate [ka]

[0221] Methyl 5-fluoro-2-iodobenzoate (10.0 g, 35.71 mmol, 1.0 eq) was dissolved in THF (200 mL) and cooled to -30 °C under nitrogen protection. A solution of isopropylmagnesium lithium chloride complex 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 for completeness. The reaction mixture was poured into water (100 mL), stirred for 10 min, suction filtered, and the filtrate was dispensed. The aqueous phase was extracted with EA (100 mL × 2), and the EA phase was then dissolved in an aqueous potassium carbonate solution (100 mL). The organic phases were combined, dried and concentrated to give the crude product (13.13 g, yield: 100%).

[0222] Step 2: Synthesis of 4-(4-bromo-2-methoxyphenyl)-7-fluorophthalazin-1-ol [ka]

[0223] 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 minutes. Complete reaction was monitored by TLC, and the reaction was cooled to room temperature, filtered, and the filter cake was dried to obtain the product (6.5 g, yield: 52.1%).

[0224] Step 3: Synthesis of 1-(4-bromo-2-methoxyphenyl)-4-chloro-6-fluorophthalazine [ka]

[0225] 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. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, water (100 mL) was added, and the pH was adjusted to 10 with sodium carbonate. The mixture was extracted with EA (100 mL × 3). The organic phase was dried, concentrated, and purified by silica gel column chromatography (DCM:PE = 1:1) to give the product (5.5 g, yield: 80.4%).

[0226] Step 4: Synthesis of 1-(4-bromo-2-methoxyphenyl)-4,6-difluorophthalazine [ka]

[0227] 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. Complete reaction was monitored by LC-MS. The reaction mixture was poured into water (20 mL) and extracted with MTBE (20 mL × 2). The combined organic phases were dried, concentrated, and purified by silica gel column chromatography (PE:EA = 5:1) to give the product (0.9 g, yield: 47.1%).

[0228] Step 5: Synthesis of (R)-3-((4-(4-bromo-2-methoxyphenyl)-7-fluorophthalazin-1-yl)amino)piperidine-1-carboxylic acid tert-butyl ester [ka]

[0229] 1-(4-Bromo-2-methoxyphenyl)-4,6-difluorophthalazine (0.9 g, 2.56 mmol, 1.0 eq), (R)-3-aminopiperidine-1-carboxylic acid tert-butyl ester (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. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude product was slurried in a 10:1 mixture of PE and EA (20 mL), filtered under suction, and the filter cake was dried to give the product (1.0 g, 73.5% yield).

[0230] Step 6: Synthesis of (R)-3-((7-fluoro-4-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)phthalazin-1-yl)amino)piperidine-1-carboxylic acid tert-butyl ester [ka]

[0231] (R)-3-((4-(4-Bromo-2-methoxyphenyl)-7-fluorophthalazin-1-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (1.0 mg, 1.88 mmol, 1.0 eq), PdCl(dppf) (133 mg, 0.19 mmol, 0.1 eq), and CuI (107 mg, 0.26 mmol, 0.3 eq) were dissolved in diisopropylamine (10 mL). Trimethylsilylacetylene (1.85 mg, 18.80 mmol, 10 eq) was added under nitrogen protection and the reaction mixture was stirred at 60 °C for 16 h. After completion of the reaction was monitored by TLC, the reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 2:1) to give the product (510 mg, 49.5% yield).

[0232] Step 7: Synthesis of (R)-5-ethynyl-2-(6-fluoro-4-(piperidin-3-ylamino)phthalazin-1-yl)phenol [ka]

[0233] (R)-3-((7-Fluoro-4-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)phthalazin-1-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (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 allowed to proceed at 0 °C for 3 h. After completion of the reaction, the reaction mixture was poured into water (20 mL), the pH was adjusted to 9 with NaHCO3, and the mixture was extracted with DCM (15 mL × 3). The organic phases were combined, dried, and concentrated to give the product (300 mg, yield: 90.9%).

[0234] Step 8: Synthesis of (R)-5-ethynyl-2-(6-fluoro-4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)phenol [ka]

[0235] (R)-5-Ethynyl-2-(6-fluoro-4-(piperidin-3-ylamino)phthalazin-1-yl)phenol (300 mg, 0.82 mmol, 1.0 eq) and aqueous formaldehyde (37%) (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 the mixture was stirred at room temperature for 5 min. After completion of the reaction was monitored by LC-MS, the reaction mixture was concentrated under reduced pressure, water (10 mL) was added, and the mixture was extracted with DCM (10 mL x 3). The combined organic phases were dried and concentrated. The crude product was purified by preparative thin-layer chromatography (DCM:MeOH = 10:1) to give the product (108 mg, 35.1% yield).

[0236] 1HNMR (400 MHz, DMSO-d6) δ(ppm): 10.01 (s, 1H), 8.32-8.29 (d, 1H), 7.71-7.66 (t, 1H), 7.57-7.53 (m, 1H),7.31-7.29 (d, 1H), 7.13-7.07 (m, 3H), 4.43 (s, 1H), 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). Molecular formula:C 22 H 21 FN4O exact mass:376.17 LC-MS(Pos, m / z)=377.11[M+H] + .

[0237] 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) [ka]

[0238] Step 1: Synthesis of 5-methyl-3-(methylsulfonyl)-1,2,4-triazine [ka]

[0239] 5-Methyl-3-(methylthio)-1,2,4-triazine (1.5 g, 10.62 mmol, 1.0 eq) was dissolved in DCM (50 mL), metachloroperbenzoic acid (4.53 g, 22.30 mmol, 2.1 eq) was added, and the mixture was allowed to react at room temperature for 0.5 h. The reaction mixture was poured into water (20 mL), the pH was adjusted to 9 with NaHCO3, and the mixture was extracted with DCM (20 mL x 2). The organic phase was dried and concentrated to give the product (1.84 g, 100% yield).

[0240] Step 2: Synthesis of (R)-3-((5-methyl-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester [ka]

[0241] 5-Methyl-3-(methylsulfonyl)-1,2,4-triazine (1.84 g, 10.62 mmol, 1.0 eq), (R)-3-aminopiperidine-1-carboxylic acid tert-butyl ester (2.13 g, 10.62 mmol, 1.5 eq), and triethanolamine (1.61 g, 15.93 mmol, 1.5 eq) were dissolved in 1,4-dioxane (20 mL) and reacted at 100°C for 1 h. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 2:1) to give the product (700 mg, yield: 22.4%).

[0242] Step 3: Synthesis of (R)-3-((6-bromo-5-methyl-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester [ka]

[0243] (R)-3-((5-methyl-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (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 h. The reaction mixture was poured into water (20 mL) and extracted with MTBE (15 mL x 3). The combined organic phases were dried and concentrated. The crude product was purified by silica gel column chromatography (PE:EA = 5:1) to give the product (300 mg, yield: 33.9%).

[0244] Step 4: Synthesis of (R)-3-((6-(4-cyano-2-(ethoxymethoxy)phenyl)-5-methyl-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester [ka]

[0245] A mixture of (R)-3-((6-bromo-5-methyl-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (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) in 1,4-dioxane (6 mL) and HO (2 mL) was heated to 110 °C under nitrogen protection for 1 h. The reaction mixture was poured into water (10 mL) and extracted with EA (20 mL × 2). The organic layers were combined, dried, and concentrated. The crude product was purified by silica gel column chromatography (PE:EA = 2:1) to give the product (280 mg, yield: 74.7%).

[0246] Step 5: Synthesis of (R)-3-hydroxy-4-(5-methyl-3-(piperidin-3-ylamino)-1,2,4-triazin-6-yl)benzonitrile [ka]

[0247] (R)-3-((6-(4-cyano-2-(ethoxymethoxy)phenyl)-5-methyl-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (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 mixture was allowed to react for 1.5 h at room temperature. After completion of the reaction was monitored by LC-MS, the reaction mixture was poured into water (10 mL) and back-extracted with DCM (10 mL x 3). The aqueous phase was adjusted to pH 10 with aqueous NaHCO3 and extracted with DCM (10 mL x 4). The combined organic phases were dried and concentrated to give the product (150 mg, 80.6% yield).

[0248] Step 6: Synthesis of (R)-3-hydroxy-4-(5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)benzonitrile [ka]

[0249] (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 aqueous formaldehyde (37%) (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 the mixture was stirred at room temperature for 5 min. After completion of the reaction was monitored by TLC, the reaction mixture was poured into water (10 mL) and extracted with DCM (30 mL x 3). The combined organic phases were dried, concentrated, and the crude product was purified by preparative thin-layer chromatography (DCM:MeOH = 10:1) to give the product (65 mg, 41.9% yield).

[0250] 1HNMR (400 MHz, 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, 1H), 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). Molecular formula:C 17 H 20 N6O exact mass: 324.17 LC-MS(Pos, m / z)=325.14[M+H] + .

[0251] Example 13: Synthesis of (R)-3,5-dimethyl-2-(3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)phenol (Compound 202) [ka]

[0252] Step 1: Synthesis of 6-bromo-3-(methylthio)-1,2,4-triazine [ka]

[0253] 6-Bromo-1,2,4-triazin-3-amine (3.0 g, 17.14 mmol, 1.0 eq) and 1,2-dimethyldisulfide (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 proceed at room temperature for 2 h. After completion of the reaction was monitored by TLC, the mixture was quenched with methanol (20 mL), concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (silica gel specification: 100-200 mesh, petroleum ether:ethyl acetate = 5:1) to give the product (1.5 g, yield: 42.4%).

[0254] Step 2: Synthesis of 6-(2-(ethoxymethoxy)-4,6-dimethylphenyl)-3-(methylthio)-1,2,4-triazine [ka]

[0255] 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 a mixture of 1,4-dioxane (12.0 mL) and water (6.0 mL). The mixture was reacted at 110 °C for 3 hours under nitrogen protection. After completion of the reaction, the mixture was cooled to room temperature, water (50.0 mL) was added, and ethyl acetate (100.0 mL) was added. The mixture was extracted with 1 mL of ethanol, 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 give the product (167.0 mg, yield: 49.0%).

[0256] Step 3: Synthesis of 6-(2-(ethoxymethoxy)-4,6-dimethylphenyl)-3-(methylsulfonyl)-1,2,4-triazine [ka]

[0257] 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). Metachloroperbenzoic acid (85%) (222.0 mg, 1.08 mmol, 2.0 eq) was added and the mixture was allowed to react at room temperature for 1 h. After completion of the reaction was monitored by TLC, saturated aqueous sodium bicarbonate (50.0 mL) was added, and the mixture was extracted with dichloromethane (50.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica gel specification: 100-200 mesh, petroleum ether:ethyl acetate = 5:1-2:1) to give the product (137.0 mg, yield: 74.4%).

[0258] Step 4: Synthesis of (R)-3-((6-(2-(ethoxymethoxy)-4,6-dimethylphenyl)-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester [ka]

[0259] 6-(2-(ethoxymethoxy)-4,6-dimethylphenyl)-3-(methylsulfonyl)-1,2,4-triazine (108.0 mg, 0.32 mmol, 1.0 eq) and (R)-3-aminopiperidine-1-carboxylic acid tert-butyl ester (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 h. The reaction was monitored by TLC for completeness. The mixture 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 give the product (60.0 mg, yield: 41.0%).

[0260] Step 5: Synthesis of (R)-3,5-dimethyl-2-(3-(piperidin-3-ylamino)-1,2,4-triazin-6-yl)phenol [ka]

[0261] (R)-3-((6-(2-(ethoxymethoxy)-4,6-dimethylphenyl)-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (60.0 mg, 0.13 mmol, 1.0 eq) was added to dichloromethane (2.0 mL), and a solution of hydrogen chloride in 1,4-dioxane (4.0 mol / L) (3.0 mL) was added dropwise. The reaction was allowed to proceed at room temperature for 1 hour, and the reaction was monitored by TLC until complete. The system was adjusted to pH 7-8 with saturated aqueous sodium bicarbonate, extracted with dichloromethane (50.0 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product (39.0 mg, yield: 99.4%).

[0262] Step 6: Synthesis of (R)-3,5-dimethyl-2-(3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)phenol [ka]

[0263] (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 aqueous formaldehyde (37%) (13.7 mg, 0.16 mmol, 1.3 eq) were added to methanol (5.0 mL) and reacted at room temperature for 0.5 h. Sodium cyanoborohydride (12.2 mg, 0.19 mmol, 1.5 eq) was added and reacted for an additional 1 h. The reaction was monitored by TLC until complete. Saturated aqueous sodium bicarbonate (20.0 mL) was added, and the mixture was extracted with dichloromethane (50.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give the product (15.0 mg, yield: 50.0%).

[0264] 1 HNMR (400 MHz, 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). Molecular formula:C 17 H 23 N5O exact mass:313.19 LC-MS(Pos, m / z)=314.15[M+H] + .

[0265] 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): [ka]

[0266] Procedure 1: Synthesis of 1-bromo-2-(ethoxymethoxy)-4-ethynylbenzene: [ka]

[0267] 4-Bromo-3-(ethoxymethoxy)benzaldehyde (8 g, 30.88 mmol, 1.0 eq), (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (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. After monitoring the absence of starting material by TLC, 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 combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE = 1:150) to give the product (3 g, yield: 38.5%).

[0268] Step 2: Synthesis of 1-bromo-2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)benzene [ka]

[0269] 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 THF solution (1.35 mL, 1.1 eq) was added dropwise. The reaction was carried out at -75°C to -70°C for 1 hour. Iodomethane (834.6 mg, 5.88 mmol, 3.0 eq) was then added dropwise, and the mixture was allowed to warm to room temperature and react for 16 hours. After LC-MS analysis, 20% of the starting material remained. Saturated aqueous ammonium chloride (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE = 1:100) to give the product (485 mg, yield: 91.9%).

[0270] Step 3: Synthesis of 2-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka]

[0271] 1-Bromo-2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)benzene (485 mg, 1.8 mmol, 1.0 eq) was dissolved in anhydrous THF (10 mL), cooled to -70°C, and a 1.6 mol / L n-butyllithium THF solution (1.5 mL, 1.3 eq) was added dropwise. The mixture was allowed to react at -70°C for 1 hour, and then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (502.4 mg, 2.7 mmol, 1.5 eq) was added dropwise. The mixture was then allowed to warm to room temperature and react for 24 hours. The absence of starting material was monitored by LC-MS, and the mixture was extracted with saturated aqueous ammonium chloride (30 mL) and 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 to EA = 100%) to obtain the product (383 mg, yield: 67.3%).

[0272] 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 [ka]

[0273] trans-Dichlorobis(triphenylphosphine)palladium(II) (70.2 mg, 0.1 mmol, 0.1 eq), anhydrous sodium carbonate (530 mg, 5 mmol, 5.0 eq) were added to 1,4-dioxane (10 mL), and under nitrogen protection, 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. The mixture was heated to 100°C under nitrogen protection and reacted for 48 hours. Water (30 mL) was added, extracted with DCM (30 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography (MeOH:DCM = 1:10) to give the product (150 mg, yield: 38%).

[0274] Step 5: Synthesis of (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(prop-1-yn-1-yl)phenol [ka]

[0275] (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 mixture was allowed to react at room temperature for 1 hour. After monitoring the absence of starting material by TLC, 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 combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product (100 mg, yield: 78.2%).

[0276] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 10.00 (s, 0.95H), 7.14-7.12 (d, 1H), 6.91-6.89 (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). Molecular formula:C 20 H 24 N4O exact mass:336.20 LC-MS(Pos, m / z)=337.30[M+H] + .

[0277] Example 15: Synthesis of (R)-2-(5-cyclopropyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)-5-ethynylphenol (Compound 179): [ka]

[0278] Step 1: Synthesis of 2-cyclopropyl-2-oxoacetaldehyde [ka]

[0279] 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) were added to 1,4-dioxane (75 mL) and heated to reflux for 2 hours. 1-Cyclopropyl ethyl ketone (10 g, 118.88 mmol, 1.0 eq) was added and the mixture was heated at reflux for 22 hours. The mixture was cooled to room temperature, filtered, and the filter cake was rinsed with 1,4-dioxane. The filtrate was used in the next step in stoichiometric amounts.

[0280] Step 2: Synthesis of 5-cyclopropyl-3-(methylthio)-1,2,4-triazine [ka]

[0281] A solution of 2-cyclopropyl-2-oxoacetaldehyde (118.88 mmol, 1.0 eq) in dioxane was added to water (150 mL), and sodium bicarbonate (20 g, 237.76 mmol, 2.0 eq) was slowly added. The mixture was cooled to -5 to 0 °C. S-methylisothiosemicarbazide hydroiodide (30.5 g, 130.77 mmol, 1.1 eq) in water (100 mL) was added dropwise. The mixture was allowed to warm to room temperature and react for 48 h. After monitoring the absence of starting material by TLC, 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, yield for 2 steps: 63.3%).

[0282] Step 3: Synthesis of 5-cyclopropyl-3-(methylsulfonyl)-1,2,4-triazine [ka]

[0283] 5-Cyclopropyl-3-(methylthio)-1,2,4-triazine (2 g, 11.96 mmol, 1.0 eq) was dissolved in DCM (40 mL), and metachloroperbenzoic acid (6 g, 29.9 mmol, 2.5 eq) (mass fraction: 85%) was added in portions. The reaction was allowed to proceed at room temperature for 1 hour. After monitoring by TLC to confirm the absence of any remaining starting material, saturated aqueous sodium carbonate (50 mL) was added, the mixture was stirred for 2 minutes, and extracted with DCM (50 mL × 3). The organic phases were combined, washed with 10% aqueous sodium thiosulfate (50 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product (2.1 g, yield: 88.2%).

[0284] Step 4: Synthesis of (R)-3-((5-cyclopropyl-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester [ka]

[0285] 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), and (R)-3-aminopiperidine-1-carboxylic acid tert-butyl ester (4.2 g, 21.08 mmol, 2.0 eq) and DIPEA (4.1 g, 31.62 mmol, 3.0 eq) were added. The mixture was heated to 80 °C and incubated for 20 h. After monitoring by TLC for the absence of residual starting material, the mixture was cooled to room temperature, water (50 mL) was added, and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE = 1:10 to 1:2) to give the product (2.5 g, yield: 73.5%).

[0286] Step 5: Synthesis of (R)-3-((6-bromo-5-cyclopropyl-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester: [ka]

[0287] (R)-3-((5-Cyclopropyl-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (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 combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE = 1:10 to 1:5) to give the product (1.5 g, yield: 48.4%).

[0288] Step 6: Synthesis of (R)-6-bromo-5-cyclopropyl-N-(piperidin-3-yl)-1,2,4-triazin-3-amine: [ka]

[0289] (R)-3-((6-bromo-5-cyclopropyl-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (1.5 g, 3.76 mmol, 1.0 eq) was dissolved in DCM (20 mL), 2,6-dimethylpyridine (2.4 g, 22.56 mmol, 6.0 eq) was added, the mixture was cooled in an ice-water bath, trimethylsilyl trifluoromethanesulfonate (2.5 g, 11.28 mmol, 3.0 eq) was added dropwise, and the reaction was continued for 0.5 hours. After monitoring by TLC that no raw materials remained, water (50 mL) was added, the pH was adjusted to around 8 with sodium carbonate, and the mixture was diluted with DCM (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (MeOH:DCM = 1:100 to 1:20) to give the product (1.1 g, yield: 100%).

[0290] Step 7: Synthesis of (R)-6-bromo-5-cyclopropyl-N-(1-methylpiperidin-3-yl)-1,2,4-triazin-3-amine: [ka]

[0291] (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 hour. Sodium cyanoborohydride (472.5 mg, 7.52 mmol, 2.0 eq) was added, and after monitoring by TLC that no remaining starting material was present, saturated aqueous sodium carbonate (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%).

[0292] Step 8: Synthesis of (R)-4-(5-cyclopropyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)-3-(ethoxymethoxy)benzaldehyde: [ka]

[0293] (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 PdCl(dppf) (182.9 mg, 0.25 mmol, 0.1 eq) were dissolved in a mixture of 1,4-dioxane (20 mL) and water (5 mL). The mixture was heated to 110 °C under nitrogen protection and reacted for 2 h. After monitoring by TLC that no raw material remained, the mixture was cooled to room temperature and washed with water (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (MeOH:DCM = 1:100 to 1:20) to give the product (1.1 g, yield: 100%).

[0294] Procedure 9: Synthesis of (R)-5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-N-(1-methylpiperidin-3-yl)-1,2,4-triazin-3-amine: [ka]

[0295] (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), anhydrous potassium carbonate (671.7 mg, 4.86 mmol, 2.0 eq) and (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (699.2 mg, 3.64 mmol, 1.5 eq) were added, and the mixture was allowed to react at room temperature for 1 hour. After monitoring by LC-MS that no remaining starting material was present, 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%).

[0296] Step 10: Synthesis of (R)-2-(5-cyclopropyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)-5-ethynylphenol: [ka]

[0297] (R)-5-Cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-N-(1-methylpiperidin-3-yl)-1,2,4-triazin-3-amine (324 mg, 0.79 mmol, 1.0 eq) was added to DCM (9 mL), trifluoroacetic acid (1 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours. The absence of raw materials was monitored by TLC, water (30 mL) was added, and the pH was adjusted to around 8 with sodium carbonate. Extraction was carried out 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 obtain the product (130 mg, yield: 47.1%).

[0298] 1HNMR (400 MHz, 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). Molecular formula:C 20 H 23 N5O exact mass:249.19 LC-MS(Pos, m / z)=350.28 [M+H] + .

[0299] Example 16 Synthesis of (R)-5-ynyl-2-(8-((1-methylpiperidin-3-yl)amino)pyrido[2,3-d]pyridazin-5-yl)phenol (Compound 203): [ka]

[0300] Step 1: Synthesis of intermediate 6,7-dihydropyrido[2,3-d]pyridazine-5,8-dione: [ka]

[0301] 2,3-Pyridinedicarboxylic anhydride (10.0 g, 67.06 mmol, 1.0 eq) was dissolved in ethanol (150 mL), and 85% hydrazine hydrate (19.74 g, 335.3 mmol, 5.0 eq) was added. The mixture was reacted at 90 °C for 16 h. The reaction was monitored by LC-MS for completeness. The reaction mixture was cooled, filtered, and the filter cake was dissolved in water (100 mL). The pH was adjusted to acidic with acetic acid. A large amount of solid precipitated, which was filtered and the filter cake was dried to give the product (7.95 g, yield: 72.6%).

[0302] Step 2: Synthesis of intermediate 5,8-dichloropyrido[2,3-d]pyridazine [ka]

[0303] 6,7-Dihydropyrido[2,3-d]pyridazine-5,8-dione (7.16 g, 43.89 mmol, 1.0 eq) was added to phosphorus oxychloride (70 mL) and N,N-dimethylaniline (7 mL), heated to 100 °C, and reacted for 1 h. The reaction was monitored by TLC for completeness. The reaction mixture 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 give the product (6.0 g, yield: 68.3%).

[0304] Step 3: Synthesis of intermediate 5-chloropyrido[2,3-d]pyridazin-8-ol [ka]

[0305] 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 monitored by TLC for complete reaction. The reaction mixture was concentrated and purified by silica gel column chromatography to obtain the 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) from the filter cake.

[0306] Step 4: Synthesis of intermediate 4-(8-hydroxypyrido[2,3-d]pyridazin-5-yl)-3-methoxybenzaldehyde [ka]

[0307] 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), 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), PdCl(dppf) (604 mg, 0.826 mmol, 0.1 eq), and water (5 mL) were added, and the mixture was heated to 100 °C under nitrogen protection for 2 h. The reaction was monitored by TLC for completion. The reaction mixture was filtered through diatomaceous earth, water (10 mL) was added to the filtrate, and the mixture was extracted with dichloromethane (20 mL × 3). The organic layers 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 to 30:1) to give the product (1.03 g, yield: 44.4%).

[0308] Step 5: Synthesis of intermediate 5-(4-ynyl-2-methoxy)pyrido[2,3-d]pyridazine-8-phenol [ka]

[0309] 4-(8-Hydroxypyrido[2,3-d]pyridazin-5-yl)-3-methoxybenzaldehyde (1.03 g, 3.66 mmol, 1.0 eq) was dissolved in methanol (10 mL), followed by the addition of potassium carbonate (1.01 g, 7.32 mmol, 2.0 eq) and (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (1.05 g, 5.49 mmol, 1.5 eq). The reaction mixture was stirred at 25 °C for 2 h, and the reaction mixture was monitored by TLC for near complete reaction. Water (20 mL) was added to the reaction mixture, which was then extracted with dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous magnesium sulfate, concentrated, and the crude product was directly used in the next step.

[0310] Step 6: Synthesis of intermediate 8-chloro-5-(4-ynyl-2-methoxy)pyrido[2,3-d]pyridazine [ka]

[0311] 5-(4-ynyl-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 incubated at 100 °C for 2 h. Completion was monitored by TLC. The reaction mixture was concentrated, poured into ice-water (10 mL), and extracted with MTBE (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (PE:EA = 5:1) to give the product (300 mg, 27.8% yield for 2 steps).

[0312] Step 7: Synthesis of intermediate 2-(8-chloropyrido[2,3-d]pyridazin-5-yl)-5-ethynylphenol [ka]

[0313] 8-Chloro-5-(4-ynyl-2-methoxy)pyrido[2,3-d]pyridazine (300 mg, 1.01 mmol, 1.0 eq) was dissolved in dichloromethane (3 mL), and boron tribromide (759 mg, 3.03 mmol, 3.0 eq) was added dropwise. The reaction was allowed to proceed at 25 °C for 30 min. The reaction mixture was monitored by TLC for near complete reaction. The reaction mixture was poured into saturated aqueous sodium bicarbonate (10 mL) and extracted with MTBE (10 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was directly used in the next step.

[0314] Step 8: Synthesis of compound (R)-3-((5-(4-ethynyl-2-hydroxyphenyl)pyrido[2,3-d]pyridazin-8-yl)amino)piperidine-1-carboxylic acid tert-butyl ester [ka]

[0315] 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), and (R)-1-tert-butoxycarbonyl-3-aminopiperidine (327 mg, 1.632 mmol, 2.0 eq) was added. The mixture was reacted at 100 °C for 24 h, and the reaction was monitored by LC-MS for near complete reaction. The reaction mixture was poured into water (10 mL), filtered, and the filter cake was dissolved in dichloromethane (10 mL), dried over anhydrous magnesium sulfate, concentrated, and the crude product was directly used in the next step.

[0316] Step 9: Synthesis of intermediate (R)-5-ynyl-2-(8-((piperidin-3-yl)amino)pyrido[2,3-d]pyridazin-5-yl)phenol [ka]

[0317] (R)-3-((5-(4-ethynyl-2-hydroxyphenyl)pyrido[2,3-d]pyridazin-8-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (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 reaction was allowed to proceed at 25 °C for 5 min, and the reaction was monitored by TLC for completeness. Water (10 mL) was added to the reaction mixture, which was then back-extracted with dichloromethane (10 mL × 2). The aqueous phase was adjusted to alkaline pH with saturated aqueous 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 give the product (232 mg, 66.5% yield for 3 steps).

[0318] Step 10: Synthesis of the compound (R)-5-ynyl-2-(8-((1-methylpiperidin-3-yl)amino)pyrido[2,3-d]pyridazin-5-yl)phenol [ka]

[0319] (R)-5-ynyl-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, and the mixture was incubated at room temperature for 5 min. The reaction was monitored for completion by TLC. The reaction mixture was concentrated, saturated brine (5 mL) was added, and the mixture was extracted with a 7:1 mixture of dichloromethane / methanol (20 mL x 3). The combined organic phases were dried, concentrated, and the crude product was purified by preparative thin-layer chromatography (dichloromethane:ammonia / methanol solution (7 mol / L) = 14:1) to give the product (40 mg, yield: 16.6%).

[0320] 1 H-NMR (400 MHz, 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). Molecular formula:C 21 H 21 N5O exact mass: 359.17 LC-MS(m / z): 360.08 [M+H] +

[0321] Example 17 Synthesis of (R)-2-(4-cyclopropyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-ethynylphenol (Compound 173): [ka]

[0322] Step 1: Synthesis of intermediate 3,6-dichloro-4-cyclopropylpyridazine [ka]

[0323] 3,6-Dichloropyridazine (20.0 g, 134.2 mmol, 1.0 eq) was dissolved in water (200 mL), cyclopropylcarboxylic acid (11.56 g, 134.2 mmol, 1.0 eq) and silver nitrate (22.8 g, 134.2 mmol, 1.0 eq) were added, and the reaction mixture was heated to 60 °C. Concentrated sulfuric acid (21.6 mL, 402.6 mmol, 3.0 eq) was then added dropwise to the reaction mixture. The mixture was then heated to 70 °C and reacted for 30 min. The reaction was monitored by TLC for completeness. The pH of the reaction mixture was adjusted to 8 with 1 mol / L aqueous sodium hydroxide solution, extracted with ethyl acetate (400 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 give a mixed product (18 g). After standing overnight, a large amount of solid precipitated. This was filtered, and the filter cake was slurried in a petroleum ether / ethyl acetate mixed solvent to give the product (17 g, yield: 67.1%).

[0324] Step 2: Synthesis of (R)-3-((6-chloro-5-cyclopropylpyridazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester [ka]

[0325] 3,6-Dichloro-4-cyclopropylpyridazine (5.0 g, 26.45 mmol, 1.0 eq) was dissolved in DMAc (50 mL), (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, and the mixture was reacted at 120 °C for 24 h. The reaction mixture was poured into water (100 mL) and extracted with MTBE (50 mL x 3). The combined organic phases were dried and concentrated. The crude product was purified by silica gel column chromatography (PE:EA = 10:1 to 4:1) to give the product (2.5 g, yield: 26.8%).

[0326] Step 3: Synthesis of intermediate (R)-3-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-formylphenyl)pyridazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester [ka]

[0327] (R)-3-((6-chloro-5-cyclopropylpyridazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 3.95 mmol, 1.0 eq) was dissolved in 1,4-dioxane (10 mL). 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), PdCl(dppf) (289 mg, 0.395 mmol, 0.1 eq), and water (2.5 mL) were added and the mixture was heated to 110 °C under nitrogen protection for 1 h. The reaction was monitored by TLC for completion. The reaction mixture was filtered through diatomaceous earth, water (20 mL) was added to the filtrate, and the mixture was extracted with MTBE (20 mL × 3). The organic layers 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 give the product (760 mg, yield: 38.8%).

[0328] Step 4: Synthesis of intermediate (R)-3-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester [ka]

[0329] (R)-3-((5-Cyclopropyl-6-(2-(ethoxymethoxy)-4-formylphenyl)pyridazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (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 (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (422 mg, 2.3 mmol, 1.5 eq) were added sequentially. The reaction mixture was stirred at 25 °C for 5 min. The reaction mixture was monitored by TLC for completeness. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL x 3). The combined organic phases were 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 give the product (340 mg, yield: 45.2%).

[0330] Step 5: Synthesis of intermediate (R)-2-(4-cyclopropyl-6-(piperidin-3-ylamino)pyridazin-3-yl)-5-ethynylphenol [ka]

[0331] (R)-3-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (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 reaction was allowed to proceed at 25°C for 5 minutes, and the reaction was monitored by TLC for completeness. The reaction mixture was concentrated, dissolved in dichloromethane (5 mL), and slowly added dropwise to saturated aqueous sodium bicarbonate (20 mL). The mixture was extracted with dichloromethane:methanol = 10:1 (20 mL × 3). The organic phases were combined, dried, and concentrated to give the product (90 mg, yield: 39.1%).

[0332] Step 6: Synthesis of compound (R)-2-(4-cyclopropyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-ethynylphenol [ka]

[0333] (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 (22 mg, 0.269 mmol, 1.0 eq), and sodium cyanoborohydride (19 mg, 0.296 mmol, 1.1 eq) were added, and the mixture was incubated at 25 °C for 5 min. The reaction was monitored for completion by TLC. The reaction mixture was concentrated, saturated brine (2 mL) was added, and the mixture was extracted with a 10:1 dichloromethane:methanol mixture (10 mL x 3). The combined organic phases were dried, and the crude product was purified by preparative thin-layer chromatography (7:1 dichloromethane:methanol) to give the product (31 mg, 33.3% yield).

[0334] 1 H-NMR (400 MHz, 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). Molecular formula:C 21 H 24 N4O exact mass: 348.20 LC-MS(m / z): 349.11 [M+H] +

[0335] Example 18 Synthesis of (R)-2-(4,5-dicyclopropyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-ethynylphenol (Compound 221): [ka]

[0336] Step 1: Synthesis of intermediate 3,6-dichloro-4,5-dicyclopropylpyridazine: [ka]

[0337] 3,6-Dichloropyridazine (8.83 g, 59.24 mmol, 1.0 eq) was dissolved in water (200 mL), 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, and the reaction mixture was heated to 60 °C. A solution of ammonium persulfate (101 g, 444.3 mmol, 7.5 eq) in water (200 mL) was added dropwise. The reaction mixture was monitored by TLC for completeness. The reaction mixture 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 give the product (5.69 g, yield: 41.9%).

[0338] Step 2: Synthesis of intermediate 4-(6-chloro-4,5-dicyclopropylpyridazin-3-yl)-3-(ethoxymethoxy)benzaldehyde [ka]

[0339] 3,6-Dichloro-4,5-dicyclopropylpyridazine (2.0 g, 8.73 mmol, 1.0 eq) was dissolved in 1,4-dioxane (20 mL), 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), PdCl(dppf) (639 mg, 0.873 mmol, 0.1 eq), and water (5 mL) were added, and the mixture was heated to 100 °C under nitrogen protection for 3 h. The reaction was monitored by TLC for completion. The reaction mixture was filtered through diatomaceous earth, water (20 mL) was added to the filtrate, and the mixture was extracted with MTBE (20 mL × 3). The organic layers 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 give the product (1.19 g, yield: 36.6%).

[0340] Step 3: Synthesis of (R)-3-((4,5-dicyclopropyl-6-(2-(ethoxymethoxy)-4-formylphenyl)pyridazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester [ka]

[0341] 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). (R)-1-tert-butoxycarbonyl-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 and the reaction was conducted under nitrogen protection at 90 °C for 16 h. The reaction was monitored by TLC for near completeness. The reaction mixture was filtered through diatomaceous earth, 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%).

[0342] Step 4: Synthesis of intermediate (R)-3-((4,5-dicyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester [ka]

[0343] (R)-3-((4,5-Dicyclopropyl-6-(2-(ethoxymethoxy)-4-formylphenyl)pyridazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (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 (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (611 mg, 3.18 mmol, 1.5 eq) were added sequentially. The reaction mixture was stirred at 25 °C for 30 min. The reaction was monitored by TLC for completeness. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with MTBE (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 3:1) to give the product (340 mg, yield: 30.1%).

[0344] Step 5: Synthesis of intermediate (R)-2-(4,5-dicyclopropyl-6-(piperidin-3-ylamino)pyridazin-3-yl)-5-ethynylphenol [ka]

[0345] (R)-3-((4,5-Dicyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (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 reaction was allowed to proceed at 25°C for 30 minutes, and the reaction was monitored by TLC for completeness. The reaction mixture was concentrated, dissolved in dichloromethane (5 mL), and slowly added dropwise to saturated sodium bicarbonate solution (10 mL). The mixture was extracted with dichloromethane:methanol = 10:1 (20 mL × 3). The organic phases were combined, dried, and concentrated to give the product (120 mg, yield: 50.2%).

[0346] Step 6: Synthesis of compound (R)-2-(4,5-dicyclopropyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-ethynylphenol [ka]

[0347] (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 (26 mg, 0.32 mmol, 1.0 eq) and sodium cyanoborohydride (22 mg, 0.35 mmol, 1.1 eq) were added, and the mixture was incubated at 25 °C for 5 min. The reaction was monitored for completion by TLC. The reaction mixture was concentrated, saturated brine (2 mL) was added, and the mixture was extracted with a 10:1 dichloromethane:methanol mixture (10 mL x 3). The combined organic phases were dried, and the crude product was purified by preparative thin-layer chromatography (8:1 dichloromethane:methanol) to give the product (30 mg, 24.2% yield).

[0348] 1 H-NMR (400 MHz, 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). Molecular formula:C 24 H 28 N4O exact mass: 388.23 LC-MS(m / z): 389.15 [M+H]+

[0349] Example 19: Synthesis of (R)-5-ethynyl-2-(4-((1-(2-hydroxyethyl)piperidin-3-yl)amino)phthalazin-1-yl)phenol (Compound 76) [ka]

[0350] Step 1: Synthesis of (R)-2-(3-((4-chlorophthalazin-1-yl)amino)piperidin-1-yl)ethan-1-ol [ka]

[0351] (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 h. After completion of the reaction was monitored by TLC, saturated aqueous ammonium chloride (100.0 mL) was added, followed by extraction 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 = 50:1-20:1) to give the product (1.2 g, yield: 68.5%).

[0352] Step 2: Synthesis of (R)-3-(ethoxymethoxy)-4-(4-((1-(2-hydroxyethyl)piperidin-3-yl)amino)phthalazin-1-yl)benzaldehyde [ka]

[0353] (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) were added to a mixture of 1,4-dioxane (10.0 mL) and water (5.0 mL). The mixture was purged with nitrogen gas for 2 minutes and reacted at 110 °C for 3 hours. Complete reaction was monitored by TLC. Water (50.0 mL) was added. The mixture was added with 100 mL of ethyl acetate and extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 80:1 to 10:1) to obtain the product (400 mg, yield: 54.4%).

[0354] Step 3: Synthesis of (R)-2-(3-((4-(2-(ethoxymethoxy)-4-ethynylphenyl)phthalazin-1-yl)amino)piperidin-1-yl)ethan-1-ol [ka]

[0355] (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), (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (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 reacted at room temperature for 2 h. The reaction was monitored by TLC for completeness. 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 give the product (293.0 mg, yield: 74.9%).

[0356] Step 4: Synthesis of (R)-5-ethynyl-2-(4-((1-(2-hydroxyethyl)piperidin-3-yl)amino)phthalazin-1-yl)phenol [ka] :

[0357] (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), and a solution of hydrogen chloride in 1,4-dioxane (4.0 mol / L, 3.0 mL) was added dropwise. The reaction was allowed to proceed at room temperature for 2 hours, and the reaction was monitored by TLC until complete. The system was adjusted to pH 8-9 with saturated aqueous sodium carbonate 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 to give the product (100.0 mg, yield: 39.3%).

[0358] 1HNMR(400MHz, DMSO-d6)δ(ppm): 10.00 (s, 1H), 8.40-8.38 (d, J=8 Hz, 1H), 7.87-7.77 (m, 2H), 7.47-7.45 (d, J=8 Hz, 1H), 7.30-7.28 (d, J=8 Hz, 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). Molecular formula:C 23 H 24 N4O2 exact mass: 388.19 LC-MS(Pos, m / z)=389.14[M+H] + .

[0359] 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) [ka]

[0360] Step 1: Synthesis of (R)-4-chloro-N-(piperidin-3-yl)phthalazin-1-amine [ka]

[0361] 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. The reaction was allowed to proceed at room temperature for 2 hours. Complete reaction was monitored by TLC, and the system was adjusted to pH 8-9 with saturated aqueous sodium carbonate solution. Extraction with dichloromethane (100.0 mL) was performed. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product (3.5 g, yield: 96.6%).

[0362] Step 2: Synthesis of (R)-2-(3-((4-chlorophthalazin-1-yl)amino)piperidin-1-yl)ethyl acetate [ka]

[0363] (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 h. After completion of the reaction was monitored by TLC, saturated aqueous ammonium chloride (100.0 mL) was added, followed by extraction 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 give the product (2.4 g, yield: 90.5%).

[0364] Step 3: Synthesis of (R)-2-(3-((4-(2-(ethoxymethoxy)-4-formylphenyl)phthalazin-1-yl)amino)piperidin-1-yl)ethyl acetate [ka]

[0365] (R)-2-(3-((4-chlorophthalazin-1-yl)amino)piperidin-1-yl)ethyl 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) were added to a mixture of 1,4-dioxane (12.0 mL) and water (6.0 mL). The mixture was purged with nitrogen gas for 2 minutes and reacted at 110 °C for 3 hours. Complete reaction was monitored by TLC. Water (50.0 mL) was added, and ethyl acetate (100.0 mL) was added. The mixture was extracted with 1 mL of HCl, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 80:1 to 40:1) to give the product (1.1 g, yield: 65%).

[0366] Step 4: Synthesis of (R)-2-(3-((4-(2-(ethoxymethoxy)-4-ethynylphenyl)phthalazin-1-yl)amino)piperidin-1-yl)ethyl acetate [ka]

[0367] (R)-2-(3-((4-(2-(ethoxymethoxy)-4-formylphenyl)phthalazin-1-yl)amino)piperidin-1-yl)ethyl acetate (1.1 g, 2.23 mmol, 1.0 eq), (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (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 h. Complete reaction was 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 give the product (550.0 mg, yield: 51.9%).

[0368] Step 5: Synthesis of (R)-2-(3-((4-(4-ethynyl-2-hydroxyphenyl)phthalazin-1-yl)amino)piperidin-1-yl)ethyl acetate [ka]

[0369] (R)-2-(3-((4-(2-(ethoxymethoxy)-4-ethynylphenyl)phthalazin-1-yl)amino)piperidin-1-yl)ethyl acetate (528.0 mg, 1.11 mmol, 1.0 eq) was added to dichloromethane (5.0 mL) and a solution of hydrogen chloride in 1,4-dioxane (4.0 mol / L, 5.0 mL) was added dropwise. The reaction was allowed to proceed at room temperature for 2 h. The reaction was monitored by TLC for completeness. The system was adjusted to pH 8-9 with saturated aqueous sodium carbonate and extracted with dichloromethane (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 80:1) to give the product (370.0 mg, yield: 79.9%).

[0370] Step 6: Synthesis of (R)-2-(3-((4-(4-ethynyl-2-hydroxyphenyl)phthalazin-1-yl)amino)piperidin-1-yl)acetic acid hydrochloride [ka]

[0371] (R)-2-(3-((4-(4-ethynyl-2-hydroxyphenyl)phthalazin-1-yl)amino)piperidin-1-yl)ethyl 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 proceed at room temperature for 2 hours. After the reaction was complete, the system was adjusted to pH 2 by adding hydrochloric acid (2.0 mol / L) dropwise. A white solid precipitated, which was then filtered. The filter cake was dried to obtain the product (365.0 mg, yield: 93.8%).

[0372] 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=8 Hz, 1H), 7.41-7.39 (d, J=8 Hz, 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=8 Hz, 1H), 3.46-3.20 (m, 3H), 2.08-1.88 (m, 4H). Molecular formula:C 23 H 23 Exact mass of ClN4O3 free base: 402.17 LC-MS (Pos, m / z) = 403.11 [M+H] + .

[0373] Example 21: Synthesis of 5-ethynyl-2-(4-((3-hydroxybenzyl)amino)phthalazin-1-yl)phenol (Compound 268) [ka]

[0374] Step 1: Synthesis of 3-(((4-chlorophthalazin-1-yl)amino)methyl)phenol [ka]

[0375] 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 h. After completion of the reaction was monitored by TLC, water (100.0 mL) was added, and the mixture was extracted with ethyl acetate (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 80:1 to 30:1) to give the product (714.0 mg, yield: 49.7%).

[0376] Step 2: Synthesis of 3-(ethoxymethoxy)-4-(4-((3-hydroxybenzyl)amino)phthalazin-1-yl)benzaldehyde [ka]

[0377] 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, 0.06 mmol, 0.05 eq) were added to a mixture of 1,4-dioxane (10.0 mL) and water (5.0 mL). The mixture was purged with nitrogen gas for 2 minutes and reacted at 110 °C for 3 hours. Complete reaction was monitored by TLC. Water (50.0 mL) was added, and ethyl acetate (100.0 mL) was added. The mixture was extracted with 1 mL of HCl, 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 (180.0 mg, yield: 30.8%).

[0378] Step 3: Synthesis of 3-((4-(2-(ethoxymethoxy)-4-ethynylphenyl)phthalazin-1-yl)amino)methyl)phenol [ka]

[0379] 3-(Ethoxymethoxy)-4-(4-((3-hydroxybenzyl)amino)phthalazin-1-yl)benzaldehyde (174.0 mg, 0.40 mmol, 1.0 eq), (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (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 reacted at room temperature for 2 h. The reaction was monitored by TLC for completeness. 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 give the product (158.0 mg, yield: 91.8%).

[0380] Step 4: Synthesis of 5-ethynyl-2-(4-((3-hydroxybenzyl)amino)phthalazin-1-yl)phenol [ka]

[0381] 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) and 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 h. The reaction was monitored by TLC for completeness. The pH of the mixture was adjusted to 8-9 with saturated aqueous sodium carbonate, and the mixture was extracted with dichloromethane (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 80:1 to 50:1) to give the product (100.0 mg, yield: 73.5%).

[0382] 1 HNMR(400MHz, DMSO-d6)δ(ppm): 9.97 (s, 1H), 9.27 (s, 1H), 8.41-8.39 (d, J=8 Hz, 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=8 Hz, 1H), 7.30-7.28 (d, J=8 Hz, 1H), 7.13-7.05 (m, 3H), 6.86-6.84 (d, J=8 Hz, 2H), 6.63-6.60 (m, 1H), 4.78-4.77 (d, J=4 Hz, 2H), 4.23 (s, 1H). Molecular formula:C 23 H 17 N3O2 exact mass: 367.13 LC-MS(Pos, m / z)=368.11[M+H] + .

[0383] Example 22: Synthesis of (R)-2-(3-((4-(2-hydroxy-4-(prop-1-yl)phenyl)phthalazin-1-yl)amino)piperidin-1-yl)acetic acid (Compound 265) [ka]

[0384] Step 1: Synthesis of (R)-2-(3-((4-(2-(ethoxymethoxy)-4-(prop-1-yl)phenyl)phthalazin-1-yl)amino)piperidin-1-yl)ethyl acetate [ka]

[0385] (R)-2-(3-((4-chlorophthalazin-1-yl)amino)piperidin-1-yl)ethyl acetate (279.5 mg, 1.20 mmol, 1.0 eq), 2-(2-(ethoxymethoxy)-4-(prop-1-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (380 mg, 0.80 mmol, 1.5 eq), PdCl(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 mixture of 1,4-dioxane (4 mL) and water (1 mL) and heated to 100 °C under nitrogen protection for 4 h. The reaction was monitored by LC-MS for completeness, cooled to room temperature, added with water (5 mL), 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%).

[0386] Step 2: Synthesis of (R)-2-(3-((4-(2-hydroxy-4-(prop-1-yl)phenyl)phthalazin-1-yl)amino)piperidin-1-yl)ethyl acetate [ka]

[0387] (R)-2-(3-((4-(2-(ethoxymethoxy)-4-(prop-1-yl)phenyl)phthalazin-1-yl)amino)piperidin-1-yl)ethyl 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 hour. After completion of the reaction was monitored by LC-MS, water (5 mL) was added, and the pH was adjusted to approximately 8 with sodium bicarbonate. The mixture was extracted with a 10:1 DCM:MeOH mixture (5 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (DCM:MeOH = 10:1) to give the product (240 mg, yield: 87.5%).

[0388] Step 3: Synthesis of (R)-2-(3-((4-(2-hydroxy-4-(prop-1-yl)phenyl)phthalazin-1-yl)amino)piperidin-1-yl)acetic acid [ka]

[0389] (R)-2-(3-((4-(2-hydroxy-4-(prop-1-yl)phenyl)phthalazin-1-yl)amino)piperidin-1-yl)ethyl acetate (240 mg, 0.54 mmol, 1.0 eq) was added to MeOH (4 mL), water (2 mL), and LiOH·HO (68.0 mg, 1.62 mmol, 3.0 eq) were added, and the mixture was allowed to react at room temperature for 2 h. The reaction was monitored by LC-MS, and the mixture was concentrated under reduced pressure. Water (5 mL) was added to the crude product, and the pH was adjusted to approximately 2 with 2N HCl to precipitate a solid. DMAc (3 mL) was added to dissolve the product, and the resulting mixture was purified by reverse-phase column chromatography (C18 column, MeCN:HO = 0 to 4:1, 30 min) to give the product (129.6 mg, yield: 57.6%).

[0390] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 8.43 (d, J = 8.4 Hz, 1H), 7.90-7.80 (m, 2H), 7.51-7.49 (m, 2H), 7.25 (d, J = 7.6 Hz, 1H), 7.03 (m, 1H), 6.98-6.96 (m, 1H), 4.61 (s, 1H), 3.52 (s, 2H), 3.43 (d, J = 8.0 Hz, 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). Molecular formula:C 24 H 24 N4O3 exact mass: 416.18 LC-MS(Pos, m / z)=417.11[M+H] + .

[0391] Example 23: Synthesis of (R)-2-(4-((1-(2-(methylsulfonyl)ethyl)piperidin-3-yl)amino)phthalazin-1-yl)-5-(prop-1-yl)phenol (Compound 266) [ka]

[0392] Step 1: Synthesis of (R)-4-chloro-N-(piperidin-3-yl)phthalazin-1-amine: [ka]

[0393] (R)-3-((4-chlorophthalazin-1-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (4.965 g, 13.68 mmol, 1.0 eq) was dissolved in DCM (25 mL) and a 4 mol / L solution of hydrogen chloride in 1,4-dioxane (15.0 mL) was added dropwise. The reaction mixture was incubated at room temperature for 2 h. After completion of the reaction was monitored by LC-MS, water (25 mL) was added, and the pH was adjusted to approximately 8 with sodium bicarbonate. The mixture was extracted with a 10:1 DCM:MeOH mixture (25 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product (3.376 g, 93.9% yield).

[0394] Step 2: Synthesis of (R)-4-(2-(ethoxymethoxy)-4-(prop-1-yl)phenyl)-N-(piperidin-3-yl)phthalazin-1-amine [ka]

[0395] (R)-4-Chloro-N-(piperidin-3-yl)phthalazin-1-amine (210.5 mg, 1.20 mmol, 1.0 eq), 2-(2-(ethoxymethoxy)-4-(prop-1-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (380 mg, 0.80 mmol, 1.5 eq), PdCl(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 mixture of 1,4-dioxane (4 mL) and water (1 mL). The mixture was heated to 100 °C under nitrogen protection for 4 h. The reaction was monitored by LC-MS for completeness, cooled to room temperature, added with water (5 mL), 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 (245.8 mg, yield: 73.6%).

[0396] Step 3: Synthesis of (R)-4-(2-(ethoxymethoxy)-4-(prop-1-yl)phenyl)-N-(1-(2-(methylsulfonyl)ethyl)piperidin-3-yl)phthalazin-1-amine [ka]

[0397] (R)-4-(2-(ethoxymethoxy)-4-(prop-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 reaction was allowed to proceed at room temperature for 48 h. The reaction was monitored for completeness by LC-MS, concentrated under reduced pressure, and purified by preparative thin-layer chromatography (DCM:MeOH = 10:1) to give the product (154.4 mg, yield: 50.0%).

[0398] Step 4: Synthesis of (R)-2-(4-((1-(2-(methylsulfonyl)ethyl)piperidin-3-yl)amino)phthalazin-1-yl)-5-(prop-1-yl)phenol [ka]

[0399] (R)-4-(2-(ethoxymethoxy)-4-(prop-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) and a 4 mol / L solution of hydrogen chloride in 1,4-dioxane (1.5 mL) was added dropwise. The reaction mixture was incubated at room temperature for 2 h. After completion of the reaction was monitored by LC-MS, water (1.5 mL) was added, the pH was adjusted to approximately 8 with sodium bicarbonate, and the mixture was extracted with a 10:1 DCM:MeOH mixture (1.5 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by preparative thin-layer chromatography (DCM:MeOH = 10:1) to give the product (57.6 mg, yield: 42.0%).

[0400] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 9.90 (s, 1H), 8.38 (d, J = 8.4 Hz, 1H), 7.87-7.77 (m, 2H), 7.48 (d, J = 8 Hz, 1H), 7.25 (d, J = 7.6 Hz, 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). Molecular formula:C 25 H 28N4O3S exact mass:464.19 LC-MS(Pos, m / z)=465.09[M+H] + .

[0401] 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) [ka]

[0402] 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 [ka]

[0403] (R)-6-Bromo-5-methyl-N-(1-methylpiperidin-3-yl)-1,2,4-triazin-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), PdCl(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 mixture of 1,4-dioxane (5 mL) and water (1 mL) and heated to 100 °C under nitrogen protection for 3 h. The absence of starting material was monitored by LC-MS, 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%).

[0404] 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 [ka]

[0405] (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 mixture was then reacted at room temperature for 1 hour. After monitoring the absence of starting material by TLC, 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 give the crude product. The mixture was slurried with tert-butyl methyl ether (4 mL), filtered, and the filter cake was dried to give the product (130 mg, yield: 70%).

[0406] 1 HNMR (400 MHz, 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). Molecular formula:C 19 H 23 N5O exact mass:337.19 LC-MS(Pos, m / z)= 338.33[M+H] + .

[0407] 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) [ka]

[0408] procedure: [ka]

[0409] Step 1: Synthesis of 2-bromo-5-iodophenol [ka]

[0410] 2-Bromo-5-iodoanisole (3.8 g, 12.14 mmol, 1.0 eq) was dissolved in DCM (40 mL) and cooled to -10 °C. Boron tribromide (6.1 g, 24.28 mmol, 2.0 eq) was added dropwise. The mixture was allowed to warm to room temperature and react for 17 h. After monitoring the absence of starting material by TLC, methanol (10 mL) was added dropwise, the mixture was stirred for 10 min, water (30 mL) was added, and the mixture was extracted with DCM (30 mL x 2). The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product (3.6 g, 100% yield).

[0411] Step 2: Synthesis of 1-bromo-2-(ethoxymethoxy)-4-iodobenzene [ka]

[0412] 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 the mixture was incubated at room temperature for 0.5 h. Chloromethyl ethyl ether (1.7 g, 18.21 mmol, 1.5 eq) was added dropwise and the mixture was incubated at room temperature for 1 h. After monitoring the absence of starting material by LC-MS, 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 was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE = 1:10) to give the product (4.3 g, 100% yield).

[0413] Step 3: Synthesis of 1-bromo-4-(cyclopropylethynyl)-2-(ethoxymethoxy)benzene [ka]

[0414] 1-Bromo-2-(ethoxymethoxy)-4-iodobenzene (3.6 g, 10.08 mmol, 1.0 eq), trans-dichlorobis(triphenylphosphine)palladium(II) (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 protection for 10 min. Cyclopropylacetylene (733 mg, 11.09 mmol, 1.1 eq) was added and the mixture was allowed to react at room temperature for 16 h. After monitoring the absence of starting material by TLC, water (100 mL) was added and extracted with ethyl acetate (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE = 1:200 to 1:100) to give the product (2.8 g, yield: 93.3%).

[0415] Step 4: Synthesis of 2-(4-(cyclopropylethynyl)-2-(ethoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka]

[0416] 1-Bromo-4-(cyclopropylethynyl)-2-(ethoxymethoxy)benzene (2.8 g, 9.48 mmol, 1.0 eq) was dissolved in anhydrous THF (30 mL), cooled to -75°C, and a 1.6 mol / L n-butyllithium THF solution (7.7 mL, 12.32 mmol, 1.3 eq) was added dropwise. The mixture was then incubated at -70°C and reacted for 1 hour. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.6 g, 14.22 mmol, 1.5 eq) was added dropwise. The mixture was then incubated at -70°C and reacted for 1 hour. The mixture was then allowed to warm to room temperature and reacted for 15 hours. The absence of starting material was monitored by TLC, and saturated aqueous ammonium chloride (30 mL) was added, stirred for 5 minutes, 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 (EA:PE = 1:100 to EA = 100%) to give the product (2.3 g, yield: 71.9%).

[0417] Step 5: Synthesis of (R)-6-(4-(cyclopropylethynyl)-2-(ethoxymethoxy)phenyl)-5-methyl-N-(1-methylpiperidin-3-yl)-1,2,4-triazin-3-amine [ka]

[0418] A mixture of (R)-6-bromo-5-methyl-N-(1-methylpiperidin-3-yl)-1,2,4-triazin-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 PdCl(dppf) (73.2 mg, 0.1 mmol, 0.1 eq) in 1,4-dioxane (10 mL) and water (2 mL) was heated to 100 °C under nitrogen protection for 3 h. The absence of starting material was monitored by LC-MS, 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%).

[0419] Step 6: Synthesis of (R)-5-(cyclopropylethynyl)-2-(5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)phenol [ka]

[0420] (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) and cooled to approximately 0 °C with ice water. A solution of TFA (0.5 mL) in DCM (5 mL) was added dropwise and the mixture was allowed to react at room temperature for 8 hours. Approximately 5% of the starting material remained, as monitored by LC-MS. 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 was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (MeOH:DCM = 1:10) to give the product (125 mg, yield: 35.4%).

[0421] 1 HNMR (400 MHz, 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). Molecular formula:C 21 H 25 N5O exact mass:363.21 LC-MS(Pos, m / z)=364.30[M+H] + .

[0422] Example 26: Synthesis of (R)-5-(cyclopropylethynyl)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol (Compound 254) [ka]

[0423] Step 1: Synthesis of (R)-6-(4-(cyclopropylethynyl)-2-(ethoxymethoxy)phenyl)-5-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine [ka]

[0424] A mixture of (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 PdCl(dppf) (43.9 mg, 0.06 mmol, 0.1 eq) in 1,4-dioxane (10 mL) and water (2 mL) was heated to 100 °C under nitrogen protection for 3 h. The absence of starting material was monitored by LC-MS, 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 give the product (183 mg, yield: 73.7%).

[0425] Step 2: Synthesis of (R)-5-(cyclopropylethynyl)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol [ka]

[0426] (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. The mixture was allowed to react at room temperature for 8 hours. Approximately 5% of the starting material remained, as monitored by LC-MS. Saturated aqueous sodium bicarbonate (30 mL) was added, the mixture was stirred for 5 minutes, and extracted with DCM (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (MeOH:DCM = 1:10) to give the product (78 mg, yield: 50%).

[0427] 1 HNMR (400 MHz, 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). Molecular formula:C 22 H 26 N4O exact mass:362.21 LC-MS(Pos, m / z)=363.07[M+H] + .

[0428] 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) [ka]

[0429] 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 [ka]

[0430] A mixture of (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 PdCl(dppf) (43.9 mg, 0.06 mmol, 0.1 eq) in 1,4-dioxane (10 mL) and water (2 mL) was heated to 100 °C under nitrogen protection for 18 h. The absence of starting material was monitored by LC-MS, 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 1:10) to give the product (166 mg, yield: 55.4%).

[0431] Step 2: Synthesis of (R)-2-(4-((1-(2-hydroxyethyl)piperidin-3-yl)amino)phthalazin-1-yl)-5-(prop-1-yn-1-yl)phenol [ka]

[0432] (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 then reacted at room temperature for 1 hour. After monitoring the absence of starting material by LC-MS, water (30 mL) was added, and the pH was adjusted to approximately 7 with sodium bicarbonate. 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 = 1:10) to give the product (72 mg, yield: 49.7%).

[0433] 1 HNMR (400 MHz, 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, 1H), 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). Molecular formula:C 24 H 26 N4O2 exact mass: 402.21 LC-MS(Pos, m / z)=403.35[M+H] + .

[0434] Example 28: Synthesis of (R)-5-bromoethynyl-2-(4-methyl-6-(1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol (Compound 259) [ka]

[0435] procedure: [ka]

[0436] Step 1: Synthesis of (R)-3-(ethoxymethoxy)-4-(4-methyl-6-(1-methylpiperidin-3-yl)amino)pyridazin-3-yl)benzaldehyde [ka]

[0437] (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), followed by 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)Cl (198 mg, 0.27 mmol, 0.1 eq). The mixture was stirred at 90 °C for 2 h under nitrogen protection. The reaction was monitored for completeness by LC-MS. The reaction mixture was concentrated, water (5 mL) was added, and the mixture was extracted with dichloromethane (5 mL × 3). The organic phase was dried and suction filtered. The filtrate was concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1 to 10:1) to give the product (520 mg, yield: 50.0%).

[0438] Step 2: Synthesis of (R)-6-(4-(2,2-dibromovinyl)-2-(ethoxymethoxy)phenyl)-5-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine [ka]

[0439] (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), carbon tetrabromide (2.07 g, 6.24 mmol, 6.0 eq) was added, and a dichloromethane solution (12 mL) of triphenylphosphine (3.27 g, 12.5 mmol, 12.0 eq) was added dropwise in an ice-water bath. The mixture was stirred for 30 min, removed from the ice-water bath, and stirred for an additional 1 h. The reaction was monitored for completeness by TLC. The reaction mixture was diluted with dichloromethane, and the crude product (900 mg) was purified by silica gel column chromatography (dichloromethane:methanol = 40:1 to 20:1).

[0440] Step 3: Synthesis of (R)-5-(2,2-dibromovinyl)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol [ka]

[0441] The 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), and a 4 mol / L solution of hydrogen chloride in 1,4-dioxane (1 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction was monitored by LC-MS for completeness. The reaction mixture was poured into water, the pH adjusted to approximately 8 with sodium bicarbonate, and the mixture was separated into portions. The mixture was extracted with dichloromethane (5 mL x 2), dried, vacuum filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 40:1 to 20:1) to afford the product (390 mg, 99.9% yield for both steps).

[0442] Step 4: Synthesis of (R)-5-bromoethynyl-2-(4-methyl-6-(1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol [ka]

[0443] (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), and TBAF trihydrate (786 mg, 2.49 mmol, 6.0 eq) was added. The mixture was stirred at 60 °C for 4 h and monitored by TLC for complete reaction. The reaction mixture was concentrated, and the crude product was purified by preparative thin-layer chromatography (dichloromethane:7% ammonia in methanol = 20:1) to give the product (100 mg, yield: 60.8%).

[0444] 1 H-NMR (400 MHz, 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). Molecular formula:C 19 H 21 BrN4O Accurate mass: 400.09 LC-MS(m / z): 401.07, 403.06 [M+H] +

[0445] Example 29: Synthesis of compound (R)-5-bromoethynyl-2-(4-cyclopropyl-6-(1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol (Compound 260) [ka]

[0446] procedure: [ka]

[0447] Step 1: Synthesis of (R)-5-cyclopropyl-(6-(4-(2,2-dibromovinyl)-2-(ethoxymethoxy)phenyl)-N-(1-methylpiperidin-3-yl)pyridazin-3-amine [ka]

[0448] (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), carbon tetrabromide (1.45 g, 4.38 mmol, 6.0 eq) was added, and a dichloromethane solution (9 mL) of triphenylphosphine (2.30 g, 8.77 mmol, 12.0 eq) was added dropwise in an ice-water bath. The mixture was stirred for 30 min, the ice-water bath was removed, and the mixture was stirred for another 30 min. Complete reaction was monitored by LC-MS. The reaction mixture was diluted with dichloromethane, and the crude product (560 mg) was purified by silica gel column chromatography (dichloromethane:methanol = 50:1-10:1).

[0449] Step 2: Synthesis of (R)-2-(4-cyclopropyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(2,2-dibromovinyl)phenol [ka]

[0450] The crude product (R)-5-cyclopropyl-(6-(4-(2,2-dibromovinyl)-2-(ethoxymethoxy)phenyl)-N-(1-methylpiperidin-3-yl)pyridazin-3-amine (560 mg) was dissolved in dichloromethane (5 mL), and a 4 mol / L solution of hydrogen chloride in 1,4-dioxane (0.5 mL) was added. The mixture was stirred at room temperature for 1 h. The reaction was monitored by LC-MS for completeness. The reaction mixture was poured into water, the pH adjusted to approximately 8 with sodium bicarbonate, and the mixture was extracted with dichloromethane (5 mL × 2). The organic phase was dried, suction filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1-10:1) to give the product (300 mg, 80.8% yield for two steps).

[0451] Step 3: Synthesis of compound (R)-5-bromoethynyl-2-(4-cyclopropyl-6-(1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol [ka]

[0452] (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), and TBAF trihydrate (931 mg, 2.95 mmol, 6.0 eq) was added. The mixture was stirred at 70 °C overnight and monitored by LC-MS for complete reaction. The reaction mixture was concentrated, and the crude product was purified by preparative thin-layer chromatography (dichloromethane:7% ammonia in methanol = 20:1) to give the product (90 mg, yield: 35.7%).

[0453] 1H-NMR (400 MHz, DMSO-d6) δ(ppm): 10.14 (s, 1H), 7.22 (d, J=7.68 Hz, 1H), 7.02-6.99 (m, 2H), 6.55 (d, J=7.48 Hz, 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), 1.58-1.51 (m, 2H), 1.34-1.25 (m, 1H), 0.88-0.85 (m, 2H), 0.61-0.60 (m, 2H). Molecular formula:C 21 H 23 BrN4O Accurate mass: 426.11 LC-MS(m / z): 427.10, 429.08 [M+H] +

[0454] Example 30: Synthesis of (R)-5-(3-hydroxypropyl-1-yn-1-yl)-2-(4-methyl-6-((1-methylpiperidin-3-yl)aminopyridazin-3-yl)phenol (Compound 262) [ka]

[0455] Step 1: Synthesis of 3-(4-bromo-3-(ethoxymethoxy)phenyl)prop-2-yn-1-yl acetate [ka]

[0456] 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) were dispersed in THF (50 mL) and cooled to 0-5 °C under nitrogen protection for 20 min. Propargyl acetate (1.65 mg, 16.8 mmol, 1.2 eq) was added and the reaction was continued for 40 min. The reaction was monitored by TLC for completeness. The reaction mixture was poured into water (100 mL) and extracted with EA (50 mL × 2). The organic phase was dried and concentrated to give the crude product (4.58 g, 100% yield).

[0457] Step 2: Synthesis of 3-(4-bromo-3-(ethoxymethoxy)phenyl)prop-2-yn-1-ol [ka]

[0458] 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 reacted at 50 °C for 5 min. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude product was dispersed in water (30 mL) and extracted with EA (30 mL × 2). The organic phase was dried, concentrated, and purified by silica gel column chromatography (EA:PE = 1:4) to give the product (2.3 g, yield: 56.7%).

[0459] Step 3: Synthesis of 1-bromo-2-(ethoxymethoxy)-4-(3-(ethoxymethoxy)prop-1-yn-1-yl)benzene [ka]

[0460] 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). 60% NaH (484 mg, 12.10 mmol, 1.5 eq) was added and the mixture was incubated at room temperature for 0.5 h. CHCl 3 ethyl ether (1.14 g, 12.10 mmol, 1.5 eq) was added and the mixture was incubated at room temperature for 1 h. After completion of the reaction was monitored by TLC, the mixture was poured into water (50 mL) and extracted with EA (20 mL × 2). The organic phase was dried, concentrated, and purified by silica gel column chromatography (EA:PE = 70:1) to give the product (2.0 g, yield: 72.5%).

[0461] 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 [ka]

[0462] 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) and cooled to -65 °C under nitrogen protection. n-Butyllithium (1.6 mol / L, 5.5 mL) was added dropwise and stirred for 1 h. Isopropoxyboronic acid pinacol ester (1.63 g, 8.74 mmol, 1.5 eq) was added and the mixture was stirred at -65 °C for 1.5 h. After completion of the reaction, the reaction mixture was poured into water (20 mL), extracted with EA (20 mL × 2), dried, concentrated, and purified by silica gel column chromatography (EA:PE = 10:1) to give the product (1.45 g, yield: 63.9%).

[0463] 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 [ka]

[0464] A mixture of (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)Cl (40 mg, 0.054 mmol, 0.1 eq), and NaHCO (91 mg, 1.08 mmol, 2.0 eq) in 1,4-dioxane (5 mL) and HO (1 mL) was heated to 110 °C under nitrogen protection for 20 h. The reaction mixture was poured into water (10 mL) and extracted with EA (20 mL×3), and the organic phase was dried and concentrated to give the crude product (253 mg, yield: 100%).

[0465] Step 6: Synthesis of (R)-5-(3-hydroxypropyl-1-yn-1-yl)-2-(4-methyl-6-((1-methylpiperidin-3-yl)aminopyridazin-3-yl)phenol [ka]

[0466] (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 the mixture was allowed to react at room temperature for 10 minutes. The reaction mixture 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 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 give the product (30 mg, yield: 15.8%).

[0467] 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). Molecular formula:C 20 H 24 N4O2 exact mass: 352.19 LC-MS(Pos, m / z)=353.18[M+H] + .

[0468] Example 31: Synthesis of compound (R)-5-ethynyl-2-(4-methyl-6-(1-(2-(methylsulfonyl)ethyl)piperidine-3-amino)pyridazin-3-yl)phenol (Compound 263) [ka]

[0469] procedure: [ka]

[0470] Step 1: Synthesis of intermediate (R)-3-(ethoxymethoxy)-4-(4-methyl-6-(piperidin-3-ylamino)pyridazin-3-yl)benzaldehyde [ka]

[0471] (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), 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), PdCl(dppf) (64 mg, 0.088 mmol, 0.1 eq), and water (0.5 mL) were added, and the mixture was heated to 100 °C under nitrogen protection for 2 h. The reaction was monitored for completion by TLC. The reaction mixture was filtered through diatomaceous earth, the filtrate was dried, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 7:1) to obtain the product (250 mg, yield: 76.7%).

[0472] Step 2: Synthesis of intermediate (R)-3-(ethoxymethoxy)-4-(4-methyl-6-(1-(2-(methylsulfonyl)ethyl)piperidin-3-amino)pyridazin-3-yl)benzaldehyde [ka]

[0473] (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), and methyl vinyl sulfone (72 mg, 0.675 mmol, 1.0 eq) was added. The reaction was allowed to proceed at 25° C. for 2 hours, and the reaction was monitored by TLC for completeness. The reaction mixture was concentrated to give the product (300 mg crude, 93.5% yield), which was directly used in the next step.

[0474] Step 3: Synthesis of intermediate (R)-6-(2-ethoxymethoxy)-4-ethynylphenyl)-5-methyl-N-(1-(2-methylsulfonyl)ethyl)piperidin-3-yl)pyridazin-3-amine [ka]

[0475] (R)-3-(Ethoxymethoxy)-4-(4-methyl-6-(1-(2-(methylsulfonyl)ethyl)piperidine-3-amino)pyridazin-3-yl)benzaldehyde (300 mg, 0.629 mmol, 1.0 eq) was dissolved in methanol (3 mL), followed by the addition of potassium carbonate (174 mg, 1.258 mmol, 2.0 eq) and (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (182 mg, 0.944 mmol, 1.5 eq). The reaction was allowed to proceed at 25°C for 5 min, and complete reaction was monitored by LC-MS. Water (10 mL) was added to the reaction mixture, which was then 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 give the product (148 mg, yield: 49.8%).

[0476] Step 4: Synthesis of compound (R)-5-ethynyl-2-(4-methyl-6-(1-(2-(methylsulfonyl)ethyl)piperidine-3-amino)pyridazin-3-yl)phenol [ka]

[0477] (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 a solution of hydrogen chloride in 1,4-dioxane (1 mL, 4 mol / L) was added dropwise. The reaction mixture was stirred at 25 °C for 5 min. The reaction was monitored by LC-MS for completeness. The reaction mixture was poured into saturated aqueous sodium bicarbonate (5 mL) and extracted with dichloromethane / methanol (10:1, 10 mL x 5). The combined organic phases were 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 give the product (59 mg, yield: 45%).

[0478] 1 H-NMR (400 MHz, DMSO-d6) δ(ppm): 10.09 (s, 1H), 7.19-7.17 (d, 1H), 7.00-6.99 (m, 2H), 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). Molecular formula:C 21 H 26 N4O3S Accurate mass: 414.17 LC-MS(m / z): 415.16 [M+H] +

[0479] Example 32: Synthesis of compound (R)-2-(4-cyclopropyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(propyl-1-yn-1-yl)phenol (Compound 264) [ka]

[0480] procedure: [ka]

[0481] Step 1: Synthesis of intermediate (R)-6-chloro-5-cyclopropyl-N-(piperidin-3-yl)pyridazin-3-amine [ka]

[0482] (R)-3-((6-chloro-5-cyclopropylpyridazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (4.0 g, 11.34 mmol) was dissolved in dichloromethane (20 mL) and added dropwise to a solution of hydrogen chloride in 1,4-dioxane (40 mL, 4 mol / L). The reaction was allowed to proceed at 25° C. for 5 minutes, and the reaction was monitored by TLC for completeness. The reaction mixture was poured into saturated aqueous sodium bicarbonate (50 mL) and extracted with dichloromethane / methanol (10:1, 50 mL). The organic phases were combined, dried, and concentrated to give the product (1.93 g, 67.2% yield).

[0483] Step 2: Synthesis of intermediate (R)-6-chloro-5-cyclopropyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine [ka]

[0484] (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), and 37% aqueous formaldehyde (620 mg, 7.64 mmol, 1.0 eq) and sodium cyanoborohydride (528 mg, 8.40 mmol, 1.1 eq) were added. The reaction was allowed to proceed at 25°C for 5 minutes, and the reaction was monitored by TLC for completeness. The 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 to 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%).

[0485] 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 [ka]

[0486] (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 added with 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), sodium bicarbonate (79 mg, 0.938 mmol, 2.0 eq), PdCl(dppf) (34 mg, 0.469 mmol, 0.1 eq) and water (0.5 mL). The mixture was heated to 100 °C under nitrogen protection for 3 h, and the reaction was monitored by LC-MS for completeness. The reaction mixture was filtered through diatomaceous earth, dried, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 50:1 to 20:1) to give the product (110 mg, yield: 55.8%).

[0487] 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 [ka]

[0488] (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 reaction mixture was stirred at 25 °C for 5 min. The reaction mixture was monitored by LC-MS for completeness. The reaction mixture was poured into saturated aqueous sodium bicarbonate (5 mL) and extracted with dichloromethane / methanol (10:1, 10 mL x 5). The combined organic phases were dried over anhydrous magnesium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 20:1) to give the product (123 mg, yield: 59.4%).

[0489] 1 H-NMR (400 MHz, 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). Molecular formula:C 22 H 26 N4O exact mass: 362.21 LC-MS(m / z): 363.20 [M+H] +

[0490] Example 33: Synthesis of compound (R)-2-(3-((5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)amino)piperidin-1-yl)acetonitrile (Compound 267) [ka]

[0491] Step 1: Synthesis of intermediate (R)-2-(5-cyclopropyl-6-(2-ethoxymethoxy)-4-formylphenyl)pyridazin-3-yl)amino)piperidin-1-yl)acetonitrile [ka]

[0492] (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). 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), PdCl(dppf) (28 mg, 0.0377 mmol, 0.1 eq), and water (0.5 mL) were added and the mixture was heated to 100 °C under nitrogen protection for 1 h. The reaction was monitored by TLC for completion. The reaction mixture was filtered through diatomaceous earth and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 70:1) to obtain the product (90 mg, yield: 54.9%).

[0493] Step 2: Synthesis of intermediate (R)-2-(5-cyclopropyl-6-(2-ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-yl)amino)piperidin-1-yl)acetonitrile [ka]

[0494] (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), followed by the addition of potassium carbonate (57 mg, 0.414 mmol, 2.0 eq) and (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (60 mg, 0.311 mmol, 1.5 eq). The reaction mixture was stirred at 25 °C for 20 min and monitored for completeness by TLC. The mixture was concentrated, water (10 mL) was added, and the resulting mixture was extracted with dichloromethane (10 mL x 3). The combined organic phases were dried over anhydrous magnesium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1) to give the crude product, which was directly used in the next step.

[0495] Step 3: Synthesis of compound (R)-2-(3-((5-cyclopropyl-6-(4-ethynyl-2-hydroxyphenyl)pyridazin-3-yl)amino)piperidin-1-yl)acetonitrile [ka]

[0496] The crude product (R)-2-(5-cyclopropyl-6-(2-ethoxymethoxy)-4-ethynylphenyl)pyridazin-3-yl)amino)piperidin-1-yl)acetonitrile from the previous step 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 reaction was allowed to proceed at 25 °C for 5 minutes, and the reaction was monitored by LC-MS for completeness. The reaction mixture was poured into saturated aqueous sodium bicarbonate (5 mL) and extracted with dichloromethane / methanol (10:1, 10 mL x 5). The combined organic phases were dried over anhydrous magnesium sulfate and concentrated. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give the product (5 mg, yield for 2 steps: 6.5%).

[0497] 1H-NMR (400 MHz, 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), 4.19 (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). Molecular formula:C 22 H 23 N5O exact mass: 373.19 LC-MS(m / z): 374.11 [M+H] +

[0498] Example 34 Synthesis of (R)-5-ethynyl-2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-4-methylpyridazin-3-yl)phenol (Compound 253) [ka]

[0499] Step 1: Synthesis of (R)-2-(3-((6-chloro-5-methylpyridazin-3-yl)amino)piperidin-1-yl)ethan-1-ol [ka]

[0500] (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), triethylamine (223 mg, 2.20 mmol, 2.0 eq) and 2-bromoethanol (275 mg, 2.20 mmol, 2.0 eq) were added, and the mixture was stirred at room temperature for 22 h. After concentration, the crude product was purified by silica gel column chromatography (DCM:MeOH = 50:1 to 15:1) to give the product (282 mg, yield: 94.4%).

[0501] Step 2: Synthesis of (R)-3-(ethoxymethoxy)-4-(6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-4-methylpyridazin-3-yl)benzaldehyde [ka]

[0502] 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 sequentially to 1,4-dioxane (10 mL). HO (5 mL) was added, and the mixture was heated to 110 °C under nitrogen protection for 2 h. The mixture was cooled to room temperature, quenched with water (30 mL), extracted with EA (30 mL × 2), the organic phase dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 50:1 to 15:1) to give the product (314 mg, yield: 72.7%).

[0503] Step 3: Synthesis of (R)-2-(3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)ethan-1-ol [ka]

[0504] (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 (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (218 mg, 1.14 mmol, 1.5 eq) were added and stirred at room temperature for 2 h. The crude product was concentrated and purified by silica gel column chromatography (DCM:MeOH = 50:1 to 15:1) to give the product (253 mg, 81.4% yield).

[0505] Step 4: Synthesis of (R)-5-ethynyl-2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-4-methylpyridazin-3-yl)phenol [ka]

[0506] (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). A solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 0.46 mL, 1.85 mmol, 3.0 eq) was added dropwise and stirred at room temperature for 2 h. The pH was adjusted to 8 with saturated aqueous NaHCO3, and the mixture was extracted with DCM (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 give the product (158 mg, yield: 72.7%).

[0507] 1 HNMR (400MHz, DMSO-d6) δ(ppm): 10.15 (s, 1H), 7.17 (d, J = 7.7 Hz, 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). Molecular formula:C 20 H 24 N4O2 exact mass: 352.19 LC-MS(Pos, m / z)=353.17[M+H] + .

[0508] Example 35 Synthesis of (R)-2-(3-((6-(4-ethynyl-2-hydroxyphenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)acetic acid (Compound 256) [ka]

[0509] Step 1: Synthesis of (R)-2-(3-((6-chloro-5-methylpyridazin-3-yl)amino)piperidin-1-yl)ethyl acetate [ka]

[0510] (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), triethylamine (223 mg, 2.20 mmol, 2.0 eq) and ethyl bromoacetate (367 mg, 2.20 mmol, 2.0 eq) were added, and the mixture was stirred at room temperature for 20 h. After concentration, the crude product was purified by silica gel column chromatography (DCM:MeOH = 50:1 to 15:1) to give the product (325 mg, yield: 94.2%).

[0511] Step 2: Synthesis of (R)-2-(3-((6-(2-(ethoxymethoxy)-4-formylphenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)ethyl acetate [ka]

[0512] 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 sequentially to 1,4-dioxane (10 mL). HO (5 mL) was added, and the mixture was heated to 110 °C under nitrogen protection for 1 h. The reaction mixture was cooled to room temperature, quenched with water (30 mL), extracted with EA (30 mL × 2), 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 give the product (402 mg, yield: 84.7%).

[0513] Step 3: Synthesis of (R)-2-(3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)methyl acetate [ka]

[0514] (R)-2-(3-((6-(2-(ethoxymethoxy)-4-formylphenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)ethyl 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 (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (254 mg, 1.32 mmol, 1.5 eq) were added and stirred at room temperature for 2 h. 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, yield: 91.2%).

[0515] Step 4: Synthesis of (R)-2-(3-((6-(4-ethynyl-2-hydroxyphenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)acetic acid [ka]

[0516] (R)-2-(3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)methyl 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 mixture was concentrated, the pH was adjusted to 2 with dilute hydrochloric acid, and the mixture was stirred at room temperature for 1 hour. The mixture was purified by reverse-phase column chromatography (ACN:HO=20:80) to give the product (182 mg, yield: 66.0%).

[0517] 1 HNMR(400MHz, DMSO-d6) δ(ppm): 10.37 (s, 1H), 7.25 (s, 1H), 7.17 (d, J = 7.8 Hz, 1H), 7.07 (d, J = 1.4 Hz, 1H), 7.01-6.99 (m, 1H), 6.80 (s, 1H), 4.34-4.33 (m, 1H), 4.21 (s, 1H), 3.85 (s, 2H), 3.54 (d, J = 10.0 Hz, 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). Molecular formula:C 20 H 22 N4O3 exact mass: 366.17 LC-MS(Pos, m / z)=367.14[M+H] + .

[0518] Example 36 Synthesis of 5-ethyl-2-(6-((3-hydroxybenzyl)amino)-4-methylpyridazin-3-yl)phenol (Compound 261) [ka]

[0519] Step 1: Synthesis of 3-(((6-chloro-5-methylpyridazin-3-yl)amino)methyl)phenol [ka]

[0520] 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 isopropyl alcohol (30 mL), heated to 85 °C, and reacted for 24 h. The mixture was concentrated, dissolved in EA (30 mL), washed with water (20 mL × 2), 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 give the product (300 mg, yield: 9.8%).

[0521] Step 2: Synthesis of 3-(ethoxymethoxy)-4-(6-((3-hydroxybenzyl)amino)-4-methylpyridazin-3-yl)benzaldehyde [ka]

[0522] 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 sequentially to 1,4-dioxane (10 mL). HO (5 mL) was added, and the mixture was heated to 110 °C under nitrogen protection for 1 h. The reaction mixture was cooled to room temperature, quenched with water (30 mL), extracted with EA (20 mL × 2), the organic phase dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 50:1) to give the product (248 mg, yield: 78.7%).

[0523] Step 3: Synthesis of 3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylpyridazin-3-yl)amino)methyl)phenol [ka]

[0524] 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 (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (182 mg, 0.945 mmol, 1.5 eq) were added, and the mixture was stirred at room temperature for 2 h. 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 (215 mg, yield: 87.6%).

[0525] Step 4: Synthesis of 5-ethyl-2-(6-((3-hydroxybenzyl)amino)-4-methylpyridazin-3-yl)phenol [ka]

[0526] 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). A solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 0.42 mL, 1.66 mmol, 3.0 eq) was added dropwise and stirred at room temperature for 1 h. The pH was adjusted to 8 with saturated aqueous NaHCO3, and the mixture was extracted with DCM (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 give the product (116 mg, yield: 63.4%).

[0527] 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 = 8.1 Hz, 1H), 7.14-7.10 (m, 1H), 6.99 (d, J = 5.6 Hz, 2H), 6.79 (d, J = 6.6 Hz, 2H), 6.71 (s, 1H), 6.63 (d, J = 8.3 Hz, 1H), 4.51 (d, J = 5.7 Hz, 2H), 4.19 (s, 1H), 2.03 (s, 3H). Molecular formula:C 20 H 17 N3O2 exact mass: 331.13 LC-MS(Pos, m / z)=332.10[M+H] + .

[0528] Example 37: Synthesis of (R)-2-(5-(dimethylamino)-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)-5-ethynylphenol (Compound 181) [ka]

[0529] Step 1: Synthesis of 6-chloro-N,N-dimethyl-3-(methylthio)-1,2,4-triazin-5-amine [ka]

[0530] 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) and reacted at room temperature for 20 min. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (EA:PE = 1:10) to give the product (1.2 g, yield: 16.8%).

[0531] Step 2: Synthesis of 4-(5-(dimethylamino)-3-(methylthio)-1,2,4-triazin-6-yl)-3-(ethoxymethoxy)benzaldehyde [ka]

[0532] 6-Chloro-N,N-dimethyl-3-(methylthio)-1,2,4-triazin-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 HO (4 mL) and reacted at 110 °C for 3 h under nitrogen protection. The reaction was monitored by TLC for completeness, poured into water (30 mL), extracted with EA (30 mL × 3), and the organic phase was dried, concentrated, and purified by silica gel column chromatography (MeOH:DCM = 1:100) to give the product (1.7 g, yield: 83.3%).

[0533] Step 3: Synthesis of 6-(2-(ethoxymethoxy)-4-ethynylphenyl)-N,N-dimethyl-3-(methylthio)-1,2,4-triazin-5-amine [ka]

[0534] 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 min, (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (1.41 g, 7.32 mmol, 1.5 eq) was added and the reaction mixture was allowed to react for 2 h. After completion of the reaction was monitored by TLC, the reaction mixture was concentrated under reduced pressure. The crude product was dispersed in water (30 mL) and extracted with EA (20 mL × 2). The organic phase was dried and concentrated to give the product (1.5 g, 89.3% yield).

[0535] Step 4: Synthesis of 6-(2-(ethoxymethoxy)-4-ethynylphenyl)-N,N-dimethyl-3-(methylsulfinyl)-1,2,4-triazin-5-amine [ka]

[0536] 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) was dissolved in DCM (30 mL), and metachloroperbenzoic acid (883 mg, 4.35 mmol, 1.0 eq) (85% mass fraction) was added. The reaction was allowed to proceed at room temperature for 30 min. Complete reaction was monitored by TLC, and the reaction mixture was concentrated under reduced pressure to give the crude product (1.57 g, 100% yield).

[0537] Step 5: Synthesis of (R)-3-((5-(dimethylamino)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester [ka]

[0538] 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)-3-aminopiperidine-1-carboxylic acid tert-butyl ester (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. After completion of the reaction, the reaction mixture was concentrated. The crude product was dispersed in water (20 mL) and extracted with EA (20 mL × 3). The organic phase was dried and concentrated to give the product (1.5 g, 69.4% yield).

[0539] Step 6: Synthesis of (R)-2-(5-(dimethylamino)-3-(piperidin-3-ylamino)-1,2,4-triazin-6-yl)-5-ethynylphenol [ka]

[0540] (R)-3-((5-(dimethylamino)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (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 mixture was allowed to react at room temperature for 2 h. After completion of the reaction was monitored by LC-MS, the reaction mixture was poured into water (30 mL), separated, and the aqueous phase was retained. The pH was adjusted to approximately 10 with aqueous NaHCO3 solution. The mixture was then extracted with DCM (20 mL × 2). The organic phase was dried and concentrated. The crude product was purified by silica gel column chromatography (MeOH:DCM = 1:15) to give the product (600 mg, yield: 58.8%).

[0541] Step 7: Synthesis of (R)-2-(5-(dimethylamino)-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)-5-ethynylphenol [ka]

[0542] (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 aqueous formaldehyde (37%) (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 the mixture was stirred at room temperature for 5 min. After completion of the reaction was monitored by TLC, the reaction mixture was concentrated under reduced pressure. The crude product was dispersed in water (10 mL) and extracted with 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 give the product (200 mg, 32.1% yield).

[0543] 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). Molecular formula:C 19 H 24 N6O exact mass:352.20 LC-MS(Pos, m / z)=353.15 [M+H] + .

[0544] 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) [ka]

[0545] Step 1: Synthesis of 6-chloro-5-methoxy-3-(methylthio)-1,2,4-triazine [ka]

[0546] 5,6-Dichloro-3-(methylthio)-1,2,4-triazine (6.85 g, 34.92 mmol, 1.0 eq) was dispersed in MeOH (50 mL) and reacted 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 give the product (1.5 g, yield: 22.4%).

[0547] Step 2: Synthesis of 3-(ethoxymethoxy)-4-(5-methoxy-3-(methylthio)-1,2,4-triazin-6-yl)benzaldehyde [ka]

[0548] 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 HO (4 mL) and reacted at 110 °C for 2 h under nitrogen protection. The reaction was monitored by TLC for completeness, poured into water (20 mL), extracted with EA (20 mL × 3), the organic phase was dried and concentrated, and the crude product was purified by silica gel column chromatography (EA:PE = 1:20) to give the product (1.0 g, yield: 38.2%).

[0549] Step 3: Synthesis of 6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methoxy-3-(methylthio)-1,2,4-triazine [ka]

[0550] 3-(Ethoxymethoxy)-4-(5-methoxy-3-(methylthio)-1,2,4-triazin-6-yl)benzaldehyde (1.0 g, 2.98 mmol, 1.0 eq), (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (859 mg, 4.47 mmol, 1.5 eq), and potassium carbonate (617 mg, 4.47 mmol, 1.5 eq) were dispersed in MeOH (20 mL) and reacted for 1 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude product was dispersed in water (30 mL) and extracted with EA (20 mL × 2). The organic phase was dried and concentrated to give the product (988 mg, 100% yield).

[0551] Step 4: Synthesis of 6-(2-(ethoxymethoxy)-4-ethynylphenyl)-N,N-dimethyl-3-(methylsulfinyl)-1,2,4-triazin-5-amine [ka]

[0552] 6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methoxy-3-(methylthio)-1,2,4-triazine (988 mg, 2.98 mmol, 1.0 eq) dissolved in DCM (20 mL) was added to 85% metachloroperbenzoic acid (605 mg, 2.98 mmol, 1.0 eq) and the mixture was allowed to react at room temperature for 20 min. After completion of the reaction was monitored by TLC, the reaction mixture 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 give the product (1.03 g, 100% yield).

[0553] Step 5: Synthesis of (R)-3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methoxy-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester [ka]

[0554] 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)-3-aminopiperidine-1-carboxylic acid tert-butyl ester (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. After completion of the reaction was monitored by LC-MS, the reaction mixture was concentrated, and the crude product was purified by silica gel column chromatography (EA:PE = 1:1) to give the product (600 mg, yield: 41.7%).

[0555] Step 6: Synthesis of (R)-5-ethynyl-2-(5-methoxy-3-(piperidin-3-ylamino)-1,2,4-triazin-6-yl)phenol [ka]

[0556] (R)-3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methoxy-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (0.6 g, 1.03 mmol, 1.0 eq) was dissolved in DCM (10 mL) and a solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 1 mL) was added dropwise. The reaction mixture was allowed to react for 2.5 h at room temperature. After completion of the reaction was monitored by LC-MS, the reaction mixture was washed with water (20 mL). The aqueous phase was retained and adjusted to pH 9 with aqueous NaHCO3. The mixture was extracted with DCM (20 mL × 2). The organic phase was dried and concentrated to give the product (250 mg, 74.6% yield).

[0557] Step 7: Synthesis of (R)-5-ethynyl-2-(5-methoxy-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)phenol [ka]

[0558] (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 the mixture was stirred at room temperature for 5 min. The reaction was monitored by TLC and concentrated under reduced pressure. 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 give the product (120 mg, 46.0% yield).

[0559] 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). Molecular formula:C 18 H 21 N5O2 exact mass: 339.17 LC-MS(Pos, m / z)=340.19 [M+H] + .

[0560] Example 39: Synthesis of compound 5-ethynyl-2-(((tetrahydrofuran-2-yl)methyl)amino)phthalazin-1-yl)phenol (Compound 63) [ka]

[0561] procedure: [ka]

[0562] Step 1: Synthesis of intermediate 4-chloro-N-(tetrahydrofuran-2-yl)methyl)phthalazin-1-amine [ka]

[0563] 1,4-Dichlorophthalazine (1.0 g, 5.0 mmol, 1.0 eq) was dissolved in NMP (10 mL), 2-tetrahydrofurfurylamine (506 mg, 5.0 mmol, 1.2 eq) and DIPEA (2.26 g, 17.5 mmol, 3.5 eq) were added, and the mixture was incubated at 80 °C for 16 h. The reaction was monitored by TLC for completeness. The reaction mixture was poured into water (20 mL) and extracted with dichloromethane (20 mL × 2). The combined organic phases were 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.

[0564] Step 2: Synthesis of compound 3-(ethoxymethoxy)-4-(4-(((tetrahydrofuran-2-yl)methyl)amino)phthalazin-1-yl)benzaldehyde [ka]

[0565] 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). 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), PdCl(dppf) (69 mg, 0.095 mmol, 0.05 eq), and water (1 mL) were added. The mixture was purged with nitrogen gas, heated to 100 °C, and reacted for 4 h. The reaction was monitored by TLC for completion. The reaction mixture was filtered through diatomaceous earth, and 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, then ethyl acetate) to give the product (377 mg, yield for 2 steps: 52.4%).

[0566] Step 3: Synthesis of intermediate 4-(2-ethoxymethoxy)-4-ethynylphenyl-N-(tetrahydrofuran-2-yl)methyl)phthalazin-1-amine [ka]

[0567] 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), followed by the addition of potassium carbonate (256 mg, 1.85 mmol, 2.0 eq) and (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (267 mg, 1.388 mmol, 1.5 eq). The reaction was allowed to proceed at 25 °C for 1 h, and the reaction was monitored by TLC for completeness. The reaction mixture was concentrated, water (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL × 3). The combined organic phases were dried over anhydrous magnesium sulfate, concentrated, and the crude product was directly used in the next step.

[0568] Step 4: Synthesis of compound 5-ethynyl-2-(4-(((tetrahydrofuran-2-yl)methyl)amino)phthalazin-1-yl)phenol [ka]

[0569] 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 reaction mixture was stirred at 25 °C for 5 min and monitored for completeness by TLC. The reaction mixture was slowly poured into saturated aqueous sodium bicarbonate (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic phases were dried and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1), then slurried in ethyl acetate (2 mL), and dried to give the product (101 mg, 31.7% yield).

[0570] 1 H-NMR (400 MHz, 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). Molecular formula:C 21 H 19 N3O2 exact mass: 345.15 LC-MS(m / z): 346.06 [M+H] +

[0571] Example 40: Synthesis of compound (R)-5-ethynyl-2-(4-((1-(2-(methylsulfonyl)ethyl)piperidin-3-yl)amino)phthalazin-1-yl)phenol (Compound 62) [ka]

[0572] procedure: [ka]

[0573] Step 1: Synthesis of intermediate (R)-3-(ethoxymethoxy)-4-(4-(piperidin-3-ylamino)phthalazin-1-yl)benzaldehyde [ka]

[0574] (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). 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), PdCl(dppf) (139 mg, 0.19 mmol, 0.1 eq), and water (1 mL) were added. The mixture was purged with nitrogen gas, heated to 100 °C, and reacted for 1 h. The reaction was monitored by TLC for completion. The reaction mixture was filtered through diatomaceous earth, washed sequentially with dichloromethane (10 mL) and water (5 mL), and the filter cake was separated. 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%).

[0575] Step 2: Synthesis of intermediate (R)-3-(ethoxymethoxy)-4-(4-((1-(2-(methylsulfonyl)ethyl)piperidine-3-amino)phthalazin-1-yl)benzaldehyde [ka]

[0576] (R)-3-(Ethoxymethoxy)-4-(4-(piperidin-3-ylamino)phthalazin-1-yl)benzaldehyde (200 mg, 0.492 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL), and methyl vinyl sulfone (52 mg, 0.492 mmol, 1.0 eq) was added. The reaction was allowed to proceed at 25° C. for 5 hours, and the reaction was monitored by TLC for completeness. The reaction mixture was concentrated and directly carried on to the next step.

[0577] Step 3: Synthesis of intermediate (R)-4-(2-ethoxymethoxy)-4-ethynylphenyl)-N-(1-(2-methylsulfonyl)ethyl)piperidin-3-yl)phthalazin-1-amine [ka]

[0578] (R)-3-(ethoxymethoxy)-4-(4-((1-(2-(methylsulfonyl)ethyl)piperidine-3-amino)phthalazin-1-yl)benzaldehyde (crude product, 0.492 mmol, 1.0 eq)) was dissolved in methanol (2 mL). Potassium carbonate (136 mg, 0.984 mmol, 2.0 eq) and (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (142 mg, 0.738 mmol, 1.5 eq) were added sequentially. The reaction was allowed to proceed at 25°C for 2.5 hours, and the reaction was monitored by TLC for completeness. The reaction mixture was concentrated, water (5 mL) was added, and the mixture was extracted with dichloromethane (10 mL x 3). The combined organic phases were dried over anhydrous magnesium sulfate, concentrated, and the crude product was directly used in the next step.

[0579] Step 4: Synthesis of compound (R)-5-ethynyl-2-(4-((1-(2-(methylsulfonyl)ethyl)piperidine-3-amino)phthalazin-1-yl)phenol [ka]

[0580] (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 mixture was stirred at 25 °C for 5 min. The reaction mixture was monitored by LC-MS for completeness. The reaction mixture was poured into saturated aqueous sodium bicarbonate (15 mL) and extracted with dichloromethane:methanol = 20:1 (20 mL × 3). The combined organic phases were 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 give the product (112 mg, yield for 3 steps: 50.7%).

[0581] 1 H-NMR (400 MHz, 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), 2.85-2.77 (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). Molecular formula:C 24 H 26N4O3S Accurate mass: 450.17 LC-MS(m / z): 451.12 [M+H] +

[0582] Example 41: Synthesis of compound (R)-3-ethynyl-2-fluoro-6-(4-((tetrahydrofuran-3-yl)amino)phthalazin-1-yl)phenol (Compound 46) [ka]

[0583] procedure: [ka]

[0584] Step 1: Synthesis of intermediate (R)-4-chloro-N-(tetrahydrofuran-3-yl)phthalazin-1-amine [ka]

[0585] 1,4-Dichlorophthalazine (1 g, 5.02 mmol, 1.0 eq) was dissolved in dimethylacetamide (10 mL), (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, and the mixture was stirred at 120 °C for 3 h. The reaction was monitored by TLC for completeness. Water (50 mL) and dichloromethane (25 mL) were added to the reaction mixture, and the aqueous phase was extracted with dichloromethane (25 mL). The combined organic phases were 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 give the product (1.25 g, yield: 99.7%).

[0586] Step 2: Synthesis of intermediate (R)-3-(ethoxymethoxy)-2-fluoro-4-(4-((tetrahydrofuran-3-yl)amino)phthalazin-1-yl)benzaldehyde [ka]

[0587] (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)Cl (117 mg, 0.16 mmol, 0.1 eq) were added sequentially and the mixture was stirred at 90 °C for 2 h under nitrogen protection. The reaction was monitored for completeness by LC-MS. The reaction mixture was concentrated, water (5 mL) was added, and the mixture was extracted with dichloromethane (5 mL × 3). The organic phase was dried and suction filtered. The filtrate was concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 50:1 to 20:1) to give the product (420 mg, yield: 63.8%).

[0588] Step 3: Synthesis of intermediate (R)-4-(2-(ethoxymethoxy)-4-ethynyl-3-fluorophenyl)-N-(tetrahydrofuran-3-yl)phthalazin-1-amine [ka]

[0589] (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). (1-Diazo-2-oxopropyl)phosphonic acid dimethyl ester (224 mg, 1.17 mmol, 1.2 eq) and potassium carbonate (251 mg, 1.82 mmol, 2.0 eq) were added sequentially and stirred at room temperature for 1 h. The reaction was monitored for completeness by LC-MS. The reaction mixture was concentrated, water (5 mL) was added, and the mixture was extracted with dichloromethane (5 mL × 3). The organic phase was dried and concentrated to give the crude product (550 mg).

[0590] Step 4: Synthesis of the compound (R)-3-ethynyl-2-fluoro-6-(4-((tetrahydrofuran-3-yl)amino)phthalazin-1-yl)phenol [ka]

[0591] The crude (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), and 4 mol / L hydrogen chloride / 1,4-dioxane solution (1.25 mL) was added. The mixture was stirred at room temperature for 30 minutes. The reaction was monitored by LC-MS for completeness. The reaction mixture was poured into water, the pH was adjusted to approximately 8 with sodium bicarbonate, and the mixture was separated. The aqueous phase was extracted with dichloromethane (5 mL × 2). The organic phase was dried, suction filtered, and concentrated. The crude product was purified by preparative thin-layer chromatography to give the product (130 mg, 38.3% yield for both steps).

[0592] 1H-NMR (400 MHz, DMSO-d6) δ(ppm): 10.23 (s, 1H), 8.45 (d, J=8.2 Hz, 1H), 7.90-7.86 (m, 1H), 7.81-7.78 (m, 1H), 7.52-7.50 (m, 2H), 7.15-7.06 (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). Molecular formula:C 20 H 16 FN3O2 exact mass: 349.12 LC-MS(m / z): 350.03 [M+H] +

[0593] Example 42: Synthesis of compound 2-fluoro-6-(4-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)phthalazin-1-yl)-3-vinylphenol (Compound 171) [ka]

[0594] procedure: [ka]

[0595] Step 1: Synthesis of intermediate (cis)-3-((4-chlorophthalazin-1-yl)amino)-1-methylcyclobutan-1-ol [ka]

[0596] 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), Pd(dba) (915 mg, 1.00 mmol, 0.1 eq), and cesium carbonate (9.78 g, 30.12 mmol, 3.0 eq) were added sequentially. The mixture was stirred overnight at 90 °C under nitrogen protection. The reaction was monitored by TLC for completeness. The mixture was filtered through diatomaceous earth with suction, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 50:1 to 10:1) to give the product (1.50 g, yield: 56.9%).

[0597] Step 2: Synthesis of intermediate 3-(ethoxymethoxy)-2-fluoro-4-(4-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)phthalazin-1-yl)benzaldehyde [ka]

[0598] (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)Cl (167 mg, 0.23 mmol, 0.1 eq) were added sequentially. The mixture was stirred at 90 °C for 2 h under nitrogen protection. The reaction was monitored for completeness by LC-MS. The reaction mixture was concentrated, water (5 mL) was added, and the mixture was extracted with dichloromethane (5 mL × 3). The organic phase was dried and suction filtered. The filtrate was concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 50:1 to 20:1) to give the product (700 mg, yield: 72.2%).

[0599] Step 3: Synthesis of intermediate (cis)-3-((4-(2-(ethoxymethoxy)-4-ethynyl-3-fluorophenyl)phthalazin-1-yl)amino)-1-methylcyclobutan-1-ol [ka]

[0600] 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). (1-Diazo-2-oxopropyl)phosphonic acid dimethyl ester (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. The reaction was monitored for completeness by LC-MS. The reaction mixture was concentrated, water (5 mL) was added, and the mixture was extracted with dichloromethane (5 mL x 3). The organic phase was dried and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give the product (300 mg, yield: 60.3%).

[0601] Step 4: Synthesis of intermediate 3-ethynyl-2-fluoro-6-(4-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)phthalazin-1-yl)phenol [ka]

[0602] (cis)-3-((4-(2-(ethoxymethoxy)-4-ethynyl-3-fluorophenyl)phthalazin-1-yl)amino)-1-methylcyclobutan-1-ol (300 mg, 0.71 mmol, 1.0 eq) obtained in the previous step was dissolved in dichloromethane (3 mL), 4 mol / L hydrogen chloride / 1,4-dioxane solution (0.9 mL) was added, and the mixture was stirred at room temperature for 30 min. The reaction was monitored by LC-MS for completeness. The reaction mixture was poured into water, the pH was adjusted to approximately 8 with sodium bicarbonate, and the mixture was separated. The aqueous phase was extracted with dichloromethane (5 mL × 2). The organic phase was dried, suction filtered, and concentrated. The crude product was purified by preparative thin-layer chromatography to give the product (220 mg, yield: 85.3%).

[0603] Step 5: Synthesis of the compound 2-fluoro-6-(4-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)phthalazin-1-yl)-3-vinylphenol [ka]

[0604] 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's catalyst (12 mg, 12 wt%) was added, and the mixture was stirred at room temperature for 1 hour. After LC-MS monitoring, a large amount of starting material remained. Lindlar's catalyst (12 mg, 12 wt%) was added and the mixture was allowed to react overnight. The reaction was monitored by LC-MS for completeness. The mixture was filtered through diatomaceous earth under suction, the filtrate was concentrated, and the crude product was purified by preparative thin-layer chromatography to give the product (25 mg, yield: 20.7%).

[0605] 1 H-NMR (400 MHz, DMSO-d6) δ(ppm): 10.03 (s, 1H), 8.45 (d, J=8.1 Hz, 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, 1H), 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). Molecular formula:C 21 H 20 FN3O2 exact mass: 365.15 LC-MS(m / z): 366.10 [M+H] +

[0606] Example 43: Synthesis of compound 5-(bromoethynyl)-2-(4-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)phthalazin-1-yl)phenol (Compound 111) [ka]

[0607] procedure: [ka]

[0608] Step 1: Synthesis of intermediate 3-(ethoxymethoxy)-4-(4-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)phthalazin-1-yl)benzaldehyde [ka]

[0609] (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)Cl (135 mg, 0.19 mmol, 0.1 eq) were added sequentially. The mixture was stirred at 90 °C for 2 h under nitrogen protection. The reaction was monitored for completeness by LC-MS. The reaction mixture was concentrated, water (5 mL) was added, and the mixture was extracted with dichloromethane (5 mL × 3). The organic phase was dried and suction filtered. The filtrate was concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 50:1 to 20:1) to give the product (450 mg, yield: 60.0%).

[0610] Step 2: Synthesis of intermediate (cis)-3-((4-(2-(ethoxymethoxy)-4-ethynylphenyl)phthalazin-1-yl)amino)-1-methylcyclobutan-1-ol [ka]

[0611] 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). (1-Diazo-2-oxopropyl)phosphonic acid dimethyl ester (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. The reaction was monitored for completeness by LC-MS. The reaction mixture was concentrated, water (5 mL) was added, and the mixture was extracted with dichloromethane (5 mL x 3). The organic phase was dried and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give the product (430 mg, yield: 96.8%).

[0612] Step 3: Synthesis of intermediate (cis)-3-((4-(4-(bromoethynyl)-2-(ethoxymethoxy)phenyl)phthalazin-1-yl)amino)-1-methylcyclobutan-1-ol [ka]

[0613] (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 the mixture was stirred at room temperature overnight. The reaction was monitored by LC-MS for completeness. The reaction mixture was concentrated, water (5 mL) was added, and the mixture was extracted with dichloromethane (5 mL × 3). The organic phase was dried and concentrated to give the product (350 mg crude).

[0614] Step 4: Synthesis of the compound 5-(bromoethynyl)-2-(4-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)phthalazin-1-yl)phenol [ka]

[0615] (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), and 4 mol / L hydrogen chloride / 1,4-dioxane solution (0.9 mL) was added. The mixture was stirred at room temperature for 30 minutes. The reaction was monitored by LC-MS for completeness. The reaction mixture was poured into water, the pH was adjusted to approximately 8 with sodium bicarbonate, and the mixture was separated. The aqueous phase was extracted with dichloromethane (5 mL × 2). The organic phase was dried, suction filtered, and concentrated. The crude product was purified by preparative thin-layer chromatography to give the product (30 mg, yield for both steps: 28.3%).

[0616] 1H-NMR (400 MHz, DMSO-d6) δ(ppm): 9.90 (s, 1H), 8.42 (d, J=8.2 Hz, 1H), 7.87-7.76 (m, 2H), 7.60 (s, 1H), 7.47 (m, d, J=8.2 Hz, 1H), 7.30 (d, J=8.0 Hz, 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). Molecular formula:C 21 H 18 BrN3O2 exact mass: 423.06 LC-MS(m / z): 423.98, 425.98 [M+H] +

[0617] Example 44: Synthesis of compound (R)-3-ethynyl-2-fluoro-6-(4-((tetrahydro-2H-pyran-3-yl)amino)phthalazin-1-yl)phenol (Compound 45) [ka]

[0618] procedure: [ka]

[0619] The compound was prepared by referring to the procedures in the above examples.

[0620] 1H-NMR (400 MHz, DMSO-d6) δ(ppm): 10.16 (s, 1H), 8.43 (d, J=8.2 Hz, 1H), 7.90-7.79 (m, 2H), 7.50 (d, J=8.2 Hz, 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). Molecular formula:C 21 H 18 FN3O2 exact mass: 363.14 LC-MS(m / z): 364.09 [M+H] +

[0621] Example 45: Synthesis of 5-ethynyl-2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazin-3-yl)phenol (Compound 55) [ka]

[0622] Step 1: Synthesis of 3-(ethoxymethoxy)-4-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazin-3-yl)benzaldehyde [ka]

[0623] A mixture of (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) in 1,4-dioxane (12.0 mL) and water (4.0 mL) was reacted at 110 °C for 3 h under nitrogen protection. The reaction was monitored by TLC for completeness. 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%).

[0624] Step 2: Synthesis of (cis)-3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylpyridazin-3-yl)amino)-1-methylcyclobutan-1-ol [ka]

[0625] 3-(Ethoxymethoxy)-4-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazin-3-yl)benzaldehyde (300.0 mg, 0.80 mmol, 1.0 eq), (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (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 reacted at room temperature for 2 h. The reaction was monitored by TLC for completeness. 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 give the product (270.0 mg, yield: 91.0%).

[0626] Step 3: Synthesis of 5-ethynyl-2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazin-3-yl)phenol [ka]

[0627] (cis)-3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylpyridazin-3-yl)amino)-1-methylcyclobutan-1-ol (270.0 mg, 0.73 mmol, 1.0 eq) was added to dichloromethane (2.0 mL), and hydrogen chloride in 1,4-dioxane (4.0 mol / L, 4.0 mL) was added dropwise. The reaction was allowed to proceed at room temperature for 1 h. The reaction was monitored by TLC for completeness. The pH was adjusted to 8-9 with saturated aqueous sodium carbonate, and the mixture was extracted with dichloromethane (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 50:1 to 20:1) to give the product (150.0 mg, yield: 66.0%).

[0628] 1HNMR(400MHz, DMSO-d6) δ(ppm): 10.09 (s, 1H), 7.18-7.16 (d, J=8 Hz, 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). Molecular formula:C 18 H 19 N3O2 molecular weight: 309.15 LC-MS(Pos, m / z)=310.11[M+H] + .

[0629] 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) [ka]

[0630] Step 1: Synthesis of methyl 4-bromo-2-methoxybenzoate [ka]

[0631] 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) and incubated at room temperature for 12 h. The reaction was monitored by TLC for completeness. Water (150.0 mL) was added, and the mixture was extracted 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 (silica gel specification: 100-200 mesh, heptane:ethyl acetate = 20:1) to give the product (15.0 g, yield: 94.3%).

[0632] Step 2: Synthesis of methyl 4-cyclopropyl-2-methoxybenzoate [ka]

[0633] 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 a mixture of 1,4-dioxane (30.0 mL) and water (6.0 mL), and the mixture was reacted at 100°C for 12 hours under nitrogen protection. After completion of the reaction, water (50.0 mL) was added, and ethyl acetate (100.0 mL) was added. The mixture was extracted with 1 mL of ethyl acetate, 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 give the product (4.4 g, yield: 80.0%).

[0634] Step 3: Synthesis of 4-cyclopropyl-2-methoxybenzoic acid [ka]

[0635] 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 mixture was allowed to react at room temperature for 12 hours. After completion of the reaction was monitored 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%).

[0636] Step 4: Synthesis of 1-bromo-4-cyclopropyl-2-methoxybenzene [ka]

[0637] 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 mL) and reacted at 100 °C for 2 h. The reaction was monitored by TLC for completeness. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (heptane:ethyl acetate = 200:1) to give the product (3.5 g, yield: 78.1%).

[0638] Step 5: Synthesis of 2-bromo-5-cyclopropylphenol [ka]

[0639] 1-Bromo-4-cyclopropyl-2-methoxybenzene (3.5 g, 15.41 mmol, 1.0 eq) was added to dichloromethane (20 mL), and boron tribromide (11.5 g, 46.23 mmol, 3.0 eq) was added dropwise in an ice-water bath. The mixture was warmed to room temperature and reacted for 1 h. The reaction was monitored by TLC for completeness, quenched with methanol (10 mL) in an ice bath, concentrated under reduced pressure, added dichloromethane (100 mL), and back-extracted with water (50 mL). The aqueous phase was adjusted to pH 7-8 with saturated aqueous sodium bicarbonate and extracted with dichloromethane (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (heptane:ethyl acetate = 10:1) to give the product (2.6 g, yield: 79.2%).

[0640] Step 6: Synthesis of 1-bromo-4-cyclopropyl-2-(ethoxymethoxy)benzene [ka]

[0641] 2-Bromo-5-cyclopropylphenol (2.1 g, 9.85 mmol, 1.0 eq) was added to dry tetrahydrofuran (20.0 mL) and cooled to 0 °C under nitrogen protection. Sodium hydride (60% mass fraction, 591.3 mg, 14.78 mmol, 1.5 eq) was added slowly in portions and allowed to react for 0.5 h. Chloromethoxyethane (1.39 g, 14.78 mmol, 1.5 eq) was added, and the mixture was warmed to room temperature and allowed to react for 2 h. The reaction was monitored by TLC for completeness. Water (20.0 mL) was added, and the mixture was extracted with ethyl acetate (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica gel specification: 100-200 mesh, heptane:ethyl acetate = 100:1) to give the product (2.5 g, yield: 96.1%).

[0642] Step 7: Synthesis of (4-cyclopropyl-2-(ethoxymethoxy)phenyl)boronic acid [ka]

[0643] 1-Bromo-4-cyclopropyl-2-(ethoxymethoxy)benzene (2.5 g, 9.21 mmol, 1.0 eq) was added to dry tetrahydrofuran (20.0 mL) and cooled to -70 °C under nitrogen protection. 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 and reacted for 1 h. Triisopropyl borate (2.25 g, 11.98 mmol, 1.3 eq) was added, and the mixture was warmed to room temperature and reacted for 3 h. The reaction was monitored by TLC for completeness. 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 give the product (1.5 g, yield: 69.1%).

[0644] Step 8: Synthesis of (R)-6-(4-cyclopropyl-2-(ethoxymethoxy)phenyl)-5-methyl-N-(1-methylpiperidin-3-yl)-1,2,4-triazin-3-amine [ka]

[0645] (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 mmol, 0.1 eq) were added to a mixture of 1,4-dioxane (10.0 mL) and water (5.0 mL). The mixture was reacted at 110 °C for 2 h under nitrogen protection. After completion of the reaction, water (50.0 mL) was added, and ethyl acetate (100.0 mL) was added. The mixture was extracted with 1 mL of HCl, 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 40:1) to obtain the product (333.0 mg, yield: 77.2%).

[0646] Step 9: Synthesis of (R)-5-cyclopropyl-2-(5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)phenol [ka]

[0647] (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 hydrogen chloride in 1,4-dioxane (4.0 mol / L, 4.0 mL) was added dropwise. The reaction was allowed to proceed at room temperature for 1 h. The reaction was monitored by TLC for completeness. The pH was adjusted to 8-9 with saturated aqueous sodium carbonate, and the mixture was extracted with dichloromethane (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give the product (200.0 mg, yield: 78.1%).

[0648] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 9.61 (s, 1H), 7.36 (s, 1H), 7.11-7.09 (d, J=8 Hz, 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). Molecular formula:C 19 H 25 N5O molecular weight:339.21 LC-MS(Pos, m / z)=340.15[M+H] + .

[0649] 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) [ka]

[0650] Step 1: Synthesis of (R)-5-methyl-N-((tetrahydrofuran-2-yl)methyl)-1,2,4-triazin-3-amine [ka]

[0651] 5-Methyl-3-(methylsulfinyl)-1,2,4-triazine (1.39 g, 8.85 mmol, 1.0 eq), (R)-(tetrahydrofuran-2-yl)methylamine (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 h. The reaction was monitored by TLC for completeness. The mixture was concentrated under reduced pressure, 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 = 100:1 to 80:1) to give the product (1.27 g, yield: 73.8%).

[0652] Step 2: Synthesis of (R)-6-bromo-5-methyl-N-((tetrahydrofuran-2-yl)methyl)-1,2,4-triazin-3-amine [ka]

[0653] (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 reacted at room temperature for 2 h. The reaction was monitored by TLC for completeness. 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 give the product (520.0 mg, yield: 29.1%).

[0654] Step 3: Synthesis of (R)-3-(ethoxymethoxy)-4-(5-methyl-3-(((tetrahydrofuran-2-yl)methyl)amino)-1,2,4-triazin-6-yl)benzaldehyde [ka]

[0655] A mixture of (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) in 1,4-dioxane (10.0 mL) and water (5.0 mL) was reacted at 110 °C for 3 h under nitrogen protection. The reaction was monitored by TLC for completeness. 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 = 100:1 to 80:1) to give the product (630.0 mg, yield: 88.9%).

[0656] Step 4: Synthesis of (R)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-N-((tetrahydrofuran-2-yl)methyl)-1,2,4-triazin-3-amine [ka]

[0657] (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), (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (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 reacted at room temperature for 2 h. The reaction was monitored by TLC for completeness. 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 give the product (290.0 mg, yield: 93.2%).

[0658] Step 5: Synthesis of (R)-5-ethynyl-2-(5-methyl-3-(((tetrahydrofuran-2-yl)methyl)amino)-1,2,4-triazin-6-yl)phenol [ka]

[0659] (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 hydrogen chloride in 1,4-dioxane (4.0 mol / L, 3.0 mL) was added dropwise. The reaction was allowed to proceed at room temperature for 1 hour, and the reaction was monitored by TLC for completeness. The pH was adjusted to 8-9 with saturated aqueous sodium carbonate, and the mixture was extracted with dichloromethane (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give the product (150.0 mg, yield: 63.6%).

[0660] 1HNMR (400 MHz, DMSO-d6) δ(ppm): 10.11 (s, 1H), 7.63 (s, 1H), 7.27-7.25 (d, J=8 Hz, 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). Molecular formula:C 17 H 18 N4O2 molecular weight: 310.14 LC-MS(Pos, m / z)=311.10[M+H] + .

[0661] 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) [ka]

[0662] 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 [ka]

[0663] (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 (mass fraction 37%, 117.1 mg, 1.02 mmol, 1.5 eq) were added to methanol (10.0 mL) and reacted at room temperature for 0.5 hours. Sodium cyanoborohydride (64.5 mg, 1.02 mmol, 1.5 eq) was added and reacted at room temperature for an additional hour. Complete reaction was monitored by TLC. Saturated aqueous sodium bicarbonate solution (50.0 mL) was added, the mixture was stirred for 30 minutes, and the mixture was extracted with dichloromethane (100.0 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol=10:1) to obtain the product (80.0 mg, yield: 28.7%).

[0664] 1 HNMR (400MHz, DMSO-d6) δ(ppm): 10.11 (s, 1H), 7.63 (s, 1H), 7.27-7.25 (d, J=8 Hz, 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). Molecular formula:C 23 H 29 N5O2 molecular weight: 407.23 LC-MS(Pos, m / z)=408.18[M+H] + .

[0665] Example 49 Synthesis of 5-ethynyl-2-(7-((cis-3-hydroxy-3-methylcyclobutyl)amino)thieno[2,3-d]pyridazin-4-yl)phenol (Compound 11) [ka]

[0666] Step 1: Synthesis of cis-3-((4-chlorothiophene[2,3-d]pyridazin-7-yl)amino)-1-methylcyclobutan-1-ol [ka]

[0667] 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 sequentially to 1,4-dioxane (50 mL) and heated to 90 °C under nitrogen protection for 2 h. The reaction mixture was cooled to room temperature, quenched by adding water (50 mL), extracted with EA (30 mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography (DCM:MeOH = 20:1) to give the product (240 mg, yield: 18.2%).

[0668] Step 2: Synthesis of 3-(ethoxymethoxy)-4-(7-((cis-3-hydroxy-3-methylcyclobutyl)amino)thiophene[2,3-d]pyridazin-4-yl)benzaldehyde [ka]

[0669] 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-chlorothiophene[2,3-d]pyridazin-7-yl)amino)-1-methylcyclobutan-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 sequentially to 1,4-dioxane (6 mL). HO (3 mL) was added and the mixture was heated to 100 °C under nitrogen protection for 2 h. The reaction mixture was cooled to room temperature, quenched with water (20 mL), extracted with EA (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 20:1) to give the product (214 mg, yield: 58.2%).

[0670] Step 3: Synthesis of cis-3-((4-(2-(ethoxymethoxy)-4-ethynylphenyl)thieno[2,3-d]pyridazin-7-yl)amino)-1-methylcyclobutan-1-ol [ka]

[0671] 3-(Ethoxymethoxy)-4-(7-((cis-3-hydroxy-3-methylcyclobutyl)amino)thiophene[2,3-d]pyridazin-4-yl)benzaldehyde (214 mg, 0.518 mmol, 1.0 eq) was dissolved in MeOH (4 mL). KCO (144 mg, 1.04 mmol, 2.0 eq) and (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (149 mg, 0.777 mmol, 1.5 eq) were added and stirred at room temperature for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 30:1) to give the product (192 mg, yield: 90.6%).

[0672] Step 4: Synthesis of 5-ethynyl-2-(7-((cis-3-hydroxy-3-methylcyclobutyl)amino)thieno[2,3-d]pyridazin-4-yl)phenol [ka]

[0673] 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 added dropwise and stirred at room temperature for 1 h. The pH was adjusted to 8 with saturated aqueous NaHCO3, and the mixture was extracted with 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 give the product (142 mg, yield: 86.2%).

[0674] 1HNMR (400MHz, DMSO-d6) δ(ppm): 11.52 (s, 1H), 8.12 (d, J = 5.3 Hz, 1H), 7.63-7.59 (m, 2H), 7.50 (d, J = 5.3 Hz, 1H), 7.07 (d, J = 6.9 Hz, 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). Molecular formula:C 19 H 17 N3O2S exact mass:351.10 LC-MS(Pos, m / z)=352.05[M+H] + .

[0675] 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) [ka]

[0676] 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 [ka]

[0677] (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 protection, a 0.5 mol / L solution of ethynylmagnesium bromide in tetrahydrofuran (2.50 mL, 1.25 mmol, 3.0 eq) was added and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with saturated aqueous ammonium chloride and 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 give the product (112 mg, yield: 65.6%).

[0678] 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 [ka]

[0679] 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 a solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 0.16 mL, 0.675 mmol, 3.0 eq) was added. The mixture was stirred at room temperature for 1 h, the pH was adjusted to 8 with saturated aqueous NaHCO3, and the mixture was 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%).

[0680] 1HNMR (400 MHz, DMSO-d6) δ(ppm): 9.89 (s, 1H), 7.14 (d, J = 7.7 Hz, 1H), 7.09 (s, 1H), 6.97 (d, J = 7.8 Hz, 1H), 6.90 (s, 1H), 6.72 (s, 1H), 6.07 (d, J = 5.9 Hz, 1H), 5.33 (d, J = 3.8 Hz, 1H), 4.25 (s, 1H), 3.51 (d, J = 1.6 Hz, 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). Molecular formula: C 20 H 24 N4O2 exact mass: 352.19 LC-MS(Pos, m / z)=353.12[M+H] + .

[0681] Example 51 Synthesis of (R)-2-(3-((6-(4-ethynyl-2-hydroxyphenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)acetonitrile (Compound 222) [ka]

[0682] Step 1: Synthesis of (R)-2-(3-((6-(2-(ethoxymethoxy)-4-formylphenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)acetonitrile [ka]

[0683] 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 sequentially to 1,4-dioxane (6 mL). HO (3 mL) was added, and the mixture was heated to 110 °C under nitrogen protection for 2 h. The reaction mixture was cooled to room temperature, quenched with water (20 mL), extracted with EA (20 mL × 2), the organic phase dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 20:1) to give the product (126 mg, yield: 40.9%).

[0684] Step 2: Synthesis of (R)-2-(3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)acetonitrile [ka]

[0685] (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). KCO (85.1 mg, 0.616 mmol, 2.0 eq) and (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (88.7 mg, 0.462 mmol, 1.5 eq) were added and stirred at room temperature for 2 h. The reaction mixture was quenched with water (20 mL) and extracted with EA (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 50:1) to give the product (72.0 mg, yield: 57.7%).

[0686] Step 3: Synthesis of (R)-2-(3-((6-(4-ethynyl-2-hydroxyphenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)acetonitrile [ka]

[0687] (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). A solution of hydrogen chloride in 1,4-dioxane (4 mol / L, 0.13 mL, 0.534 mmol, 3.0 eq) was added and stirred at room temperature for 1 h. The pH was adjusted to 8 with saturated aqueous NaHCO3, and the mixture was extracted with DCM (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 50:1) to give the product (26.0 mg, yield: 42.1%).

[0688] 1HNMR (400 MHz, DMSO-d6) δ(ppm): 10.12 (s, 1H), 7.17 (d, J = 7.6 Hz, 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 = 87.3 Hz, 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). Molecular formula:C 20 H 21 N5O2 exact mass: 347.17 LC-MS(Pos, m / z)=348.14[M+H] + .

[0689] Example 52 Synthesis of (R)-2-(5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)-5-vinylphenol (Compound 189) [ka]

[0690] Step 1: Synthesis of (R)-2-(5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)-5-vinylphenol [ka]

[0691] (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), Lindlar's catalyst (8 mg, 10%) was added, the mixture was purged with nitrogen gas, and the reaction was carried out at room temperature for 1 hour. The mixture was filtered through diatomaceous earth with suction, and the filtrate was concentrated under reduced pressure and slurried in a 5:1 PE:EA mixed solvent to give the product (65.0 mg, yield: 80.7%).

[0692] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 9.96 (s, 1H), 7.61 (s, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.05 (d, J = 7.5 Hz, 2H), 5.75-6.68 (m, 1H), 5.79 (d, J = 17.6 Hz, 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). Molecular formula:C 18 H 23 N5O exact mass:325.19 LC-MS(Pos, m / z)=326.12[M+H] + .

[0693] 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) [ka]

[0694] Step 1: Synthesis of 1-amino-S-methylisothiosemicarbazide hydroiodide [ka]

[0695] 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), heated to 80°C, and reacted for 16 hours. After cooling to room temperature, a solid precipitated. The solid was filtered under suction and the filter cake was dried to obtain the product (233 g, yield: 91.1%).

[0696] Step 2: Synthesis of 5-methyl-3-(methylthio)-1,2,4-triazine [ka]

[0697] A 40% aqueous solution of methylglyoxal (180 g, 1.00 mol, 1.0 eq) was dissolved in HO (500 mL) and cooled to 0 °C in an ice-water bath. NaHCO (84.0 g, 1.00 mol, 1.0 eq) was added. 1-Amino-S-methylisothiosemicarbazide hydroiodide (233 g, 1.00 mol, 1.0 eq) was dissolved in water and added dropwise to the aqueous solution of methylglyoxal at 0 °C for 6 h. The mixture was extracted with DCM (300 mL × 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 product. The crude product was recrystallized from a PE:EA = 20:1 mixed solvent to obtain the product (85.0 g, yield: 60.2%).

[0698] Step 3: Synthesis of 5-methyl-3-(methylsulfinyl)-1,2,4-triazine [ka]

[0699] 5-Methyl-3-(methylthio)-1,2,4-triazine (2.00 g, 0.0142 mol, 1.0 eq) was dissolved in DCM (20 mL) and stirred at room temperature. Metachloroperbenzoic acid (2.88 g, 0.0142 mol, 1.0 eq) was added in portions and stirred at room temperature for 1 h. The mixture was filtered under suction, and the filtrate was concentrated under reduced pressure and directly used in the next step.

[0700] Step 4: Synthesis of cis-1-methyl-3-((5-methyl-1,2,4-triazin-3-yl)amino)cyclobutan-1-ol [ka]

[0701] 5-Methyl-3-(methylsulfinyl)-1,2,4-triazine was dissolved in 1,4-dioxane (30 mL), 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, and the mixture was heated to 100 °C for 1 h. The mixture was cooled to room temperature, quenched with water (100 mL), extracted with EA (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 20:1) to give the product (2.10 g, 76.3% yield for 2 steps).

[0702] Step 5: Synthesis of cis-3-((6-bromo-5-methyl-1,2,4-triazin-3-yl)amino)-1-methylcyclobutan-1-ol [ka]

[0703] 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) was dissolved in DCM (20 mL), and dibromohydantoin (3.53 g, 12.4 mmol, 2.0 eq) was added. The mixture was allowed to react at room temperature for 1 h. The reaction mixture was quenched with saturated aqueous sodium thiosulfate and extracted with DCM (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 20:1) to give the product (550 mg, yield: 32.6%).

[0704] Step 6: Synthesis of 3-(ethoxymethoxy)-4-(3-((cis-3-hydroxy-3-methylcyclobutyl)amino)-5-methyl-1,2,4-triazin-6-yl)benzaldehyde [ka]

[0705] 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-methylcyclobutan-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 sequentially to 1,4-dioxane (10 mL). HO (5 mL) was added and the mixture was heated to 110 °C under nitrogen protection for 2 h. The reaction mixture was cooled to room temperature, quenched with water (30 mL), extracted with EA (30 mL × 2), the organic phase dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 20:1) to give the product (510 mg, yield: 74.8%).

[0706] Step 7: Synthesis of cis-3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-1,2,4-triazin-3-yl)amino)-1-methylcyclobutan-1-ol [ka]

[0707] 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 (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (395 mg, 2.06 mmol, 1.5 eq) were added, and the mixture was stirred at room temperature for 2 h. The mixture was concentrated, and the crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 20:1) to give the product (495 mg, yield: 98.1%).

[0708] Procedure...

Claims

1. A compound represented by general formula (A) or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof, 【Chemistry 1】 Where: W is 【Chemistry 2】 Selected from X 1 , X 2 are each independently selected from C or N; R 1 is hydrogen, hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen, carbonyl group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkoxy group, C 1-6 Alkoxy group, halogen-substituted C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl groups, 3- to 7-membered heterocyclic groups, 3- to 7-membered cycloalkyl groups, aryl groups, 5- to 7-membered heteroaryl groups, -N(C 1-6 (alkyl group) 2 , -SC 1-6 an alkyl group or absence; R 2 is hydrogen, hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen, carbonyl group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkoxy group, C 1-6 Alkoxy group, halogen-substituted C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl groups, 3- to 7-membered heterocyclic groups, 3- to 7-membered cycloalkyl groups, aryl groups, 5- to 7-membered heteroaryl groups, -N(C 1-6 (alkyl group) 2 , -SC 1-6 an alkyl group or absence; R 1 , R 2 are respectively hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen, carbonyl group, and C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen-substituted C 1-6 substituted with 1 to 3 substituents arbitrarily selected from an alkoxy group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group; or R 1 , R 2 form a 5-12-membered ring A together with the C or N atom to which they are attached, and the 5-12-membered ring A is a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen, a carbonyl group, C 1-6 Alkyl group, -NH-C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen-substituted C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylsulfonyl group, -N(C 1-6 (alkyl group) 2 is substituted with 1 to 4 substituents arbitrarily selected from R 3 is -(C 1-6 (alkylene group) 0-2 -NR 4 R 5 , -(C 1-6 (alkylene group) 0-2 -NR 4 -COR 5 , -(C 1-6 (alkylene group) 0-2 -CO-NR 4 -R 5 , -(C 1-6 (alkylene group) 0-2 -NR 4 -C 1-6 Alkylene group -R 5 Selected from R 4 is hydrogen or C 1-6 selected from alkyl groups, R 5 is selected from a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group, 5 is a halogen, a cyano group, an amino group, a hydroxyl group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 2-6 Alkenylcarbonyl group, sulfonyl group, C 1-6 substituted with 1 to 4 substituents arbitrarily selected from alkylcarbonyl groups; R 5 is replaced by R 5 C is a substituent in 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy groups, 3- to 7-membered heterocyclic groups, 3- to 7-membered cycloalkyl groups, aryl groups, 5- to 7-membered heteroaryl groups, and sulfonyl groups are not limited to halogens, cyano groups, amino groups, hydroxy groups, carbonyl groups, and C 1-6 Alkyl group, 3-6 membered cycloalkyl group, 3-6 membered heterocyclic group, carboxy group, C 1-6 substituted with 1 to 3 substituents arbitrarily selected from alkylsulfonyl groups; Y is selected from an aryl group, a 5- to 14-membered heteroaryl group, a 3- to 14-membered heterocyclic group, and a 3- to 12-membered cycloalkyl group; (1)X 1 , X 2 are each selected from C, The Y is C 2-6 Alkenyl group, C 2-6 Alkynyl groups are substituted, and halogens, cyano groups, amino groups, hydroxy groups, carbonyl groups, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylamino group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkyl sulfonyl group, aminocarbonyl group, C 1-6 substituted with 1 to 2 substituents arbitrarily selected from an alkylaminocarbonyl group and a sulfonyl group; (2)X 1 , X 2 When either or both of the following are selected from N: The Y is C 2-6 Alkenyl group, C 2-6 Alkynyl group, halogen, cyano group, amino group, hydroxy group, carbonyl group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylamino group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkyl sulfonyl group, aminocarbonyl group, C 1-6 Alkylaminocarbonyl group, sulfonyl group, -N(C 1-6 (alkyl group) 2 , -SC 1-6 is substituted with 1 to 3 substituents arbitrarily selected from alkyl groups; In the above (1) and (2), when Y is replaced, Substituent C in Y 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy groups, 3- to 7-membered heterocyclic groups, 3- to 7-membered cycloalkyl groups, aryl groups, 5- to 7-membered heteroaryl groups, and sulfonyl groups are not limited to halogens, cyano groups, amino groups, hydroxy groups, carbonyl groups, and C 1-6 substituted by 1 to 3 substituents arbitrarily selected from an alkyl group and a 3- to 6-membered cycloalkyl group; Substituent C in Y 2-6 Alkenyl group, C 2-6 Alkynyl groups are substituted with halogen, cyano, amino, hydroxy, carbonyl, unsubstituted or substituted with hydroxy groups. 1-6 Alkyl groups, 3-6 membered cycloalkyl groups unsubstituted or substituted with hydroxy groups, halogen-substituted C 1-6 A compound represented by general formula (A), which is substituted by 1 to 3 substituents arbitrarily selected from alkyl groups, or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof.

2. 2. The compound according to claim 1, having the structure shown in general formula (I) or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof, 【Chemistry 3】 Where: R 1 is hydrogen, hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen-substituted C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 selected from an alkynyl group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group; R 2 is hydrogen, hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen-substituted C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 selected from an alkynyl group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group; R 1 , R 2 are respectively hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen, carbonyl group, and C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen-substituted C 1-6 substituted by 1 to 3 substituents arbitrarily selected from an alkoxy group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group; or R 1 , R 2 form a 5-12 membered ring A together with the carbon atom to which they are attached, and the 5-12 membered ring A is selected from the group consisting of a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen atom, a carbonyl group, C 1-6 Alkyl group, -NH-C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen-substituted C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylsulfonyl group, -N(C 1-6 (alkyl group) 2 is substituted with 1 to 4 substituents arbitrarily selected from R 3 is -(C 1-6 (alkylene group) 0-2 -NR 4 R 5 , -(C 1-6 (alkylene group) 0-2 -NR 4 -COR 5 , -(C 1-6 (alkylene group) 0-2 -CO-NR 4 -R 5 , -(C 1-6 (alkylene group) 0-2 -NR 4 -C 1-6 Alkylene group -R 5 Selected from R 4 is hydrogen or C 1-6 selected from alkyl groups, R 5 is selected from a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group, 5 is a halogen, a cyano group, an amino group, a hydroxyl group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 2-6 Alkenylcarbonyl group, sulfonyl group, C 1-6 substituted with 1 to 4 substituents arbitrarily selected from alkylcarbonyl groups; Y is selected from an aryl group, a 5- to 14-membered heteroaryl group, a 3- to 14-membered heterocyclic group, and a 3- to 12-membered cycloalkyl group, and said Y is 2-6 Alkenyl group, C 2-6 Alkynyl groups are substituted, and halogens, cyano groups, amino groups, hydroxy groups, carbonyl groups, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylamino group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkyl sulfonyl group, aminocarbonyl group, C 1-6 substituted with 1 to 2 substituents arbitrarily selected from an alkylaminocarbonyl group and a sulfonyl group; R 5 is replaced by R 5 C is a substituent in 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy groups, 3- to 7-membered heterocyclic groups, 3- to 7-membered cycloalkyl groups, aryl groups, 5- to 7-membered heteroaryl groups, and sulfonyl groups are not limited to halogens, cyano groups, amino groups, hydroxy groups, carbonyl groups, and C 1-6 Alkyl groups, 3-6 membered cycloalkyl groups, C 1-6 substituted with 1 to 3 substituents arbitrarily selected from alkylsulfonyl groups; When Y is replaced, Substituent C in Y 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy groups, 3- to 7-membered heterocyclic groups, 3- to 7-membered cycloalkyl groups, aryl groups, 5- to 7-membered heteroaryl groups, and sulfonyl groups are not limited to halogens, cyano groups, amino groups, hydroxy groups, carbonyl groups, and C 1-6 substituted by 1 to 3 substituents arbitrarily selected from an alkyl group and a 3- to 6-membered cycloalkyl group; Substituent C in Y 2-6 Alkenyl group, C 2-6 Alkynyl groups are halogens, cyano groups, amino groups, hydroxy groups, carbonyl groups, C 1-6 Alkyl groups, 3-6 membered cycloalkyl groups, halogen substituted C 1-6 The compound according to claim 1, or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is substituted with 1 to 3 substituents arbitrarily selected from an alkyl group.

3. A compound represented by the general formula (I) or a pharma- ceutically acceptable salt, stereoisomer or tautomer thereof according to claim 2, 【Chemistry 4】 Where: R 1 is hydrogen, hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen-substituted C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 selected from an alkynyl group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group; R 2 is hydrogen, hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen-substituted C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 selected from an alkynyl group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group; R 1 , R 2 are respectively hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen, carbonyl group, and C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen-substituted C 1-6 substituted by 1 to 3 substituents arbitrarily selected from an alkoxy group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group; or R 1 , R 2 form a 5-12 membered ring A together with the carbon atom to which they are attached, and the 5-12 membered ring A is selected from the group consisting of a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen atom, a carbonyl group, C 1-6 Alkyl group, -NH-C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen-substituted C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylsulfonyl group, -N(C 1-6 (alkyl group) 2 is substituted with 1 to 4 substituents arbitrarily selected from R 3 is -(C 1-6 (alkylene group) 0-2 -NR 4 R 5 , -(C 1-6 (alkylene group) 0-2 -NR 4 -COR 5 , -(C 1-6 (alkylene group) 0-2 -CO-NR 4 -R 5 Selected from R 4 is hydrogen or C 1-6 selected from alkyl groups, R 5 is selected from a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group, 5 is a halogen, a cyano group, an amino group, a hydroxyl group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 2-6 Alkenylcarbonyl group, sulfonyl group, C 1-6 substituted with 1 to 4 substituents arbitrarily selected from alkylcarbonyl groups; Y is selected from an aryl group, a 5- to 14-membered heteroaryl group, a 3- to 14-membered heterocyclic group, and a 3- to 12-membered cycloalkyl group, and said Y is 2-6 Alkenyl group, C 2-6 Alkynyl groups are substituted, and halogens, cyano groups, amino groups, hydroxy groups, carbonyl groups, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylamino group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkyl sulfonyl group, aminocarbonyl group, C 1-6 substituted with 1 to 2 substituents arbitrarily selected from an alkylaminocarbonyl group and a sulfonyl group; R 5 is replaced by R 5 C is a substituent in 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy groups, 3- to 7-membered heterocyclic groups, 3- to 7-membered cycloalkyl groups, aryl groups, 5- to 7-membered heteroaryl groups, and sulfonyl groups are not limited to halogens, cyano groups, amino groups, hydroxy groups, carbonyl groups, and C 1-6 substituted by 1 to 3 substituents arbitrarily selected from an alkyl group and a 3- to 6-membered cycloalkyl group; When Y is replaced, Substituent C in Y 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy groups, 3- to 7-membered heterocyclic groups, 3- to 7-membered cycloalkyl groups, aryl groups, 5- to 7-membered heteroaryl groups, and sulfonyl groups are not limited to halogens, cyano groups, amino groups, hydroxy groups, carbonyl groups, and C 1-6 substituted by 1 to 3 substituents arbitrarily selected from an alkyl group and a 3- to 6-membered cycloalkyl group; Substituent C in Y 2-6 Alkenyl group, C 2-6 The compound of claim 2, wherein the alkynyl group is unsubstituted, as represented by the general formula (I), or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof.

4. The compound according to claim 1, having a structure represented by general formula (B) or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof, 【Chemistry 5】 Where: R 1 is hydrogen, hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen, carbonyl group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkoxy group, C 1-6 Alkoxy group, halogen-substituted C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl groups, 3- to 7-membered heterocyclic groups, 3- to 7-membered cycloalkyl groups, aryl groups, 5- to 7-membered heteroaryl groups, -N(C 1-6 (alkyl group) 2 , -SC 1-6 an alkyl group or absence; R 2 is hydrogen, hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen, carbonyl group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkoxy group, C 1-6 Alkoxy group, halogen-substituted C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl groups, 3- to 7-membered heterocyclic groups, 3- to 7-membered cycloalkyl groups, aryl groups, 5- to 7-membered heteroaryl groups, -N(C 1-6 (alkyl group) 2 , -SC 1-6 an alkyl group or absence; R 1 , R 2 are respectively hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen, carbonyl group, and C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen-substituted C 1-6 substituted by 1 to 3 substituents arbitrarily selected from an alkoxy group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, an aryl group, and a 5- to 7-membered heteroaryl group; X 1 , X 2 are selected from N; Y is replaced with a hydroxy group, and C 2-6 Alkenyl group, C 2-6 Alkynyl group, halogen, cyano group, amino group, hydroxy group, carbonyl group, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, C 1-6 Alkylamino group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkyl sulfonyl group, aminocarbonyl group, C 1-6 Alkylaminocarbonyl group, sulfonyl group, -N(C 1-6 (alkyl group) 2 , -SC 1-6 The compound according to claim 1, or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is substituted with 1 to 2 substituents arbitrarily selected from an alkyl group.

5. A compound according to any one of claims 1 to 3, having a structure represented by general formula (II) or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof, 【Chemistry 6】 Where: Ring A is selected from a 5-7 membered cycloalkenyl group, a 5-7 membered cycloalkyl group, a 5-7 membered heterocyclic group, a phenyl group, and a 5-7 membered heteroaryl group, and Ring A is selected from a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen, a C 1-6 Alkyl group, -NH-C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen-substituted C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, aryl group, 5- to 7-membered heteroaryl group, C 1-6 Alkylsulfonyl group, -N(C 1-6 (alkyl group) 2 The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is substituted with 1 to 4 substituents arbitrarily selected from the group consisting of:

6. 6. A compound according to claim 5 or a pharma- ceutically acceptable salt, stereoisomer or tautomer thereof, Ring A is selected from a phenyl group and a 5- to 7-membered heteroaryl group, and Ring A is selected from a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen, C 1-6 Alkyl group, -NH-C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen-substituted C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, C 1-6 Alkylsulfonyl group, -N(C 1-6 (alkyl group) 2 The compound according to claim 5, or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is substituted with 1 to 4 substituents arbitrarily selected from the group consisting of:

7. A compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof, Y is selected from a phenyl group, a 5- to 7-membered heteroaryl group, a 3- to 8-membered heterocyclic group, and a 3- to 7-membered cycloalkyl group; 2-6 Alkenyl group, C 2-6 Alkynyl groups are substituted, and halogens, cyano groups, amino groups, hydroxy groups, carbonyl groups, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, C 1-6 Alkylamino group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkyl sulfonyl group, aminocarbonyl group, C 1-6 substituted with 1 to 2 substituents arbitrarily selected from an alkylaminocarbonyl group and a sulfonyl group; When Y is replaced, C which is a substituent on Y 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy groups, 3- to 7-membered heterocyclic groups, 3- to 7-membered cycloalkyl groups, and sulfonyl groups are not limited to halogens, cyano groups, amino groups, hydroxy groups, carbonyl groups, and C 1-6 The compound according to any one of claims 1 to 3, wherein the compound is substituted with 1 to 3 substituents arbitrarily selected from alkyl groups, or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof.

8. 7. The compound of claim 6 or a pharma- ceutically acceptable salt, stereoisomer or tautomer thereof, Y is selected from a phenyl group, a 5- to 7-membered heteroaryl group, a 3- to 8-membered heterocyclic group, and a 3- to 7-membered cycloalkyl group; 2-6 Alkenyl group, C 2-6 Alkynyl groups are substituted, and halogens, cyano groups, amino groups, hydroxy groups, carbonyl groups, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, C 1-6 Alkylamino group, C 1-6 Alkylcarbonylamino group, C 1-6 Alkyl sulfonyl group, aminocarbonyl group, C 1-6 substituted with 1 to 2 substituents arbitrarily selected from an alkylaminocarbonyl group and a sulfonyl group; When Y is replaced, C which is a substituent on Y 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy groups, 3- to 7-membered heterocyclic groups, 3- to 7-membered cycloalkyl groups, and sulfonyl groups are not limited to halogens, cyano groups, amino groups, hydroxy groups, carbonyl groups, and C 1-6 is substituted with 1 to 3 substituents arbitrarily selected from alkyl groups; R 3 is -NH-R 5 Selected from R 5 is C 1-6 The compound according to claim 6, which is a 3- to 7-membered heterocyclic group substituted by 1 to 2 substituents selected from an alkyl group, or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof.

9. A compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof, The compound according to any one of claims 1 to 3, wherein ring A is selected from a 5-12 membered cycloalkyl group, a 5-12 membered cycloalkenyl group, a 5-12 membered heterocyclic group, an aryl group, and a 5-12 membered heteroaryl group, and preferably ring A is selected from a 5-8 membered cycloalkyl group, a 5-8 membered cycloalkenyl group, a 5-8 membered heterocyclic group, a phenyl group, and a 5-8 membered heteroaryl group, or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof.

10. A compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof, R 3 -NR 4 R 5 , -NR 4 -C 1-6 Alkylene group -R 5 Selected from R 4 is selected from hydrogen, R 5 is selected from a 3- to 7-membered cycloalkyl group and a 3- to 7-membered heterocyclic group, preferably R 3 Ha-NHR 5 Selected from R 5 is selected from a 4-6 membered cycloalkyl group and a 4-6 membered heterocyclic group, or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof according to any one of claims 1 to 3.

11. 11. The compound of claim 10 or a pharma- ceutically acceptable salt, stereoisomer or tautomer thereof, Y is selected from the group consisting of a phenyl group and a 5- to 6-membered heteroaryl group, and said Y is 2-6 Alkenyl group, C 2-6 Alkynyl groups are substituted, halogens, cyano groups, amino groups, hydroxy groups, carbonyl groups, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 substituted with 1 to 2 substituents arbitrarily selected from an alkoxy group, a 3- to 7-membered heterocyclic group, and a 3- to 7-membered cycloalkyl group; 2-6 Alkenyl group, C 2-6 Alkynyl groups are halogens, cyano groups, amino groups, hydroxy groups, carbonyl groups, C 1-6 Alkyl groups, 3-6 membered cycloalkyl groups, halogen substituted C 1-6 The compound according to claim 10, wherein the alkyl group is substituted with 1 to 3 substituents selected from an alkyl group, or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof.

12. 6. A compound according to claim 5 or a pharma- ceutically acceptable salt, stereoisomer or tautomer thereof, Ring A is 【Chemistry 7】 Ring A is selected from a hydroxy group, an amino group, a carboxy group, a cyano group, a nitro group, a halogen, C 1-6 Alkyl group, -NH-C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen-substituted C 1-6 Alkoxy group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, C 1-6 Alkylsulfonyl group, -N(C 1-6 (alkyl group) 2 The compound according to claim 5, or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is substituted with 1 to 4 substituents arbitrarily selected from the group consisting of:

13. 11. The compound of claim 10 or a pharma- ceutically acceptable salt, stereoisomer or tautomer thereof, Ring A is 【Chemistry 8】 Ring A is selected from a cyano group, a nitro group, a halogen, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy groups, 3-7 membered cycloalkyl groups, 5-7 membered heteroaryl groups, C 1-6 Alkylsulfonyl group, -N(C 1-6 (alkyl group) 2 The compound according to claim 10, or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is substituted with one or two substituents arbitrarily selected from the group consisting of:

14. 11. A compound according to claim 4 or 10, or a pharma- ceutically acceptable salt, stereoisomer or tautomer thereof, Y is 【Chemistry 9】 11. The compound according to claim 4 or 10, or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof, selected from:

15. The following compound or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof: 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 【Chemistry 18】 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】

16. 16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharma- ceutically acceptable carrier.

17. Use of a compound according to any one of claims 1 to 15 or a pharma- ceutically acceptable salt, stereoisomer, tautomer, or pharmaceutical composition according to claim 16 in the preparation of a medicament for the prevention and / or treatment of an NLRP3 inflammasome-associated disease.

18. Use of a compound according to any one of claims 1 to 15 or a pharma- ceutically acceptable salt, stereoisomer, tautomer or pharmaceutical composition according to claim 16 in the preparation of a medicament for the prevention and / or treatment of an inflammasome-associated disease, an immune disease, an inflammatory disease, an autoimmune disease or an autoinflammatory disease.

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