Pyridazine NLRP3 inhibitor compounds, pharmaceutical compositions, and methods for preparing and using the same

Abstract

The present invention provides a pyridazine compound represented by formula (I), a pharmaceutical composition, and a preparation method and use thereof. The compound has good NLRP3 inhibitory activity and can regulate NLRP3 protein alone or in combination with other drugs, and can be used to treat NLRP3-mediated disorders and / or diseases, and to prepare drugs for preventing or treating such disorders or diseases. [Formula 1] JPEG2026501600000134.jpg25169

Description

Detailed Description of the Invention

[0001] [Technical field] This application is Priority of a prior application filed with the State Intellectual Property Office of China on December 28, 2022, with patent application number 202211701092.7 and titled "Pyridazine NLRP3 inhibitor compounds, pharmaceutical compositions, and preparation methods and uses thereof"; Priority of a prior application filed with the State Intellectual Property Office of China on January 17, 2023, with patent application number 202310058136.7 and titled "Pyridazine NLRP3 inhibitor compounds, pharmaceutical compositions, and preparation methods and uses thereof"; Priority of a prior application filed with the State Intellectual Property Office of China on March 10, 2023, with patent application number 202310230219.X and titled "Pyridazine NLRP3 inhibitor compounds, pharmaceutical compositions, and preparation methods and uses thereof"; Priority of a prior application filed with the State Intellectual Property Office of China on May 26, 2023, with patent application number 202310607935.5 and titled "Pyridazine NLRP3 inhibitor compounds, pharmaceutical compositions, and preparation methods and uses thereof"; Priority of a prior application filed with the State Intellectual Property Office of China on September 27, 2023, with patent application number 202311262132.7 and titled "Pyridazine NLRP3 inhibitor compounds, pharmaceutical compositions, and preparation methods and uses thereof"; The patent claims priority from a prior application filed with the State Intellectual Property Office of China on December 21, 2023, bearing patent application number 202311779751.3 and entitled "Pyridazine NLRP3 inhibitor compounds, pharmaceutical compositions, and methods for preparing and using the same." The above prior applications are incorporated herein by reference in their entirety.

[0002] The present invention relates to the field of medicine, specifically to pyridazine-based NLRP3 inhibitor compounds, pharmaceutical compositions, and preparation methods and uses thereof.

[0003] [Background technology] NOD-like receptor heat protein domain-related protein 3 (NLRP3) is an important member of the NOD-like receptor family. NLRP3 contains three domains: a heat protein domain (PYD), a nucleotide-binding domain (NBD), and a leucine-rich repeat (LRR). When cells are stimulated by sterile inflammatory danger signals, NLRP3 interacts with the adaptor proteins apoptosis-associated speck-like protein (ASC) and pro-caspase-1 to form the NLRP3 inflammasome complex. Activation of the NLRP3 inflammasome leads to the release of IL-1β and IL-18.

[0004] NLRP3 inflammasome activation generally requires two steps. Step 1 involves signal induction, in which Toll-like receptors recognize pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) and transmit the signal intracellularly, mediating activation of the NF-κB signaling pathway and upregulating the transcription levels of inactive NLRP3 and NLRP3 inflammasome-associated components, including pro-IL-1β. Step 2 involves signal activation, in which, after signal stimuli such as P2X7 receptors (ATP, nigericin, etc.) are received, NLRP3 monomers oligomerize to form NLRP3 oligomers, which then recruit and assemble ASC and pro-caspase-1 to form the NLRP3 inflammasome complex. This triggers the transformation of pro-caspase-1 to caspase-1, which cleaves pro-IL-1β and pro-IL-18, promoting the production and secretion of mature IL-1β and IL-18.

[0005] NLRP3 inflammasome activation is associated with 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, type 1 and type 2 diabetes and related complications (e.g., nephropathy, retinopathy), neuroinflammatory disorders (e.g., multiple sclerosis, brain infections, acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g., hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g., colorectal cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelofibrosis).

[0006] Currently, there are only a few types of NLRP3 inflammasome inhibitors under development, and the development of NLRP3 inflammasome inhibitors with higher activity and better drug development potential is clinically necessary.

[0007] [Summary of the Invention] In order to solve the above technical problems, the present invention provides a compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope marker, solvate, crystalline polymorph, pharmaceutically acceptable salt or prodrug compound thereof,

[0008] [ka]

[0009] wherein ring A is unsubstituted or contains one, two or more R a C optionally substituted with 3-14 carbocycle, C 6-14 is a ring selected from an aryl ring, a 5- to 14-membered heteroaryl ring, and a 3- to 14-membered heterocyclic ring, and each R a are the same or different and independently of each other are H, deuterium, OH, halogen, cyano group, NH, unsubstituted or one, two or more R a1 C optionally substituted with 1-12 Alkyl group, C 2-12 Alkenyl group, C 2-12 Alkynyl group, C1-12 Alkoxy group, R a11 -C(=O)-NH-, R a12 -C(=O)-, R a13 -S(=O)2-NH-, R a14 -S(=O)2-, -P(=O)(R a15 )(R a16 ), (R a17 )(R a18 )NC(=O)-, C 6-14 Aryl group, 5- to 14-membered heteroaryl group, 3- to 14-membered heterocyclyl group, C 3-14 cycloalkyl groups, and each R a1 are the same or different and independently represent H, deuterium, OH, halogen, CN, C 1-12 Alkyl group, C 3-12 Cycloalkyl groups, C 1-12 Alkoxy group, haloC 1-12 alkyl groups, and R a11 , R a12 , R a13 , R a14 , R a15 , R a16 , R a17 , R a18 are the same or different and independently represent H, deuterium, halogen, CN, C 1-12 Alkyl group, C 1-12 alkoxy groups, Ring B may be unsubstituted or may contain one, two or more R b C optionally substituted with 6-14 Aryl ring, 5- to 14-membered heteroaryl ring, 3- to 14-membered heterocycle, C 3-14 a ring selected from carbocycles, and each R b are the same or different and independently of each other are H, deuterium, OH, halogen, cyano group, NH, unsubstituted or one, two or more R b1 C optionally substituted with 1-12 Alkyl group, C 1-12 alkoxy groups, and each R b1 are the same or different and independently represent H, deuterium, halogen, CN, C 1-12Alkyl group, C 1-12 alkoxy groups, R1 is H, deuterium, halogen, CN, hydroxy group, amino group, C 1-6 Alkyl group, halo C 1-6 Alkyl group, cyano C 1-6 Alkyl group, C 3-8 cycloalkyl groups, Q is a chemical bond or C 1-6 alkylene groups, R2 is unsubstituted or one, two or more R 2a C optionally substituted with 1-12 Alkyl group, C 1-12 Alkoxy group, C 6-14 Aryl group, 5- to 14-membered heteroaryl group, 3- to 14-membered heterocyclyl group, C 3-14 cycloalkyl groups, and each R 2a are the same or different and independently of each other, H, deuterium, halogen, CN, OH, carboxyl group, unsubstituted or one, two or more R 2a1 C optionally substituted with 1-12 Alkyl group, C 1-12 Alkoxy group, R 21 -C(=O)-(CH2) m -, or two R 2a are C together with the carbon atoms connected to them. 3-8 form a cycloalkyl group or a 3- to 8-membered heterocyclyl group, and each R 2a1 are the same or different and independently represent H, deuterium, halogen, CN, carboxyl group, C 1-12 Alkyl group, C 1-12 Alkoxy group, R 22 -C(=O)-, and each R 21 , R 22 are the same or different and independently represent H, deuterium, halogen, CN, OH, amino group, C 1-12 Alkylamino group, (C 1-12 alkyl)2 amino group, C 3-12 Cycloalkylamino group, C 1-12 Alkyl group, C1-12 Alkoxy group, C 3-8 cycloalkyl groups, and 3- to 14-membered heterocyclyl groups, and m is an integer selected from 0 to 6; Or, R2 is unsubstituted or has one, two or more R e optionally replaced with

[0010] [ka]

[0011] wherein ring E is selected from C 3-8 cycloalkyl groups, R 11 , R 12 are the same or different and independently represent H, halogen, C 1-6 Alkyl group, halo C 1-6 Alkyl group, cyano-C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, haloC 3-8 Cycloalkyl group or cyano-C 3-8 cycloalkyl groups, and each R e are the same or different and independently of each other are H, OH, halogen, cyano group, NH, unsubstituted or one, two or more R e1 C optionally substituted with 1-6 Alkyl group, C 3-8 cycloalkyl groups, and each R e1 are the same or different and are independently selected from H, OH, halogen, cyano group, Or, R2 is unsubstituted or has one, two or more R f optionally replaced with

[0012] [ka]

[0013] wherein ring F is selected from 4- to 8-membered heterocycles; 13is H, unsubstituted or one, two or more R 13a C optionally substituted with 1-6 Alkyl group, C 3-8 Cycloalkyl group, R 13b -C(=O)-(CH2) s -, and R 13b is C 1-6 Alkyl group, C 3-8 a cycloalkyl group or an amino group, and each R 13a are the same or different and independently represent H, OH, halogen, cyano group, C 1-6 alkyl group, s is an integer selected from 0 to 6, and each R f are the same or different and independently of each other are H, OH, halogen, cyano group, NH, unsubstituted or one, two or more R f1 C optionally substituted with 1-6 Alkyl group, C 3-8 cycloalkyl groups, and each R f1 are the same or different and are independently selected from H, OH, halogen, and cyano groups.

[0014] According to some embodiments, ring A is unsubstituted or contains one, two or more R a C optionally substituted with 3-8 carbocycle, C 6-10 is a ring selected from an aryl ring, a 5- to 10-membered heteroaryl ring, and a 3- to 10-membered heterocyclic ring, and each R a are the same or different and independently of each other are H, deuterium, OH, halogen, cyano group, NH, unsubstituted or one, two or more R a1 C optionally substituted with 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, R a11 -C(=O)-NH-, R a12 -C(=O)-, R a13 -S(=O)2-NH-, R a14-S(=O)2-, -P(=O)(R a15 )(R a16 ), (R a17 )(R a18 )NC(=O)-, C 6-10 Aryl group, 5- to 10-membered heteroaryl group, 3- to 10-membered heterocyclyl group, C 3-10 cycloalkyl groups, and each R a1 are the same or different and independently represent H, deuterium, OH, halogen, CN, C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 alkoxy groups, R a11 , R a12 , R a13 , R a14 , R a15 , R a16 , R a17 , R a18 are the same or different and independently represent H, deuterium, halogen, CN, C 1-6 Alkyl group, C 1-6 alkoxy groups, According to some embodiments, ring A is unsubstituted or contains one, two or more R a C optionally substituted with 6-10 an aryl ring, a 5- to 10-membered heteroaryl ring, and each R a are the same or different and independently of each other are H, deuterium, OH, halogen, cyano group, NH, unsubstituted or one, two or more R a1 C optionally substituted with 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, R a12 -C(=O)-, R a14 -S(=O)2-, (R a17 )(R a18 )NC(=O)-, C 6-10 aryl group, and 5- to 10-membered heteroaryl group, a1 are the same or different and independently represent H, deuterium, OH, halogen, CN, C 1-6Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 alkoxy groups, R a12 , R a14 , R a17 , R a18 are the same or different, and independently of each other, H, C 1-6 Alkyl group, C 1-6 alkoxy groups, According to some embodiments, ring A is unsubstituted or contains one, two or more R a a benzene ring or a pyridine ring optionally substituted with a are the same or different and independently represent H, a cyano group, -C(=O)-NH2, CH3-S(=O)2-,

[0015] [ka]

[0016] 1-propynyl group, 2-cyclopropylethynyl group,

[0017] [ka]

[0018] acetyl group,

[0019] [ka]

[0020] is selected from According to some embodiments, ring A is

[0021] [ka]

[0022] is selected from According to some embodiments,

[0023] [ka]

[0024] teeth,

[0025] [ka]

[0026] is selected from.

[0027] According to some embodiments, ring B is unsubstituted or contains one, two or more R b C optionally substituted with 6-10 Aryl ring, 5- to 10-membered heteroaryl ring or C 3-10 a ring selected from carbocycles, and each R b are the same or different and independently of each other are H, OH, halogen, cyano group, NH, unsubstituted or one, two or more R b1 C optionally substituted with 1-6 Alkyl group, C 1-6 alkoxy groups, and each R b1 are the same or different and independently represent H, halogen, CN, C 1-6 Alkyl group, C 1-6 alkoxy groups, According to some embodiments, ring B is unsubstituted or contains one, two or more R b and each R is selected from a benzene ring, a benzothiophene ring, or an indane ring optionally substituted with b are the same or different and independently represent H, OH, halogen, cyano group, C 1-6 Alkyl group, halo C 1-6 Alkyl group, halo C 1-6 alkoxy groups, According to some embodiments, ring B is unsubstituted or contains one, two or more R band each R is selected from a benzene ring, a benzothiophene ring, or an indane ring optionally substituted with b are the same or different and are independently selected from H, OH, F, Cl, a methyl group or CF3.

[0028] According to some embodiments, Ring B is

[0029] [ka]

[0030] is selected from.

[0031] According to some embodiments, Ring B is

[0032] [ka]

[0033] is selected from.

[0034] According to some embodiments, R1 is selected from H, deuterium, or a methyl group, and is preferably H.

[0035] According to some embodiments, Q is a chemical bond, —(CH) q -or-(CH2) q -CH(CH3)-, where q is selected from 0, 1 or 2; According to some embodiments, Q is selected from a chemical bond, —CH 2 —, or —CH(CH 3 )—.

[0036] According to some embodiments, R2 is unsubstituted or has one, two or more R 2a C optionally substituted with 1-6 Alkyl group, C 1-6 Alkoxy group, C 6-10 Aryl group, 5- to 10-membered heteroaryl group, 3- to 10-membered heterocyclyl group, C 3-10cycloalkyl groups, and each R 2a are the same or different and independently of each other, H, deuterium, halogen, CN, OH, carboxyl group, unsubstituted or one, two or more R 2a1 C optionally substituted with 1-6 Alkyl group, C 1-6 Alkoxy group, R 21 -C(=O)-(CH2) m -, or two R 2a are C together with the carbon atoms connected to them. 3-8 Form a cycloalkyl group, and each R 2a1 are the same or different and independently represent H, deuterium, halogen, CN, carboxyl group, C 1-6 Alkyl group, C 1-6 Alkoxy group, R 22 -C(=O)-, and each R 21 , R 22 are the same or different and independently represent H, OH, an amino group, C 1-6 Alkylamino group, (C 1-6 alkyl)2 amino group, C 3-6 Cycloalkylamino group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-8 and m is selected from 0, 1, or 2.

[0037] According to some embodiments, R2 is unsubstituted or has one, two or more R 2a C optionally substituted with 1-6 Alkyl group, C 6-10 Aryl group, 5- to 10-membered heteroaryl group, 3- to 8-membered heterocyclyl group, C 3-8 cycloalkyl groups, and each R 2a are the same or different and independently of each other are H, CN, OH, a carboxyl group, unsubstituted or one, two or more R 2a1 C optionally substituted with 1-6 Alkyl group, R 21-C(=O)-(CH2) m -, or two R 2a are C together with the carbon atoms connected to them. 3-6 Form a cycloalkyl group, and each R 2a1 are the same or different and independently represent H, deuterium, halogen, CN, carboxyl group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkylamino group, 3-6 membered N-containing heterocyclyl group, R 22 -C(=O)-, and each R 21 , R 22 are the same or different and are independently selected from H, OH, an amino group, a methyl group, a methoxy group, and a cyclopropyl group; and m is selected from 0, 1, or 2.

[0038] According to some embodiments, R2 is unsubstituted or has one, two or more R 2a C optionally substituted with 1-6 alkyl group, tetrahydropyrrolyl group, piperidinyl group, phenyl group, cyclohexyl group, cyclobutane group, or tetrahydropyranyl group, and each R 2a are the same or different and independently of each other are H, CN, OH, a carboxyl group, unsubstituted or one, two or more R 2a1 C optionally substituted with 1-6 Alkyl group, R 21 -C(=O)-(CH2) m -, or two R 2a are C together with the carbon atoms connected to them. 3-6 Form a cycloalkyl group, and each R 2a1 are the same or different and independently represent H, deuterium, halogen, CN, carboxyl group, C 1-6 Alkyl group, C 1-6 Alkoxy group, R 22 -C(=O)-, and each R 21 , R 22are the same or different and are independently selected from H, OH, amino, methyl, methoxy, cyclopropyl, cyclopropylamino, and tetrahydropyrrolyl; and m is selected from 0, 1, or 2.

[0039] According to some embodiments, R2 is unsubstituted or has one, two or more R 2a C optionally substituted with 1-6 alkyl group, tetrahydropyrrolyl group, piperidinyl group, phenyl group, cyclohexyl group, cyclobutane group, or tetrahydropyranyl group, and each R 2a are the same or different and independently represent H, OH, a carboxyl group, a methyl group,

[0040] [ka]

[0041] NC-CH2-,

[0042] [ka]

[0043] HOOC-CH2-, HOOC-CH2-CH2-,

[0044] [ka]

[0045] or two R 2a are C together with the carbon atoms connected to them. 3-6 forming a cycloalkyl group, According to some embodiments, R2 is

[0046] [ka]

[0047] and ring E is selected from C 4-7 cycloalkyl groups, and r is an integer selected from 0 to 6.

[0048] According to some embodiments, R 11 , R 12 are the same or different and are independently selected from H, halogen (e.g., F, Cl).

[0049] According to some embodiments, each R e are the same or different and are independently selected from H, OH.

[0050] According to some embodiments, R2 is

[0051] [ka]

[0052] and ring F is selected from 4- to 7-membered heterocycles.

[0053] According to some embodiments, R2 is

[0054] [ka]

[0055] is selected from.

[0056] According to some embodiments, R 13 is H, unsubstituted or one, two or more R 13a C optionally substituted with 1-3 Alkyl group, C 3-6 Cycloalkyl group, R 13b -C(=O)-(CH2) s -, and R 13b is C 1-3 Alkyl group, C 3-6a cycloalkyl group or an amino group, and each R 13a are the same or different and independently represent H, OH, halogen, cyano group, C 1-3 alkyl groups, and s is selected from 0, 1, 2 or 3.

[0057] According to some embodiments, R 13 is hydroxy-C 1-6 Alkyl group -, NH2-C(=O)-(CH2) s -, and s is selected from 0, 1, 2 or 3.

[0058] According to some embodiments, R 13 is HOCH2CH2-,

[0059] [ka]

[0060] is selected from.

[0061] According to some embodiments, R2 is

[0062] [ka]

[0063] HOOC-CH2-,

[0064] [ka]

[0065] is selected from.

[0066] According to some embodiments, the compound of formula (I) is selected from the following structures:

[0067] [ka]

[0068] Here, ring A, ring B, Q, R2, R a , R b has the definition described herein, and n is selected from 0, 1, 2, 3, 4, or 5.

[0069] According to some embodiments, the compound of formula (I) has the structure:

[0070] [ka]

[0071] where Q, R2, and R a has the definition set forth herein.

[0072] According to some embodiments, the compound of formula (I) has the structure:

[0073] [ka]

[0074] where R 2a , R a has the definition set forth herein.

[0075] According to some embodiments, the compound of formula (I) has the structure:

[0076] [ka]

[0077] Here, rings F, Q, R2, R b , R 13 , R f , n independently of each other have the definitions described herein; p is selected from 0, 1, 2, 3 or 4; and t is selected from 0, 1, 2, 3 or 4.

[0078] According to some embodiments, the compound of formula (I) is selected from the following structures:

[0079] [ka] JPEG2026501600000027.jpg241169JPEG2026501600000028.jpg233169JPEG2026501600000029.jpg255164JPEG2026501600000030.jpg160169

[0080] According to some embodiments, the compound of formula (I) is selected from the following structures:

[0081] [ka] JPEG2026501600000032.jpg162169

[0082] The present invention further provides a method for preparing a compound of formula (I),

[0083] [ka]

[0084] Step (1) of reacting compound a with compound b to obtain compound c; and step (2) reacting compound c with compound d to obtain a compound represented by formula (I), wherein ring A, ring B, R1, R2 and Q each independently have the definitions described herein; X1 and X2 are the same or different and each independently selected from leaving groups, e.g., halogens such as F, Cl, Br, I, and the like; Y is a leaving group, e.g., halogens such as F, Cl, Br, I, or a boronic acid group (

[0085] [ka]

[0086] ) is selected.

[0087] The present invention further provides pharmaceutical compositions, which comprise a therapeutically effective amount of at least one of a compound of formula (I), its racemate, stereoisomer, tautomer, isotopic marker, solvate, crystalline polymorph, pharmaceutically acceptable salt, or prodrug compound thereof.

[0088] According to an embodiment of the present invention, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0089] According to embodiments of the present invention, the pharmaceutical composition may further comprise one or more additional therapeutic agents.

[0090] The present invention further provides a method for treating an NLRP3-mediated disease, comprising administering to a patient a prophylactically or therapeutically effective amount of at least one of a compound of formula (I), its racemate, stereoisomer, tautomer, isotopic marker, solvate, crystalline polymorph, pharmaceutically acceptable salt, or prodrug compound thereof.

[0091] The present invention further provides a method for treating an NLRP3-mediated disease, which comprises administering to a patient a prophylactically or therapeutically effective amount of the pharmaceutical composition described above.

[0092] The NLRP3-mediated disease is selected from 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, gouty arthritis, pericarditis, type I and type II diabetes and related complications (e.g., nephropathy, retinopathy), neuroinflammatory-related disorders (e.g., multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g., hypertension), obesity, hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelofibrosis).

[0093] In some embodiments, the patient comprises a mammal, preferably a human.

[0094] The present invention further provides at least one of a compound represented by formula (I), its racemate, stereoisomer, tautomer, isotopic marker, solvate, crystalline polymorph, pharmaceutically acceptable salt or prodrug compound thereof, or a pharmaceutical composition thereof for treating an NLRP3-mediated disease.

[0095] The present invention further provides the use of at least one of the compounds of formula (I), their racemates, stereoisomers, tautomers, isotopic markers, solvates, crystalline polymorphs, pharmaceutically acceptable salts or prodrug compounds thereof in the manufacture of drugs.

[0096] According to an embodiment of the present invention, the use may be in the manufacture of a medicament for treating an NLRP3-mediated disorder and / or disease, for example, in the manufacture of an NLRP3 inhibitor medicament.

[0097] According to embodiments of the present invention, the disease is, for example, autoinflammatory fever syndromes such as cryopyrin-associated periodic fever syndromes (CAPS), sickle cell disease, systemic lupus erythematosus (SLE), chronic liver disease, non-alcoholic steatohepatitis (NASH), gout, gouty arthritis, pericarditis, type I and type II diabetes and related complications (e.g., nephropathy, retinopathy), neuroinflammatory-related disorders (e.g., multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g., hypertension), obesity, hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelofibrosis).

[0098] [Beneficial effects] The compounds of the present invention have good NLRP3 inflammasome inhibitory activity, and the compounds obtained by structural optimization have good in vivo activity, good metabolic properties, and good safety.The compounds can be used alone or in combination with other drugs to regulate NLRP3 protein, and can be used to treat NLRP3-mediated disorders and / or diseases, and to manufacture drugs for treating such disorders or diseases.

[0099] [Brief description of the drawing] FIG. 1 is a schematic diagram comparing the results of ankle circumference measurements in rats with an MSU-induced acute gouty arthritis model.

[0100] FIG. 2 is a schematic diagram comparing the results of detecting inflammatory factors in the MSU-induced rat air pouch model.

[0101] [Figure 3] A schematic diagram comparing the statistical results of the thickness of the pericardial wall layer detected by H&E staining in a pericarditis model.

[0102] [FIG. 4] A schematic diagram comparing the results of ELISA detection of IL-1β production in pericardial fluid.

[0103] [Figure 5] Schematic diagram of comparison of body weight measurement results in mouse NASH model studies (Sem: semaglutide).

[0104] [Figure 6] Schematic diagram comparing the results of food intake measurements in mice in a mouse NASH model test (Sem: semaglutide).

[0105] [Figure 7] This shows a comparison of the detection results of mouse serum ALT, AST, LDL, and HDL in a mouse NASH model test (Sem: semaglutide).

[0106] [Term definitions and explanations] Unless otherwise stated, the radical and term definitions in the specification and claims of this application, including their exemplary definitions, exemplary definitions, preferred definitions, definitions in the tables, definitions of specific compounds in the examples, etc., may be combined with each other in any combination, and it should be understood that such combined radical definitions and compound structures are within the scope of the description and / or claims of this application.

[0107] Unless otherwise specified, the numerical ranges described in this specification and claims are equivalent to at least describing each specific integer value. For example, the numerical range "1 to 14" is equivalent to describing each integer value in the numerical range "1 to 14," i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14.

[0108] The term "optionally" (or "optionally" or "optionally") in the definition of the general formula of the present application means a situation in which there is substitution with zero, one, or more substituents. For example, "optionally substituted with one, two, or more R" means that there may be no substitution with R (be unsubstituted), or there may be substitution with one, two, or more R.

[0109] "More" means three or more.

[0110] "C 1-12 The term "alkyl group" should be understood to represent straight and branched chain alkyl groups having 1 to 12 carbon atoms, and "C 1-8 "Alkyl group" refers to straight and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; 1-6The term "alkyl group" refers to straight-chain and branched-chain alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of the alkyl group include methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, and 1,2-dimethylbutyl groups, and isomers thereof.

[0111] "C 2-12 An "alkenyl group" is to be understood to preferably represent a linear or branched monovalent hydrocarbon group, which contains one or more double bonds and has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, more preferably "C 2-8 "Alkenyl group" and "C 2~8 An "alkenyl group" should be understood to preferably represent a linear or branched monovalent hydrocarbon group, which contains one or more double bonds and has 2, 3, 4, 5, 6, 7 or 8 carbon atoms, for example 2, 3, 4, 5 or 6 carbon atoms (i.e., C 2~6 alkenyl groups), having 2 or 3 carbon atoms (i.e., C 2~3alkenyl group). It should be understood that when the alkenyl group contains one or more double bonds, the double bonds may be separate or conjugated. The alkenyl group may be, for example, a vinyl group, an allyl group, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-pent- 1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl group, 2-methylprop-2-enyl, 1-methylprop-2 -enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methyl (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, and 1-isopropylvinyl.

[0112] "C 2-12 The term "alkynyl group" should be understood to preferably denote a linear or branched monovalent hydrocarbon group, which contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, for example, 2, 3, 4, 5, 6, 7 or 8 carbon atoms (i.e., "C 2-8alkynyl groups) having 2, 3, 4, 5, or 6 carbon atoms (i.e., "C 2-6 alkynyl groups), having 2 or 3 carbon atoms ("C 2-3 Examples of the alkynyl group include ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methyl pent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl or 3,3-dimethylbut-1-ynyl. In particular, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

[0113] "C 3-12 The term "cycloalkyl group" should be understood to represent a saturated monovalent monocyclic, bicyclic (e.g., fused, bridged, spiro) hydrocarbon ring or tricyclic alkane, having 3 to 12 carbon atoms, preferably "C 3-10 cycloalkyl group," and more preferably, "C 3-8 "Cycloalkyl group". 3-12The term "cycloalkyl group" should be understood to represent a saturated monovalent monocyclic, bicyclic (e.g., bridged, spirocyclic) hydrocarbon ring or tricyclic alkane, which has 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. 3-12 The cycloalkyl group may be a monocyclic hydrocarbon group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group, or a cyclodecyl group; or a bicyclic hydrocarbon group such as a bornyl group, an indolyl group, a hexahydroindolyl group, a tetrahydronaphthyl group, a decahydronaphthyl group, a bicyclo[2.1.1]hexyl, a bicyclo[2.2.1]heptyl, a bicyclo[2.2.1]heptenyl, a 6,6-dimethylbicyclo[3.1.1]heptyl, a 2,6,6-trimethylbicyclo[3.1.1]heptyl, a bicyclo[2.2.2]octyl, a 2,7-diazaspiro[3.5]nonyl, a 2,6-diazaspiro[3,4]octanyl; or a tricyclic hydrocarbon group such as an adamantyl group.

[0114] "C 3-12 The term "cycloalkenyl group" should be understood to represent a monovalent monocyclic, bicyclic (e.g., fused, bridged, spiro) or tricyclic alkene containing a carbon-carbon double bond, which has 3 to 12 carbon atoms, preferably "C 3-10 cycloalkenyl group," and more preferably, "C 3-8 A cycloalkenyl group is a "cycloalkenyl group," which may have 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. 3-12 The cycloalkenyl group may be a monocyclic hydrocarbon group such as a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, a cyclooctenyl group, a cyclononenyl group or a cyclodecenyl group, or a bicyclic hydrocarbon group such as spiro[2.5]oct-5-enyl, spiro[3.5]non-6-enyl or spiro[4.5]dec-7-enyl.

[0115] "C 6-14It is to be understood that the term "aryl group" preferably denotes a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 14 carbon atoms, which may be a monocyclic aromatic ring or polycyclic aromatic rings fused together, and preferably denotes a "C 6-10 "C" is an aryl group. 6-14 The term "aryl group" refers to a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms ("C 6-14 aryl groups"), in particular rings having 6 carbon atoms ("C6 aryl groups"), such as phenyl or biphenyl groups, or rings having 9 carbon atoms ("C9 aryl groups"), such as indanyl or indenyl groups, or rings having 10 carbon atoms ("C 10 aryl group"), such as a tetralinyl group, a dihydronaphthyl group or a naphthyl group, or a ring having 13 carbon atoms ("C 13 aryl group), such as a fluorenyl group, or a ring having 14 carbon atoms ("C 14 It should be understood that it is preferable that the C represents an aryl group, for example, an anthryl group. 6-20 When substituted, the aryl group may be mono- or polysubstituted, and there is no limitation on the substitution site, for example, it may be ortho-, para-, or meta-substituted.

[0116] A "5- to 14-membered heteroaryl group" should be understood to include a monovalent monocyclic, bicyclic (e.g., fused, bridged, spiro) or tricyclic aromatic ring system containing 5 to 14 ring atoms and 1 to 5 heteroatoms independently selected from N, O and S, such as a "5- to 10-membered heteroaryl group." The term "5- to 14-membered heteroaryl group" should be understood to mean a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, containing 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O and S, and which in each case may be benzo-fused. A "heteroaryl group" also refers to a group in which the heteroaromatic ring is fused to one or more aryl, alicyclic or heterocyclyl rings, where the base or point of attachment is on the heteroaromatic ring. Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7- or 8-indolizinyl groups, 1-, 3-, 4-, 5-, 6- or 7-isoindolyl groups, 2-, 3-, 4-, 5-, 6- or 7-indolyl groups, 2-, 3-, 4-, 5-, 6- or 7-indazolyl groups, 2-, 4-, 5-, 6-, 7- or 8-purinyl groups, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-quinolidinyl group, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl group, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl group, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl group, 2-, 3-, 4-, 5- or 6-naphthyridinyl group, 2-, 3-, 5-, 6- 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl, 2-, 4-, 6-, or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-carbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8- or 9-carbolinyl group, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenanthridinyl group, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl group, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-dinyl group, 2-, 3-, 4-, 5-, 6-, 8-, 9- or 10-phenanthrolinyl group, 1-,2-, 3-, 4-, 6-, 7-, 8- or 9-phenazinyl group, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenoxazinyl group, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenazinyl group, 2-, 3-, 4-, 5-, 6- or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-benzoisoquinolinyl group, 2-, 3-, 4- or thieno[2,3-b]furanyl group, 2-, 3-, 5-, 6- -, 7-, 8-, 9-, 10- or 11-7H-pyrazino[2,3-c]carbazolyl, 2-, 3-, 5-, 6- or 7-2H-furo[3,2-b]-pyranyl, 2-, 3-, 4-, 5-, 7- or 8-5H-pyrido[2,3-d]-o-azinyl, 1-, 3- or 5-1H-pyrazolo[4,3-d]azolyl, 2-, 4- or 54H-imidazo[4,5-d]thiazolyl, 3-, 5- or 8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5- or 6-imidazo[2,1-b]thiazolyl, 1-, 3-, 6-, 7-, 8- or 9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10- or 11-4H-pyrido[2,3-c]carbazolyl, 2-, 3-, 6- or 7-imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thienyl, 2-, 4-, 5-, 6- or 7-benzoazolyl group, 2-, 4-, 5- , 6- or 7-benzimidazolyl group, 2-, 4-, 4-, 5-, 6- or 7-benzothiazolyl group, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-benzoxapinyl group, 2-, 4-, 5-, 6-, 7- or 8-benzoazinyl group, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-4H-pyrrolo[1,2-b][2]benzazepinyl. Typical fused heteroaryl groups include 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl groups, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl groups, 2-, 3-, 4-, 5-, 6- or 7-indolyl groups, 2-, 3-, 4-, 5-, 6- or 7-benzo[b]thienyl groups, 2-, 4-, 5-, 6- or 7-benzoazolyl groups, 2-, 4-, 5-, 6- or 7-benzimidazolyl groups and 2-, 4-, 5-, 6- or 7-benzothiazolyl groups.However, the present invention is not limited thereto. When the 5- to 14-membered heteroaryl group is linked to another group to form the compound of the present invention, a carbon atom in the 5- to 14-membered heteroaryl ring may be linked to the other group, or a heteroatom in the 5- to 14-membered heteroaryl ring may be linked to the other group. When the 5- to 14-membered heteroaryl group is substituted, it may be mono- or polysubstituted. There is no limitation on the substitution site; for example, a hydrogen atom linked to a carbon atom in the heteroaryl ring may be substituted, or a hydrogen atom linked to a heteroatom in the heteroaryl ring may be substituted.

[0117] Unless otherwise defined, the term "3- to 14-membered heterocyclyl group" refers to a saturated or unsaturated non-aromatic ring or ring system, for example, a 4-, 5-, 6-, or 7-membered monocyclic ring, a 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring (e.g., fused, bridged, spirocyclic ring), or a 10-, 11-, 12-, 13-, or 14-membered tricyclic ring system, and containing at least one, e.g., 1, 2, 3, 4, 5, or more, heteroatoms selected from O, S, and N, wherein N and S may also be optionally oxidized to various oxidation states to form nitrogen oxides, -S(O)-, or -S(O)2-. Preferably, the heterocyclyl group may be selected from "3- to 10-membered heterocyclyl groups." The term "3- to 10-membered heterocyclyl group" is intended to refer to a saturated or unsaturated non-aromatic ring or ring system containing at least one heteroatom selected from O, S, and N. The heterocyclyl group can be linked to the rest of the molecule through any one of the carbon atoms or, if present, a nitrogen atom. The heterocyclyl group may include fused or bridged rings and spiro rings. In particular, the heterocyclyl group may include, but is not limited to, a 4-membered ring such as an azetidinyl group or an oxetanyl group, a 5-membered ring such as a tetrahydrofuranyl group, a dioxolyl group, a pyrrolidinyl group, an imidazolidinyl group, a pyrazolidinyl group, a pyrrolinyl group, a 6-membered ring such as a tetrahydropyranyl group, a piperidine group, a morpholinyl group, a dithianyl group, a thiomorpholinyl group, a piperazinyl group, or a trithianyl group, or a 7-membered ring such as a diazepanyl group. Optionally, the heterocyclyl group may be benzo-fused.The heterocyclyl group may be bicyclic, for example, but not limited to, a 5,5-membered ring such as a hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclic ring such as a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The heterocyclyl group may be partially unsaturated, i.e., it may contain one or more double bonds, for example, but not limited to, dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl, or 4H-[1,4]thiazinyl, or it may be benzo-fused, for example, but not limited to, dihydroisoquinolinyl. When the 3- to 14-membered heterocyclyl group is linked to another group to form the compound of the present invention, a carbon atom in the 3- to 14-membered heterocyclyl group may be linked to the other group, or a heterocyclic atom in the 3- to 14-membered heterocyclyl ring may be linked to the other group. For example, when the 3- to 14-membered heterocyclyl group is selected from a piperazinyl group, a nitrogen atom in the piperazinyl group may be linked to the other group. Or, when the 3- to 14-membered heterocyclyl group is selected from a piperidine group, a nitrogen atom in the piperidine ring and a carbon atom at the para-position thereof may be linked to the other group.

[0118] The term "spirocycle" refers to a ring system in which two rings share one ring-forming atom.

[0119] The term "fused ring" refers to a ring system in which two rings share two ring-forming atoms.

[0120] The term "bridged ring" refers to a ring system in which two rings share three or more ring-forming atoms.

[0121] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0122] "Halogenated" refers to substitution with one or more halogens.

[0123] As will be appreciated by those skilled in the art, the compounds of formula (I) can exist in a variety of pharmaceutically acceptable salt forms: if they contain a basic center, they can form acid addition salts; if they contain an acidic center, they can form base addition salts; and if they contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they can also form internal salts.

[0124] The compounds of the present invention can exist in the form of solvates (e.g., hydrates), in which the compounds of the present invention contain a polar solvent, in particular, for example, water, methanol, or ethanol, as a component of the compound's crystal lattice. The amount of polar solvent, in particular water, can be present in a stoichiometric or non-stoichiometric ratio.

[0125] Depending on their molecular structure, the compounds of the present invention may be chiral and therefore may exist in various enantiomeric forms. Therefore, these compounds can exist in racemic or optically active forms. The compounds of the present invention encompass isomers or mixtures thereof, racemates, in which each chiral carbon is in the R or S configuration. The compounds of the present invention or their intermediates can be isolated into enantiomeric compounds by chemical or physical methods known to those skilled in the art, or can be used in synthesis in such forms. In the case of racemic amines, diastereomers were prepared from the mixture by reacting with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline), or various optically active camphorsulfonic acids. Chromatographic enantiomeric resolution can be advantageously carried out with optically active resolving agents (e.g., dinitrobenzoylphenylglycine, cellulose triacetate, or other carbohydrate derivatives, or chiral derivatized methacrylate polymers immobilized on silica gel). Suitable eluents for this purpose are water or alcohol-containing solvent mixtures, e.g., hexane / isopropanol / acetonitrile.

[0126] The corresponding stable isomers can be separated according to known methods, such as extraction, filtration or column chromatography.

[0127] The term "patient" refers to any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse or primate, and most preferably a human.

[0128] The term "therapeutically effective amount" refers to an amount of an active compound or drug that elicits the biological or medical response a researcher, veterinarian, physician, or other clinician is looking for in a tissue, system, animal, individual, or human, including one or more of the following: (1) prevention of disease: e.g., preventing a disease, disorder, or disorder in an individual who is susceptible to the disease, disorder, or disorder but has not yet experienced or developed the pathology or symptoms of the disease; (2) inhibition of disease: e.g., inhibiting a disease, disorder, or disorder (i.e., preventing further progression of the pathology and / or symptoms) in an individual who is experiencing or has developed the pathology or symptoms of the disease, disorder, or disorder; or (3) amelioration of disease: e.g., ameliorating a disease, disorder, or disorder (i.e., reversing the pathology and / or symptoms) in an individual who is experiencing or has developed the pathology or symptoms of the disease, disorder, or disorder.

[0129] [Mode for Carrying Out the Invention] The following provides a more detailed description of the technical solutions of the present invention through specific examples. It should be understood that the following examples are merely for illustrative purposes and are not intended to limit the scope of protection of the present invention. Any technology realized based on the above content of the present invention is included within the intended scope of protection of the present invention.

[0130] Unless otherwise specified, all raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0131] The structures of the compounds were confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR displacements (δ) were 10 -6 The NMR data were given in units of ppm. NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetometer in deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0132] MS measurements were performed using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatograph mass spectrometer (manufacturer: Agilent, MS model number: 6110 / 6120 Quadrupole MS), a Waters ACQuity UPLC-QD / SQD (manufacturer: Waters, MS model number: Waters ACQuity Qda Detector / Waters SQ Detector), and a THERMO Ultimate 3000- Q Exactive (manufacturer: THERMO, MS model number: THERMO Q Exactive).

[0133] High performance liquid chromatography (HPLC) analysis was performed using Agilent 1260II HPLC and Waters Acquity UPLC H-Class high performance liquid chromatography.

[0134] Chiral HPLC analysis was performed using a Waters Acquity UPCC high performance liquid chromatograph.

[0135] High-performance liquid preparative chromatography was performed using Waters MS-triggered Prep-LC with an SQD2 detector, Waters MS-triggered Prep-LC with an Acquity QDA detector, Waters MS-triggered Prep-LC with a QDA detector, and GILSON Prep LC with a UV detector.

[0136] The CombiFlash high-speed fraction collection device used was Combiflash Rf200 (TELEDYNE ISCO).

[0137] The silica gel plates used for thin-layer chromatography were Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plates. The silica gel plates used in thin-layer chromatography (TLC) were 0.15 mm to 0.2 mm in diameter, and the separation and purification of the products by thin-layer chromatography were 0.4 mm to 0.5 mm in diameter.

[0138] Silica gel column chromatography generally used Yantai Yellow Sea silica gel with 200-300 mesh as the carrier.

[0139] Kinase mean inhibition rate and IC 50 The values ​​were measured using a NovoStar microplate reader (BMG GmbH, Germany).

[0140] Known starting materials of the present disclosure can be synthesized using or according to methods known in the art or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc.), and Darui Chemical.

[0141] Unless otherwise stated in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0142] An argon or nitrogen atmosphere refers to an argon or nitrogen gas balloon with a volume of about 1 L connected to the reaction flask.

[0143] A hydrogen atmosphere refers to a hydrogen gas balloon with a volume of approximately 1 L attached to the reaction flask.

[0144] The pressurized hydrogenation reaction was carried out using a Parr 3916EKX hydrogenation apparatus and a Seiran QL-500 hydrogen gas generator or an HC2-SS hydrogenation apparatus.

[0145] The hydrogenation reaction was usually carried out by evacuating the reactor and introducing hydrogen gas, and the procedure was repeated three times.

[0146] The microwave reaction was carried out using a CEM Discover-S 908860 microwave reaction apparatus.

[0147] Unless otherwise stated in the examples, solutions refer to aqueous solutions.

[0148] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0149] In the examples, the progress of the reaction was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the eluent system of column chromatography used to purify the compound, and the developing solvent system of thin layer chromatography comprised A: dichloromethane / methanol system and B: n-hexane / ethyl acetate system, and the volume ratio of the solvents was adjusted according to the polarity of the compound, and may also be adjusted by adding small amounts of alkaline or acidic reagents such as triethylamine and acetic acid.

[0150] Example 1 1-(4-chloro-2-hydroxyphenyl)-4-((2-hydroxy-2-methylpropyl)amino)phthalazine-6-carbonitrile (001)

[0151] [ka]

[0152] Step 1. Preparation of 1-chloro-4-((2-hydroxy-2-methylpropyl)amino)phthalazine-6-carbonitrile (001b) 1,4-Dichlorophthalazine-6-carbonitrile 001a (200 mg, 0.89 mmol) and 1-amino-2-methyl-2-propanol (159 mg, 1.78 mmol) were dissolved in N-methylpyrrolidone (5 mL), and N,N-diisopropylethylamine (346 mg, 2.68 mmol) was added. The reaction mixture was stirred at 100°C for 2 hours. After completion of the reaction, the residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 001b (125 mg, yield: 50.6%). MS m / z (ESI): 277.08 (M+1) + . 1 H NMR (400 MHz, DMSO-d6) δ = 9.13 (s, 1H), 8.36 - 8.33 (m, 1H), 8.20 - 8.17(m, 1H), 7.70 (t, J=4.4 Hz, 1H), 4.76 (s, 1H), 3.61 (d, J=6.0 Hz, 2H), 1.19 (s, 6H).

[0153] Step 2 Preparation of 1-(4-chloro-2-hydroxyphenyl)-4-((2-hydroxy-2-methylpropyl)amino)phthalazine-6-carbonitrile (001) Compound 001b (125 mg, 0.45 mmol), (4-chloro-2-hydroxyphenyl)boronic acid (116.8 mg, 0.68 mmol), and sodium carbonate (143.6 mg, 1.36 mmol) were dissolved in a dioxane / water mixture (5 mL, V / V = 10:1), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (99 mg, 0.14 mmol) was added. The reaction mixture was stirred at 100 °C for 4 hours. After the reaction was completed, the mixture was extracted with dichloromethane, and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by preparative high-performance liquid chromatography (Waters MS triggered Prep-LC with Acquity QDA detector, chromatography column: Welch C18 250*21.2 mm, 10 μm; mobile phase 1: water (containing 0.1% aqueous ammonia); mobile phase 2: acetonitrile; 20-minute gradient, gradient ratio: acetonitrile phase 23% to 33%, flow rate: 25 mL / min) to obtain the title compound 001 (16 mg, yield: 9.6%). MS m / z (ESI): 369.1 (M+1) + . 1 H NMR (400 MHz, DMSO-d6) δ = 9.08 (s, 1H), 8.12 (d, J=8.4 Hz, 1H), 7.60-7.60(m, 2H), 7.32 (d, J=7.6 Hz, 1H), 7.02 (s, 1H), 6.99 (s,1H), 5.03 (s, 1H), 3.67 (d, J=5.6 Hz, 2H), 1.23 (s, 6H).

[0154] Example 2 1-(4-chloro-2-hydroxyphenyl)-4-((2-hydroxy-2-methylpropyl)amino)phthalazine-6-carboxamide (002)

[0155] [ka]

[0156] Step 1. Preparation of 1-(4-chloro-2-hydroxyphenyl)-4-((2-hydroxy-2-methylpropyl)amino)phthalazine-6-carboxamide (002) 1-(4-Chloro-2-hydroxyphenyl)-4-((2-hydroxy-2-methylpropyl)amino)phthalazine-6-carbonitrile 001 (20 mg, 0.05 mmol) was dissolved in ethanol (0.6 mL) and tetrahydrofuran (0.6 mL). The mixture was added with 1 mol / L sodium hydroxide (0.2 mL) and stirred at 25 °C for 16 h. After completion of the reaction, the crude product was purified by preparative high-performance liquid chromatography (Waters MS triggered Prep-LC with Acquity QDA detector, chromatography column: Welch C18, 250 × 21.2 mm, 10 μm; mobile phase 1: water (containing 0.1% aqueous ammonia); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 5% to 40%, flow rate: 25 mL / min) to obtain the title compound 002 (5.26 mg, yield: 25%). MS m / z (ESI): 387.1 (M+1) + . 1 H NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H), 8.87 (s, 1H), 8.19 (d, J=7.2 Hz, 2H), 7.73 (s, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.43 (t, J=5.2 Hz,1H), 7.32 (d, J=8.0 Hz, 1H), 7.01 (d, 8.4 Hz, 1H), 5.30 (s, 1H), 3.65 (d, J=7.0 Hz, 2H), 1.23 (s, 6H).

[0157] Example 3 (R)-1-(4-chloro-2-hydroxyphenyl)-4-((1-(cyclopropylformyl)piperidin-3-yl)amino)phthalazine-6-carbonitrile (005)

[0158] [ka]

[0159] Step 1. Preparation of tert-butyl (R)-3-((4-chloro-7-cyanophthalazin-1-yl)amino)piperidine-1-carboxylate (005a) 1,4-Dichlorophthalazine-6-carbonitrile 001a (200 mg, 0.89 mmol) and (R)-tert-butyl 3-aminopiperidine-1-carboxylate (216 mg, 1.07 mmol) were dissolved in N-methylpyrrolidone (5 mL), and N,N-diisopropylethylamine (346 mg, 2.68 mmol) was added thereto. The reaction mixture was stirred at 100°C for 2 hours. After the reaction was completed, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 005a (120 mg, yield: 34.7%). MS m / z (ESI): 388.1 (M+1) + . 1 H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.36 (dd, J=8.4 Hz, 1.2 Hz, 1H), 8.21 (d, J=8.4 Hz, 1H), 7.54 (s, 1H), 2.09-2.05 (m, 1H), 1.91-1.82(m, 1H), 1.67 (s, 1H), 1.52-1.44 (m, 2H), 1.38-1.31 (d, J=7.1, 4H), 1.23 (s, 9H).

[0160] Step 2: Preparation of (R)-1-chloro-4-(piperidin-3-ylamino)phthalazine-6-carbonitrile (005b) Compound 005a (120 mg, 0.31 mmol) was dissolved in a 2 M solution of hydrochloric acid in ethyl acetate (5 mL), and the reaction was stirred for 2 hours at 20° C. After completion of the reaction, the reaction solution was directly concentrated under reduced pressure to obtain the title compound 005b (90 mg, yield: 89.9%). MS m / z (ESI): 288.1 (M+1) + .

[0161] Step 3 Preparation of (R)-1-chloro-4-((1-(cyclopropylformyl)piperidin-3-yl)amino)phthalazine-6-carbonitrile (005c) Compound 005b (80 mg, 0.21 mmol) was dissolved in dichloromethane (5 mL) and triethylamine (62.44 mg, 0.62 mmol) was added. After the reaction mixture became clear, cyclopropanecarbonyl chloride (21.5 mg, 0.21 mmol) was added dropwise at 0°C, and the reaction mixture was stirred at 0°C for 30 minutes. After the reaction was complete, the reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using eluent system B to obtain the title compound 005c (50 mg, yield: 68.3%). MS m / z (ESI): 356.1 (M+1) + .

[0162] Step 4: Preparation of (R)-1-(4-chloro-2-hydroxyphenyl)-4-((1-(cyclopropylformyl)piperidin-3-yl)amino)phthalazine-6-carbonitrile (005) Compound 005c (50 mg, 0.14 mmol), 2-hydroxy-4-chlorophenylboronic acid (29.06 mg, 0.17 mmol), and sodium carbonate (44.67 mg, 0.42 mmol) were dissolved in a 1,4-dioxane / water mixture (2.2 mL, V / V = 10:1), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10.2 mg, 0.014 mmol) was added. The reaction mixture was heated at 100°C for 4 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was collected, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative high-performance liquid chromatography (Waters MS triggered Prep-LC with Acquity QDA detector, chromatography column: Welch C18 250*21.2 mm, 10 μm; mobile phase 1: water (containing 0.1% aqueous ammonia); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 30% to 100%, flow rate: 25 mL / min) to obtain the title compound 005 (15.4 mg, yield: 24.5%). MS m / z (ESI): 448.1 (M+1) + . 1 H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 9.04 (d, J=30.4 Hz, 1H), 8.13 (d, J=8.4 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.49 (d, J=6.4 Hz, 1H), 7.32 (d, J=8.4 Hz,2H), 6.98 (s, 2H), 4.60 (d, J=10.4 Hz,1H), 4.38-4.19 (m, 2H), 4.01(d, J=12.4 Hz, 1H), 3.43-3.39 (m, 1H), 3.20-3.02 (m, 1H), 2.73-2.67 (m, 1H),2.19-2.13(m,1H),2.04-1.99 (m, 1H), 1.76-1.48(m, 1H), 0.87-0.66 (m, 2H), 0.49-0.39 (m, 2H).

[0163] Example 4 4-((2-hydroxy-2-methylpropyl)amino)-1-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)phthalazine-6-carbonitrile (007)

[0164] [ka]

[0165] Step 1: 4-((2-hydroxy-2-methylpropyl)amino)-1-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)phthalazine-6-carbonitrile (007) Compound 007a (20 mg, 0.087 mmol, produced by the method disclosed on pages 38-39 of the specification of patent application "US2020361899A1") was dissolved in a mixed solvent of 1,4-dioxane and water (2.2 mL, V / V=10:1), and compound 001b (20 mg, 0.072 mmol), sodium carbonate (23 mg, 0.22 mmol), and tetrakis(triphenylphosphine)palladium (8.35 mg, 0.0072 mmol) were added thereto. The reaction system was reacted at 100°C for 1 hour under nitrogen gas protection. After the reaction was completed, the reaction solution was filtered, the filtrate was collected, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative high-performance liquid chromatography (Waters MS triggered Prep-LC with Acquity QDA detector, chromatography column: Welch C18 250*21.2 mm, 10 μm; mobile phase 1: water (containing 0.1% aqueous ammonia); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 30% to 100%, flow rate: 25 mL / min) to obtain the title compound 007 (7.84 mg, yield: 26%). MS m / z (ESI): 417.1 (M+1) + . 1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.09 (d, J=8.4 Hz, 1H), 7.58 (t, J=5.6 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.14 (s, 1H), 7.05 (s, 1H),5.01 (s, 1H),3.67 (ddd, J=44 Hz, 13.2 Hz, 5.6 Hz, 2H), 1.97 (m, 3H), 1.23 (s,6H).

[0166] Example 5 (R)-2-(3-((1-(4-chloro-2-hydroxyphenyl)pyrido[3,4-d]pyridazin-4-yl)amino)piperidin-1-yl)acetamide (009)

[0167] [ka]

[0168] Step 1. Preparation of (R)-tert-butyl 3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)piperidine-1-carboxylate (009b) Compound 009a (1 g, 5 mmol) was dissolved in N-methylpyrrolidone (10 mL), and (R)-tert-butyl 3-aminopiperidine-1-carboxylate (1 g, 5 mmol) and N,N-diisopropylethylamine (1.29 g, 10 mmol) were added. The reaction mixture was stirred at 100 °C for 1 hour. After the reaction was completed, the mixture was diluted with water, extracted with dichloromethane, washed with saturated brine, and the organic phase was collected. The solvent was evaporated to dryness to obtain the crude product. The product was purified by silica gel column chromatography using eluent system B to obtain the title compound 009b (1.7 g, yield: 93%). MS m / z (ESI): 364.1 (M+1) + .

[0169] Step 2: Preparation of (R)-1-chloro-N-(piperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine (009c) Compound 009b (1.7 g, 4.7 mmol) was dissolved in a 2 M hydrochloric acid solution in ethyl acetate (5 mL). The reaction mixture was allowed to react at 25 °C for 1 hour. After completion of the reaction, the solvent was removed by rotary evaporation to obtain a crude product. The crude product was purified by preparative high-performance liquid chromatography (Waters MS triggered Prep-LC with Acquity QDA detector, chromatography column: Welch C18 150*19 mm, 5 μm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 5-minute gradient, gradient ratio: acetonitrile phase 2% to 10%, flow rate: 25 mL / min) to obtain the title compound 009c (1.1 g, yield: 90%). MS m / z (ESI): 264.1 (M+1) + .

[0170] Step 3 Preparation of (R)-2-(3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)piperidin-1-yl)acetamide (009d) Compound 009c (200 mg, 0.76 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (230 mg, 2.28 mmol) and bromoacetamide (115 mg, 0.83 mmol) were added sequentially. The reaction was stirred at 25 °C for 2 hours. After completion of the reaction, the reaction solution was directly rotovapped, and the residue was purified by silica gel column chromatography using eluent system A to give the title compound 009d (220 mg, yield: 90%). MS m / z (ESI): 321.1 (M+1) + .

[0171] Step 4: Preparation of (R)-2-(3-((1-(4-chloro-2-hydroxyphenyl)pyrido[3,4-d]pyridazin-4-yl)amino)piperidin-1-yl)acetamide (009) Compound 009d (220 mg, 0.69 mmol) was dissolved in a 1,4-dioxane / water mixture (1.1 mL, V / V = 10:1), and (4-chloro-2-hydroxyphenyl)boronic acid (118 mg, 0.69 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (100 mg, 0.14 mmol), and sodium carbonate (145 mg, 1.37 mmol) were added. The reaction mixture was heated to 100°C for 2 hours under nitrogen gas protection. After completion of the reaction, the reaction solution was filtered and then the filtrate was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatography column: Oxbridge C18 150 × 19 mm, 5 μm; mobile phase 1: water (containing 0.1% TFA); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 18% to 28%, flow rate: 20 mL / min) to obtain the title compound 009 (34.66 mg, yield: 12%). MS m / z (ESI): 413.1(M+1) + . 1 H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 10.07 (s, 1H), 9.81 (s, 1H), 8.93 (s, J=5.6 Hz,1H), 7.96 (s, 1H), 7.69 (s, 1H), 7.37-7.34 (m, 2H), 7.07-7.05 (m, 2H), 4.81 (s, 2H), 3.99 (s, 2H), 3.84-2.99 (m, 3H), 2.15-1.73 (m,4H).

[0172] Example 6 (R)-(3-((1-(4-chloro-2-hydroxyphenyl)pyrido[3,4-d]pyridazin-4-yl)amino)piperidin-1-yl)(cyclopropyl)methanone (006)

[0173] [ka]

[0174] Step 1. Preparation of (R)-(3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)piperidin-1-yl)(cyclopropyl)methanone (006b) (R)-1-chloro-N-(piperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine 009c (200 mg, 0.76 mmol) was dissolved in dichloromethane (10 mL), triethylamine (153 mg, 1.52 mmol) was added, and cyclopropanecarbonyl chloride (95 mg, 0.91 mmol) was added at 0° C. The reaction mixture was stirred at 25° C. for 2 hours. After completion of the reaction, the reaction mixture was directly rotary evaporated, and the resulting residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 006b (175 mg, yield: 63%). MS m / z (ESI): 332.1 (M+1) + .

[0175] Step 2: Preparation of (R)-(3-((1-(4-chloro-2-hydroxyphenyl)pyrido[3,4-d]pyridazin-4-yl)amino)piperidin-1-yl)(cyclopropyl)methanone (006) Compound 006b (175 mg, 0.53 mmol) was dissolved in a dioxane / water mixture (11 mL, V / V = 10:1), and (4-chloro-2-hydroxyphenyl)boronic acid (91 mg, 0.53 mmol), sodium carbonate (112 mg, 1.05 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (39 mg, 0.05 mmol) were added. The reaction mixture was stirred at 100°C for 4 hours. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (Waters MS triggered Prep-LC with Acquity QDA detector, chromatography column: Welch C18 250*21.2 mm, 10 μm; mobile phase 1: water (containing 0.1% aqueous ammonia); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 17% to 37%, flow rate: 25 mL / min) to obtain the title compound 006 (15.54 mg, yield: 6.9%). MS m / z (ESI): 424.1 (M+1) + . 1 H NMR (400 MHz, DMSO-d6) δ 9.78 (d, J = 20.4 Hz, 1H), 8.86 (d, J = 5.6 Hz, 1H), 7.70 (s, 1H), 7.32 (t, J = 7.2 Hz, 2H), 7.00 (d, J = 7.2 Hz, 2H), 4.43-4.33 (m, 1H), 4.33 - 4.04 (m, 2H), 3.21 - 3.14 (m, 1H), 2.95-2.72 (m, 1H), 2.17 (s, 1H), 1.87 - 1.50 (m, 4H), 0.76 - 0.45 (m, 4H).

[0176] Example 7 (R)-3-((1-(4-chloro-2-hydroxyphenyl)pyrido[3,4-d]pyridazin-4-yl)amino)piperidine-1-carboxamide (008)

[0177] [ka]

[0178] Step 1. Preparation of (R)-3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)piperidine-1-carboxamide (008a) Compound 009c (150 mg, 0.57 mmol) was dissolved in dichloromethane, triethylamine (173 mg, 1.71 mmol) was added, and then phenyl carbamate (78 mg, 0.59 mmol) was slowly added dropwise. The reaction mixture was allowed to react at room temperature for 1 hour. After the reaction was completed, the solvent was removed by rotary evaporation to obtain the crude product. The resulting residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 008a (170 mg, yield: 97%). MS m / z (ESI): 307.1 (M+1) + .

[0179] Step 2: Preparation of (R)-3-((1-(4-chloro-2-hydroxyphenyl)pyrido[3,4-d]pyridazin-4-yl)amino)piperidine-1-carboxamide (008) Compound 008a (100 mg, 0.33 mmol) was dissolved in 1,4-dioxane and water (6 mL, V / V = 5:1), and (4-chloro-2-hydroxyphenyl)boronic acid (67 mg, 0.39 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (48 mg, 0.07 mmol), and sodium carbonate (69 mg, 0.65 mmol) were added. The reaction mixture was stirred at 100 °C for 2 hours under nitrogen gas protection. After completion of the reaction, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography (Waters MS triggered Prep-LC with Acquity QDA detector, chromatography column: Welch C18 250 * 21.2 mm, 10 μm; mobile phase 1: water (containing 0.1% aqueous ammonia); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 12% to 27%, flow rate: 25 mL / min) to obtain the title compound 008 (4.83 mg, yield: 4%). MS m / z (ESI): 307.1 (M+1) + . 1 H NMR (400 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.84 (d, J = 5.6 Hz, 1H), 7.67 (d, J = 7.2 Hz, 1H), 7.34 (s, 1H), 7.29 (d, J = 8.0 Hz, 1H), 6.91 (s, 2H), 5.99 (s, 2H), 4.30 (d, J = 6.8 Hz, 1H), 4.20 (d, J = 12.4 Hz, 1H), 3.88 (d, J = 13.2 Hz, 1H), 2.77 (dd, J = 12.4, 10.0 Hz, 2H), 2.13 (d, J = 8.8 Hz, 1H), 1.75 (d, J = 3.6 Hz, 1H), 1.65 (dd, J = 23.6, 12.0 Hz, 1H), 1.51 (t, J = 12.0 Hz, 1H).

[0180] Example 8 (R)-3-((1-(4-chloro-2-hydroxyphenyl)pyrido[3,4-d]pyridazin-4-yl)amino)piperidine-1-carboxylate methyl ester (010)

[0181] [ka]

[0182] Step 1. Preparation of (R)-methyl 3-(1-chloropyrido[3,4-d]pyridazin-4-ylamino)piperidine-1-carboxylate (010a) Compound 009c (200 mg, 0.76 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (115.4 mg, 1.14 mmol) was added at 0°C. The mixture was stirred for 10 minutes. Methyl chloroformate (57 mg, 0.61 mmol) was then added at 0°C, and the mixture was stirred for 40 minutes at 0°C. After completion of the reaction, the reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 010a (153 mg, yield: 62.5%). MS m / z (ESI): 322.1 (M+1) + .

[0183] Step 2: Preparation of (R)-3-((1-(4-chloro-2-hydroxyphenyl)pyrido[3,4-d]pyridazin-4-yl)amino)piperidine-1-carboxylate (010) Compound 010a (153 mg, 0.48 mmol), 2-hydroxy-4-chlorophenylboronic acid (123 mg, 0.71 mmol), and sodium carbonate (151.6 mg, 1.43 mmol) were dissolved in a mixed solvent of 1,4-dioxane and water (5 mL, V / V = 4:1), and 1,1'-bisdiphenylphosphinoferrocenedichloropalladium (104.6 mg, 0.14 mmol) was added. The reaction was carried out at 100°C for 4 hours under nitrogen gas protection. After completion of the reaction, the reaction solution was filtered and concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (Waters MS triggered Prep-LC with Acquity QDA detector, chromatography column: Welch C18, 250*21.2 mm, 10 μm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 20-minute gradient, gradient ratio: acetonitrile phase 25% to 55%, flow rate: 30 mL / min) to obtain the title compound 010 (6.35 mg, yield: 3.2%). MS m / z (ESI): 414.1 (M+1) + . 1 H NMR (400 MHz, DMSO-d6): δ 10.30 (s, 1H), 9.78 (s, 1H), 8.86 (d, J=5.6 Hz, 1H), 7.70 (d, J=7.2 Hz, 1H), 7.36(d, J=8.4 Hz, 1H), 7.31 (d, J=5.6 Hz, 1H), 7.05 (s, 2H), 4.35-4.27 (m, 2H), 3.90 (d, J=13.2 Hz, 1H), 3.58 (s, 3H), 2.94-2.89 (m, 2H), 2.14 -2.11(m, 1H), 1.86-1.83 (m, 1H), 1.74-1.66 (m, 1H), 1.58-1.48 (m, 1H).

[0184] Example 9 2-(((1-(4-chloro-2-hydroxyphenyl)pyrido[3,4-d]pyridazin-4-yl)amino)methyl)pyrrolidine-1-carboxamide (012)

[0185] [ka]

[0186] Step 1. Preparation of tert-butyl 2-(((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)methyl)pyrrolidine-1-carboxylate (012a) Compound 009a (200 mg, 1.00 mmol) was dissolved in N-methylpyrrolidone (5 mL), and tert-butyl [2-(aminomethyl)pyrrolidin-1-yl]carboxylate (211 mg, 1.00 mmol) and N,N-diisopropylethylamine (388 mg, 3.00 mmol) were added. The reaction mixture was reacted at 100°C for 2 hours. After completion of the reaction, the reaction mixture was directly rotary evaporated, and the resulting residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 012a (230 mg, yield: 63%). MS m / z (ESI): 364.1 (M+1) + .

[0187] Step 2: 1-chloro-N-(pyrrolidin-2-ylmethyl)pyrido[3,4-d]pyridazin-4-amine (012b) A 4 M solution of hydrochloric acid in dioxane (15 mL) was added to compound 012a (100 mg, 0.27 mmol), and the mixture was stirred at 25° C. for 2 hours. After completion of the reaction, the reaction solution was directly rotary evaporated to obtain the title compound 012b (75 mg, yield: 97%). MS m / z (ESI): 264.1 (M+1) + .

[0188] Step 3: 2-(((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)methyl)pyrrolidine-1-carboxamide (012c) Compound 012b (700 mg, 0.76 mmol) was dissolved in dichloromethane (10 mL), and phenyl carbamate (104 mg, 0.76 mmol) and triethylamine (306.97 mg, 3.03 mmol) were added. The reaction mixture was stirred at 25°C for 4 hours. After completion of the reaction, the reaction mixture was directly rotary evaporated, and the resulting residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 012c (200 mg, yield: 86.0%). MS m / z (ESI): 307.0 (M+1) + . 1 H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 9.23 (s, 1H), 9.12-9.02 (m, 2H), 6.31 (s, 2H), 4.13 (s, 1H), 3.73-3.47 (m, 2H), 1.91 (d, J=5.9, 6H).

[0189] Step 4: 2-(((1-(4-chloro-2-hydroxyphenyl)pyrido[3,4-d]pyridazin-4-yl)amino)methyl)pyrrolidine-1-carboxamide (012) Compound 012c (100 mg, 0.326 mmol) and sodium carbonate (103 mg, 0.978 mmol) were dissolved in a mixed solvent of 1,4-dioxane and water (11 mL, V / V = 10:1), and (4-chloro-2-hydroxyphenyl)boronic acid (62 mg, 0.36 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (48 mg, 0.065 mmol) were added. The reaction mixture was stirred at 100 °C for 14 hours. After completion of the reaction, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (Waters MS triggered Prep-LC with Acquity QDA detector, chromatography column: Welch C18, 250*21.2 mm, 10 μm; mobile phase 1: water (containing 0.1% aqueous ammonia); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 15% to 100%, flow rate: 25 mL / min) to obtain the title compound 012 (1.75 mg, mixture of two enantiomers, yield: 1.35%). MS m / z (ESI): 399.0 (M+1) + . 1 H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.86 (d, J=5.2 Hz, 1H), 8.78 (s, 1H), 7.31 (d, J=6.4 Hz, 2H), 6.97 (s, 2H), 6.40 (s, 2H), 4.15 (s, 1H), 3.74 (s, 1H),3.22 (m, 2H), 1.94-1.91 (m, 4H).

[0190] Example 10 1-(2-(1-(4-chloro-2-hydroxyphenyl)pyrido[3,4-d]pyridazin-4-ylamino)methyl)pyrrolidin-1-yl)ethan-1-one (011)

[0191] [ka]

[0192] Step 1: 1-(2-((1-chloropyrido[3,4-d]pyridazin-4-ylamino)methyl)pyrrolidin-1-yl)ethan-1-one (011a) Compound 012b (200 mg, 0.76 mmol) was dissolved in dichloromethane (8 mL) and triethylamine (383.7 mg, 3.79 mmol) was added. After stirring at 0°C for 5 minutes, a solution of acetyl chloride (30 mg, 0.38 mmol) in dichloromethane (2 mL) was slowly added dropwise. The reaction mixture was stirred at 0°C for 30 minutes. After completion of the reaction, the reaction mixture was quenched with water and extracted with dichloromethane. The organic layer was collected and dried over anhydrous sodium sulfate. The residue obtained was purified by silica gel column chromatography using eluent system A to obtain the title compound 011a (120 mg, yield: 51.9%). MS m / z (ESI): 306 (M+1). + .

[0193] Step 2. Preparation of 1-(2-(1-(4-chloro-2-hydroxyphenyl)pyrido[3,4-d]pyridazin-4-ylamino)methyl)pyrrolidin-1-yl)ethan-1-one (011) Compound 011a (120 mg, 0.39 mmol) was dissolved in a mixed solvent of 1,4-dioxane and water (11 mL, V / V = 10:1), and 4-chloro-2-hydroxyphenylboronic acid (81 mg, 0.47 mmol), sodium carbonate (125 mg, 1.18 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (57 mg, 0.078 mmol) were added. The reaction mixture was stirred at 100 °C for 2 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative high-performance liquid chromatography (Waters MS triggered Prep-LC with Acquity QDA detector, chromatography column: Xtimate C18, 250*30 mm, 10 μm; mobile phase 1: water (containing 0.05% aqueous ammonia); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 12% to 35%, flow rate: 25 mL / min) to obtain the title compound 011 (5.7 mg, mixture of two enantiomers, yield: 3.7%). MS m / z (ESI): 398 (M+1) + . 1 H NMR (400 MHz, DMSO-d6) δ 9.69 (s,1H), 8.84 (t, J=5.6 Hz, 1H), 8.26 (s, 1H), 7.34-7.29 (m, 2H), 6.95 (s, 2H), 4.45-4.34 (m, 1H), 3.84-3.70 (m, 2H), 3.58-3.50(m,2H), 2.20 (s, 1.5 H), 2.08-2.06 (m, 1H), 2.02 (s,1.5 Hz), 1.93-1.89 (m, 3H).

[0194] Example 11 2-(3-((1-(4-chloro-2-hydroxyphenyl)pyrido[3,4-d]pyridazin-4-yl)amino)phenyl)-2-methylpropanenitrile (014)

[0195] [ka]

[0196] Step 1: 2-(3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)phenyl)-2-methylpropanenitrile (014a) Compound 009a (200.0 mg, 1.2 mmol) and 2-(3-aminophenyl)-2-methylpropanenitrile (250 mg, 1.2 mmol) were dissolved in N-methylpyrrolidone (5 mL), and N,N-diisopropylethylamine (484 mg, 3.7 mmol) was added. The reaction mixture was stirred at 100°C for 2 hours. After the reaction was completed, the mixture was extracted with ethyl acetate, and the organic phase was collected and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 014a (200 mg, yield: 39%). MS m / z (ESI): 324.1 (M+1) + .

[0197] Step 2: Preparation of 2-(3-((1-(4-chloro-2-hydroxyphenyl)pyrido[3,4-d]pyridazin-4-yl)amino)phenyl)-2-methylpropanenitrile (014) Compound 014a (100.0 mg, 0.3 mmol) and (4-chloro-2-hydroxyphenyl)boronic acid (80 mg, 0.4 mmol) were dissolved in a 1,4-dioxane / water mixture (11 mL, V / V = 1:10), to which 1,1-bis(diphenylphosphino)ferrocenedichloropalladium (113.0 mg, 0.15 mmol) and sodium carbonate (98 mg, 0.9 mmol) were added. The reaction was stirred at 90°C for 6 hours under nitrogen atmosphere. After the reaction was completed, the solvent was removed by rotary evaporation to obtain a crude product. The crude product was separated and purified by preparative high-performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, chromatography column: WELCH Xtimate C18, 21.2 × 250 mm, 10 μm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 18-minute gradient, gradient ratio: acetonitrile phase 5% to 100%; flow rate: 30 mL / min) to obtain the title compound 014 (4.2 mg, yield: 3.2%). MS m / z (ESI): 416.1 (M+1) + . 1 H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 10.02 (s, 1H), 9.79 (s, 1H), 8.95 (d, J = 5.6 Hz, 1H), 8.10 (dd, J = 4.0, 2.0 Hz, 2H), 7.49-7.45 (m, 1H), 7.42-7.39 (m, 2H), 7.24 (d, J = 8.4 Hz, 1H), 7.07-7.05 (m, 2H), 1.74 (s, 6H).

[0198] Example 12 2-(4-((1-(4-chloro-2-hydroxyphenyl)pyrido[3,4-d]pyridazin-4-yl)amino)phenyl)-2-methylpropanenitrile (015)

[0199] [ka]

[0200] Step 1. Preparation of 2-(4-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)phenyl)-2-methylpropanenitrile (015a) 1,4-Dichloropyrido[3,4-d]pyridazine 009a (200 mg, 1.00 mmol) was dissolved in N-methylpyrrolidone (5 mL), and 2-(4-aminophenyl)-2-methylpropanenitrile (160 mg, 1.00 mmol) and N,N-diisopropylethylamine (388 mg, 3.00 mmol) were added. The reaction mixture was stirred at 100 °C for 2 h. After completion of the reaction, the reaction mixture was directly rotary evaporated, and the resulting residue was purified by silica gel column chromatography using eluent system A to give the title compound 015a (200 mg, yield: 59%). MS m / z (ESI): 324.1 (M+1) + .

[0201] Step 2: Preparation of 2-(4-((1-(4-chloro-2-hydroxyphenyl)pyrido[3,4-d]pyridazin-4-yl)amino)phenyl)-2-methylpropanenitrile (015) Compound 015a (100 mg, 0.31 mmol) was dissolved in a dioxane / water mixture (11 mL, V / V = 10:1), and (4-chloro-2-hydroxyphenyl)boronic acid (53 mg, 0.31 mmol), sodium carbonate (65 mg, 0.62 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (23 mg, 0.03 mmol) were added. The reaction mixture was stirred at 100°C for 2 hours. After the reaction was completed, the reaction solution was directly rotary evaporated and concentrated. The resulting mixture was then purified by preparative high-performance liquid chromatography (Waters MS triggered Prep-LC with Acquity QDA detector, chromatography column: Welch C18, 250*21.2 mm, 10 μm; mobile phase 1: water (containing 0.1% aqueous ammonia); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 37% to 47%, flow rate: 25 mL / min) to obtain the title compound 015 (2.54 mg, yield: 1.9%). MS m / z (ESI): 416.1 (M+1) + . 1 H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 9.64 (s, 1H), 8.83 (d, J = 5.6 Hz, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 4.0 Hz, 1H), 7.51 (d, J = 8.8 Hz,2H), 7.15 - 7.13 (m, 1H), 6.48-6.35 (d, 2H), 1.71 (s, 6H).

[0202] Example 13 5-chloro-2-(4-((2-hydroxy-2-methylpropyl)amino)-6-(1-propyn-1-yl)phthalazin-1-yl)-3-methylphenol (024) (R)-5-chloro-2-(4-((2-hydroxy-2-methylpropyl)amino)-6-(propyl-1-yn-1-yl)phthalazin-1-yl)-3-methylphenol (S)-5-chloro-2-(4-((2-hydroxy-2-methylpropyl)amino)-6-(propyl-1-yn-1-yl)phthalazin-1-yl)-3-methylphenol

[0203] [ka]

[0204] Step 1 Preparation of 1-((7-bromo-4-chlorophthalazin-1-yl)amino)-2-methylprop-2-ol (024b) 6-Bromo-1,4-dichlorophthalazine 024a (1 g, 3.6 mmol) and 1-amino-2-methyl-2-propanol (350 mg, 3.96 mmol) were dissolved in N-methylpyrrolidone (15 mL), and N,N-diisopropylethylamine (1.4 g, 10.8 mmol) was added thereto. The reaction mixture was heated at 100°C for 2 hours. After completion of the reaction, the reaction mixture was washed with saturated brine and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified using silica gel column chromatography with eluent system B to obtain the title compound 024b (500 mg, yield: 41.7%). MS m / z (ESI): 330.0 (M+1). 1 H NMR (400 MHz, DMSO-d6) δ 8.82 (d, 1H), 8.16 (dd, 1H), 7.98 (d, 1H), 7.59 (t, 1H), 4.83 (s, 1H), 3.60 (d, 2H), 1.19 (s, 6H).

[0205] Step 2: Preparation of 1-((4-chloro-7-(propyn-1-yl)phthalazin-1-yl)amino)-2-methylprop-2-ol (024c) Compound 024b (100 mg, 0.30 mmol) was dissolved in N,N-dimethylacetamide (11 mL), and cesium carbonate (147.8 mg, 0.45 mmol), cuprous iodide (23 mg, 0.12 mmol), 1-(trimethylsilyl)propyne (33.9 mg, 0.30 mmol), and bis(triphenylphosphine)palladium(II) dichloride (42.5 mg, 0.061 mmol) were added. 0.05 mL of water was added. The reaction mixture was heated at 100°C for 1 hour under nitrogen gas protection. After completion of the reaction, the reaction mixture was washed with saturated brine and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The resulting residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 024c (60 mg, yield: 60.9%). MS m / z (ESI): 290.1 ​​(M+1).

[0206] Step 3: Preparation of 5-chloro-2-(4-((2-hydroxy-2-methylpropyl)amino)-6-(1-propyn-1-yl)phthalazin-1-yl)-3-methylphenol (024) Compound 024c (50 mg, 0.17 mmol) was dissolved in a mixed solvent of 1,4-dioxane and water (3.3 mL, V / V = 10:1), and then (4-chloro-2-hydroxy-6-methylphenyl)boronic acid 024d (35 mg, 0.19 mmol), potassium carbonate (72 mg, 0.52 mmol), and 1,1'-bisdiphenylphosphinoferrocenedichloropalladium (12.5 mg, 0.017 mmol) were added. The reaction was carried out at 100°C for 2 hours under nitrogen gas protection. After completion of the reaction, the reaction solution was filtered, the filtrate was collected, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative high-performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatography column: Xbridge 5 μm C18 150 × 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 27% to 100%, flow rate: 20 mL / min) to obtain the title compound 024 (15.2 mg, yield: 20.8%, a pair of axially asymmetric isomers). MS m / z (ESI): 396.1 (M+1). 1 H NMR (400 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.51 (s, 1H), 7.73 (d, 1H), 7.39 (s, 1H), 7.23 (d, 1H), 6.91 (s, 1H), 6.85 (s, 1H), 3.68-3.54 (m, 2H), 2.13 (s, 3H), 1.88 (s, 3H), 1.21 (s, 6H).

[0207] Step 4: (R)-5-chloro-2-(4-((2-hydroxy-2-methylpropyl)amino)-6-(propyl-1-yn-1-yl)phthalazin-1-yl)-3-methylphenol (S)-5-chloro-2-(4-((2-hydroxy-2-methylpropyl)amino)-6-(propyl-1-yn-1-yl)phthalazin-1-yl)-3-methylphenol Compound 024 (20 mg) was purified by SFC preparative chromatography (SFC 150 chromatography column: Daicel CHIRALCEL AZ, 250 mm × 30 mm ID, 10 μm; mobile phase 1: carbon dioxide; mobile phase 2: ethanol (0.2% aqueous ammonia); 6-minute gradient, gradient ratio: carbon dioxide:ethanol phase = 60 / 40, flow rate: 2 mL / min) to give the title compound 024-1 (8 mg, short retention time, yield: 40%) and the title compound 024-2 (9 mg, long retention time, yield: 45%). Single configuration isomer (short retention time) MS m / z (ESI): 396.1 (M+1). 1 H NMR (400 MHz, CD3OD) δ 8.29 (s, 1H), 7.70 (dd, 1H), 7.34 (d, 1H), 6.87 (d, 1H), 6.79 (d, 1H), 3.68 (d, 2H), 2.08 (s, 3H), 1.93 (s, 3H), 1.29 (s, 6H). Single configuration isomer (long retention time) MS m / z (ESI): 396.1 (M+1). 1 H NMR (400 MHz, CD3OD) δ 8.31 (s, 1H), 7.72 (d, 1H), 7.36 (d, 1H), 6.88 (s, 1H), 6.82 (d, 1H), 3.70 (d, 2H), 2.10 (s, 3H), 1.96 (s, 3H), 1.30 (s, 6H).

[0208] Example 14 5-chloro-2-(4-(R)-2-hydroxypropyl)amino)-6-(prop-1-yn-1-yl)phthalazin-1-yl)-3-methylphenol (035)

[0209] [ka]

[0210] Using the synthetic route of Example 13, the starting material 1-amino-2-methyl-2-propanol in Step 1 was replaced with (R)-(-)-1-amino-2-propanol (500 mg, 6.65 mmol, Shanghai Haohong Biopharmaceutical Technology Co., Ltd.). The reaction product of Step 3 was purified by preparative high-performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatography column: Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 25% to 100%, flow rate: 20 mL / min) to obtain the title product 035 (13 mg, yield: 24.7%, a pair of axially asymmetric isomers). MS m / z (ESI): 382.1 (M+1). 1 H NMR (400 MHz, CD3OD) δ 8.32 (s, 1H), 7.73 (d, 1H), 7.36 (d, 1H), 6.90 (s, 1H), 6.82 (s, 1H), 4.59 (s, 1H), 4.19 (d, 1H), 3.77-3.66 (m, 1H), 3.57 (td, 1H), 2.10 (s, 3H), 1.97 (s, 3H), 1.28 (d, 3H).

[0211] Example 15 5-chloro-2-(4-((2-hydroxy-2-methylpropyl)amino)-6-(propyl-1-yn-1-yl)phthalazin-1-yl)phenol (036)

[0212] [ka]

[0213] Using the synthetic route of Example 13, the starting material (4-chloro-2-hydroxy-6-methylphenyl)boronic acid 024d in Step 3 was replaced with (4-chloro-2-hydroxyphenyl)boronic acid (50 mg, 0.29 mmol). The reaction product of Step 3 was purified by preparative high-performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatography column: Xbridge 5 μm C18 150 × 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 23% to 100%, flow rate: 20 mL / min) to give the title product 036 (10 mg, yield: 23.6%). MS m / z (ESI): 382.1 (M+1). 1 H NMR (400 MHz, CD3OD) δ 8.31 (s, 1H), 7.76 (dd, 1H), 7.57 (d, 1H), 7.31 (d, 1H), 7.02-6.99 (m, 2H), 3.70 (s, 2H), 2.11 (s, 3H), 1.31 (s, 6H).

[0214] Example 16 (R)-5-chloro-2-(4-((2-hydroxypropyl)amino)-6-(propyl-1-yn-1-yl)phthalazin-1-yl)phenol (037)

[0215] [ka]

[0216] Using the synthetic route of Example 14, the starting material (4-chloro-2-hydroxy-6-methylphenyl)boronic acid 024d in Step 3 was replaced with (4-chloro-2-hydroxyphenyl)boronic acid (50 mg, 0.29 mmol). The reaction product of Step 3 was purified by preparative high-performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatography column: Xbridge 5 μm C18 150 × 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 22% to 100%, flow rate: 20 mL / min) to give the title product 037 (15 mg, yield: 28.6%). MS m / z (ESI): 368.1 (M+1). 1 H NMR (400 MHz, CD3OD) δ 8.33 (s, 1H), 7.74 (d, 1H), 7.58(d,1H), 7.38 (d, 1H), 6.91 (s, 1H), 6.83 (s, 1H), 4.60 (s, 1H), 4.20 (d, 1H), 3.79-3.67 (m, 1H), 3.58 (td, 1H), 2.11 (s, 3H), 1.29 (d, 3H).

[0217] Example 17 5-chloro-2-(4-((2-hydroxy-2-methylpropyl)amino)-6-(1-methyl-1H-pyrazol-4-yl)phthalazin-1-yl)phenol (004)

[0218] [ka]

[0219] Step 1. Preparation of 1-((4-chloro-7-(1-methyl-1H-pyrazol-4-yl)phthalazin-1-yl)amino)-2-methylprop-2-ol (004a) Compound 024b (100 mg, 0.30 mmol) was dissolved in a mixed solvent of 1,4-dioxane and water (6 mL, V / V = 5:1). 1-Methyl-1H-pyrazole-4-boronic acid pinacol ester (63 mg, 0.3 mmol), potassium carbonate (84 mg, 0.61 mmol), and 1,1'-bis(diphenylphosphinoferrocenedichloropalladium) (44 mg, 0.06 mmol) were added. The reaction mixture was then heated at 80 °C for 2 hours under nitrogen gas protection. After completion of the reaction, the mixture was cooled to room temperature, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 004a (60 mg, yield: 47.8%). MS m / z (ESI): 332.1 (M+1).

[0220] Step 2: Preparation of 5-chloro-2-(4-((2-hydroxy-2-methylpropyl)amino)-6-(1-methyl-1H-pyrazol-4-yl)phthalazin-1-yl)phenol (004) Compound 004a (30 mg, 0.091 mmol) was dissolved in a mixed solvent of 1,4-dioxane and water (3.3 mL, V / V = 10:1), and then (4-chloro-2-hydroxyphenyl)boronic acid (19 mg, 0.11 mmol), sodium carbonate (29 mg, 0.27 mmol), and 1,1'-bisdiphenylphosphinoferrocenedichloropalladium (7 mg, 0.0091 mmol) were added. The reaction was carried out at 100°C for 2 hours under nitrogen gas protection. After completion of the reaction, the reaction solution was filtered, the filtrate was collected, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative high-performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatography column: Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 21% to 100%, flow rate: 20 mL / min) to obtain the title compound 004 (8.7 mg, yield: 22.8%). MS m / z (ESI): 424.1 (M+1). 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.34 (s, 1H), 8.26 (s, 1H), 8.10 (s, 1H), 8.01 (d, 1H), 7.48 (s, 1H), 7.46 (d, 1H), 7.32 (d, 1H),7.04 (d, 1H), 7.02-6.99 (m, 1H), 3.92 (s, 3H), 3.66 (s, 2H), 1.23 (s, 6H).

[0221] Example 18 5-chloro-2-(4-((2-hydroxy-2-methylpropyl)amino)-6-(1-methyl-1H-pyrazol-4-yl)phthalazin-1-yl)3-methylbenzene (038)

[0222] [ka]

[0223] Step 1. Preparation of 1-(4-chloro-7-(1-methylpyrazol-4-yl)phthalazine-1-amino)-2-methyl-2-propanol (004a) Compound 024b (100 mg, 0.30 mmol) was dissolved in a dioxane / water mixture (5 mL, V / V = 5:1), and 1-methylpyrazole-4-boronic acid pinacol ester (57 mg, 0.27 mmol), potassium carbonate (84 mg, 0.61 mmol), and 1,1'-bis(diphenylphosphinoferrocenedichloropalladium) (22 mg, 0.03 mmol) were added. The reaction was heated at 80 °C for 1 h under nitrogen gas protection. After completion of the reaction, the organic phase was collected, rotary evaporated, and concentrated. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 004a (60 mg, yield: 57%). MS m / z (ESI): 332.1 (M+1).

[0224] Step 2: Preparation of 5-chloro-2-(4-((2-hydroxy-2-methylpropyl)amino)-6-(1-methyl-1H-pyrazol-4-yl)phthalazin-1-yl)3-methylbenzene (038) Compound 004a (50 mg, 0.15 mmol) was dissolved in a 1,4-dioxane / water mixture (5.5 mL, V / V = 10:1), and (4-chloro-2-hydroxy-6-methylphenyl)boronic acid (57 mg, 0.27 mmol), potassium carbonate (62 mg, 0.45 mmol), and 1,1'-bis(diphenylphosphinoferrocenedichloropalladium) (11 mg, 0.015 mmol) were added. The reaction was carried out at 100 °C for 1 hour under nitrogen gas protection. After completion of the reaction, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (Waters MS triggered Prep-LC with Acquity QDA detector, chromatography column: Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 24% to 100%, flow rate: 25 mL / min) to obtain the title compound 038 (11.8 mg, yield: 17.7%, a pair of axially asymmetric isomers). MS m / z (ESI): 438.1 (M+1). 1 H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H),8.32 (s, 1H),8.31(s, 1H) 8.08 (s, 1H), 7.96 (d, 1H), 7.44 (s, 1H), 7.23 (d, 1H),6.89 (d, 2H), 3.92 (s, 3H), 3.72(d, 2H), 1.89 (s, 3H), 1.23 (s, 6H).

[0225] Example 19 5-chloro-2-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-4-((2-hydroxy-2-methylpropyl)amino)phthalazin-1-yl)-3-methylphenol (039)

[0226] [ka]

[0227] Using the synthetic route of Example 18, the starting material 1-methylpyrazole-4-boronic acid pinacol ester in Step 1 was replaced with 1-cyclopropylpyrazole-4-boronic acid pinacol ester (60 mg, 0.26 mmol). The reaction product of Step 2 was purified by preparative high-performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatography column: Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 20% to 100%, flow rate: 20 mL / min) to obtain the title product 039 (9 mg, yield: 15.6%, a pair of axially asymmetric isomers). MS m / z (ESI): 464.2 (M+1). 1 H NMR (400 MHz, CD3OD) δ 8.52 (s, 1H), 8.30(s,1H),8.08 (s, 1H), 8.04 (d, 1H), 7.43 (d, 1H), 6.90 (s, 1H), 6.83 (d, 1H), 3.75 (d, 2H), 2.03-2.00 (m, 1H), 1.98 (s, 3H), 1.34 (s, 6H), 1.19-1.15 (m, 2H), 1.13-1.08 (m, 2H).

[0228] Example 20 5-chloro-2-(4-((2-hydroxy-2-methylpropyl)amino)-6-(1-methyl-1H-pyrazol-3-yl)phthalazin-1-yl)-3-methylphenol (040)

[0229] [ka]

[0230] Using the synthetic route of Example 18, the starting material 1-methylpyrazole-4-boronic acid pinacol ester in Step 1 was replaced with 1-methylpyrazole-3-boronic acid pinacol ester (60 mg, 0.29 mmol). The reaction product of Step 2 was purified by preparative high-performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatography column: Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 22% to 100%, flow rate: 20 mL / min) to obtain the title product 040 (10.3 mg, yield: 19.6%, a pair of axially asymmetric isomers). MS m / z (ESI): 438.1 (M+1). 1 H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.19 (s, 1H), 8.16 (s, 1H), 7.81 (d, 1H), 7.53 (s, 1H), 7.26 (d, 1H), 6.91 (d, 1H), 6.88 (d, 1H), 6.84 (d, 1H), 3.91 (s, 3H), 3.72-3.50 (m, 2H), 1.86 (s, 3H), 1.20 (s, 6H).

[0231] Example 21 4-((2-hydroxy-2-methylpropyl)amino)-1-(4-hydroxybenzo[b]thiophen-5-yl)phthalazine-6-carbonitrile (018)

[0232] [ka]

[0233] Step 1. Preparation of 4-((2-hydroxy-2-methylpropyl)amino)-1-(4-hydroxybenzothiophen-5-yl)phthalazine-6-carbonitrile (018) Compound 001b (86 mg, 0.44 mmol) was dissolved in a mixed solvent of 1,4-dioxane and water (3 mL, V / V=5:1), and (4-hydroxybenzo[b]thiophen-5-yl)boronic acid 018a (123 mg, 0.44 mmol, produced by the method of Example 26 of the specification of patent application "WO2022166890A1"), 1,1-bis(diphenylphosphine)ferrocenedichloropalladium (64 mg, 0.087 mmol), and sodium carbonate (11 mg, 1.3 mmol) were added. The mixture was purged with nitrogen gas three times, and the reaction solution was stirred at 100°C for 3 hours. The reaction mixture was directly concentrated under reduced pressure, and the crude product was purified by preparative high-performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatography column: Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 26% to 100%, flow rate: 20 mL / min) to obtain the title compound 018 (2.4 mg, yield: 0.02%). MS m / z (ESI): 391.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.37 (s, 1H), 8.12 (d, 1H), 7.71 (s, 2H), 7.63 (m, 3H), 7.31 (d, 1H), 3.69 (d, 2H),1.24 (s, 6H).

[0234] Example 22 1-(2-fluoro-4-hydroxybenzo[b]thiophen-5-yl)-4-((2-hydroxy-2-methylpropyl)amino)phthalazine-6-carbonitrile (019)

[0235] [ka]

[0236] Using the synthetic route described in Example 21, the starting material (4-hydroxybenzo[b]thiophen-5-yl)boronic acid 018a in Step 1 was replaced with (2-fluoro-4-hydroxybenzo[b]thiophen-5-yl)boronic acid 019a (60 mg, 0.28 mmol, prepared by the method described in Example 44 of patent application WO2022166890A1). The final product was purified by preparative high-performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatography column: Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: 22% to 100% acetonitrile phase, flow rate: 20 mL / min) to give the title product 019 (2.3 mg, yield: 2.1%). MS m / z (ESI): 409.1 (M+1). 1 H NMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 9.34 (s, 1H), 8.31 (d,1H), 7.75 (d, 1H), 7.60 (d, 1H), 7.33-7.31 (m, 2H), 3.71 (d, 2H), 1.28 (s, 6H).

[0237] Example 23 (S)-2-((R)-3-((1-(4-chloro-2-hydroxyphenyl)pyrido[3,4-d]pyridazin-4-yl)amino)piperidin-1-yl)propanamide (R)-2-((R)-3-((1-(4-chloro-2-hydroxyphenyl)pyrido[3,4-d]pyridazin-4-yl)amino)piperidin-1-yl)propanamide

[0238] [ka]

[0239] Step 1. Preparation of 2-((R)-3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)piperidin-1-yl)propanamide (016a) Compound 009c (430 mg, 1.63 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then 2-bromopropanamide (322 mg, 2.12 mmol), triethylamine (495 mg, 4.89 mmol), and sodium iodide (245 mg, 1.63 mmol) were added sequentially. The reaction mixture was reacted at 50° C. for 12 hours. After the reaction was completed, the solvent was removed by rotary evaporation to obtain a crude product. The crude product was purified by silica gel column chromatography using eluent system A to obtain the title compound 016a (400 mg, yield: 73%). MS m / z (ESI): 335.1 (M+1).

[0240] Step 2: Preparation of 2-((R)-3-((1-(4-chloro-2-hydroxyphenyl)pyrido[3,4-d]pyridazin-4-yl)amino)piperidin-1-yl)propanamide (016b) Compound 016a (40 mg, 0.12 mmol) was dissolved in a 1,4-dioxane and water mixture (3.6 mL, V / V = 5:1), and 2-hydroxy-4-chlorophenylboronic acid (25 mg, 0.14 mmol), sodium carbonate (38 mg, 0.36 mmol), and 1,1'-bis(diphenylphosphine)ferrocenedichloropalladium (17 mg, 0.02 mmol) were added. The reaction mixture was stirred at 100 °C for 4 hours under nitrogen gas protection. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using eluent system A to obtain the title compound 016b (5.2 mg, yield: 10.1%). MS m / z (ESI): 427.1 (M+1).

[0241] Step 3: Preparation of (S)-2-((R)-3-((1-(4-chloro-2-hydroxyphenyl)pyrido[3,4-d]pyridazin-4-yl)amino)piperidin-1-yl)propanamide (016) Preparation of (R)-2-((R)-3-((1-(4-chloro-2-hydroxyphenyl)pyrido[3,4-d]pyridazin-4-yl)amino)piperidin-1-yl)propanamide (017) The crude compound 016b (20 mg) was purified by SFC preparative chromatography (SFC 150 chromatography column: Daicel CHIRALCEL AZ, 250 mm × 30 mm ID, 10 μm; mobile phase 1: carbon dioxide; mobile phase 2: ethanol (0.2% aqueous ammonia); 6-minute gradient, gradient ratio carbon dioxide:ethanol phase = 65 / 35, flow rate: 2 mL / min) to give the title compound 016 (2.43 mg, short retention time, yield: 12%) and the title compound 017 (2.32 mg, long retention time, yield: 11.6%). Single-configuration compound 016 (short retention time) MS m / z (ESI): 427.1 (M+1). 1 H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 9.78 (s, 1H), 8.84 (d, 1H), 7.61 (d, 1H), 7.35-7.33 (m, 2H), 7.29(d, 1H),7.04-7.02 (m, 3H), 4.51 (s, 1H), 3.15-3.07 (m, 2H), 2.68 (d, 1H), 2.35 (t, 1H), 2.26-2.21(m, 1H), 2.02-1.98(m, 1H), 1.82-1.77(m, 1H), 1.65-1.48 (m, 2H),1.11 (d, 3H). Single-configuration compound 017 (long retention time) MS m / z (ESI): 427.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 9.78 (s, 1H), 8.85 (d, 1H), 7.61 (d,, 1H), 7.35-7.33 (d,2H), 7.29(d, 1H),7.04-7.01 (m, 3H), 4.51 (s, 1H), 3.12-3.06 (m, 2H), 2.73-2.67(m, 1H), 2.33-2.23 (m,2H), 2.01-1.97(m, 1H), 1.82-1.78(m, 1H), 1.63-1.51(m, 2H), 1.11 (d, 3H).

[0242] Example 24 5-chloro-2-(4-((2-hydroxy-2-methylpropyl)amino)-6-(1H-pyrazol-1-yl)phthalazin-1-yl)-3-methylphenol (026)

[0243] [ka]

[0244] Step 1. Preparation of 1-((4-chloro-7-(1H-pyrazol-1-yl)phthalazin-1-yl)amino)-2-methylprop-2-ol (026a) Compound 024b (30 mg, 0.09 mmol) was dissolved in N,N-dimethylformamide (5 mL), and pyrazole (6 mg, 0.09 mmol), copper(I) oxide (2.6 mg, 0.02 mmol), cesium carbonate (88.66 mg, 0.27 mmol), and ferrous tris(acetylacetonate) (4.61 mg, 0.02 mmol) were added. The reaction flask was protected with nitrogen gas. Under nitrogen gas protection, the reaction mixture was reacted at 110 °C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using eluent system A to obtain the title compound 026a (30 mg, yield: 86.8%). MS m / z (ESI): 318.1 (M+1).

[0245] Step 2: Preparation of 5-chloro-2-(4-((2-hydroxy-2-methylpropyl)amino)-6-(1H-pyrazol-1-yl)phthalazin-1-yl)-3-methylphenol (026) Compound 026a (30 mg, 0.09 mmol) and (4-chloro-2-hydroxy-6-methylphenyl)boronic acid (19.36 mg, 0.10 mmol) were dissolved in a mixed solvent of 1,4-dioxane and water (3.3 mL, V / V=10:1), and then potassium carbonate (39.14 mg, 0.28 mmol) was added thereto. 1,1'-bisdiphenylphosphinoferrocenedichloropalladium (13.7 mg, 0.02 mmol) was added thereto, and the reaction system was stirred at 100°C for 2 hours under nitrogen gas protection. After the reaction was completed, the reaction solution was filtered, and the filtrate was collected and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative high-performance liquid chromatography (GILSON Prep LC with UV detector, chromatography column: Xtimate 10 μm C18 250 x 30 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 22% to 95%, flow rate: 50 mL / min) to obtain the title compound 026 (5 mg, yield: 12.5%, a pair of axially asymmetric isomers). MS m / z (ESI): 424.1 (M+1). 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.78 (d, 1H), 8.69 (d, 1H), 8.31 (dd, 1H), 7.88 (d, 1H), 7.51 (t, 1H), 7.41 (d, 1H), 6.93 (d, 1H), 6.88 (d, 1H), 6.69 (t,1H), 3.71 (m, 2H), 1.91 (s, 3H), 1.24 (s, 6H).

[0246] Example 25 2-((R)-3-((1-(4-chloro-2-hydroxyphenyl)pyrido[3,4-d]pyridazin-4-yl)amino)piperidin-1-yl)-N-cyclopropylpropanamide (041)

[0247] [ka]

[0248] Step 1. Preparation of methyl 2-((R)-3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)piperidin-1-yl)propionate (041a) Compound 009c (180 mg, 0.60 mmol) and methyl 2-bromopropionate (100 mg, 0.60 mmol) were dissolved in ultra-dry acetonitrile (10 mL), potassium carbonate (166 mg, 1.2 mmol) was added, and the reaction mixture was stirred at 80 °C for 16 h. The mixture was then extracted with ethyl acetate (10 mL × 3), washed with saturated brine, and the organic phase was collected and evaporated to give the crude product. The crude product was purified by silica gel column chromatography using eluent system B to give the title compound 041a (180 mg, 86% yield). MS m / z (ESI): 350.2 (M+1).

[0249] Step 2: Preparation of 2-((R)-3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)piperidin-1-yl)propionic acid (041b) Compound 041a (180 mg, 0.50 mmol) was dissolved in a mixed solvent of tetrahydrofuran and water (2 mL, V / V=1:1), and lithium hydroxide (37 mg, 1.50 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, and then the solvent was evaporated to dryness to give crude compound 041b (150 mg). The product was directly used in the next step without further purification. MS m / z (ESI): 336.1 (M+1).

[0250] Step 3 Preparation of 2-((R)-3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)piperidin-1-yl)-N-cyclopropylpropanamide (041c) Compound 041b (170 mg, 0.50 mmol) and cyclopropylamine (29 mg, 0.50 mmol) were dissolved in tetrahydrofuran (5 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (231 mg, 0.6 mmol) and N,N-diisopropylethylamine (131 mg, 1.00 mmol) were added. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography using eluent system A to obtain the title compound 041c (180 mg, yield: 95%). MS m / z (ESI): 375.2 (M+1).

[0251] Step 4. Preparation of 2-((R)-3-((1-(4-chloro-2-hydroxyphenyl)pyrido[3,4-d]pyridazin-4-yl)amino)piperidin-1-yl)-N-cyclopropylpropanamide (041) Compound 041c (180 mg, 0.48 mmol) was dissolved in a mixed solvent of dioxane and water (5.5 mL, V / V=10:1), and (4-chloro-2-hydroxyphenyl)boronic acid (91 mg, 0.53 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (70 mg, 0.10 mmol), and sodium carbonate (112 mg, 0.96 mmol) were added, and the reaction system was stirred at 100° C. for 1 hour. After completion of the reaction, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatography column: Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 10-minute gradient, gradient ratio: acetonitrile phase 18% to 28%, flow rate: 20 mL / min) to obtain the title compound 041 (5.34 mg, yield: 2%, a pair of non-enantiomer mixture). MS m / z (ESI): 467.2 (M+1). 1 H NMR (400 MHz, DMSO-d6) δ 9.78 (d, 1H), 8.85 (d, 1H), 8.29 (s, 1H), 7.82 (dd, 1H), 7.58 (d, 1H), 7.33 (dd, 1H), 7.29 (d, 1H), 7.03 (d, 2H), 4.50-4.48 (m, 1H), 3.06-3.00 (m, 2H), 2.68-2.65(m, 1H), 2.36-2.29 (m, 2H), 2.24-2.17 (m, 1H), 2.00-1.94 (m, 1H), 1.87-1.70 (m, 1H), 1.66-1.49 (m, 2H), 1.09 (t, 3H), 0.59-0.50 (m, 2H), 0.44-0.33 (m, 2H).

[0252] Example 26 2-(R)-3-((1-(4-chloro-2-hydroxyphenyl)pyrido[3,4-d]pyridazin-4-yl)amino)piperidin-1-yl)-1-(pyrrolidin-1-yl)prop-1-one (042)

[0253] [ka]

[0254] Using the synthetic route of Example 25, the starting material cyclopropylamine in Step 3 was replaced with tetrahydropyrrole (60 mg, 0.84 mmol). The final product was purified by preparative high-performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatography column: Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 20% to 40%, flow rate: 20 mL / min) to give the title product 042 (5 mg, yield: 11.7%). MS m / z (ESI): 481.2 (M+1). 1H NMR (400 MHz, CD3OD) δ 9.71 (d, 1H), 8.84 (d, 1H), 7.49 (d, 1H), 7.36 (dd, 1H), 7.03 (d, 2H), 4.62-4.58 (m, 1H), 3.87-3.79 (m, 1H), 3.65-3.59 (m, 1H), 3.58-3.52 (m, 1H), 3.50-3.46 (m, 1H), 3.45-3.39 (m, 2H), 2.86-2.69 (m, 1H), 2.68-2.60 (m, 1H), 2.60-2.50 (m, 1H), 1.97-1.65 (m, 8H), 1.26 (dd, 3H).

[0255] Example 27 (R)-2-(3-((1-(4-chloro-2-hydroxyphenyl)pyrido[3,4-d]pyridazin-4-yl)amino)piperidin-1-yl)-N-cyclopropyl-2-methylpropanamide (043)

[0256] [ka]

[0257] Using the synthetic route of Example 25, the starting material methyl 2-bromopropionate in Step 1 was replaced with ethyl 2-bromo-2-methylpropionate (300 mg, 1.54 mmol). The final product was purified by preparative high-performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatography column: Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 25% to 45%, flow rate: 20 mL / min) to give the title product 043 (8 mg, yield: 12.1%). MS m / z (ESI): 481.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 9.80 (s, 1H), 8.85 (d, 1H), 7.69 (d, 1H), 7.54 (d, 1H), 7.35-7.33 (m, 1H), 7.29 (d, 1H), 7.04-7.02 (m, 2H), 4.57-4.53 (m, 1H), 2.89-2.93 (m, 1H), 2.33-2.22 (m, 3H), 2.02-1.95 (m, 1H), 1.84-1.82 (m, 1H), 1.66-1.55 (m, 2H), 1.47-1.27 (m, 1H), 1.08 (d, 6H), 0.54-0.47 (m, 2H), 0.44-0.34(m, 2H).

[0258] Example 28 1-(1-(4-chloro-2-hydroxyphenyl)-4-((2-hydroxy-2-methylpropyl)amino)phthalazin-6-yl)ethan-1-one (057)

[0259] [ka]

[0260] Step 1. Preparation of 1-(1-chloro-4-((2-hydroxy-2-methylpropyl)amino)phthalazin-6-yl)ethan-1-one (057a) Compound 024b (100 mg, 0.30 mmol) was dissolved in ultra-dry dioxane (10 mL), bis(triphenylphosphine)palladium(II) dichloride (42 mg, 0.06 mmol) and tributyl(1-ethoxyvinyl)stannane (109 mg, 0.30 mmol) were added, and the reaction was stirred at 90 °C for 30 min under nitrogen gas protection. After completion of the reaction, the mixture was quenched by the dropwise addition of aqueous potassium fluoride (10 mL), stirred at room temperature for 10 min, and then extracted with ethyl acetate (15 mL x 3). The organic phase was collected and the solvent was evaporated to dryness to obtain the crude product. The crude product was dissolved in tetrahydrofuran (6 mL), concentrated hydrochloric acid (0.1 mL, 12 mol / L) was added, and the mixture was stirred at room temperature for 5 min. After the reaction was completed, the pH of the system was adjusted to neutral with saturated sodium bicarbonate solution, extracted with ethyl acetate (10 mL × 3), washed with saturated brine, and the organic phase was collected and the solvent was evaporated to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography with eluent system B to obtain the title compound 057a (40 mg, yield: 45%). MS m / z (ESI): 294.0 (M+1).

[0261] Step 2: Preparation of 1-(1-(4-chloro-2-hydroxy-6-methylphenyl)-4-((2-hydroxy-2-methylpropyl)amino)phthalazin-6-yl)ethyl-1-one (057) Compound 057a (40 mg, 0.13 mmol) was dissolved in a dioxane / water mixture (2.2 mL, V / V = 1:1), and (4-chloro-2-hydroxy-6-methylphenyl)boronic acid (30 mg, 0.16 mmol), 1,1'-bis(diphenylphosphinoferrocenedichloropalladium) (20 mg, 0.03 mmol), and potassium carbonate (9 mg, 0.27 mmol) were added. Under nitrogen gas protection, the reaction mixture was stirred at 100 °C for 2 hours. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative high-performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatography column: Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 10-minute gradient, gradient ratio: acetonitrile phase 32% to 100%, flow rate: 20 mL / min) to obtain the title compound 057 (1.53 mg, yield: 3%). MS m / z (ESI): 400.1 (M+1). 1 H NMR (400 MHz, CD3OD) δ 8.97 (d, 1H), 8.33 (dd, 1H), 7.54 (d, 1H), 6.99-6.78 (m, 2H), 3.83-3.69 (m, 2H), 2.77 (s, 3H), 1.97 (s, 3H), 1.34 (s, 6H).

[0262] Example 29 5-chloro-2-(6-(1-ethyl-1H-pyrazol-4-yl)-4-((2-hydroxy-2-methylpropyl)amino)phthalazin-1-yl)-3-methylphenol (051)

[0263] [ka]

[0264] Using the synthetic route of Example 18, the starting material 1-methylpyrazole-4-boronic acid pinacol ester in Step 1 was replaced with 1-ethylpyrazole-4-boronic acid pinacol ester (50 mg, 0.23 mmol). The reaction product of Step 2 was purified by preparative high-performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatography column: Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 18% to 100%, flow rate: 20 mL / min) to obtain the title product 051 (2.5 mg, yield: 12.6%, a pair of axially asymmetric isomers). MS m / z (ESI): 452.1 (M+1). 1 H NMR (400 MHz, CD3OD) δ 8.54 (d, 1H), 8.26 (s, 1H), 8.10 (s, 1H), 8.05 (dd, 1H), 7.45 (d, 1H), 6.91 (s, 1H), 6.84 (d, 1H), 4.26 (q, 2H), 3.74 (d, 2H), 1.99 (s, 3H), 1.52 (t, 3H), 1.35 (s, 6H).

[0265] Example 30 5-chloro-2-(4-((2-hydroxy-2-methylpropyl)amino)-6-(2H-1,2,3-triazol-2-yl)phthalazin-1-yl)-3-methylphenol (028)

[0266] [ka]

[0267] Using the synthetic route of Example 24, the starting material pyrazole in Step 1 was replaced with 1,2,3-triazole (20 mg, 0.29 mmol). The reaction product of Step 2 was purified by preparative high-performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatography column: Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 25% to 100%, flow rate: 20 mL / min) to obtain the title product 028 (2 mg, yield: 10.6%, a pair of axially asymmetric isomers). MS m / z (ESI): 425.1 (M+1). 1 H NMR (400 MHz, CD3OD) δ 9.02 (d, 1H), 8.57(dd, 1H), 8.05 (s, 2H), 7.64 (d, 1H), 6.92 (d, 1H), 6.85 (d, 1H), 3.76 (d, 2H), 2.01 (s, 3H), 1.34 (s, 6H).

[0268] Example 31 5-chloro-2-(4-((2-hydroxy-2-methylpropyl)amino)-6-(1H-1,2,3-triazol-1-yl)phthalazin-1-yl)-3-methylphenol (058)

[0269] [ka]

[0270] Using the synthetic route of Example 24, the starting material pyrazole in Step 1 was replaced with 1,2,3-triazole (20 mg, 0.29 mmol). The reaction product of Step 2 was purified by preparative high-performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatography column: Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 25% to 100%, flow rate: 20 mL / min) to obtain the title product 058 (3 mg, yield: 15.9%, a pair of axially asymmetric isomers). MS m / z (ESI): 425.1 (M+1). 1 H NMR (400 MHz, CD3OD) δ 9.28 (d, 1H), 8.79 (d, 1H), 8.60 (dd, 1H), 8.04 (d, 1H), 7.87 (d, 1H), 6.99 (d, 1H), 6.89 (d, 1H), 3.77 (d, 2H), 2.10 (s, 3H), 1.42 (s, 6H).

[0271] Example 32 (S)-3-((4-(4-chloro-2-hydroxyphenyl)-7-(prop-1-yn-1-yl)phthalazin-1-yl)amino)propane-1,2-diol (062)

[0272] [ka]

[0273] Step 1. Preparation of (S)-3-((7-bromo-4-chlorophthalazin-1-yl)amino)propane-1,2-diol (062a) Compound 024a (4 g, 0.014 mol) and (S)-3-aminopropane-1,2-diol (1.31 g, 0.014 mmol) were dissolved in ethanol (25 mL), heated to 80° C., and reacted for 4 hours. After completion of the reaction, the reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 062a (1.2 g, yield: 25%). MS m / z (ESI): 332.1 (M+1).

[0274] Step 2: Preparation of (S)-3-((4-chloro-7-(propyl-1-yn-1-yl)phthalazin-1-yl)amino)propane-1,2-diol (062b) Compound 062a (600 mg, 1.98 mmol), 1-(trimethylsilyl)propyne (178 mg, 1.59 mmol), cuprous iodide (151 mg, 0.79 mmol), cesium carbonate (646 mg, 1.98 mmol), and bis(triphenylphosphine)palladium(II) dichloride (278 mg, 0.39 mmol) were dissolved in a mixed solvent of N,N-dimethylacetamide and water (22 mL, V / V=10:1), heated to 100°C, and reacted for 4 hours. After completion of the reaction, the reaction solution was added to saturated ammonium chloride solution, extracted with ethyl acetate (10 mL x 3), filtered, and concentrated to obtain a crude product. The residue obtained was purified using silica gel column chromatography with eluent system A to obtain the title compound 062b (70 mg, yield: 13.5%). MS m / z (ESI): 292.1 (M+1).

[0275] Step 3: Preparation of (S)-3-((4-(4-chloro-2-hydroxyphenyl)-7-(prop-1-yn-1-yl)phthalazin-1-yl)amino)propane-1,2-diol (062) Compound 062b (50 mg, 0.17 mmol) was dissolved in a mixed solvent of dioxane and water (2.2 mL, V / V=10:1), and (4-chloro-2-hydroxyphenyl)boronic acid (30 mg, 0.17 mmol), 1,1'-bisdiphenylphosphinoferrocenedichloropalladium (12 mg, 0.02 mmol), and potassium carbonate (47 mg, 0.34 mmol) were added. The reaction mixture was stirred at 100°C for 1 hour under nitrogen gas protection. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (Waters MS triggered Prep-LC with Acquity QDA detector, chromatography column: Welch 10 μm C18 250 x 21.2 mm; mobile phase 1: water (containing 0.1% NH3); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 15% to 100%, flow rate: 25 mL / min) to obtain the title compound 062 (4.4 mg, yield: 6.7%). MS m / z (ESI): 384.1 (M+1) + . 1 H NMR (400 MHz, CD3OD) δ 8.25 (s, 1H), 7.72 (dd, 1H), 7.55 (d, 1H), 7.29 (d, 1H), 7.01 (d, 1H), 6.99 (s, 2H), 4.02-3.95 (m, 1H), 3.85-3.79 (m, 1H), 3.75-3.69 (m, 1H), 3.61 (d, 2H), 2.10 (s, 3H).

[0276] Example 33 (2S)-3-((4-(4-chloro-2-fluoro-6-hydroxyphenyl)-7-(prop-1-yn-1-yl)phthalazin-1-yl)amino)propane-1,2-diol (063)

[0277] [ka]

[0278] Step 1. Preparation of (2S)-3-((4-(4-chloro-2-fluoro-6-methoxyphenyl)-7-(propyl-1-yn-1-yl)phthalazin-1-yl)amino)propane-1,2-diol (063a) Compound 062b (80 mg, 0.27 mmol), 2-(4-chloro-2-fluoro-6-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (86.4 mg, 0.30 mmol, produced by the synthetic method disclosed in patent "WO2023275366A1"), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (21.6 mg, 0.027 mmol), and potassium carbonate (113.7 mg, 0.82 mmol) were dissolved in a mixed solvent of 1,4-dioxane and water (1.1 mL, V / V = 10:1), and the mixture was heated to 120 °C under nitrogen gas protection and reacted for 1 hour. After completion of the reaction, the reaction solution was filtered and concentrated, and the resulting residue was purified by silica gel column chromatography using eluent system A to give the title compound 063a (20 mg, yield: 18%). MS m / z (ESI): 416.1 (M+1).

[0279] Step 2: Preparation of (2S)-3-((4-(4-chloro-2-fluoro-6-hydroxyphenyl)-7-(propyl-1-yn-1-yl)phthalazin-1-yl)amino)propane-1,2-diol (063) Compound 063a (20 mg, 0.048 mmol) and lithium iodide (64.4 mg, 0.471 mmol) were dissolved in 2,4,6-trimethylpyridine (0.5 mL), and the reaction mixture was stirred at 130 °C for 1 h. After completion of the reaction, the crude product was purified by preparative high-performance liquid chromatography (Waters MS triggered Prep-LC with Acquity QDA detector, chromatography column Welch 10 μm C18 250 x 21.2 mm; mobile phase 1: water (containing 0.1% ammonia); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 15% to 100%, flow rate: 25 mL / min) to obtain the title compound 063 (1.02 mg, yield: 5.3%). MS m / z (ESI): 402.1 (M+1). 1 H NMR (400 MHz, CD3OD) δ 8.13 (s, 1H), 7.60 (dd, 1H), 7.48 (d, 1H), 6.46 (d, 1H), 6.25 (dd, 1H),5.25 (t, 1H), 3.91-3.85 (m, 1H), 3.75-3.65 (m, 2H), 3.52 (d, 2H), 2.01 (s, 3H).

[0280] Example 34 (2S)-3-((4-(2-fluoro-6-hydroxy-4-(trifluoromethyl)phenyl)-7-(prop-1-yn-1-yl)phthalazin-1-yl)amino)propane-1,2-diol (064)

[0281] [ka]

[0282] Step 1. Preparation of (2S)-3-((4-(2-fluoro-6-methoxy-4-(trifluoromethyl)phenyl)-7-(propyl-1-yn-1-yl)phthalazin-1-yl)amino)propane-1,2-diol (064a) Compound 062b (160 mg, 0.55 mmol), 2-(2-fluoro-6-methoxy-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (211 mg, 0.66 mmol, produced by the synthetic method disclosed in patent "WO2023275366A1"), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (43 mg, 0.055 mmol), and potassium carbonate (227 mg, 1.645 mmol) were dissolved in a mixed solvent of 1,4-dioxane and water (3.3 mL, V / V = 10:1), and the reaction system was heated to 100 ° C under nitrogen gas protection and reacted for 1 hour. After completion of the reaction, the reaction solution was filtered and concentrated, and the resulting residue was purified by silica gel column chromatography using eluent system A to give the title compound 064a (70 mg, yield: 28%). MS m / z (ESI): 450.1 (M+1).

[0283] Step 2: Preparation of (2S)-3-((4-(2-fluoro-6-hydroxy-4-(trifluoromethyl)phenyl)-7-(prop-1-yn-1-yl)phthalazin-1-yl)amino)propane-1,2-diol (064) Compound 064a (70 mg, 0.16 mmol) and lithium iodide (209 mg, 1.56 mmol) were dissolved in 2,4,6-trimethylpyridine (0.5 mL), and the reaction mixture was stirred at 130 °C for 1 hour. After completion of the reaction, the crude product was purified by preparative high-performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, chromatography column Welch 10 μm C18 250 x 21.2 mm; mobile phase 1: water (containing 0.1% ammonia); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 25% to 100%, flow rate: 25 mL / min) to obtain the title compound 064 (20 mg, yield: 15%). MS m / z (ESI): 436.1 (M+1). 1H NMR (400 MHz, CD3OD) δ 8.36 (s, 1H), 7.79 (dd, 1H), 7.45 (d, 1H), 7.11 (d, 2H), 4.06-3.99 (m, 1H), 3.85 (dd, 1H), 3.75 (dd, 1H), 3.63 (d, 2H), 2.11 (s, 3H).

[0284] Example 35 (S)-3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)-7-(prop-1-yn-1-yl)phthalazin-1-yl)amino)propane-1,2-diol (056)

[0285] [ka]

[0286] Step 1: Preparation of (S)-3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)-7-(prop-1-yn-1-yl)phthalazin-1-yl)amino)propane-1,2-diol (056) Compound 062b (70 mg, 0.24 mmol), 1,1-bis(diphenylphosphino)ferrocenedichloropalladium (17.6 mg, 0.024 mmol), (4-trifluoromethyl-2-hydroxyphenyl)boronic acid (54.6 mg, 0.26 mmol), and sodium carbonate (50.9 mg, 0.48 mmol) were dissolved in a mixed solvent of 1,4-dioxane and water (6 mL, V / V = 5:1), and the reaction system was heated to 90°C under nitrogen gas protection and reacted for 1 hour. After completion of the reaction, the reaction solution was filtered and concentrated, and the crude product was purified by preparative high-performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, chromatography column Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 25% to 100%, flow rate: 25 mL / min) to obtain the title compound 056 (11.4 mg, yield: 11.4%). MS m / z (ESI): 418.1 (M+1). 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.29 (d, 1H), 7.73 (d, 1H), 7.67 (s, 1H), 7.51 (d, 1H), 7.38 (d, 1H), 7.28 (d, 2H), 3.85 (dd, 1H), 3.70 (d, 1H), 3.54 (d, 1H), 3.42 (s, 2H), 2.13 (s, 3H).

[0287] Example 36 2-(4-(((1S,3S)-3-hydroxy-3-methylcyclobutyl)amino)-6-(prop-1-yn-1-yl)phthalazin-1-yl)-5-(trifluoromethyl)phenol (065)

[0288] [ka]

[0289] Step 1 (1S,3S)-3-((7-bromo-4-chlorophthalazin-1-yl)amino)-1-methylcyclobut-1-ol (065a) Compound 024a (1 g, 3.6 mmol) was dissolved in N-methylpyrrolidone (5 mL), and (1S,3S)-3-amino-1-methylcyclobut-1-ol (0.36 g, 3.6 mmol) and N,N-diisopropylethylamine (2.33 g, 18 mmol) were added. The reaction mixture was stirred at 100°C for 3 hours. After completion of the reaction, the reaction mixture was washed three times with saturated brine and ethyl acetate. The organic phase was collected, rotary evaporated, and concentrated. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 065a (200 mg, yield: 17%). MS m / z (ESI): 342.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, 1H), 8.14 (dd, 1H), 7.98 (d, 1H), 7.85 (d, 1H), 5.01 (s, 1H), 4.16-4.07 (m, 1H), 2.45 (ddd, 2H), 2.20-2.07 (m, 2H), 1.32 (s, 3H).

[0290] Step 2 Preparation of (1S,3S)-3-((4-chloro-7-(prop-1-yn-1-yl)phthalazin-1-yl)amino)-1-methylcyclobut-1-ol (065b) Compound 065a (50 mg, 0.15 mmol) was dissolved in a mixed solvent of N,N-dimethylacetamide, methanol, and water (6 mL, V / V / V = 1:1:1), and 1-(trimethylsilyl)propyne (13.1 mg, 0.12 mmol), bis(triphenylphosphine)palladium(II) dichloride (10 mg, 0.015 mmol), copper iodide (2.8 mg, 0.015 mmol), and cesium carbonate (71 mg, 0.22 mmol) were added. The reaction mixture was stirred at 80°C for 2 hours under nitrogen gas protection. After completion of the reaction, the reaction mixture was concentrated, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 065b (25 mg, yield: 57%). MS m / z (ESI): 302.1 (M+1).

[0291] Step 3: Preparation of 2-(4-((1S,3S)-3-hydroxy-3-methylcyclobutyl)amino)-6-(prop-1-yn-1-yl)phthalazin-1-yl)-5-(trifluoromethyl)phenol (065) Compound 065b (40 mg, 0.13 mmol) was dissolved in a dioxane / water mixture (5.5 mL, V / V = 10:1), and (4-trifluoromethyl-2-hydroxyphenyl)boronic acid (21.8 mg, 0.11 mmol), sodium carbonate (42 mg, 0.40 mmol), and 1,1'-bis(diphenylphosphinoferrocenedichloropalladium) (9.7 mg, 0.013 mmol) were added. The reaction mixture was stirred at 100 °C under nitrogen gas protection for 1 hour. After completion of the reaction, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (Waters MS triggered Prep-LC with Acquity QDA detector, chromatography column: Welch 10 μm C18 250 x 21.2 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 25% to 100%, flow rate: 25 mL / min) to obtain the title compound 065 (7 mg, yield: 12.4%). MS m / z (ESI): 428.1 (M+1). 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.75-7.65 (m, 2H), 7.50 (d, 1H), 7.37 (d, 1H), 7.32-7.24 (m, 2H), 5.00 (s, 1H), 4.23 (dd, 1H), 2.48-2.42 (m, 2H), 2.18 (d, 2H), 2.13 (s, 3H), 1.34 (s, 3H).

[0292] Example 37 3-Fluoro-2-(4-(((1S,3S)-3-hydroxy-3-methylcyclobutyl)amino)-6-(prop-1-yn-1-yl)phthalazin-1-yl)-5-(trifluoromethyl)phenol (066)

[0293] [ka]

[0294] Using the synthetic route of Example 34, starting material 062b in Step 1 was replaced with 065a (100 mg, 0.33 mmol). The final product was purified by preparative high-performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatography column: Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 20% to 100%, flow rate: 20 mL / min) to give the title compound 066 (13.8 mg, yield: 18%). MS m / z (ESI): 446.1 (M+1). 1 H NMR (400 MHz, CD3OD) δ 8.55 (s, 1H), 7.85 (dd, 1H), 7.50 (d, 1H), 7.13 (d, 1H), 7.11 (s, 1H), 4.26-4.16 (m, 1H), 2.75-2.66 (m, 2H), 2.32 (dd, 2H), 2.12 (s, 3H), 1.45 (s, 3H).

[0295] Example 38 2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)-6-(prop-1-yn-1-yl)phthalazin-1-yl)-5-(trifluoromethyl)phenol (061)

[0296] [ka]

[0297] Using the synthetic route of Example 36, the starting material (1S,3S)-3-amino-1-methylcyclobut-1-ol in Step 1 was replaced with (1R,2R)-2-aminocyclohexan-1-ol (1.3 g, 10.8 mmol). The final product was purified by preparative high-performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatography column: Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 29% to 100%, flow rate: 20 mL / min) to give the title compound 061 (10 mg, yield: 8%). MS m / z (ESI): 442.1 (M+1). 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.25 (s, 1H), 7.70 (d, 1H), 7.49 (d, 1H), 7.36 (d, 1H), 7.31-7.20 (m, 3H), 2.69-2.64 (m, 1H), 2.35-2.31 (m, 1H), 2.12 (s, 3H), 2.01-1.94 (m, 2H), 1.75-1.64 (m, 2H), 1.34-1.26 (m,, 4H).

[0298] Example 39 (3R,4R)-3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)-7-(prop-1-yn-1-yl)phthalazin-1-yl)amino)tetrahydro-2H-pyran-4-ol (067)

[0299] [ka]

[0300] Using the synthetic route of Example 36, the starting material (1S,3S)-3-amino-1-methylcyclobut-1-ol in Step 1 was replaced with (3R,4R)-3-aminotetrahydro-2H-pyran-4-ol (460 mg, 3.96 mmol). The final product was purified by preparative high-performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatography column: Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 28% to 38%, flow rate: 20 mL / min) to give the title compound 067 (1.73 mg, yield: 4%). MS m / z (ESI): 444.2 (M+1) + . 1 H NMR (400 MHz, CD3OD) δ 8.36 (s, 1H), 7.71 (d, 1H), 7.50 (d, 2H), 7.27 (d, 1H), 7.22 (s, 1H), 4.40-4.33 (m, 1H), 4.24(dd, 1H), 4.00-3.90 (m, 2H), 3.56-3.48 (m, 2H), 2.09 (s, 3H), 1.81-1.66 (m, 2H).

[0301] Example 40 (R)-2-(4-((1-methylpiperidin-3-yl)amino)-6-(prop-1-yn-1-yl)phthalazin-1-yl)-5-(trifluoromethyl)phenol (068)

[0302] [ka]

[0303] Using the synthetic route of Example 36, the starting material (1S,3S)-3-amino-1-methylcyclobut-1-ol in Step 1 was replaced with (R)-1-methylpiperidin-3-amine (0.41 g, 3.6 mmol). The final product was separated and purified by preparative high-performance liquid chromatography (Waters MS triggered Prep-LC with Acquity QDA detector, chromatography column: Xtimate C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 25% to 100%, flow rate: 25 mL / min;) to obtain the title compound 068 (6 mg, yield: 7.1%). MS m / z (ESI): 441.1 (M+1). 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.35 (s, 1H), 7.72 (d, 1H), 7.51 (d, 1H), 7.37 (d, 1H), 7.29-7.27 (m, 2H), 7.22 (d,1H), 4.42-4.38(m, 1H), 2.73-2.67 (m, 2H), 2.21 (s, 3H), 2.13 (s, 3H), 1.99-1.96(m, 1H), 1.93-1.87 (m, 2H), 1.77-1.74 (m, 1H), 1.64-1.57 (m, 1H), 1.49-1.41 (m, 1H).

[0304] Example 41 2-(4-((2-hydroxy-2-methylpropyl)amino)-6-(prop-1-yn-1-yl)phthalazin-1-yl)-5-(trifluoromethyl)phenol (069)

[0305] [ka]

[0306] Using the synthetic route of Example 36, the starting material (1S,3S)-3-amino-1-methylcyclobut-1-ol in Step 1 was replaced with 1-amino-2-methyl-2-propanol (175 mg, 2.0 mmol). The final product was purified by preparative high-performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatography column Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% trifluoroacetic acid); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 42% to 100%, flow rate: 20 mL / min) to obtain the title compound 069 (2.1 mg, yield: 2.8%). MS m / z (ESI): 416.1 (M+1). 1 H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.85 (s, 1H), 7.96 (d, 1H), 7.55 (t, 2H), 7.35 (d, 2H), 3.66 (d, 2H), 2.17 (s, 3H), 1.27 (s, 6H).

[0307] Example 42 2-(4-((1R,3S)-3-hydroxycyclohexyl)amino)-6-(prop-1-yn-1-yl)phthalazin-1-yl)-5-(trifluoromethyl)phenol (070)

[0308] [ka]

[0309] Using the synthetic route of Example 36, the starting material (1S,3S)-3-amino-1-methylcyclobut-1-ol in Step 1 was replaced with (1S,3R)-3-aminocyclohexan-1-ol (0.55 g, 3.6 mmol). The final product was purified by preparative high-performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, chromatography column: Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 30% to 100%, flow rate: 25 mL / min) to give the title compound 070 (12.4 mg, yield: 10%). MS m / z (ESI): 442.1 (M+1). 1 H NMR (400 MHz, CD3OD) δ 8.37 (s, 1H), 7.75 (dd, 1H), 7.55 (d, 1H), 7.53 (d, 1H), 7.31 (d, 1H), 7.26 (s,1H), 4.35-4.29 (m, 1H), 3.81-3.75 (m, 1H), 2.43 (d, 1H), 2.12 (s, 3H), 2.00 (d, 1H), 1.95-1.84 (m, 1H), 1.56-1.40 (m, 3H), 1.40-1.23 (m, 2H).

[0310] Example 43 3-Fluoro-2-(4-(((S)-2-hydroxypropyl)amino)-6-(prop-1-yn-1-yl)phthalazin-1-yl)-5-(trifluoromethyl)phenol (071)

[0311] [ka]

[0312] Step 1: Preparation of (S)-1-(7-bromo-4-chlorophthalazin-1-yl)amino)propan-2-ol (071a) Compound 024a (2.5 g, 9 mmol) and (S)-1-amino-2-propanol (0.68 g, 9 mmol) were dissolved in N-methyl-2-pyrrolidinone (25 mL), N,N-diisopropylethylamine (1.2 g, 9 mmol) was added, and the mixture was heated to 100 °C and reacted for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate (150 mL x 3), and the organic solvent was concentrated to give the crude product. The crude product was purified by silica gel column chromatography using eluent system B to give the title compound 071a (1.3 g, yield: 45%). MS m / z (ESI): 316.1 (M+1).

[0313] The subsequent synthetic route used the synthetic route of Example 34, replacing starting material 062b in Step 1 with 071a (500 mg, 1.59 mmol). The final product was purified by preparative high-performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, chromatography column Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 25% to 100%, flow rate: 25 mL / min) to give the title compound 071 (2.05 mg, yield: 5%). MS m / z (ESI): 420.1 (M+1). 1 H NMR (400 MHz, CD3OD) δ 8.23 ​​(s, 1H), 7.65 (d, 1H), 7.31 (d, 1H), 6.99-6.98 (m, 2H), 4.10 (dd, 1H), 3.64 (dd, 1H), 3.49 (dd, 1H), 2.01 (s, 3H), 1.18 (d, 3H).

[0314] Example 44 (R)-4-((4-(4-chloro-2-hydroxyphenyl)-7-(prop-1-yn-1-yl)phthalazin-1-yl)amino)-1-(2-hydroxyethyl)pyrrolidin-2-one (073)

[0315] [ka]

[0316] Step 1: Preparation of ethyl (R)-2-(4-((tert-butoxycarbonyl)amino)-2-oxopyrrolidin-1-yl)acetate (073b) The compound (R)-tert-butyl(5-oxopyrrolidin-3-yl)aminocarboxylate 073a (600 mg, 3.00 mmol) was dissolved in tetrahydrofuran (40 mL), and NaH (180 mg, 7.49 mmol) was slowly added at 0° C. The reaction mixture was stirred at 0° C. for 1 hour, and then ethyl bromoacetate (600 mg, 3.60 mmol) was added. The reaction was allowed to proceed at room temperature for 3 hours. After completion of the reaction, the mixture was quenched by adding ammonium chloride solution (5 mL). The mixture was extracted with ethyl acetate, and the organic phase was collected, dried, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography purification system B to obtain the title compound 073b (850 mg, 89%) as a white solid. MS m / z (ESI): 287.3 (M+1).

[0317] Step 2: Preparation of tert-butyl (R)-(1-(2-hydroxyethyl)-5-oxopyrrolidin-3-yl)aminocarboxylate (073c) Compound 073b (850 mg, 2.85 mmol) was dissolved in tert-butanol / methanol (16.8 mL, V / V=10:1), and then sodium borohydride (297 mg, 7.85 mmol) was added and the reaction was stirred at 80° C. for 2 hours. After completion of the reaction, the mixture was quenched by adding ice water, concentrated under reduced pressure, extracted with ethyl acetate, and the organic phase was collected, dried, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography purification system B to obtain the title compound 073c (720 mg, 85.20%). MS m / z (ESI): 245.2 (M+1) Step 3 Preparation of (R)-4-amino-1-(2-hydroxyethyl)pyrrolidin-2-one (073d) Compound 073c (720 mg, 2.95 mmol) was dissolved in a 4 M solution of hydrochloric acid in dioxane (10 mL) and stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to give crude product 073d (620 mg, 87.55%). MS m / z (ESI): 145.1 (M+1).

[0318] Step 4 Preparation of (R)-4-((7-bromo-4-chlorophthalic acid-1-yl)amino)-1-(2-hydroxyethyl)pyrrolidin-2-one (073e) Compound 073d (620 mg, 4.31 mmol) was dissolved in N-methylpyrrolidone (10 mL), and then compound 024a (1.2 g, 4.32 mmol) and N,N-diisopropylethylamine (3 mL) were added. The reaction mixture was stirred at 100° C. for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography System A to obtain the title compound 073e (500 mg, 37.60%). MS m / z (ESI): 386.6 (M+1).

[0319] Step 5 Preparation of (R)-4-((4-chloro-7-(prop-1-yn-1-yl)phthalazin-1-yl)amino)-1-(2-hydroxyethyl)pyrrolidin-2-one (073f) Compound 073e (200 mg, 0.051 mmol) was dissolved in N,N-dimethylacetamide (3 mL), followed by the addition of copper iodide (30 mg, 0.52 mmol), bis(triphenylphosphine)palladium(II) dichloride (55 mg, 0.078 mmol), 1-(trimethylsilyl)propyne (18 mg, 0.45 mmol), and cesium carbonate (180 mg, 0.55 mmol). The reaction mixture was stirred at 50°C for 2 hours under nitrogen gas protection. After completion of the reaction, the reaction mixture was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography purification system A to obtain the title compound 073f (110 mg, 55.36%). MS m / z (ESI): 345.1 (M+1).

[0320] Step 6. Preparation of (R)-4-((4-(4-chloro-2-hydroxyphenyl)-7-(prop-1-yn-1-yl)phthalazin-1-yl)amino)-1-(2-hydroxyethyl)pyrrolidin-2-one (073) Compound 073f (30 mg, 0.087 mmol) was dissolved in a mixed solvent of dioxane and water (5 mL, V / V=10:1), and the compound (4-chloro-2-hydroxyphenyl)boronic acid (17 mg, 0.096 mmol), sodium carbonate (18 mg, 0.17 mmol), and 1,1′-bis(di-tert-butylphosphino)ferrocenedichloropalladium (13 mg, 0.02 mmol) were added. The reaction mixture was stirred at 100°C for 1 hour under nitrogen gas protection. After completion of the reaction, the mixture was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative high-performance liquid chromatography (Waters MS triggered Prep-LC with Acquity QDA detector, chromatography column: Welch 10µm C18 250 x 21.2mm; mobile phase 1: water (containing 0.1% FA); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 20% to 100%, flow rate: 20mL / min) to obtain the title compound 073 (4mg, yield: 10.5%). MS m / z (ESI): 437.8(M+1) 1H NMR (400 MHz, CD3OD) δ 8.37 (s, 1H), 7.76 (d, 1H), 7.60 (d, 1H), 7.34 (d, 1H), 7.05 (d, 2H), 4.89 (s, 1H),4.16-4.12 (m, 1H), 3.75-3.74 (m, 2H), 3.67-3.65 (m, 1H), 3.50-3.49 (m, 2H), 3.05-2.99 (m, 1H), 2.74-2.69 (m, 1H), 2.12 (s, 3H).

[0321] Example 45 (R)-3-((4-(4-chloro-2-hydroxyphenyl)-7-(prop-1-yn-1-yl)phthalazin-1-yl)amino)-1-(2-hydroxyethyl)pyrrolidin-2-one (074)

[0322] [ka]

[0323] Using the synthetic route of Example 44, the starting material (R)-(5-oxopyrrolidin-3-yl)aminocarboxylate tert-butyl ester in Step 1 was replaced with (R)-(2-oxopyrrolidin-3-yl)aminocarboxylate tert-butyl ester (500 mg, 2.5 mmol). The final product was purified by preparative high-performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, chromatography column: Gemini 5 μm C18 100 x 21.2 mm; mobile phase 1: water (containing 0.1% FA); mobile phase 2: acetonitrile; 10-minute gradient, gradient ratio: acetonitrile phase 24% to 100%, flow rate: 25 mL / min) to obtain the title compound 074 (2.5 mg, yield: 7%). MS m / z (ESI): 437.1 (M+1). 1H NMR (400 MHz, CD3OD) δ 8.26 (s, 1H), 7.72 (d, 1H), 7.55 (d, 1H), 7.29 (d, 1H), 7.03-6.97 (m, 2H), 3.76 (dd, 2H), 3.70-3.61 (m, 2H), 3.52-3.44 (m, 2H), 2.65 (dt, 1H), 2.32-2.14 (m, 2H), 2.10 (s, 3H).

[0324] Example 46 (R)-3-((4-(4-chloro-2-hydroxyphenyl)-7-(prop-1-yn-1-yl)phthalazin-1-yl)amino)-1-(2-hydroxyethyl)piperidin-2-one (075)

[0325] [ka]

[0326] Using the synthetic route of Example 44, the starting material (R)-(5-oxopyrrolidin-3-yl)aminocarboxylate tert-butyl ester in Step 1 was replaced with (R)-(2-oxopiperidin-3-yl)aminocarboxylate tert-butyl ester (1.5 g, 7 mmol). The final product was purified by preparative high-performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatography column Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 20% to 100%, flow rate: 20 mL / min) to give the title compound 075 (1.42 mg, yield: 5%). MS m / z (ESI): 451.1 (M+1). 1H NMR (400 MHz, CD3OD) δ 8.17 (s, 1H), 7.63 (d, 1H), 7.45 (d, 1H), 7.20 (d, 1H), 6.91 (d, 2H), 4.72-4.61 (m, 1H), 3.67-3.40 (m, 6H), 2.29-2.10 (m, 2H), 1.99 (s, 3H), 1.96-1.91 (m, 2H).

[0327] Example 47 (R)-5-((4-(4-chloro-2-hydroxyphenyl)-7-(prop-1-yn-1-yl)phthalazin-1-yl)amino)-1-(2-hydroxyethyl)piperidin-2-one (076)

[0328] [ka]

[0329] Using the synthetic route of Example 44, the starting material (R)-(5-oxopyrrolidin-3-yl)aminocarboxylate tert-butyl ester in Step 1 was replaced with (R)-(6-oxopiperidin-3-yl)aminocarboxylate tert-butyl ester (600 mg, 3 mmol). The crude product was purified by preparative high-performance liquid chromatography (Waters MS triggered Prep-LC with Acquity QDA detector, chromatography column Welch 10 μm C18 250 x 21.2 mm; mobile phase 1: water (containing 0.1% aqueous ammonia); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 30% to 100%, flow rate: 25 mL / min) to obtain the title compound 076 (1.07 mg, yield: 2%). MS m / z (ESI): 451.1 (M+1). 1H NMR (400 MHz, CD3OD) δ 8.25 (s, 1H), 7.63 (d, 1H), 7.46 (d, 1H), 7.20 (d, 1H), 6.90-6.86 (m, 2H), 4.68-4.60 (m, 1H), 3.84-3.82 (m, 1H), 3.65-3.63 (m, 2H), 3.58-3.26 (m, 3H), 2.49 (t, 2H), 2.08- 2.06 (m, 1H), 2.00 (s, 3H), 1.94-1.92 (m, 1H).

[0330] Example 48 2-(4-(((1S,2S)-3-(difluoroethylene)-2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol 2-(4-(((1R,2R)-3-(difluoroethylene)-2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol

[0331] [ka]

[0332] Step 1. Preparation of N-(4-methoxybenzyl)cyclohex-2-en-1-amine (077b) Compound 3-bromocyclohexene 077a (10 g, 0.062 mol) was dissolved in acetonitrile (100 mL), and compound 4-methoxybenzylamine (17.04 g, 0.12 mol) and potassium carbonate (8.58 g, 0.062 mol) were added sequentially. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction mixture was filtered. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography using eluent system B to obtain the title compound 077b (10 g, 66.7%). MS m / z (ESI): 218.1(M+1).

[0333] Step 2 Preparation of tert-butyl cyclohex-2-en-1-yl(4-methoxybenzyl)aminocarboxylate (077c) Compound 077b (10 g, 0.046 mol) was dissolved in ethyl acetate (100 mL), and di-tert-butyl dicarbonate (10.04 g, 0.046 mol) was added to the reaction mixture, followed by stirring at room temperature for 4 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography, System B, to obtain the title compound 077c (14.8 g, 91%). MS m / z (ESI): 318.4(M+1).

[0334] Step 3 Preparation of tert-butyl (2,3-dihydroxycyclohexyl)(4-methoxybenzyl)aminocarboxylate (077d) Compound 077c (14.8 g, 0.047 mol) was dissolved in a tert-butanol / water mixture (100 mL, V / V = 5:1), and 1-methylpiperidine 1-oxide (5.99 g, 0.051 mol) and potassium osmate dihydrate (1.46 g, 0.0047 mol) were added sequentially. The reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the mixture was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography using Separation System B to obtain the title compound 077d (17.6 g, 91%, a pair of enantiomers). MS m / z (ESI): 352.4 (M+1).

[0335] Step 4. Preparation of 7-hydroxy-3-(4-methoxybenzyl)hexahydrobenzo[d]oxazol-2(3H)-one (077e) Compound 077d (17.6 g, 0.0050 mol) was dissolved in N,N-dimethylformamide (80 mL), and compound NaH (3.59 g, 0.14 mol) was added. The reaction was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was quenched by adding ice water and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography separation system B to obtain the title compound 077e (12.6 g, 77.3%, a pair of enantiomers). MS m / z (ESI): 277.3 (M+1).

[0336] Step 5. Preparation of 3-(4-methoxybenzyl)tetrahydrobenzo[d]oxazole-2,7(3H,4H)-dione (077f) Compound 077e (12 g, 0.043 mol) was dissolved in dichloromethane (100 mL) and compound pyridinium chlorochromate (28 g, 0.13 mol) was added. The reaction was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified using separation system B of silica gel column chromatography to obtain the title compound 077f (8.6 g, 64.9%, a pair of enantiomers). MS m / z (ESI): 275.3 (M+1).

[0337] Step 6 Preparation of 7-(difluoromethylene)-3-(4-methoxybenzyl)hexahydrobenzo[d]oxazol-2(3H)-one (0.77g) Compound 077f (2.4 g, 8.7 mmol) was dissolved in N-methylpyrrolidone (20 mL), and difluoro(triphenylphosphonio)acetate (3.72 g, 10.44 mmol) was added. Under a nitrogen gas atmosphere, the reaction mixture was stirred at 80 ° C for 12 hours. After the reaction was completed, saturated aqueous ammonium chloride solution was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified using separation system B of silica gel column chromatography to obtain the title compound 077g (240 mg, 10.3%, a pair of enantiomers). MS m / z (ESI): 310.1 (M+1).

[0338] Step 7 Preparation of 7-(difluoromethylene)hexahydrobenzo[d]oxazol-2(3H)-one (077h) Compound 077g (100 mg, 0.32 mmol) was dissolved in a mixed solvent of acetonitrile and water (6 mL, V / V = 5:1), and cerium(IV) ammonium nitrate (886.2 mg, 1.6 mmol) was added to the reaction solution and stirred at room temperature for 1 hour. Saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified using separation system B of silica gel column chromatography to obtain the title compound 077h (30 mg, 44.1%). MS m / z (ESI): 190.2 (M+1).

[0339] Step 8 Preparation of 2-amino-6-(difluoroylidene)cyclohex-1-ol (077i) Compound 077h (30 mg, 0.15 mmol) was dissolved in 10% aqueous lithium hydroxide solution (2 mL), and the reaction mixture was stirred at 80°C for 1 hour. After the reaction was completed, the mixture was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound 077i (20 mg, 70%, a pair of enantiomers). MS m / z (ESI): 164.2 (M+1).

[0340] Step 9 Preparation of 2-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)-6-(difluoroylidene)cyclohex-1-ol (077j) Compound 077i (40 mg, 0.24 mmol) was dissolved in N-methylpyrrolidone (2 mL), and compound 009a (49 mg, 0.24 mmol) and N,N-diisopropylethylamine (95 mg, 0.73 mmol) were added. The reaction mixture was stirred at 100°C for 1 hour. After the reaction was completed, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified using silica gel column chromatography separation system B to obtain the title compound 077j (40 mg, 50.3%, a pair of enantiomers). MS m / z (ESI): 327.1 (M+1).

[0341] Step 10 2-(4-((-3-(difluoroethylene)-2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol 077 Compound 077j (40 mg, 0.12 mmol) was dissolved in a dioxane / water mixture (2.2 mL, V / V = 10:1), and the compound (4-trifluoromethyl-2-hydroxyphenyl)boronic acid (30.2 mg, 0.15 mmol), sodium carbonate (38.92 mg, 0.36 mmol), and 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (8.88 mg, 0.012 mmol) were added. The reaction mixture was stirred at 100 °C for 1 hour under nitrogen gas protection. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (Waters MS triggered Prep-LC with Acquity QDA detector, chromatography column: Welch 10 μm C18 250 x 21.2 mm; mobile phase 1: water (containing 0.1% aqueous ammonia); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 35% to 100%, flow rate: 25 mL / min) to obtain the title compound 077 (14 mg, yield: 8%, a pair of enantiomers). MS m / z (ESI): 453.4 (M+1).

[0342] Step 11 2-(4-(((1S,2S)-3-(difluoroethylene)-2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol 2-(4-(((1R,2R)-3-(difluoroethylene)-2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol Compound 077k (13 mg) was purified by SFC preparative chromatography (SFC 150 chromatography column: Daicel CHIRALCEL IC, 250 mm × 30 mm ID, 10 μm; mobile phase 1: carbon dioxide; mobile phase 2: methanol (0.2% aqueous ammonia, 7 M methanol solution); 6-minute gradient, gradient ratio carbon dioxide:methanol phase = 80 / 20, flow rate: 2 mL / min) to give the title compound 077-1 (6.00 mg) and the title compound 077-2 (6.2 mg). 077-1: (Single configuration compound with short retention time) MS m / z (ESI): 453.4 (M+1). 1 H NMR (400 MHz, CD3OD) δ 9.74 (s, 1H), 8.83 (d, 1H), 7.54 (d, 1H), 7.48 (d, 1H), 7.26-7.22 (m, 2H), 4.43-4.38 (m, 1H), 2.26-2.02 (m, 3H), 1.97-1.92 (m, 1H), 1.84-1.74 (m, 2H), 1.59-1.48 (m, 1H). 077-2: (single configuration compound with long retention time) MS m / z (ESI): 453.4 (M+1). 1H NMR (400 MHz, CD3OD) δ 9.68 (s, 1H), 8.80 (d, 1H), 7.53 (d, 1H), 7.44 (d, 1H), 7.26 (d, 1H), 7.21 (s, 1H), 4.57-4.55 (m, 1H), 2.26-2.12 (m,3H), 2.02-1.97 (m, 1H), 1.89-1.82 (m, 2H), 1.69-1.65 (m, 1H).

[0343] Example 49 5-chloro-2-(4-(((1S,2S)-3-(difluoroethylene)-2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol 5-chloro-2-(4-(((1R,2R)-3-(difluoroethylene)-2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol

[0344] [ka]

[0345] Compound 077j (40 mg, 0.12 mmol) was dissolved in a dioxane / water mixture (2.2 mL, V / V = 10:1), and (4-chloro-2-hydroxyphenyl)boronic acid (23 mg, 0.13 mmol), sodium carbonate (38.9 mg, 0.36 mmol), and 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (9 mg, 0.012 mmol) were added. The reaction mixture was stirred at 100 °C under nitrogen gas protection for 1 hour. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 078. The crude product was purified by preparative high-performance liquid chromatography (Waters MS triggered Prep-LC with Acquity QDA detector, chromatography column: Welch 10 μm C18 250 x 21.2 mm; mobile phase 1: water (containing 0.1% aqueous ammonia); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 27% to 100%, flow rate: 25 mL / min) to obtain the racemic compound (15 mg). This was then purified by SFC preparative chromatography (SFC 150, chromatography column: Daicel CHIRALCEL IC, 250 mm x 30 mm). Purification was performed using a 6-minute gradient (ID, 10 μm; mobile phase 1: carbon dioxide; mobile phase 2: methanol (0.2% aqueous ammonia, 7 M methanol solution); gradient ratio: carbon dioxide:methanol phase = 80 / 20, flow rate: 2 mL / min) to obtain the title compound 078-1 (6.8 mg) and the title compound 078-2 (7.02 mg). 078-1: (Single configuration compound with short retention time) MS m / z (ESI): 419.0 (M+1). 1 H NMR (400 MHz, CD3OD) δ 9.61 (s, 1H), 8.75 (d, 1H), 7.41 (d, 1H), 7.27 (d, 1H), 6.95-6.92 (m, 2H), 4.51 (d, 1H), 2.22-2.06 (m, 3H), 1.96-1.86 (m, 1H), 1.83-1.76 (m, 2H), 1.64-1.62 (m, 1H). 078-2: (single configuration compound with long retention time) MS m / z (ESI): 419.0 (M+1). 1 H NMR (400 MHz, CD3OD) δ 9.58 (s, 1H), 8.71 (d, 1H), 7.38 (d, 1H), 7.25 (d, 1H), 6.92-6.89 (m, 2H), 4.50 (d, 1H), 2.18-2.08 (m, 3H), 1.94-1.88 (m, 1H), 1.77-1.73 (m, 2H), 1.61-1.58 (m, 1H).

[0346] Example 50 (S)-3-((4-(4-chloro-2-hydroxyphenyl)-7-(cyclopropylethynyl)phthalazin-1-yl)amino)propane-1,2-diol (079)

[0347] [ka]

[0348] Using the synthetic route of Example 32, the starting material 1-(trimethylsilyl)propyne in Step 2 was replaced with cyclopropylacetylene (52 mg, 0.782 mmol). The final product was purified by preparative high-performance liquid chromatography (Waters MS triggered Prep-LC with Acquity QDA detector, chromatography column Welch 10 μm C18 250 x 21.2 mm; mobile phase 1: water (containing 0.1% ammonia); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 30% to 100%, flow rate: 25 mL / min) to give the title compound 079 (31 mg, yield: 22%). MS m / z (ESI): 410.1 (M+1). 1H NMR (400 MHz, CD3OD) δ 8.26 (d, 1H), 7.72 (dd, 1H), 7.56 (d, 1H), 7.31 (d, 1H), 7.04-7.00 (m, 2H), 4.04-3.97 (m, 1H), 3.84 (dd, 1H), 3.74 (dd, 1H), 3.63 (d, 2H), 1.57 (tt, 1H), 1.00-0.95 (m, 2H), 0.86-0.80 (m, 2H).

[0349] Example 51 (R)-5-chloro-2-(4-((3-(difluoromethylene)cyclohexyl)amino)pyridine[3,4-d]pyridazin-1-yl)phenol (080)

[0350] [ka]

[0351] Step 1: Preparation of (R)-tert-butyl (3-(difluoromethylene)cyclohexyl)aminocarboxylate (080b) Under a nitrogen gas atmosphere, potassium tert-butoxide (235 mg, 2.1 mmol) was dissolved in N,N-dimethylformamide (5 mL), the temperature was lowered to -55 ° C, and the compound (R)-(3-oxocyclohexyl)aminocarboxylate tert-butyl 080a (300 mg, 1.4 mmol) and the compound 2-((difluoromethyl)sulfonyl)pyridine (289 mg, 1.5 mmol) were sequentially added. The reaction mixture was maintained at -55 ° C and stirred for 1 hour. After completion of the reaction, saturated aqueous ammonium chloride solution was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified using silica gel column chromatography purification system B to obtain the title compound 080b (150 mg, 43%). MS m / z (ESI): 248.1 (M+1).

[0352] Step 2 Preparation of (R)-3-(difluoromethylene)cyclohexan-1-amine hydrochloride (080c) Compound 080b (150 mg, 0.61 mmol) was dissolved in 4 M hydrochloric acid / 1,4-dioxane solution (5 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give crude compound 080c (110 mg, 99%). The product was used directly in the next step without further purification. MS m / z (ESI): 148.1 (M+1).

[0353] Step 3: Preparation of (R)-1-chloro-N-(3-(difluoromethylene)cyclohexyl)pyrido[3,4-d]pyridazin-4-amine (080d) Compound 080c (110 mg, 0.6 mmol) was dissolved in N-methylpyrrolidone (5 mL), and compound 009a (110 mg, 0.6 mmol) and N,N-diisopropylethylamine (0.3 mL, 1.8 mmol) were added. The reaction mixture was stirred at 100°C for 3 hours. After completion of the reaction, the mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography purification system B to give the title compound 080d (80 mg, 43%). MS m / z (ESI): 311.0 (M+1).

[0354] Step 4: Preparation of (R)-5-chloro-2-(4-((3-(difluoromethylene)cyclohexyl)amino)pyridine[3,4-d]pyridazin-1-yl)phenol (080) Compound 080d (50 mg, 0.17 mmol) was dissolved in a mixed solvent of 1,4-dioxane and water (3.3 mL, V / V = 10:1), followed by the addition of (4-chloro-2-hydroxy-6-methylphenyl)boronic acid (30.5 mg, 0.18 mmol), sodium carbonate (51.16 mg, 0.48 mmol), and 1,1'-bisdiphenylphosphinoferrocenedichloropalladium (11.68 mg, 0.016 mmol). The reaction was stirred at 100 °C for 1 hour under nitrogen gas protection. After completion of the reaction, the reaction solution was filtered, and the filtrate was collected and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (Waters MS triggered Prep-LC with Acquity QDA detector, chromatography column: Welch 10 μm C18 250 x 21.2 mm; mobile phase 1: water (containing 0.1% aqueous ammonia); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 50% to 100%, flow rate: 25 mL / min) to obtain the title compound 080 (14 mg, yield: 21.75%). MS m / z (ESI): 403.0 (M+1). 1 H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 8.83 (d, 1H), 7.72 (d, 1H), 7.33 (d, 1H), 7.28 (d, 1H), 6.89-6.86 (m, 2H), 4.33-4.28 (m, 1H), 2.88(d, 1H), 2.39 (d, 1H), 2.13-2.11 (m, 1H), 2.02-1.87(m, 4H), 1.65-1.56 (m, 1H), 1.49-1.44 (m, 1H).

[0355] Using synthetic methods similar to those in the above examples, the compounds in the following table were prepared.

[0356] [Table 1]

[0357] Biological evaluation Test Example 1: IC of NLRP3 inhibitors by reducing IL-1β secretion levels in THP-1 cells 50 Experiment to detect The chemical names and structural formulae of the compounds of the present invention used in the experiments are as shown in the Preparation Examples for each compound.

[0358] 1. Experimental Principle: This experiment investigated the inhibitory activity of NLRP3 inhibitors on cellular IL-1β secretion using the human monocytic cell line THP-1. Human THP-1 cells were treated with phorbol 12-myristate 13-acetate (PMA) and differentiated into mature macrophages. Next, the cells were sequentially stimulated with lipopolysaccharide (LPS) and nigericin to promote the extracellular release of IL-1β by THP-1 cells, following the two stages of inflammasome formation (assembly and activation). The first stage of inflammasome formation was stimulated with LPS (lipopolysaccharide), an agonist of the Toll-like receptor (TLR4), which activates the expression of inflammasome-associated proteins NLRP3, caspase 1, and the IL-1β precursor pro-IL-1β. The second step in inflammasome formation involves the addition of nigericin, a potassium ion vector, which alters the membrane potential in THP-1 cells, disrupting the cellular membrane structure and causing potassium ion extrusion. This then stimulates NLRP3 monomers to oligomerize, forming NLRP3 oligomers, and triggers the recruitment of ASC and pro-caspase-1, resulting in the assembly of the NLRP3 inflammasome complex containing large amounts of pro-caspase-1. The pro-caspase-1 in the activated NLRP3 inflammasome then autoactivates to form large amounts of active caspase-1, which then further proteolytically cleaves pro-IL-1β to secrete mature IL-1β. During this process, NLRP3 inhibitors can effectively inhibit nigericin-induced NLRP3 maturation and activation and downstream caspase-1 activation, thereby inhibiting IL-1β maturation and secretion.

[0359] 2. Experimental Reagents and Instruments

[0360] [Table 2]

[0361] 3. Experimental steps (1) The cell suspension was collected. The cells were centrifuged at 1000 rpm for 4 minutes, the supernatant was discarded, and the cells were resuspended in 1 mL of test medium. The cell medium was gently pipetted up and down with a pipette and gun head to dissociate cell clumps. After cell counting, the THP-1 cells were resuspended in complete RPMI medium 1640 containing PMA and seeded into a 96-well plate. The cells were cultured in an incubator at 37°C with 5% CO2 for 72 hours.

[0362] (2) The medium was removed from each well using an automated plate washer dispenser (EL406) and each well was washed twice with PBS. 96 μL of LPS-containing RPMI 1640 medium was added to each well. The cells were cultured for 4 hours in an incubator at 37°C with 5% CO2.

[0363] (3) 2 μL of compound and 2 μL of nigericin sodium salt were added to each well, with the final compound concentrations for screening being 5000 nM, 1000 nM, 200 nM, 40 nM, 8 nM, 1.6 nM, 0.32 nM, and 0 nM, respectively. The cells were incubated at 37°C in a 5% CO2 incubator for 1 hour.

[0364] (4) An appropriate amount of the supernatant was taken and diluted 100-fold, and the content of IL-1β in the supernatant was detected using a Human IL-1 beta Varcine ELISA kit.

[0365] 4. Experimental Results The experimental results are shown in Table 1.

[0366] Table 1. IC of NLRP3 inhibitors using THP-1 cells 50 Detection experiment test results

[0367] [Table 3] JPEG2026501600000089.jpg49169

[0368] Conclusion: The compounds of the present invention have significant inhibitory activity on the maturation and secretion of IL-1β in THP-1 cells.

[0369] Test Example 2: Mouse acute peritonitis model evaluation experiment Male C57BL / 6 mice were orally administered a test compound or control vehicle at a dose of 10 mg / kg and, one hour later, intraperitoneally injected with 1 μg of an ultrapure E. coli 055:B5 lipopolysaccharide (LPS) suspension. Two hours later, they were intraperitoneally injected with 0.5 mL of a 30 mM disodium ATP suspension (in PBS; the pH of the ATP solution was adjusted to 7.2 before injection). Thirty minutes later, all animals were euthanized with carbon dioxide, and blood and peritoneal lavage fluid were collected. The peritoneal lavage fluid was stored at 4°C.

[0370] Preparation of peritoneal lavage fluid: The peritoneal cavity was lavaged with 3 mL of cold PBS containing 25 U / mL heparin and 10% heat-inactivated FBS. A protease inhibitor mixture was added at 1 tablet per 50 mL of buffer before use. The collected lavage fluid was centrifuged (1000 g, 4°C, 10 min) to remove cells and cell debris, and the clarified sample was stored at -80°C for measurement of the cytokine IL-1β.

[0371] The changes in IL-1β cytokine levels in peritoneal lavage fluid and serum were measured using a mouse IL-1β / IL-1F2 DuoSet ELISA kit (R&D Systems), and the inhibitory rates of the compounds against IL-1β were calculated by comparing with those in the vehicular group. The experimental results are shown in Table 2.

[0372] [Table 4]

[0373] Conclusion: Some compounds showed inhibitory effects on IL-1β in animal in vivo model evaluation experiments, among which compound 062 showed the most significant inhibitory effect.

[0374] Test Example 3: Evaluation test of MSU-induced rat gouty arthritis model In this study, male SD rats were used to establish an acute gouty arthritis model by injecting a 64 mg / mL monosodium urate (MSU) crystal suspension into the ankle joint cavity of the right hind paw. Seven animals per group were randomly divided into a normal control group, a model control group, and groups receiving different doses of the test compound. The compound group was orally administered 1 hour before and 1 hour after modeling, while the normal and model control groups received the same volume of vehicle. Foot circumference and diameter were measured 24 hours before and 24 hours after modeling.

[0375] The experimental results are shown in Figure 1. Compound 062 showed a dose-dependent improvement in the degree of ankle swelling in an MSU-induced rat acute gouty arthritis model, and its effect was significantly superior to that of the control compound.

[0376] Test Example 4 MSU-induced rat air pouch model test In this study, a dorsal air-pouch model was created using male SD rats after an acclimation period. On days 1, 4, and 7 of modeling, 20 mL of sterile air was subcutaneously injected into the rat's back using a syringe needle to maintain the air pouch filled. On day 8, different doses of compound or vehicle control were administered orally by gavage. 25 mg of sodium urate suspension was injected into the dorsal air pouch, and the air-pouch exudate was collected 5 hours later. The exudate was centrifuged at 1500 rpm for 20 minutes, the supernatant was collected, and IL-1β production was detected by ELISA (R&D, Rat IL-1β kit).

[0377] The experimental results are shown in Figure 2. Compound 062 significantly inhibited IL-1β production in the air pouch in the MSU-induced air pouch model, and its effect was superior to that of colchicine and tofacitinib.

[0378] Test Example 5 Zymosan A-induced rat pericarditis model test In this study, SD rats were intrapericardially injected with 150 μL of 50 mg / mL zymosan A in saline to induce a rat pericarditis model and conduct a pharmacodynamic observation study. The day of modeling was designated as Day 1. On the day before modeling, animals were weighed and randomly assigned to groups: G1 normal group, G2 model group, G3 compound O62-10 mg / kg group, G4 compound O62-30 mg / kg group, and G5 colchicine-100 μg / kg group. Each group consisted of 7 + 1 animals (one extra animal was reserved in each group to account for the possibility of animal death during model establishment). After the model was established, oral administration of Zymosan A was initiated once daily for 7 consecutive days. At the end of the study, the animals were euthanized, and the muscles in the third and fourth rib regions were incised to expose the heart. The pericardium was carefully lifted with forceps, and as much pericardial fluid (if present) as possible was removed using a 1 mL syringe. The fluid was centrifuged at 5000 rpm at 4°C for 5 minutes, and the supernatant was collected and frozen at -80°C for subsequent detection of IL-1β levels. After the fluid collection was complete, the heart was perfused (ensuring the integrity of the pericardium), removed, and fixed in 10% formalin for subsequent pathological detection.

[0379] The experimental results are shown in Figures 3 and 4. Compound 062 significantly inhibited the production of IL-1β in the pericardium and pericardial fluid in the Zymosan A-induced pericarditis model, improving the severity of pericardial inflammation, and its effect was comparable to that of colchicine.

[0380] Test Example 6 Mouse NASH model test After the animals arrived and were allowed to acclimate for one week, they were randomly divided into two groups. 48 mice were fed a high-fat diet (HFD) and provided with 15% fructose water (v / w) ad libitum. After 20 weeks of feeding, the animals were fasted for 6 hours, fasting blood glucose (FBG) was monitored using a blood glucose meter, and all animals were bled via the orbit, centrifuged, and serum was collected to detect serum ALT levels. The animals were randomly divided into six groups based on body weight, FBG, and serum ALT levels. The high-fat diet (HFD) was then replaced with a modified high-fat diet (mHFD) and provided with 15% fructose water (v / w) ad libitum. Another group of eight mice was given normal chow and water.

[0381] End point of the first experiment: After 8 weeks of administration, the animals were euthanized with CO2, and serum was collected by orbital blood sampling and stored at -80°C for insulin and biochemical analysis. The animals' livers were then removed and their weights recorded. One portion was rapidly frozen in liquid nitrogen for biochemical analysis, one portion was placed in tissue fixative for pathological analysis, one portion was stored in RNAlater for qPCR detection (backup for future use), and one portion was rapidly frozen in liquid nitrogen and retained as a sample for subsequent potential detection.

[0382] End point of the second experiment: Three mice from each group were kept and observed continuously for six weeks. End point weights were recorded and they were fasted for six hours. Fasting blood glucose was measured using a blood glucose meter. Afterwards, the mice were euthanized with CO2, and serum was collected by orbital blood collection and stored at -80°C for insulin and biochemical analysis. The livers of the animals were removed and their weights were recorded. The livers were divided into four parts: one part was flash-frozen in liquid nitrogen for biochemical analysis, one part was placed in tissue fixative for pathological analysis, one part was stored in RNAlater for qPCR detection (backup for future use), and one part was flash-frozen in liquid nitrogen and used as a sample for subsequent detection.

[0383] The experimental results are shown in Figures 5 to 7. The group administered compound 062 in combination with 0.025mpk semaglutide significantly suppressed the rebound in mouse weight after discontinuation of administration, without affecting food intake. However, the control compound and semaglutide combination group, and the low / high dose semaglutide alone groups, did not suppress the rebound in weight after discontinuation of administration. Blood biochemistry index detection showed that the group administered compound 062 in combination with 0.025mpk semaglutide significantly suppressed the levels of ALT, AST, LDL, and HDL after discontinuation of administration.

[0384] Test Example 7: 14-day toxicological experiment on rats 7.1 Test Purpose Compound 062 and the control compound were orally administered to SD rats by force once a day for a total of 14 doses, and the toxicological responses of 062 and the control compound were observed and their toxicokinetic properties were studied.

[0385] 7.2 Test sample preparation method and dosage setting 7.2.1 Preparation of Vehicle Formulations Vehicle 1: [0.2% CMC-Na] For example, to prepare 100 mL, measure out an appropriate amount of ultrapure water and place it in a suitable container. Then, weigh out 0.2 g of CMC-Na and add it to the container while stirring. Continue stirring until a clear solution is obtained, then add water up to 100 mL. This is ready for use. Store at 2-8°C and the expiration date is one month.

[0386] Vehicle control group administration formulation [5% Solutol HS15 in 95% (0.2% CMC-Na)]: Take the preparation of 100mL as an example: take an appropriate amount of vehicle 1 and put it into a suitable container; take a certain amount of Solutol HS15 and dissolve it thoroughly at 40~60℃; then measure out 5mL and slowly add the dissolved Solutol HS15 dropwise while stirring; continue stirring for at least 30 minutes until a clear, transparent liquid is obtained; cover with a lid or plastic wrap while stirring to prevent water evaporation; store at 2~8℃ and ready to use; the expiration date is 1 month.

[0387] 7.2.2 Administration formulations of test compound 062 and test compound control compounds An appropriate amount of test compound was weighed (weighed amount = theoretically required amount / content), thoroughly ground and dispersed in a mortar (made of agate or ceramic), and then an appropriate amount of 5% Solutol HS15 in 95% (0.2% CMC-Na) was added and ground until no obvious large particles remained. Next, the mortar was washed several times with 5% Solutol HS15 in 95% (0.2% CMC-Na) until no drug powder residue was visible to the naked eye. The mixture was then transferred to an appropriate container and stirred to achieve a uniform mixture. The remaining 5% Solutol HS15 in 95% (0.2% CMC-Na) was then added to the required volume (marked volume method), and stirred for at least 20 minutes to achieve a uniform mixture, thereby obtaining the test compound dosage form.

[0388] The prepared drug formulations are labeled with the concentration, and the label includes at least the test number, sample code or name, concentration, dosage, storage conditions, preparation date, preparer and expiration date. 7.2.3 Dosage The dosage settings are as shown in Table 3.

[0389] [Table 5]

[0390] 7.3 Experimental animals Genus / species / strain: SD rat, SPF grade.

[0391] Sex and number of animals for screening: 67 female animals, 67 male animals.

[0392] Sex and number of animals for the study: 56 female animals, 56 male animals.

[0393] Weight and age at group allocation: male animals: 160-300 g, 6-9 weeks old; female animals: 160-300 g, 6-9 weeks old.

[0394] Animal supplier: Zhejiang Wetong Lihua Experimental Animal Technology Co., Ltd.

[0395] 7.4 Test Method 7.4.1 Administration The animals were administered orally by gavage. They were stirred for at least 30 minutes before administration and continued to be stirred during administration. The administration frequency was once a day for 14 consecutive days, and the dose was 10 mL / kg (the dose was calculated based on the most recent weighed body weight).

[0396] 7.4.2 Observation and inspection 7.4.2.1 Death and dying Dosing Phase: All surviving animals were observed at least once daily.

[0397] 7.4.2.2 General Observations Acclimation period: All animals were observed once a day (at least one day before grouping, including the day of grouping).

[0398] Treatment Phase: All surviving animals in the main study group were observed twice daily, once before and once after treatment, and in detail at least once a week.

[0399] Observation items: The main observation items include (but are not limited to) the survival status, injection site, skin, fur, eyes, ears, nose, oral cavity, chest, abdomen, urogenital area, limbs, etc., as well as breathing, movement, urination, defecation, mental or behavioral changes, etc.

[0400] Note: If symptoms are observed at other times, the symptoms and time of observation should be recorded in a timely manner.

[0401] 7.4.2.3 Weight Acclimatization period: all animals were weighed once before group allocation, ie group allocation weight (D-1).

[0402] Dosing Phase: Animal weights were measured at least weekly for all surviving animals. Animal weights for toxicokinetic (TK) groups were used for dose calculations only; no statistical analysis was performed on the weight data; they were presented as individual data in the summary report.

[0403] Scheduled Necropsy: For all animals in the main study group, animal weights (fasted overnight) will be weighed prior to scheduled necropsy and will be used only for anesthetic dose calculations; fasted weight data will be presented in the summary report.

[0404] 7.4.2.4 Food intake Administration period: For surviving animals in the main test group, animal food intake was weighed at least once a week, and the average food intake was expressed in g / animal / day.

[0405] 7.4.3 Toxicological studies (TK) 7.4.3.1 Blood Collection Date at different time points before and after D1 and D14 administration.

[0406] 7.4.3.2 Animals All TK group animals survived.

[0407] 7.4.3.3 Time of blood collection Group 1: before administration and 4 h after administration.

[0408] Groups 2 to 7: before administration and 0.5 h, 1 h, 2 h, 4 h, 8 h and 24 h after administration (before administration on D2 and / or D15).

[0409] Note: The error range for blood sampling time after the end of administration is ±5 min at 0.5 to 1 h, ±10 min at 2 to 8 h, and ±1 h at 24 h.

[0410] 7.4.3.4 Blood collection site Jugular vein.

[0411] 7.4.3.5 Blood collection amount Approximately 0.2mL whole blood / animal / time point 7.4.3.6 Anticoagulants EDTA-K2.

[0412] 7.4.3.7 Blood Collection Preparation and Blood Sample Processing Whole blood was collected into EDTA-K2-containing blood collection tubes, immediately inverted several times to thoroughly and uniformly mix, and placed on crushed ice / ice packs. Within 1 hour of collection, blood was centrifuged (2000 g, 10 min) at 4°C (set temperature, acceptable temperature range: 2-8°C). Plasma was collected and aliquoted into two labeled EP tubes (one for testing and one for preparation) and stored in an ultra-low temperature refrigerator (-70°C to -90°C) within 2 hours of collection. Samples were kept frozen on dry ice during transport and transportation.

[0413] 7.4.3.8 TK Group Animal Treatment After the final blood sample was taken, surviving TK animals were euthanized with carbon dioxide overdose.

[0414] 7.4.3.9 Data Processing Plasma drug concentrations were analyzed using an LC-MS / MS method to provide cross-checked blood drug concentration data, and the main toxicokinetic parameters (AUC0-t, Cmax, and Tmax) were calculated and compared.

[0415] 7.4.4 Clinical pathology 7.4.4.1 Detection of hematological and blood coagulation parameters At the end of the administration period: once Blood collection route: abdominal aorta, Animals: Live animals for planned dissections; Blood was collected and placed in a test tube containing an anticoagulant (EDTA-K2), and hematological indices were detected using a Sysmex XN-1000V fully automated hematology analyzer. Blood was collected and placed in an anticoagulant tube containing citrate, and blood coagulation indices were detected using a Sysmex CS-5100 blood coagulation analyzer. The specific detection indices are as follows:

[0416] [Table 6] JPEG2026501600000093.jpg54169

[0417] 7.4.4.2 Detection of serum biochemical indicators At the end of the administration period: once Blood collection route: abdominal aorta, Animals: Live animals for planned dissections; The animals were fasted overnight, and whole blood was collected and placed in a test tube containing a coagulant and separating gel. The blood was centrifuged to obtain serum, and the serum biochemical indicators were detected using a Hitachi-7180 ​​biochemical analyzer. The specific detection indicators were as follows:

[0418] [Table 7]

[0419] 7.4.5 End-of-Test Procedures 7.4.5.1 Unplanned animal deaths All animals that died unplanned (including moribund animals) were subjected to gross necropsy (see 7.4.5.2 for examination details) and any abnormal organs / tissues collected were preserved. Blood was collected from moribund animals whenever possible and examined for clinical pathological indicators.

[0420] The carcasses of animals that died outside working hours were stored at 2–8°C and subjected to gross dissection on the next working day.

[0421] 7.4.5.2 Gross anatomy Dissection time: end of administration period (D15), Anesthesia method: The anesthetic mixture consisted of 37.5 mg / mL ketamine and 2.5 mg / mL xylazine. The euthanasia dose was 2-4 mL / kg of the mixture (the anesthetic dose for animals scheduled for dissection was calculated based on the body weight after overnight fasting; the concentration was recorded in the original record and presented in the summary report; the dose could be adjusted depending on the anesthetic effect). The mixture was injected intraperitoneally.

[0422] Sacrifice method: After anesthesia, the animals were sacrificed by exsanguination from the abdominal aorta.

[0423] [Table 8]

[0424] Gross anatomical observations: At the time of necropsy, all animals were examined and recorded for gross abnormalities in the collected tissues and organs, and the following features were observed (including, but not limited to): 1. the carcass and musculoskeletal system, 2. the animal's body surface and natural foramina, 3. the cranial cavity and the external surface of the brain, 4. the thoracic, abdominal, and pelvic cavities and their internal organs.

[0425] If an abnormality is found, the location, color, shape and size of the abnormal tissue or organ should be recorded, and the abnormal organ or tissue should be sampled and preserved.

[0426] 7.4.6 Statistical analysis Body weight (including weight gain), hematology, coagulation and serum biochemistry indices are all expressed as mean ± standard deviation (by sex). When comparing groups 2 to 7 with n ≥ 3 and group 1, the following statistical methods were used: (1) Levene's test was used to detect homogeneity of variance in the data. If the variances were homogeneous (P > 0.05), one-way analysis of variance (ANOVA) was performed. If the variances were not homogeneous (P ≤ 0.05), the data were transformed into common logarithms (logarithmic transformation). Then, Levene's test was used to detect homogeneity of variance in the log data again. If the variances were homogeneous (P > 0.05), one-way analysis of variance (ANOVA) was performed using the log data. If the variances were not homogeneous (P ≤ 0.05), rank transformation was performed on the log data, followed by Kruskal-Wallis detection (rank data). (2) If the ANOVA results (P ≤ 0.05) showed a statistically significant difference, Dunnett's (2) If the Kruskal-Wallis test results show a statistically significant difference (P≦0.05), the statistics are terminated. (3) If the Kruskal-Wallis test results show a statistically significant difference (P≦0.05), the Dunnett t-test is used to compare the rank data. If the Kruskal-Wallis test results show a statistically significant difference (P>0.05), the statistics are terminated. (4) If n=2, the data are expressed as mean ± standard deviation by sex, and no statistical inference is performed.

[0427] Moribund / death observations, food consumption and general observations were not statistically recorded but were presented as individual data and / or frequencies.

[0428] 7.5 Experimental Results 7.5.1 Toxicokinetic Data for Reference Compound and Compound 062 Control Compound:

[0429] [Table 9]

[0430] Compound 062:

[0431] [Table 10]

[0432] 7.5.2 Safety Data of Reference Compound and Compound 062

[0433] [Table 11] JPEG2026501600000099.jpg129169

[0434] Conclusion: Compound 062 had a good safety profile, and its safety profile was far superior to that of the control compound when the high-dose group exposure was 4.8 times that of the control compound.

[0435] Unless otherwise stated, the reference compounds described in this application document are compounds known in the prior art and have the structure:

[0436] [ka]

[0437] is.

[0438] The above is an illustrative description of the embodiments of the technical solutions of the present invention. It should be understood that the protection scope of the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made by those skilled in the art within the spirit and principle of the present invention should be included in the protection scope of the claims of this application. [Brief explanation of the drawings]

[0439] [Figure 1] FIG. 1 is a schematic diagram comparing experimental results of measuring rat ankle joint circumference in an MSU-induced rat acute gouty arthritis model. [Figure 2]FIG. 1 is a schematic diagram showing a comparison of the detection results of inflammatory factors in the MSU-induced rat air pouch model. [Figure 3] FIG. 1 is a schematic diagram showing a comparison of statistical results of the thickness of the pericardial wall layer detected by H&E staining method in a pericarditis model. [Figure 4] FIG. 1 is a schematic diagram comparing the results of ELISA detection of IL-1β production in pericardial fluid. [Figure 5] Schematic diagram of comparison of body weight measurement results in a mouse NASH model study (Sem: semaglutide). [Figure 6] Schematic diagram of a comparison of food intake measurement results in mice in a mouse NASH model test (Sem: semaglutide). [Figure 7] This is an illustration of a comparison of the detection results of mouse serum ALT, AST, LDL, and HDL in a mouse NASH model test (Sem: semaglutide).

Claims

1. A compound represented by formula (I), its racemate, stereoisomer, tautomer, isotopic marker, solvate, crystalline polymorph, pharmaceutically acceptable salt or prodrug compound thereof, 【Chemistry 1】 wherein ring A is unsubstituted or has one, two or more R ａ C optionally substituted with ３－１４ carbocycle, C ６－１４ is a ring selected from an aryl ring, a 5- to 14-membered heteroaryl ring, and a 3- to 14-membered heterocyclic ring; ａ are the same or different and independently represent H, deuterium, OH, halogen, cyano group, NH ２ , unsubstituted or one, two or more R ａ１ C optionally substituted with １－１２ Alkyl group, C ２－１２ Alkenyl group, C ２－１２ Alkynyl group, C １－１２ Alkoxy group, R ａ１１ -C(=O)-NH-, R ａ１２ -C(=O)-, R ａ１３ -S(=O) ２ -NH-, R ａ１４ -S(=O) ２ -, -P(=O)(R ａ１５ ) (R ａ１６ ), (R ａ１７ ) (R ａ１８ )NC(=O)-,C ６－１４ an aryl group, a 5- to 14-membered heteroaryl group, a 3- to 14-membered heterocyclyl group, C ３－１４ cycloalkyl groups, and each R ａ１ are the same or different and independently represent H, deuterium, OH, halogen, CN, C １－１２ Alkyl group, C ３－１２ Cycloalkyl group, C １－１２ Alkoxy group, halo C １－１２ alkyl groups, R ａ１１ , R ａ１２ , R ａ１３ , R ａ１４ , R ａ１５ , R ａ１６ , R ａ１７ , R ａ１８ are the same or different and independently represent H, deuterium, halogen, CN, C １－１２ Alkyl group, C １－１２ alkoxy groups, Ring B is unsubstituted or contains one, two or more R ｂ C optionally substituted with ６－１４ Aryl ring, 5- to 14-membered heteroaryl ring, 3- to 14-membered heterocycle, C ３－１４ a ring selected from carbocycles, and each R ｂ are the same or different and independently represent H, deuterium, OH, halogen, cyano group, NH ２ , unsubstituted or one, two or more R ｂ１ C optionally substituted with １－１２ Alkyl group, C １－１２ alkoxy groups, and each R ｂ１ are the same or different and independently represent H, deuterium, halogen, CN, C １－１２ Alkyl group, C １－１２ alkoxy groups, R １ is H, deuterium, halogen, CN, hydroxy group, amino group, C １－６ Alkyl group, halo C １－６ Alkyl group, cyano C １－６ Alkyl group, C ３－８ cycloalkyl groups, Q is a chemical bond or C １－６ alkylene groups, R ２ is unsubstituted or has one, two or more R ２ａ C optionally substituted with １－１２ Alkyl group, C １－１２ Alkoxy group, C ６－１４ an aryl group, a 5- to 14-membered heteroaryl group, a 3- to 14-membered heterocyclyl group, C ３－１４ cycloalkyl groups, and each R ２ａ are the same or different and independently represent H, deuterium, halogen, CN, OH, carboxyl group, unsubstituted or one, two or more R ２ａ１ C optionally substituted with １－１２ Alkyl group, C １－１２ Alkoxy group, R ２１ -C(=O)-(CH ２ ) ｍ -, or two R ２ａ are C together with the carbon atoms connected to them. ３－８ form a cycloalkyl group or a 3- to 8-membered heterocyclyl group, and each R ２ａ１ are the same or different and independently represent H, deuterium, halogen, CN, a carboxyl group, C １－１２ Alkyl group, C １－１２ Alkoxy group, R ２２ —C(═O)—, and each R ２１ , R ２２ are the same or different and independently represent H, deuterium, halogen, CN, OH, an amino group, C １－１２ alkylamino group, (C １－１２ alkyl) ２ Amino group, C ３－１２ cycloalkylamino group, C １－１２ Alkyl group, C １－１２ Alkoxy group, C ３－８ cycloalkyl groups, and 3- to 14-membered heterocyclyl groups, and m is an integer selected from 0 to 6; Or, R ２ is unsubstituted or has one, two or more R ｅ optionally replaced with 【Chemistry 2】 wherein ring E is selected from C ３－８ cycloalkyl groups, R １１ , R １２ are the same or different and independently represent H, halogen, C １－６ Alkyl group, halo C １－６ Alkyl group, cyano-C １－６ Alkyl group, C ３－８ Cycloalkyl group, halo C ３－８ Cycloalkyl group or cyano-C ３－８ cycloalkyl groups, and each R ｅ are the same or different and independently represent H, OH, halogen, cyano group, NH ２ , unsubstituted or one, two or more R ｅ１ C optionally substituted with １－６ Alkyl group, C ３－８ cycloalkyl groups, and each R ｅ１ are the same or different and are independently selected from H, OH, halogen, cyano group, Or, R ２ is unsubstituted or has one, two or more R ｆ optionally replaced with 【Transformation 3】 wherein ring F is selected from a 4- to 8-membered heterocycle; １３ is H, unsubstituted or one, two or more R １３ａ C optionally substituted with １－６ Alkyl group, C ３－８ Cycloalkyl group, R １３ｂ -C(=O)-(CH ２ ) ｓ -, and R １３ｂ is C １－６ Alkyl group, C ３－８ a cycloalkyl group or an amino group, and each R １３ａ are the same or different and independently represent H, OH, halogen, cyano group, C １－６ alkyl groups, s is an integer selected from 0 to 6, and each R ｆ are the same or different and independently represent H, OH, halogen, cyano group, NH ２ , unsubstituted or one, two or more R ｆ１ C optionally substituted with １－６ Alkyl group, C ３－８ cycloalkyl groups, and each R ｆ１ are the same or different and are independently selected from H, OH, halogen, and cyano groups, and a compound, a racemate, a stereoisomer, a tautomer, an isotopic marker, a solvate, a crystalline polymorph, a pharmaceutically acceptable salt, or a prodrug compound thereof.

2. Ring A is unsubstituted or contains one, two or more R ａ C optionally substituted with ３－８ carbocycle, C ６－１０ is a ring selected from an aryl ring, a 5- to 10-membered heteroaryl ring, and a 3- to 10-membered heterocyclic ring, ａ are the same or different and independently represent H, deuterium, OH, halogen, cyano group, NH ２ , unsubstituted or one, two or more R ａ１ C optionally substituted with １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, R ａ１１ -C(=O)-NH-, R ａ１２ -C(=O)-, R ａ１３ -S(=O) ２ -NH-, R ａ１４ -S(=O) ２ -, -P(=O)(R ａ１５ ) (R ａ１６ ), (R ａ１７ ) (R ａ１８ )NC(=O)-,C ６－１０ an aryl group, a 5- to 10-membered heteroaryl group, a 3- to 10-membered heterocyclyl group, C ３－１０ cycloalkyl groups, and each R ａ１ are the same or different and independently represent H, deuterium, OH, halogen, CN, C １－６ Alkyl group, C ３－６ Cycloalkyl group, C １－６ alkoxy groups, R ａ１１ , R ａ１２ , R ａ１３ , R ａ１４ , R ａ１５ , R ａ１６ , R ａ１７ , R ａ１８ are the same or different and independently represent H, deuterium, halogen, CN, C １－６ Alkyl group, C １－６ alkoxy groups, Preferably, ring A is unsubstituted or has one, two or more R ａ C optionally substituted with ６－１０ an aryl ring, a 5- to 10-membered heteroaryl ring, and ａ are the same or different and independently represent H, deuterium, OH, halogen, cyano group, NH ２ , unsubstituted or one, two or more R ａ１ C optionally substituted with １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, R ａ１２ -C(=O)-, R ａ１４ -S(=O) ２ -, (R ａ１７ ) (R ａ１８ )NC(=O)-,C ６－１０ aryl group, and 5- to 10-membered heteroaryl group; ａ１ are the same or different and independently represent H, deuterium, OH, halogen, CN, C １－６ Alkyl group, C ３－６ Cycloalkyl group, C １－６ alkoxy groups, R ａ１２ , R ａ１４ , R ａ１７ , R ａ１８ are the same or different, and independently of each other, H, C １－６ Alkyl group, C １－６ alkoxy groups, Preferably, ring A is unsubstituted or has one, two or more R ａ a benzene ring or a pyridine ring optionally substituted with ａ are the same or different and independently represent H, a cyano group, —C(═O)—NH ２ , C.H. ３ -S(=O) ２ -, 【Chemistry 4】 1-propynyl group, 2-cyclopropylethynyl group, 【Transformation 5】 acetyl group, 【Transformation 6】 is selected from Preferably, ring A is 【Transformation 7】 is selected from Preferably, 【Transformation 8】 teeth, 【Chemistry 9】 2. The compound of claim 1, wherein the compound is selected from the group consisting of:

3. Ring B is unsubstituted or contains one, two or more R ｂ C optionally substituted with ６－１０ an aryl ring, a 5- to 10-membered heteroaryl ring, or C ３－１０ a ring selected from carbocycles, and each R ｂ are the same or different and independently represent H, OH, halogen, cyano group, NH ２ , unsubstituted or one, two or more R ｂ１ C optionally substituted with １－６ Alkyl group, C １－６ alkoxy groups, and each R ｂ１ are the same or different and independently represent H, halogen, CN, C １－６ Alkyl group, C １－６ alkoxy groups, Preferably, ring B is unsubstituted or has one, two or more R ｂ a benzene ring, a benzothiophene ring, or an indane ring optionally substituted with ｂ are the same or different and independently represent H, OH, halogen, cyano group, C １－６ Alkyl group, halo C １－６ Alkyl group, halo C １－６ alkoxy groups, Preferably, ring B is unsubstituted or has one, two or more R ｂ a benzene ring, a benzothiophene ring, or an indane ring optionally substituted with ｂ are the same or different and independently represent H, OH, F, Cl, a methyl group or CF ３ is selected from Preferably, ring B is 【Chemistry 10】 is selected from Preferably, ring B is 【Chemistry 11】 is selected from Preferably, R １ is selected from H, deuterium or a methyl group, preferably R １ is H, Preferably, Q is a chemical bond, —(CH ２ ) ｑ - or - (CH ２ ) ｑ -CH(CH ３ )-, and q is selected from 0, 1 or 2; Preferably, Q is a chemical bond, —CH ２ - or -CH(CH ３ 3. The compound according to claim 1, wherein the compound is selected from the group consisting of:

4. R ２ is unsubstituted or has one, two or more R ２ａ C optionally substituted with １－６ Alkyl group, C １－６ Alkoxy group, C ６－１０ an aryl group, a 5- to 10-membered heteroaryl group, a 3- to 10-membered heterocyclyl group, C ３－１０ cycloalkyl groups, and each R ２ａ are the same or different and independently represent H, deuterium, halogen, CN, OH, carboxyl group, unsubstituted or one, two or more R ２ａ１ C optionally substituted with １－６ Alkyl group, C １－６ Alkoxy group, R ２１ -C(=O)-(CH ２ ) ｍ -, or two R ２ａ are C together with the carbon atoms connected to them. ３－８ form a cycloalkyl group, and each R ２ａ１ are the same or different and independently represent H, deuterium, halogen, CN, a carboxyl group, C １－６ Alkyl group, C １－６ Alkoxy group, R ２２ —C(═O)—, and each R ２１ , R ２２ are the same or different and independently represent H, OH, an amino group, C １－６ alkylamino group, (C １－６ alkyl) ２ Amino group, C ３－６ cycloalkylamino group, C １－６ Alkyl group, C １－６ Alkoxy group, C ３－８ cycloalkyl groups, and 3- to 8-membered heterocyclyl groups, and m is selected from 0, 1, or 2; Preferably, R ２ is unsubstituted or has one, two or more R ２ａ C optionally substituted with １－６ Alkyl group, C ６－１０ an aryl group, a 5- to 10-membered heteroaryl group, a 3- to 8-membered heterocyclyl group, C ３－８ cycloalkyl groups, and each R ２ａ are the same or different and independently represent H, CN, OH, a carboxyl group, unsubstituted or one, two or more R ２ａ１ C optionally substituted with １－６ alkyl group, R ２１ -C(=O)-(CH ２ ) ｍ -, or two R ２ａ are C together with the carbon atoms connected to them. ３－６ form a cycloalkyl group, and each R ２ａ１ are the same or different and independently represent H, deuterium, halogen, CN, a carboxyl group, C １－６ Alkyl group, C １－６ Alkoxy group, C ３－６ cycloalkylamino group, 3- to 6-membered N-containing heterocyclyl group, R ２２ —C(═O)—, and each R ２１ , R ２２ are the same or different and are independently selected from H, OH, amino, methyl, methoxy, and cyclopropyl groups; m is selected from 0, 1, or 2; Preferably, R ２ is unsubstituted or has one, two or more R ２ａ C optionally substituted with １－６ alkyl, tetrahydropyrrolyl, piperidinyl, phenyl, cyclohexyl, cyclobutane, or tetrahydropyranyl; ２ａ are the same or different and independently represent H, CN, OH, a carboxyl group, unsubstituted or one, two or more R ２ａ１ C optionally substituted with １－６ alkyl group, R ２１ -C(=O)-(CH ２ ) ｍ -, or two R ２ａ are C together with the carbon atoms connected to them. ３－６ form a cycloalkyl group, and each R ２ａ１ are the same or different and independently represent H, deuterium, halogen, CN, a carboxyl group, C １－６ Alkyl group, C １－６ Alkoxy group, R ２２ —C(═O)—, and each R ２１ , R ２２ are the same or different and are independently selected from H, OH, amino, methyl, methoxy, cyclopropyl, cyclopropylamino, tetrahydropyrrolyl, and m is selected from 0, 1 or 2; Preferably, R ２ is unsubstituted or has one, two or more R ２ａ C optionally substituted with １－６ alkyl, tetrahydropyrrolyl, piperidinyl, phenyl, cyclohexyl, cyclobutane, or tetrahydropyranyl; ２ａ are the same or different and independently represent H, OH, a carboxyl group, a methyl group, 【Chemistry 12】 NC-CH ２ -、 【Chemistry 13】 HOOC-CH ２ -HOOC-CH ２ -CH ２ - 【Chemistry 14】 or two R ２ａ are C together with the carbon atoms connected to them. ３－６ forming a cycloalkyl group, Preferably, R ２ teeth, 【Chemistry 15】 and ring E is selected from C ４－７ cycloalkyl groups, and r is an integer selected from 0 to 6; Preferably, R １１ , R １２ are the same or different and are independently selected from H, halogen (e.g., F, Cl), Preferably, each R ｅ are the same or different and are independently selected from H, OH, Preferably, R ２ teeth, 【Chemistry 16】 and ring F is selected from a 4- to 7-membered heterocycle; Preferably, R ２ teeth, 【Chemistry 17】 is selected from Preferably, R １３ is H, unsubstituted or one, two or more R １３ａ C optionally substituted with １－３ Alkyl group, C ３－６ Cycloalkyl group, R １３ｂ -C(=O)-(CH ２ ) ｓ -, and R １３ｂ is C １－３ Alkyl group, C ３－６ a cycloalkyl group or an amino group, and each R １３ａ are the same or different and independently represent H, OH, halogen, cyano group, C １－３ alkyl groups, and s is selected from 0, 1, 2, or 3; Preferably, R １３ is hydroxy-C １－６ Alkyl group -, NH ２ -C(=O)-(CH ２ ) ｓ -, s is selected from 0, 1, 2 or 3; Preferably, R １３ HOCH ２ CH ２ -, [Chemistry 18] is selected from Preferably, R ２ teeth, 【Chemistry 19】 HOOC-CH ２ - 【Chemistry 20】 The compound according to any one of claims 1 to 3, characterized in that it is selected from

5. The compound of formula (I) is selected from the following structures: 【Chemistry 21】 Here, ring A, ring B, Q, R ２ , R ａ , R ｂ have, independently of one another, the definitions according to any one of claims 1 to 4, and n is selected from 0, 1, 2, 3, 4 or 5, Preferably, the compound of formula (I) has the following structure: 【Chemistry 22】 Here, Q and R ２ , R ａ have, independently of one another, the definitions according to any one of claims 1 to 4, Preferably, the compound of formula (I) has the following structure: 【Chemistry 23】 Here, R ２ａ , R ａ have, independently of one another, the definitions according to any one of claims 1 to 4, Preferably, the compound of formula (I) has the following structure: 【Chemistry 24】 Here, rings F, Q, R ２ , R ｂ , R １３ , R ｆ have, independently of one another, the definitions according to any one of claims 1 to 4, n is selected from 0, 1, 2, 3, 4 or 5, p is selected from 0, 1, 2, 3 or 4 and t is selected from 0, 1, 2, 3 or 4.

6. The compound has the following structure: 【Chemistry 25】 【change】 【change】 【change】 【change】 Preferably, the compound of formula (I) is 【Chemistry 26】 【change】 The compound according to any one of claims 1 to 5, characterized in that it is selected from the following structures:

7. A method for producing the compound according to any one of claims 1 to 6, comprising the steps of: 【Chemistry 27】 Step (1) of reacting compound a with compound b to obtain compound c; and step (2) reacting compound c with compound d to obtain a compound of formula (I), Here, ring A, ring B, R １ , R ２ and Q independently have the definitions described herein; １ and X ２ are the same or different and are independently selected from leaving groups, for example, halogens such as F, Cl, Br, I, and the like; Y is a leaving group, for example, halogens such as F, Cl, Br, I, or a boronic acid group ( 【Chemistry 28】 ) A manufacturing method selected from the following.

8. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compounds according to any one of claims 1 to 6, its racemate, stereoisomer, tautomer, isotopic marker, solvate, crystalline polymorph, pharmaceutically acceptable salt or prodrug compound thereof; Preferably, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

9. A method for treating an NLRP3-mediated disease, comprising administering to a patient a prophylactically or therapeutically effective amount of at least one of the compounds according to any one of claims 1 to 6, their racemates, stereoisomers, tautomers, isotopic markers, solvates, crystalline polymorphs, pharmaceutically acceptable salts or prodrug compounds thereof, or the pharmaceutical composition according to claim 8; Preferably, the NLRP3-mediated disease is selected from autoinflammatory fever syndromes such as cryopyrin-associated periodic fever syndromes (CAPS), sickle cell disease, systemic lupus erythematosus (SLE), chronic liver disease, non-alcoholic steatohepatitis (NASH), gout, gouty arthritis, pericarditis, type I and type II diabetes and related complications (e.g., nephropathy, retinopathy), neuroinflammatory-related disorders (e.g., multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g., hypertension), obesity, hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelofibrosis).

10. A use of at least one of the compound according to any one of claims 1 to 6, its racemate, stereoisomer, tautomer, isotope marker, solvate, crystalline polymorph, pharmaceutically acceptable salt or prodrug compound thereof, or the pharmaceutical composition according to claim 8 in the manufacture of a drug, comprising: Preferably, the use may be in the manufacture of a medicament for treating an NLRP3-mediated disorder and / or disease, such as in the manufacture of an NLRP3 inhibitor medicament; Preferably, the disease is, for example, autoinflammatory fever syndromes such as cryopyrin-associated periodic fever syndromes (CAPS), sickle cell disease, systemic lupus erythematosus (SLE), chronic liver disease, non-alcoholic steatohepatitis (NASH), gout, gouty arthritis, pericarditis, type I and type II diabetes and related complications (e.g., nephropathy, retinopathy), neuroinflammatory related disorders (e.g., multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g., hypertension), obesity, hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelofibrosis).

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