Pharmaceutical use of substituted heteroarylphthalazine derivatives and methods for preparing them

Abstract

The present invention provides a substituted heteroarylphthalazine derivative represented by formula (I-0) having excellent NLRP3 inhibitory activity, its use as an NLRP3 inhibitor, and a preparation method thereof. JPEG2024535475000146.jpg4488

Description

[Technical Field]

[0001] This disclosure relates to the pharmaceutical field, and more particularly to NLRP3 inhibitors comprising a compound represented by chemical formula (I) or a pharmaceutically acceptable salt thereof, as well as to methods of use and preparation thereof. [Background technology]

[0002] Inflammation is the body's defense response to stimuli and includes infectious and sterile inflammation. Inflammation primarily manifests as redness, swelling, fever, pain, and functional impairment, which is due to increased permeability of vascular endothelial cells and exudation of immune cells into the plasma. The inflammatory response quickly subsides once tissue is repaired, but excessive cytokine production can trigger an inflammatory storm and damage the body. Inflammatory disorders are an important pathogenesis of many human diseases.

[0003] Innate immunity plays a crucial role in inflammation. Cells such as macrophages, dendritic cells, epithelial cells, endothelial cells, and fibroblasts are involved in the innate immune response. Innate immunity recognizes pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) through pattern recognition receptors. Currently, five types of pattern recognition receptors have been identified, including Toll-like receptors (TLRs), C-type lectin receptors (CLRs), retinoic acid-inducible gene-I-like receptors (RLRs), cytoplasmic DNA sensors, and NOD-like receptors (nucleotide-binding and oligomerization domain-like receptors, NLRs). These pattern recognition receptors are expressed in both immune and non-immune cells. After pattern recognition receptors recognize their corresponding ligands, they initiate the activation of various innate immune signaling pathways, leading to the production of a range of cytokines and type I interferons that promote inflammation.

[0004] NLRs are intracellular pattern recognition receptors. Widely expressed in various immune and epithelial cells, NLRs can initiate innate immune responses by recognizing PAMPs and DAMPs (such as cellular stress receptors) taken into cells. The high evolutionary conservation of NLRs has also proven crucial for maintaining immune homeostasis in living organisms. NLRs regulate inflammatory responses by promoting the production of cytokines and chemokines and the expression of antimicrobial-related genes, and are therefore closely associated with human diseases such as infections, tumors, autoimmune diseases, and inflammatory disorders.

[0005] NLRs consist of a C-terminal LRR domain, an intermediate NOD domain, and an N-terminal effector domain. The C-terminal LRR domain is responsible for ligand recognition and binding, the intermediate NOD domain has dNTPase (deoxynucleoside triphosphohydrolase) enzymatic activity and is responsible for oligomerization of NLR proteins, and the N-terminal effector domain exerts effector function through interaction with other proteins. Currently, four types of N-terminal effector domains have been discovered: the AD domain (acidic transactivation domain), the BIR domain (baculoviral inhibitory repeat-like domain), the CARD domain (caspase activation and recruitment domain), and the PYD domain (pyrin domain). Based on the differences in the N-terminal effector domain, NOD-like receptors are divided into four subfamilies: the NLRA subfamily (acidic domain containing), the NLRB subfamily (BIR domain containing), the NLRC subfamily (CARD domain containing), and the NLRP subfamily (pyrin domain containing). The NLRP subfamily includes 14 members, namely NLRP 1-14.

[0006] The inflammasome is a polyprotein complex that can mediate the activation of caspase-1. Activated caspase-1 promotes the processing and maturation of inflammatory cytokines IL-1β and IL-18, and also induces pyroptosis. Pyroptosis leads to the release of more DAMPs, further enhancing the immune response. Currently, it has been discovered that eight types of NLRs—NLRP1, NLRP2, NLRP3, NLRP6, NLRP7, NLRP12, NLRC4, and NAIP—form inflammasomes when activated.

[0007] The NLRP3 inflammasome consists of the pattern recognition receptor NLRP3, the linker protein ASC, and the effector protein pro-caspase-1. NLRP3 comprises an N-terminal PYD domain, an intermediate NACHT domain, and a C-terminal LRR domain. Activation of the NLRP3 inflammasome leads to the production of active caspase-1 and further promotes pyroptosis. The NLRP3 inflammasome recognizes a variety of stimulants, including protozoa (malaria parasites, amoebas, etc.), viruses (adenoviruses, influenza viruses, Sendai viruses, etc.), fungi (Saccharomyces cerevisiae, Candida albicans, etc.), and bacteria (Listeria monocystis, Escherichia coli, Staphylococcus aureus, etc.). NLRP3 can also recognize many endogenous DAMPs, including uric acid crystals, ATP, pancreatic islet amyloid polypeptides, and beta-amyloid plaques.

[0008] Furthermore, abnormal activation of the NLRP3 inflammasome is a significant factor in many major human diseases, including rheumatoid arthritis, gouty arthritis, atherosclerosis, myocardial infarction, Parkinson's syndrome, Alzheimer's disease, infectious lung injury, pulmonary fibrosis, sepsis, ulcerative colitis, type 2 diabetes, bacterial inflammation, familial Mediterranean fever, nephrotic syndrome, and myocarditis. Therefore, NLRP3 inhibitors have some therapeutic potential for these diseases with inflammatory pathological features. [Overview of the project] [Problems that the invention aims to solve]

[0009] The object of this disclosure is to provide substituted heteroarylphthalazine derivatives that have NLRP3 inhibitory activity. [Means for solving the problem]

[0010] This disclosure provides a compound represented by the following chemical formula (I-0) or a pharmaceutically acceptable salt thereof.

[0011] [ka]

[0012] (Here, n is 0 or 1, m is selected from integers of 1 to 5, p is selected from 1 or 2, X1, X2, X5 are each independently selected from CH2, NH, CH, O, S or N, X3, X4 are each independently selected from CH2, CH or N, R1 is hydrogen, deuterium, C 1~6 alkyl, C 1~6 alkoxy, C 3~6 cycloalkyl, halogen, phosphine oxide, hydroxy, cyano, and the C 1~6 alkyl, C 3~6 cycloalkyl, C 1~6 alkoxy, phosphine oxide are optionally substituted by one or more halogens, C 1~3 alkyl, and here, m R1s are the same as or different from each other, R3 is hydrogen, deuterium, C 1~6 alkyl, C 1~6 alkoxy, C 3~6 cycloalkyl, halogen, phosphine oxide, carboxy, cyano, and the C 1~6 alkyl, C 1~6 alkoxy, C 3~6 cycloalkyl, phosphine oxide are optionally substituted by one or more halogens, C 1~3 alkyl, and here, p R3s are the same as or different from each other, A is a single bond or a C 1~3 alkylene chain, and one or more hydrogens on the methylene in the C 1~3 alkylene chain are optionally substituted by C 1~3 alkyl, M is -NR 10 -, -O- or -S-, R4 is C 1~6 alkyl, C 3~9 cycloalkyl, C 5~9Selected from aryl, 3-9 member heterocycloalkyl, 5-9 member heteroaryl, and 9-12 member partially unsaturated heterocyclic bicyclic compounds, the C 1~6 Alkyl, C 3~9 Cycloalkyl, C 5~9 Aryl, 3-9 membered heterocycloalkyl, 5-9 membered heteroaryl, and 9-12 membered partially unsaturated heterocyclic dicyclic compounds contain one or more halogens, hydroxyl, and C. 1~3 Alkyl, C 1~6 The acyl, =O, and -NR8R9 are arbitrarily substituted, R8, R9, R 10 These are, independently, hydrogen and C 1~3 Selected from alkyl groups.

[0013] Specifically, this disclosure relates to a compound having the structure represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0014] [ka]

[0015] (Here, n is either 0 or 1. m is selected from integers between 1 and 5. p is selected from 1 or 2. X1, X2, and X5 are each independently selected from CH2, NH, CH, O, S, or N. X3 and X4 are independently selected from CH2, CH, or N. R1 is hydrogen, deuterium, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~6 Selected from cycloalkyl, halogen, phosphine oxide, hydroxy, and cyano, the C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Alkoxy and phosphine oxides are composed of one or more halogens, C 1~3 It is optionally substituted with alkyl, where m R1s are identical or different from each other. R3 is hydrogen, deuterium, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~6 Selected from cycloalkyl, halogen, phosphine oxide, carboxy, and cyano, the C 1~6 Alkyl, C 1~6 Alkoxy, C 3~6 Cycloalkyl phosphine oxides are composed of one or more halogens, C 1~3 It is optionally substituted with alkyl, where p R3s are identical or different from each other. A is a single bond or C 1~3 It is an alkylene chain, and the C 1~3 One or more hydrogen atoms on the methylene group in the alkylene chain may optionally be C 1~3 Substituted with alkyl, R4 is C 1~6 Alkyl, C 3~9 Cycloalkyl, C 5~9 Selected from aryl, 3-9 member heterocycloalkyl, 5-9 member heteroaryl, and 9-12 member partially unsaturated heterocyclic bicyclic compounds, the C 1~6 Alkyl, C 3~9 Cycloalkyl, C 5~9 Aryl, 3-9 membered heterocycloalkyl, 5-9 membered heteroaryl, and 9-12 membered partially unsaturated heterocyclic dicyclic compounds contain one or more halogens, hydroxyl, and C. 1~3 Alkyl, C 1~6 The acyl, =O, and -NR8R9 are arbitrarily substituted, R8 and R9 are independently hydrogen and C 1~3 Selected from alkyl groups.

[0016] Preferably, R4 is C 1~6 Alkyl, C 3~9 Cycloalkyl, C 5~9 Selected from aryl, 3-9 member heterocycloalkyl, 5-9 member heteroaryl, and 9-12 member partially unsaturated heterocyclic bicyclic compounds, the C 1~6 Alkyl, C 3~9 Cycloalkyl, C 5~9Aryl, 3-9 membered heterocycloalkyl, 5-9 membered heteroaryl, and 9-12 membered partially unsaturated heterocyclic dicyclic compounds contain one or more halogens, hydroxyl, and C. 1~3 Alkyl, C 1~6 The acyl is optionally replaced by -NR8R9.

[0017] Preferably, R1 is C 1~3 Alkyl, C 1~3 Alkoxy, C 3~6 Selected from cycloalkyl, phosphine oxide, hydroxy, cyano, and halogen, the C 1~3 Alkyl, C 1~3 Alkoxy, C 3~6 Cycloalkyl and phosphine oxides contain 1 to 3 halogens, C 1~3 It is optionally substituted with alkyl groups.

[0018] Preferably, R1 is C 1~3 Alkyl, C 1~3 Selected from alkoxy, hydroxy, cyano, halogen, and phosphine oxide, the C 1~3 Alkyl, C 1~3 Alkoxy and phosphine oxides are optionally substituted with 1 to 3 fluorine or methyl groups.

[0019] Preferably, R1 is selected from trifluoromethyl, difluoromethyl, methyl, fluorine, hydroxy, dimethylphosphine oxide, or trifluoromethoxy.

[0020] Preferably, R1 is selected from trifluoromethyl, methyl, fluorine, hydroxy, dimethylphosphine oxide, or trifluoromethoxy.

[0021] Preferably, R1 is selected from trifluoromethyl, methyl, or hydroxy.

[0022] Preferably, R3 is hydrogen, C 1~3 Alkyl, C 3~6 Cycloalkyl, C 1~3Selected from alkoxy, halogen, phosphine oxide, said C 1~3 alkyl, C 1~3 alkoxy, C 3~6 cycloalkyl, phosphine oxide is optionally substituted by 1 to 3 halogens, C 1~3 alkyl.

[0023] Preferably, R3 is C 1~3 alkyl, C 1~3 alkoxy, C 3~6 cycloalkyl, phosphine oxide selected from, said C 1~3 alkyl, C 1~3 alkoxy, C 3~6 cycloalkyl, phosphine oxide is optionally substituted by 1 to 3 fluorines, methyl.

[0024] Preferably, R3 is selected from hydrogen, methyl, methoxy, cyclopropyl, ethyl, fluorine, trifluoromethyl or dimethylphosphine oxide.

[0025] Preferably, R3 is selected from hydrogen, methyl, methoxy. <00oo441>

[0026] Preferably, A is a single bond or C 1~3 an alkylene chain, said C 1~3 one or more hydrogens on methylene in the alkylene chain are optionally substituted by methyl.

[0027] Preferably, A is a single bond, -CH2-, -(CH3)CH-, -CH2CH2-.

[0028] Preferably, A is a single bond.

[0029] Preferably, R4 is C 1~6 alkyl, C 5~8Selected from cycloalkyl, phenyl, 5- to 7-membered heterocycloalkyl containing 1 to 2 atoms independently selected from N, O, S respectively, 5- to 7-membered heteroaryl containing 1 to 2 atoms independently selected from N, O, S respectively, 9- to 12-membered partially unsaturated heterocyclic bicyclic containing 1 to 2 atoms independently selected from N, O, S respectively, and said C 1~6 alkyl, C 5~8 cycloalkyl, phenyl, 5- to 7-membered heterocycloalkyl containing 1 to 2 atoms independently selected from N, O, S respectively, 5- to 7-membered heteroaryl containing 1 to 2 atoms independently selected from N, O, S respectively, 9- to 12-membered partially unsaturated heterocyclic bicyclic containing 1 to 2 atoms independently selected from N, O, S respectively are optionally substituted by one or more halogens, hydroxy, C 1~3 alkyl, C 1~6 acyl, halo C 1~3 alkyl, =O, -NR8R9.

[0030] Preferably, R4 is C 1~6 alkyl, C 5~8 cycloalkyl, phenyl, 5- to 7-membered heterocycloalkyl containing 1 to 2 atoms independently selected from N, O, S respectively, 5- to 7-membered heteroaryl containing 1 to 2 atoms independently selected from N, O, S respectively, 9- to 12-membered partially unsaturated heterocyclic bicyclic containing 1 to 2 atoms independently selected from N, O, S respectively, and said C 1~6 alkyl, C 5~8 cycloalkyl, phenyl, 5- to 7-membered heterocycloalkyl containing 1 to 2 atoms independently selected from N, O, S respectively, 5- to 7-membered heteroaryl containing 1 to 2 atoms independently selected from N, O, S respectively, 9- to 12-membered partially unsaturated heterocyclic bicyclic containing 1 to 2 atoms independently selected from N, O, S respectively are optionally substituted by one or more halogens, hydroxy, C 1~3 alkyl, C 1~6 acyl, -NR8R9.

[0031] Preferably, R4 is C 1~6 Alkyl, C 5~8 Selected from cycloalkyl, phenyl, 5-7 member heterocycloalkyl containing 1-2 atoms independently selected from N and O, 5-7 member heteroaryl containing 1 N atom, and 9-12 member partially unsaturated heterocyclic bicycle containing 1 N atom, the C 1~6 Alkyl, C 5~8 Cycloalkyls, phenyls, 5-7 member heterocycloalkyls containing 1-2 atoms independently selected from N and O, 5-7 member heteroaryls containing 1 N atom, and 9-12 member partially unsaturated heterocyclic dicyclics containing 1 N atom, contain one or more halogens, hydroxyls, and C. 1~3 Alkyl, C 1~6 Ashiru, Halo C 1~3 It is optionally substituted with alkyl, =O, or -NR8R9.

[0032] Preferably, R4 is C 1~6 Alkyl, C 5~8 Selected from cycloalkyl, phenyl, 5-7 member heterocycloalkyl containing 1-2 atoms independently selected from N and O, 5-7 member heteroaryl containing 1 N atom, and 9-12 member partially unsaturated heterocyclic bicycle containing 1 N atom, the C 1~6 Alkyl, C 5~8 Cycloalkyls, phenyls, 5-7 member heterocycloalkyls containing 1-2 atoms independently selected from N and O, 5-7 member heteroaryls containing 1 N atom, and 9-12 member partially unsaturated heterocyclic dicyclics containing 1 N atom, contain one or more halogens, hydroxyls, and C. 1~3 Alkyl, C 1~6 The acyl is optionally replaced by -NR8R9.

[0033] Preferably, R4 is selected from n-butyl, cyclohexyl, phenyl, piperidyl, pyridyl, pyrrolyl, pyrrolidinyl, morpholinyl, tetrahydropyranyl, and the group represented by the following formula, wherein cyclohexyl, phenyl, piperidyl, pyridyl, pyrrolyl, and pyrrolidinyl are one or more halogens, hydroxy, and C 1~3 Alkyl, C 1~6 Ashiru, Halo C 1~3 It is optionally substituted with alkyl, =O, or -NR8R9.

[0034] [ka]

[0035] Preferably, R4 is selected from n-butyl, cyclohexyl, phenyl, piperidyl, pyridyl, pyrrolyl, pyrrolidinyl, morpholinyl, and the group represented by the following formula, wherein the cyclohexyl, phenyl, piperidyl, pyridyl, pyrrolyl, and pyrrolidinyl are one or more halogens, hydroxy, and C 1~3 Alkyl, C 1~6 The acyl is optionally replaced by -NR8R9.

[0036] [ka]

[0037] Preferably, R4 is selected from n-butyl, cyclohexyl, phenyl, piperidyl, pyridyl, pyrrolidinyl, morpholinyl, tetrahydropyranyl, and the group represented by the following formula, wherein the cyclohexyl, phenyl, piperidyl, pyridyl, and pyrrolidinyl groups consist of 1-2 fluorine, hydroxy, methyl, ethyl, acetyl, and halo C groups. 1~3 It is optionally substituted with alkyl, =O, or -N(CH3)2.

[0038] [ka]

[0039] Preferably, R4 is selected from n-butyl, cyclohexyl, phenyl, piperidyl, pyridyl, pyrrolidinyl, morpholinyl, and the group represented by the following formula, wherein the cyclohexyl, phenyl, piperidyl, pyridyl, and pyrrolidinyl groups are optionally substituted with 1 to 2 fluorine, hydroxy, methyl, ethyl, acetyl, or -N(CH3)2 molecules.

[0040] [ka]

[0041] Preferably, R4 is selected from n-butyl, -C(CH3)2OH, phenyl, and the group represented by the following formula.

[0042] [ka]

[0043] Preferably, R4 is selected from n-butyl, -C(CH3)2OH, phenyl, and the group represented by the following formula.

[0044] [ka]

[0045] Preferably, R4 is selected from the group represented by the following formula.

[0046] [ka]

[0047] Preferably, R8 and R9 are methyl.

[0048] This disclosure relates to a compound having the structure represented by formula (II) or a pharmaceutically acceptable salt thereof.

[0049] [ka]

[0050] (Here, n, X1, X2, X3, X4, X5, R3, R4, and A are the same as those described above.

[0051] Preferably, R 11 is hydrogen, deuterium, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~6 Selected from cycloalkyl, halogen, and phosphine oxide, the C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Alkoxy and phosphine oxides are composed of one or more halogens, C 1~3 It is optionally substituted with alkyl groups.

[0052] Preferably, R 11 is hydrogen, C 1~3 Alkyl, C 1~3 Alkoxy, phosphine oxide, halogen, C 3~6 Selected from cycloalkyl, the C 1~3 Alkyl, C 1~3 Alkoxy, C 3~6 Cycloalkyl and phosphine oxides contain 1 to 3 halogens, C 1~3 It is optionally substituted with alkyl groups.

[0053] Preferably, R 11 is hydrogen, C 1~3 Alkyl, C 1~3 Selected from alkoxy, halogen, and phosphine oxide, the C 1~3 Alkyl, C 1~3 Alkoxy and phosphine oxides are optionally substituted with 1 to 3 fluorine or methyl groups.

[0054] Preferably, R 11 This is selected from hydrogen, trifluoromethyl, methyl, fluorine, dimethylphosphine oxide, or trifluoromethoxy.

[0055] Preferably, R 11 The compound is selected from trifluoromethyl, methyl, trifluoromethoxy, and fluorine.

[0056] R2 is hydrogen, deuterium, C 1~6 Selected from alkyl, hydroxy, halogen, cyano, and difluoromethyl.

[0057] Preferably, R2 is hydrogen, deuterium, C 1~6 Selected from alkyl, hydroxy, halogen, and cyano.

[0058] Preferably, R2 is selected from hydroxy and difluoromethyl compounds.

[0059] Preferably, R2 is selected from hydroxyl.

[0060] R5, R6, and R7 are independently hydrogen, halogen, and C. 1~3 Selected from alkyl groups.

[0061] Preferably, R5, R6, and R7 are each independently selected from hydrogen, fluorine, and methyl.

[0062] This disclosure relates to a compound having the structure represented by formula (III) or a pharmaceutically acceptable salt thereof.

[0063] [ka]

[0064] (Here, n, X1, X2, R 11 R3, R4, and A are synonymous with those mentioned above.

[0065] This disclosure relates to a compound having the structure represented by formula (IV) or a pharmaceutically acceptable salt thereof.

[0066] [ka]

[0067] (Here, X1, X2, R 11 R3, R4, and A are synonymous with those mentioned above.

[0068] This disclosure relates to compounds having the structure represented by formula (IVa), (IVb), (IVc), (IVd), or (IVe), or pharmaceutically acceptable salts thereof.

[0069] [ka]

[0070] (Here, R1, R3, R4, and A are the same as those described above.

[0071] This disclosure also relates to compounds represented by formula (V) or formula (VI) or pharmaceutically acceptable salts thereof.

[0072] [ka]

[0073] (Here, R3, R4, and A are synonymous with those mentioned above.

[0074] This disclosure relates to a compound represented by formula (I-1) or a pharmaceutically acceptable salt thereof.

[0075] [ka]

[0076] (Here, n is either 0 or 1. m is selected from integers between 1 and 5. p is selected from 1 or 2. X1, X2, X5, and X6 are each independently selected from CH2, NH, CH, O, S, or N. X3 and X4 are independently selected from CH2, CH, or N. R1 is hydrogen, deuterium, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~6 Selected from cycloalkyl, halogen, phosphine oxide, hydroxy, and cyano, the C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Alkoxy and phosphine oxides are composed of one or more halogens, C 1~3 It is optionally substituted with alkyl, where m R1s are identical or different from each other. R3 is hydrogen, deuterium, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~6 Selected from cycloalkyl, halogen, phosphine oxide, carboxy, and cyano, the C 1~6 Alkyl, C 1~6 Alkoxy, C 3~6 Cycloalkyl phosphine oxides are composed of one or more halogens, C 1~3 It is optionally substituted with alkyl, where p R3s are identical or different from each other. A is a single bond or C 1~3 It is an alkylene chain, and the C 1~3 One or more hydrogen atoms on the methylene group in the alkylene chain may optionally be C 1~3 Substituted with alkyl, R4 is C 1~6 Alkyl, C 3~9 Cycloalkyl, C 5~9 Selected from aryl, 3-9 member heterocycloalkyl, 5-9 member heteroaryl, and 9-12 member partially unsaturated heterocyclic bicyclic compounds, the C 1~6 Alkyl, C 3~9 Cycloalkyl, C 5~9 Aryl, 3-9 membered heterocycloalkyl, 5-9 membered heteroaryl, and 9-12 membered partially unsaturated heterocyclic dicyclic compounds contain one or more halogens, hydroxyl, and C. 1~3 Alkyl, C1~6 The acyl, =O, and -NR8R9 are arbitrarily substituted, R8 and R9 are independently hydrogen and C 1~3 Selected from alkyl groups, Preferably, X6 is selected from S.

[0077] This disclosure relates to the following compounds or pharmaceutically acceptable salts thereof.

[0078] [ka]

[0079] [ka]

[0080] [ka]

[0081] [ka]

[0082] [ka]

[0083] [ka]

[0084] [ka]

[0085] [ka]

[0086] This disclosure relates to step 1, in which compound A0 is dissolved in POCl3, heated to 100°C, reacted overnight, confirmed to be complete by TLC, the reaction solution is directly concentrated to remove POCl3, the oily crude is slowly added dropwise to ice water, extracted with ethyl acetate, and separated by column chromatography to obtain the target compound A1.

[0087] Step 2 involves dissolving compound A1, the corresponding amine, and Na2CO3 in dry DMF, placing this mixture in a sealed tube, heating it to 120°C, allowing it to react overnight, confirming that the conversion of the starting materials is complete by TLC, adding the reaction mixture to water, extracting with ethyl acetate, and separating it by column chromatography to obtain the target compound A2.

[0088] The present invention relates to a method for preparing the above compound or a pharmaceutically acceptable salt thereof, comprising step 3: adding compound A2, boric acid, sodium carbonate, and Pd(dppf)Cl2 to a mixed solvent of dioxane and water, purging with nitrogen three times, heating to 110°C, reacting for 3 hours, adding the reaction solution to water, extracting with ethyl acetate, and separating by column chromatography to obtain the target compound I-0.

[0089] [ka]

[0090] In one embodiment, the method comprises step 1, dissolving compound A0' in POCl3, heating to 100°C, allowing the reaction to proceed overnight, confirming completion of the reaction by TLC, directly concentrating the reaction solution, removing the POCl3, slowly adding the oily crude to ice water, extracting with ethyl acetate, and separating by column chromatography to obtain the target compound A1'.

[0091] Step 2 involves dissolving compound A1', the corresponding amine, and Na2CO3 in dry DMF, placing this mixture in a sealed tube, heating it to 120°C, allowing it to react overnight, confirming that the conversion of the starting materials is complete by TLC, adding the reaction mixture to water, extracting with ethyl acetate, and separating by column chromatography to obtain the target compound A2'.

[0092] Step 3 includes adding compound A2', boric acid, sodium carbonate, and Pd(dppf)Cl2 to a mixed solvent of dioxane and water, purging with nitrogen three times, heating to 110°C, reacting for 3 hours, adding the reaction solution to water, extracting with ethyl acetate, and separating by column chromatography to obtain the target compound II.

[0093] [ka]

[0094] Another aspect of this disclosure provides stereoisomers, solvates, or prodrugs thereof of the compounds described in any one of the preceding paragraphs.

[0095] This disclosure relates to a pharmaceutical composition comprising a compound described in any one of the above paragraphs or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable auxiliary material.

[0096] This disclosure relates to the use of any of the compounds described in any one of the above paragraphs or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions described above, in the preparation of drugs for treating NLRP3-mediated disorders.

[0097] This disclosure relates to the use of the compounds described in any one of the above paragraphs or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions described above, in the preparation of NLRP3 inhibitors.

[0098] This disclosure relates to a method for inhibiting NLRP3 in patients requiring such inhibition, comprising administering the compound described in any one of the above paragraphs or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition, to a patient requiring such inhibition.

[0099] This disclosure relates to a method for treating NLRP3-mediated disorders in a patient, comprising administering the compound or a pharmaceutically acceptable salt thereof described in any one of the above paragraphs, or the above pharmaceutical composition, to the patient in need thereof, wherein the NLRP3-mediated disorders preferably include, but are not limited to, rheumatoid arthritis, gouty arthritis, atherosclerosis, myocardial infarction, Parkinson's syndrome, Alzheimer's disease, infectious lung injury, pulmonary fibrosis, sepsis, ulcerative colitis, type 2 diabetes, bacterial inflammation, familial Mediterranean fever, nephrotic syndrome, and myocarditis.

[0100] Another aspect of this disclosure provides the use of NLRP3 inhibitors comprising the compounds described in any one of the preceding paragraphs or pharmaceutically acceptable salts thereof, pharmaceutical compositions, in the treatment of heart disease.

[0101] Another aspect of this disclosure provides the use of NLRP3 inhibitors comprising the compounds described in any one of the preceding paragraphs or pharmaceutically acceptable salts thereof, pharmaceutical compositions, in the treatment of inflammatory diseases.

[0102] Another aspect of this disclosure provides the use of NLRP3 inhibitors comprising the compounds described in any one of the preceding paragraphs or pharmaceutically acceptable salts thereof, pharmaceutical compositions, in the treatment of infectious diseases.

[0103] The compounds relating to this disclosure have NLRP3 inhibitory activity. [Modes for carrying out the invention]

[0104] I. Definition Based on the above-mentioned content of this disclosure, various other forms of modifications, substitutions, or changes can be made without departing from the basic technical idea of ​​this disclosure, in light of the general technical knowledge and customary means of those skilled in the art.

[0105] Unless otherwise explicitly indicated, throughout the specification and claims, any variation thereof such as “includes,” “contains,” or “contains” shall be understood to include the described element or component without excluding any other element or component.

[0106] The compounds relating to this disclosure may be asymmetric, and for example, may have one or more stereoisomers. Unless otherwise specified, all stereoisomers include enantiomers and diastereomers. Compounds containing asymmetric carbon atoms relating to this disclosure can be isolated in an optically active pure form or in a racemic form. The optically active pure form can be separated from a racemic mixture or synthesized using chiral starting materials or chiral reagents. Racemates, diastereomers, and enantiomers are all included within the scope of this disclosure.

[0107] In this disclosure,

[0108] JPEG0007849912000026.jpg267

[0109] This indicates the position where the substituent is attached.

[0110] In this disclosure, a numerical range means individual integers within a given range. For example, "C1-6" means that the group may have one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms, or six carbon atoms. "C1-3" means that the group may have one carbon atom, two carbon atoms, or three carbon atoms.

[0111] The terms “optional” or “optional” mean that the events or circumstances described below may or may not occur, and this statement includes the occurrence or non-occurrence of such events or circumstances.

[0112] The terms “substituted” or “substituted” mean that any one or more hydrogen atoms on a particular atom or group are substituted by a substituent, provided that the valence of that atom or group is normal and the substituted compound is stable. If the substituent is a ketone group (i.e., =O), it means that two hydrogen atoms are substituted. Unless otherwise specified, the type and number of substituents may be arbitrary as long as it is chemically possible. Substituents may be, but are not limited to, one, two, or more substituents selected from deuterium, halogen groups, cyano, nitro, -C(=O)R, -C(=O)OR', -OC(=O)R', imide, amide, hydroxy, substituted or unsubstituted amine groups, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, and substituted or unsubstituted heteroaryl.

[0113] Any variable (e.g., R n If a group appears multiple times in the composition or structure of a compound, its definition is independent for each instance. Therefore, for example, if a group is substituted with 1 to 3 R atoms, the group may be optionally substituted with 3 or fewer R atoms, and each R atom may have an independent selection. Furthermore, combinations of substituents and / or their variants are only permissible if such combinations produce a stable compound.

[0114] The term "alkyl" refers to a saturated aliphatic hydrocarbon group that contains a straight-chain or branched saturated hydrocarbon group having the indicated number of carbon atoms. For example, "C 1~6 The term "alkyl" includes C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl groups, and includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, n-hexyl, 2-hexyl, and 3-hexyl groups. These may also be divalent groups such as methylene and ethylene.

[0115] The term "alkoxy" may refer to a linear, branched, or cyclic alkoxy. The number of carbon atoms in an alkoxy is not particularly limited, but is preferably 1 to 20. Specific examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, i-propyloxy, n-butoxy, isobutoxy, t-butoxy, s-butoxy, n-pentoxy, neopentyloxy, isopentoxy, n-hexyloxy, 3,3-dimethylbutoxy, 2-ethylbutoxy, n-octyloxy, n-nonyloxy, and n-decoxy.

[0116] The term "phosphine oxide" is -P(=O)(R m )(R n ) is the structure, and here R m and R n These are identical or different, and each is independently hydrogen, deuterium, a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. Specific examples of phosphine oxides include alkylphosphine oxides and arylphosphine oxides, and more specifically, diphenylphosphine oxide, dinaphthylphosphine oxide, etc., but are not limited thereto.

[0117] The terms "alkylene" or "alkylene chain" refer to a fully saturated linear or branched divalent hydrocarbon chain group having 1 to 12 carbon atoms, and are generally represented as C1-C12 alkylenes. Preferred alkylenes are C1-C6 alkylenes, and more preferably C1-C4 alkylenes. Non-limiting examples of C1-C12 alkylenes include methylene, ethylene, propylene, and n-butylene. The alkylene chain is linked to the rest of the molecule by single bonds and to the group by single bonds. The sites of bonding to the rest of the molecule and the sites of bonding to the group may be one or two carbon atoms within the chain. Unless otherwise specified herein, alkylene chains may be optionally substituted.

[0118] In this disclosure, examples of halogen groups may include fluorine, chlorine, bromine, or iodine.

[0119] In this disclosure, the term "cycloalkyl" means a monocyclic saturated hydrocarbon system that does not contain heteroatoms and double bonds. For example, "C 3~9 Examples of the term "cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclononyl.

[0120] In this disclosure, the term "aryl" means an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π-electron system obtained by removing one hydrogen atom from a single carbon atom of a parent aromatic ring system. This includes bicyclic groups containing a saturated ring, a partially unsaturated ring, or an aromatic ring fused to an aromatic carbocyclic ring. Specific examples include, but are not limited to, phenyl and naphthyl.

[0121] In this disclosure, the term "heterocycloalkyl" means a 5-12 member saturated non-aromatic system having a cyclic carbon atom and one or two cyclic heteroatoms. Specific examples of heterocyclic groups include, but are not limited to, piperidinyl and tetrahydropyrrolyl.

[0122] In this disclosure, the term "heteroaryl" means a monovalent aryl compound containing at least one atom independently selected from nitrogen, oxygen, and sulfur atoms. A heteroaryl may be monocyclic, or it may be a polycyclic compound such as a bicyclic compound, where two or more rings exist in the form of parallel rings, bridging rings, or spiro rings, and at least one ring contains one or more heteroatoms. Specific examples of heteroaryls include, but are not limited to, pyridyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, furyl, pyrazinyl, thiazolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, imidazopyridyl, benzofuryl, pyridazinyl, and isoindolyl.

[0123] In this disclosure, when a heteroaryl is substituted, it may include, but is not limited to, a group represented by the following formula.

[0124] [ka]

[0125] The term "heterocyclic" refers to a 5-12 membered saturated non-aromatic system having a cyclic carbon atom and one or two cyclic heteroatoms, where the heteroatoms are independently selected from nitrogen, sulfur, or oxygen atoms. In a heterocyclic group containing one or more nitrogen atoms, the bond sites may be carbon atoms or nitrogen atoms, as long as the valence allows. Heterocyclics may be monocyclic or polycyclic systems, such as two or more rings existing in the form of parallel rings, bridging rings, or spiro rings, where at least one ring contains one or more heteroatoms.

[0126] As used herein, the term “partially unsaturated” means a ring moiety containing at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple unsaturated moies, but not to include aryl or heteroaryl moies as defined herein.

[0127] Pharmaceuticals or pharmaceutical compositions The term "pharmaceutically acceptable" means a compound, material, composition and / or dosage form that is appropriate for use in contact with human and animal tissues, within reasonable medical judgment, in proportion to a reasonable benefit / risk ratio, without excessive toxicity, irritation, allergic reactions, or other problems or complications.

[0128] The term "pharmaceutically acceptable salt" refers to a salt of a particular compound that maintains the biological potency of the free acid or base without causing any biological adverse effects. Examples include acid addition salts (including organic and inorganic acids) and base addition salts (including organic and inorganic bases).

[0129] The pharmaceutically acceptable salts relating to this disclosure can be synthesized from a parent compound containing an acid group or a base by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in the form of a free acid or base with a stoichiometrically appropriate base or acid in water, an organic solvent, or a mixture thereof.

[0130] The drugs or pharmaceutical compositions of this disclosure may be administered orally, topically, parenterally, or mucosally (for example, orally, by inhalation, or rectally) in dose-unit formulations comprising a conventional non-toxic, pharmaceutically acceptable carrier.

[0131] When administered orally in tablet or capsule form, the pharmacoactive ingredient may be used in combination with non-toxic, pharmaceutically acceptable auxiliary substances, such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol, and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica, stearic acid, sodium stearyl fumarate, glycerin docosaate, calcium stearate, etc.); disintegrants (e.g., potato starch or sodium hydroxyacetate starch); humectants (e.g., sodium lauryl sulfate), colorants and flavoring agents, gelatin, sweeteners, natural and synthetic gums (e.g., gum arabic, tragacanth gum, alginates), buffer salts, carboxymethylcellulose, polyethylene glycol, waxes, etc. When administered orally in liquid form, the drug component may be combined with a non-toxic, pharmaceutically acceptable inert carrier (e.g., ethanol, glycerin, water), an anti-sedimentation agent (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fat), an emulsifier (e.g., lecithin or gum arabic), a non-aqueous carrier (e.g., mandel oil, oils and fats, ethanol, or fractionated vegetable oil), a preservative (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, or sorbic acid), etc. Furthermore, stabilizers such as antioxidants (BHA, BHT, propyl citrate, sodium ascorbate, citric acid) may be added to stabilize the dosage form.

[0132] Tablets containing the active compound can be coated in a manner well known to those skilled in the art. The compositions relating to this disclosure, comprising the compound of formula I which is the active compound, may further incorporate small beads, microspheres, or microcapsules, such as those constructed from polyglycolic acid / lactic acid (PGLA). Liquid formulations for oral administration may take the form of, for example, solutions, syrups, emulsions, or suspensions, or they may be presented as dry products that can be reconstituted with water or other suitable auxiliary substances before use. Formulations for oral administration may be appropriately formulated to allow controlled or delayed release of the active compound.

[0133] The drugs or pharmaceutical compositions relating to this disclosure can be administered extragastrointestinally, i.e., intravenous (iv), intraventricular (icv), subcutaneous (sc), intraperitoneal (ip), intramuscular (im), subcutaneous (sd), or intradermal (id) by direct injection, for example, by rapid infusion or continuous infusion. Formulations for injection can be presented in unit dosage form, for example, in ampoule bottles or multi-dose containers with preservatives added. The compositions can take the form of excipients, suspensions in oil or aqueous carriers, solutions, or emulsions, and may contain compounding agents such as anti-settling agents, stabilizers, and / or dispersants. Alternatively, the active ingredient can be reconstituted in powder form before use using a suitable carrier (e.g., sterile pyrogen-free water).

[0134] The drugs or pharmaceutical compositions relating to this disclosure may also be formulated for rectal administration, such as suppositories or retained enemas (including, for example, conventional suppository matrices such as cocoa butter or other glycerides).

[0135] The term "treatment" includes inhibiting, alleviating, preventing or eliminating one or more symptoms or side effects associated with the disease, condition, or disorder being treated.

[0136] The terms “reduction,” “inhibition,” “mitigation,” or “reduction” are used in relation to a control. Those skilled in the art can easily determine an appropriate control for each experiment. For example, the reduced response in subjects or cells treated with the compound can be compared to the response in subjects or cells not treated with the compound.

[0137] As used herein, the terms “effective dose” or “therapeutic effective dose” mean a dose sufficient to treat, inhibit, or alleviate one or more symptoms of the disease condition being treated, or to otherwise provide the desired pharmacological and / or physiological effect. The exact dose will vary depending on various factors such as subject-dependent variables (e.g., age, immune system health), disease or illness, and the treatment administered. The effect of the effective dose may be relative to a control. These controls are known to those skilled in the art and are discussed herein, and may, for example, be the state of a subject before or without administration of a combination of drugs or pharmaceutical compositions, or, in the case of a combination of drugs, the effect of the combination may be compared to the effect of administering only one drug.

[0138] The term “excipient” is used herein to include other compounds that may be present in or on particulate matter, but are not therapeutic or biologically active compounds. Therefore, excipients should generally be pharmaceutically or biologically acceptable, or related to such, being non-toxic to the subject. “Excipients” may include a single compound, or may include multiple such compounds.

[0139] The term "pharmaceutical composition" means a composition comprising a compound relating to this disclosure or a pharmaceutically acceptable salt thereof, and at least one selected from pharmaceutically acceptable components, including but not limited to carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, dispersants, thermosensitive materials, temperature regulators, adhesives, stabilizers, suspension aids, etc., depending on the method of administration and the nature of the dosage form.

[0140] Use and treatment methods Terms such as "patient", "subject", "individual", etc. may be used interchangeably herein and refer to any animal or its cells that follow the methods described herein, whether in vitro or in situ. In some non-limiting embodiments, the patient, subject, or individual is human.

[0141] According to the methods of the present disclosure, the compound or composition is useful for administration in any amount and by any route of administration effective to treat or reduce the severity of a disease associated with NRLP3.

[0142] The present disclosure relates to a method of inhibiting NRLP3 in a biological sample, the method comprising contacting the biological sample with a compound of the present disclosure or a composition comprising this compound.

[0143] The term "biological sample" includes, but is not limited to, cell cultures or extracts thereof, biopsy materials obtained from mammals or extracts thereof, and blood, saliva, urine, feces, semen, tears, other body fluids or extracts thereof. Agonists of enzymes in biological samples can be used to achieve various purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, biological assays, gene expression studies, and biological target identification.

[0144] A method of inhibiting NRLP3 in a patient according to the present disclosure comprises administering to the patient a compound according to the present disclosure or a composition comprising a compound according to the present disclosure.

[0145] <00009%18>The compounds provided are NRLP3 inhibitors and are thus useful for the treatment of one or more disorders associated with NRLP3 activity. Thus, in some embodiments, the present disclosure provides a method for treating an NRLP3-mediated disorder comprising administering to a patient in need thereof a compound according to the present disclosure or a pharmaceutically acceptable composition thereof.

[0146] As used herein, the terms “NRLP3-mediated” disorders, diseases, and / or conditions refer to any disease or other adverse condition on which NRLP3 or its mutants are known to act, as intended herein. Accordingly, another embodiment of this disclosure relates to treating or mitigating the severity of one or more diseases on which NRLP3 or its mutants are known to act.

[0147] Combination therapy This disclosure provides combination therapies of compounds relating to this disclosure with other therapeutic agents. As used in this disclosure, the term “combination therapy” includes administering these agents sequentially, i.e., administering each therapeutic agent at different times, and administering these therapeutic agents, or at least two agents, substantially simultaneously. Sequential or substantially simultaneous administration of each agent may be influenced by any suitable route, including, but not limited to, oral, intravenous, intramuscular, subcutaneous, and direct absorption via mucosal tissue. The agents may be administered via the same or different routes. For example, the first agent may be administered orally and the second agent intravenously. Furthermore, a selected combination agent may be administered by intravenous injection, while other combination agents may be administered orally. Alternatively, for example, two or more agents may be administered by intravenous or subcutaneous injection. [Examples]

[0148] II. Examples The present disclosure will be further described below with reference to examples. The description of specific exemplary embodiments of the present disclosure is for illustrative and illustrative purposes only. These descriptions are not intended to limit the present disclosure to the exact form disclosed, and it is clear that many modifications and changes are possible in accordance with the teachings herein. The selection and description of exemplary embodiments is intended to illustrate the specific principles of the present disclosure and their practical application, thereby enabling those skilled in the art to implement and utilize various different exemplary embodiments, as well as various different choices and modifications, of the present disclosure.

[0149] The experimental methods used in the following examples are conventional methods unless otherwise specified.

[0150] Unless otherwise specified, the materials, reagents, etc., used in the following examples are commercially available.

[0151] Example 1: Synthesis of (R)-2-(4-((1-methylpiperidine-3-yl)amine)phthalazine-1-yl)-5-(trifluoromethyl)phenol

[0152] [ka]

[0153] Step 1: Dissolve the compound phthalic anhydride (1a) (1.0 g, 6.75 mmol) and N2H4·H2O (1.01 g, 20.25 mmol) in acetic acid (20 mL), heat to 120 °C, and reflux overnight. Confirm the completion of the reaction by TLC, concentrate the reaction solution to dryness, add water (20 mL) to disperse the solid, filter, suction dry the filter cake, and vacuum dry overnight to obtain the target compound 1b (2,3-dihydrophthalazine-1,4-dione) (0.75 g, yield: 68.51%, LCMS m / z = 163.2 [M+1]). + ) was obtained.

[0154] Step 2: Compound (1b) (0.20 g, 1.23 mmol) was dissolved in POCl3 (2 mL), heated to 100°C, and reacted overnight. After confirming the completion of the reaction by TLC, the reaction solution was directly concentrated, and after removing the POCl3, the oily crude was slowly added dropwise to ice water (20 mL), stirred thoroughly, and the pH was adjusted to 8 with 2N sodium hydroxide aqueous solution. Extraction was performed with ethyl acetate (10 mL x 3), the organic phase was combined, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PE:EA = 20:1) to obtain the target compound 1c (1,4-dichlorophthalazine) (0.21 g, yield: 85.54%, LCMS m / z = 199.2 [M+1]). + ) was obtained.

[0155] Step 3: Compound (1c) (0.20 g, 1.00 mmol), (R)-1-methylpiperidine-3-amine (0.126 g, 1.11 mmol), and Na2CO3 (0.21 g, 2.01 mmol) were dissolved in dry DMF (2 mL). This mixture was placed in a sealed tube, heated to 120 °C, and allowed to react overnight. After confirming the completion of raw material conversion by TLC, the reaction mixture was added to water (20 ml), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound (1d)((R)-4-chloro-N-(1-methylpiperidine-3-yl)phthalazine-1-amine) (0.06 g, yield: 21.57%, LCMS m / z = 277.2 [M+1]). + ) was obtained.

[0156] Step 4: Compound (1d) (0.05 g, 0.18 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (0.045 g, 0.217 mmol), sodium carbonate (0.04 g, 0.36 mmol) and Pd(dppf)Cl2 (15.00 mg, 0.02 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v = 4:1). The mixture was purged with nitrogen three times, heated to 110 °C and reacted for 3 hours. Water (50 mL) was added to the reaction solution for quenching, and the mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine (3 × 30 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure from the filtrate. The residue was separated by column chromatography (DCM:CH3OH = 10:1) to obtain compound 1 ((R)-2-(4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)-5-(trifluoromethyl)phenol) (0.01 g, yield: 13.76%, LCMS m / z = 403.2 [M+1] + ) was obtained.

[0157] Example 2: Synthesis of (R)-2-(4-((1-methylpiperidin-3-yl)amino)-5,6,7,8-tetrahydrophthalazin-1-yl)-5-(trifluoromethyl)phenol

[0158] [Chemical formula]

[0159] Step 1: Compound 4,5,6,7-tetrahydroisobenzofuran-1,3-dione (2a) (1.0 g, 6.57 mmol) and N2H4·H2O (0.98 g, 19.72 mmol) were dissolved in acetic acid (20 mL), heated to 120 °C and refluxed overnight. After confirming the completion of the reaction by TLC, the reaction solution was concentrated directly to dryness, water (20 ml) was added to disperse the solid, filtered, and the filter cake was dried by suction and then dried under vacuum overnight to obtain the target compound 2b (2,3,5,6,7,8-hexahydrophthalazine-1,4-dione) (0.60 g, yield: 54.93%, LCMS m / z = 167.2 [M+1] + ) was obtained.

[0160] Step 2: Compound (2b) (0.20 g, 1.20 mmol) was dissolved in POCl3 (2 mL) and heated to 100°C, reacting overnight. After confirming the completion of the reaction by TLC, the reaction solution was directly concentrated, and after removing the POCl3, the crude oily product was slowly added to ice water (20 mL), stirred thoroughly, and the pH was adjusted to 8 using 2N sodium hydroxide aqueous solution. Extraction was performed with ethyl acetate (10 mL x 3), the organic phase was combined, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PE:EA = 20:1) to obtain the target compound (2c) (1,4-dichloro-5,6,7,8-tetrahydrophthalazine) (0.15 g, yield: 61.38%, LCMS m / z = 204.2 [M+1]). + ) was obtained.

[0161] Step 3: Compound (2c) (0.15 g, 0.738 mmol), (R)-1-methylpiperidine-3-amine (0.093 g, 0.81 mmol), and Na2CO3 (0.16 g, 1.48 mmol) were dissolved in dry DMF (2 mL). This mixture was placed in a sealed tube, heated to 120°C, and allowed to react overnight. After confirming that the raw material conversion was complete using TLC, the reaction mixture was added to water (20 ml), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound (2d)((R)-4-chloro-N-(1-methylpiperidine-3-yl)-5,6,7,8-tetrahydrophthalazine-1-amine) (0.05 g, yield: 24.11%, LCMS m / z = 281.2 [M+1]). + ) was obtained.

[0162] Step 4: Compound (2d) (0.05 g, 0.18 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (0.044 g, 0.214 mmol), sodium carbonate (0.037 g, 0.36 mmol), and Pd(dppf)Cl2 (15.00 mg, 0.02 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), combined with the organic phase, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound 2((R)-2-(4-((1-methylpiperidine-3-yl)amino)-5,6,7,8-tetrahydrophthalazine-1-yl)-5-(trifluoromethyl)phenol) (0.011 g, yield: 15.20%, LCMS m / z = 407.2 [M+1]). + ) was obtained.

[0163] Example 3: Synthesis of (R)-2-(7-methyl-4-((1-methylpiperidine-3-yl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol

[0164] [ka]

[0165] Step 1: Compound 4-methylphthalic anhydride (3a) (2.0 g, 12.33 mmol) and N2H4·H2O (1.85 g, 37.00 mmol) were dissolved in acetic acid (30 mL), heated to 120 °C, and refluxed overnight. After confirming completion of the reaction by TLC, the reaction solution was concentrated directly to dryness, water (20 mL) was added to disperse the solid, and the mixture was filtered. The filtered cake was vacuum-dried and then vacuum-dried overnight to obtain the target compound 3b (6-methyl-2,3-dihydrophthalazine-1,4-dione) (1.51 g, yield: 69.03%, LCMS m / z = 177.2 [M+1]). + ) was obtained.

[0166] Step 2: Compound (3b) (1.51 g, 8.57 mmol) was dissolved in POCl3 (10 mL), heated to 100°C, and reacted overnight. After confirming the completion of the reaction by TLC, the reaction solution was directly concentrated, and after removing the POCl3, the crude oily product was slowly added to ice water (50 mL), stirred thoroughly, and the pH was adjusted to 8 with 2N sodium hydroxide aqueous solution. Extraction was performed with ethyl acetate (10 mL x 3), the organic phase was combined, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PE:EA = 10:1) to obtain the target compound (3c) (1,4-dichloro-6-methylphthalazine) (1.45 g, yield: 79.40%, LCMS m / z = 213.2 [M+1]). + ) was obtained.

[0167] Step 3: Compound (3c) (0.20 g, 0.94 mmol), (R)-1-methylpiperidine-3-amine (0.12 g, 1.04 mmol), and Na2CO3 (0.20 g, 1.89 mmol) were dissolved in dry DMF (2 mL). This mixture was placed in a sealed tube and heated to 120°C, and reacted overnight. After confirming that the starting material conversion was complete by TLC, the reaction mixture was added to water (20 mL), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain a mixture of target compounds (3d) and (4d) (0.08 g, yield: 29.31%, LCMS m / z = 291.2 [M+1]). + ) was obtained.

[0168] Step 4: A mixture of compounds (3d) and (4d) (0.08 g, 0.27 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (0.074 g, 0.357 mmol), sodium carbonate (0.058 g, 0.55 mmol), and Pd(dppf)Cl2 (19.75 mg, 0.027 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), combined with the organic phase, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by PTLC (DCM:CH3OH=10:1) to obtain the target compound 3((R)-2-(7-methyl-4-((1-methylpiperidine-3-yl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol) (0.011 g, yield: 8.73%, LCMS m / z = 417.2 [M+1]). + ) was obtained.

[0169] Example 4: Synthesis of (R)-2-(6-methyl-4-((1-methylpiperidine-3-yl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol

[0170] [ka]

[0171] Step 1: Compound (3c) (0.20 g, 0.94 mmol), (R)-1-methylpiperidine-3-amine (0.12 g, 1.04 mmol), and Na2CO3 (0.20 g, 1.89 mmol) were dissolved in dry DMF (2 mL). This mixture was placed in a sealed tube and heated to 120°C, and reacted overnight. After confirming that the starting material conversion was complete by TLC, the reaction mixture was added to water (20 mL), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain a mixture of the target compounds (4d) and (3d) (0.08 g, yield: 29.31%, LCMS m / z = 291.2 [M+1]). + ) was obtained.

[0172] Step 2: A mixture of compounds (3d) and (4d) (0.08 g, 0.27 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (0.074 g, 0.357 mmol), sodium carbonate (0.058 g, 0.55 mmol), and Pd(dppf)Cl2 (19.75 mg, 0.027 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), combined with the organic phase, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by PTLC (DCM:CH3OH=10:1) to obtain the target compound 4((R)-2-(6-methyl-4-((1-methylpiperidine-3-yl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol) (0.008 g, yield: 6.98%, LCMS m / z = 417.2 [M+1]). + ) was obtained.

[0173] Example 5: Synthesis of (R)-2-(7-methoxy-4-((1-methylpiperidine-3-yl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol

[0174] [ka]

[0175] Step 1: Compound 4-methoxyphthalic anhydride (5a) (2.0 g, 11.23 mmol) and N2H4·H2O (1.69 g, 33.68 mmol) were dissolved in acetic acid (30 mL) and heated to 120 °C and refluxed overnight. After confirming the completion of the reaction by TLC, the reaction mixture was concentrated directly to dryness, water (20 mL) was added to disperse the solid, and the mixture was filtered. The filtered cake was vacuum-dried and then vacuum-dried overnight to obtain the target compound 5b (6-methoxy-2,3-dihydrophthalazine-1,4-dione) (1.42 g, yield: 65.82%, LCMS m / z = 193.2 [M+1]). + ) was obtained.

[0176] Step 2: Compound (5b) (1.42 g, 7.39 mmol) was dissolved in POCl3 (10 mL) and heated to 100°C and reacted overnight. After confirming the completion of the reaction by TLC, the reaction solution was directly concentrated, and after removing the POCl3, the crude oily product was slowly added to ice water (50 mL), stirred thoroughly, and the pH was adjusted to 8 with 2N sodium hydroxide aqueous solution. Extraction was performed with ethyl acetate (10 mL x 3), the organic phase was combined, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PE:EA = 10:1) to obtain the target compound (5c) (1,4-dichloro-6-methoxyphthalazine) (1.20 g, yield: 70.90%, LCMS m / z = 229.2 [M+1]). + ) was obtained.

[0177] Step 3: Compound (5c) (0.20 g, 0.87 mmol), (R)-1-methylpiperidine-3-amine (0.11 g, 0.96 mmol), and Na2CO3 (0.20 g, 1.89 mmol) were dissolved in dry DMF (2 mL). This mixture was placed in a sealed tube, heated to 120°C, and reacted overnight. After confirming that the starting material conversion was complete by TLC, the reaction mixture was added to water (20 mL), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain a mixture of target compounds (5d) and (6d) (0.09 g, yield: 33.60%, LCMS m / z = 307.2 [M+1]). + ) was obtained.

[0178] Step 4: A mixture of compounds (5d) and (6d) (0.09 g, 0.29 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (78.53 mg, 0.38 mmol), sodium carbonate (62.18 mg, 0.58 mmol), and Pd(dppf)Cl2 (19.75 mg, 0.027 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), combined with the organic phase, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by PTLC (DCM:CH3OH=10:1) to obtain the target compound 5((R)-2-(7-methoxy-4-((1-methylpiperidine-3-yl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol) (0.01 g, yield: 7.88%, LCMS m / z = 433.2 [M+1]). + ) was obtained.

[0179] Example 6: Synthesis of (R)-2-(6-methoxy-4-((1-methylpiperidine-3-yl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol

[0180] [ka]

[0181] Step 1: Compound (5c) (0.20 g, 0.87 mmol), (R)-1-methylpiperidine-3-amine (0.11 g, 0.96 mmol), and Na2CO3 (0.20 g, 1.89 mmol) were dissolved in dry DMF (2 mL). This mixture was placed in a sealed tube and heated to 120°C, and reacted overnight. After confirming that the starting material conversion was complete by TLC, the reaction mixture was added to water (20 mL), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain a mixture of the target compounds (6d) and (5d) (0.09 g, yield: 33.60%, LCMS m / z = 307.2 [M+1]). + ) was obtained.

[0182] Step 2: A mixture of compounds (5d) and (6d) (0.09 g, 0.29 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (78.53 mg, 0.38 mmol), sodium carbonate (62.18 mg, 0.58 mmol), and Pd(dppf)Cl2 (19.75 mg, 0.027 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), combined with the organic phase, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by PTLC (DCM:CH3OH=10:1) to obtain the target compound 6((R)-2-(6-methoxy-4-((1-methylpiperidine-3-yl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol) (0.008 g, yield: 6.31%, LCMS m / z = 433.2 [M+1]). + ) was obtained.

[0183] Example 7: Synthesis of (R)-2-(4-((1-phenylethyl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol

[0184] [ka]

[0185] Step 1: Compound (1c) (0.20 g, 1.00 mmol), (R)-1-methylbenzylamine (0.15 g, 1.21 mmol), and Na2CO3 (0.21 g, 2.01 mmol) were dissolved in dry DMF (2 mL). This mixture was placed in a sealed tube, heated to 120°C, and allowed to react overnight. After confirming that the raw material conversion was complete using TLC, the reaction mixture was added to water (20 ml), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PE:EA = 3:1) to obtain the target compound (7a) ((R)-4-chloro-N-(1-phenylethyl)phthalazine-1-amine) (0.14 g, yield: 49.10%, LCMS m / z = 284.2 [M+1]). + ) was obtained.

[0186] Step 2: Compound (7a) (0.05 g, 0.17 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (39.91 mg, 0.19 mmol), sodium carbonate (37.35 mg, 0.35 mmol), and Pd(dppf)Cl2 (10.24 mg, 0.014 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), combined with the organic phase, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PE:EA = 3:1) to obtain the target compound 7((R)-2-(4-((1-phenylethyl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol) (0.02 g, yield: 27.72%, LCMS m / z = 410.2 [M+1]). + ) was obtained.

[0187] Example 8: Synthesis of (S)-2-(4-((1-phenylethyl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol

[0188] [ka]

[0189] Step 1: Compound (1c) (0.20 g, 1.00 mmol), (S)-1-methylbenzylamine (0.15 g, 1.21 mmol), and Na2CO3 (0.21 g, 2.01 mmol) were dissolved in dry DMF (2 mL). This mixture was placed in a sealed tube, heated to 120°C, and allowed to react overnight. After confirming that the raw material conversion was complete using TLC, the reaction mixture was added to water (20 ml), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PE:EA = 3:1) to obtain the target compound (8a) ((S)-4-chloro-N-(1-phenylethyl)phthalazine-1-amine) (0.14 g, yield: 49.10%, LCMS m / z = 284.2 [M+1]). + ) was obtained.

[0190] Step 2: Compound (8a) (0.05 g, 0.17 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (39.91 mg, 0.19 mmol), sodium carbonate (37.35 mg, 0.35 mmol), and Pd(dppf)Cl2 (10.24 mg, 0.014 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), combined with the organic phase, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PE:EA = 3:1) to obtain the target compound 8((S)-2-(4-((1-phenylethyl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol) (0.02 g, yield: 27.72%, LCMS m / z = 410.2 [M+1]). + ) was obtained.

[0191] Example 9: Synthesis of (R)-2-(4-((1-(4-fluorophenyl)ethyl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol

[0192] [ka]

[0193] Step 1: Compound (1c) (0.20 g, 1.00 mmol), (R)-1-(4-fluorophenyl)ethane-1-amine (0.16 g, 1.20 mmol), and Na2CO3 (0.21 g, 2.01 mmol) were dissolved in dry DMF (2 mL). This mixture was placed in a sealed tube, heated to 120 °C, and allowed to react overnight. After confirming the completion of raw material conversion by TLC, the reaction mixture was added to water (20 ml), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PE:EA = 3:1) to obtain the target compound (9a)(R)-4-chloro-N-(1-(4-fluorophenyl)ethyl)phthalazine-1-amine) (0.12 g, yield: 39.58%, LCMS m / z = 302.2 [M+1]). + ) was obtained.

[0194] Step 2: Compound (9a) (0.05 g, 0.16 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (37.53 mg, 0.18 mmol), sodium carbonate (35.12 mg, 0.33 mmol), and Pd(dppf)Cl2 (10.24 mg, 0.014 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), combined with the organic phase, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PE:EA = 3:1) to obtain the target compound 9(((R)-2-(4-((1-(4-fluorophenyl)ethyl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol) (0.02 g, yield: 28.24%, LCMS m / z = 428.2 [M+1]). + ) was obtained.

[0195] Example 10: Synthesis of (S)-2-(4-((1-(4-fluorophenyl)ethyl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol

[0196] [ka]

[0197] Step 1: Compound (1c) (0.20 g, 1.00 mmol), (S)-1-(4-fluorophenyl)ethane-1-amine (0.16 g, 1.20 mmol), and Na2CO3 (0.21 g, 2.01 mmol) were dissolved in dry DMF (2 mL). This mixture was placed in a sealed tube, heated to 120 °C, and allowed to react overnight. After confirming the completion of raw material conversion by TLC, the reaction mixture was added to water (20 ml), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PE:EA = 3:1) to obtain the target compound (10a) ((S)-4-chloro-N-(1-(4-fluorophenyl)ethyl)phthalazine-1-amine) (0.12 g, yield: 39.58%, LCMS m / z = 302.2 [M+1]). + ) was obtained.

[0198] Step 2: Compound (10a) (0.05 g, 0.16 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (37.53 mg, 0.18 mmol), sodium carbonate (35.12 mg, 0.33 mmol), and Pd(dppf)Cl2 (10.24 mg, 0.014 mol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), combined with the organic phase, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PE:EA = 3:1) to obtain the target compound 10(((S)-2-(4-((1-(4-fluorophenyl)ethyl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol) (0.015 g, yield: 21.18%, LCMS m / z = 428.2 [M+1]). + ) was obtained.

[0199] Example 11: Synthesis of 2-(4-(butylamino)phthalazine-1-yl)-5-(trifluoromethyl)phenol

[0200] [ka]

[0201] Step 1: Compound (1c) (0.10 g, 0.50 mmol), n-butylamine (0.036 g, 0.50 mmol), and Na2CO3 (0.11 g, 1.00 mmol) were dissolved in dry DMF (2 mL). This mixture was placed in a sealed tube, heated to 120 °C, and allowed to react overnight. After confirming that the starting material conversion was complete by TLC, the reaction mixture was added to water (20 mL), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PE:EA = 3:1) to obtain the target compound (11a) (n-butyl-4-chlorophthalazine-1-amine) (0.05 g, yield: 42.22%, LCMS m / z = 236.2 [M+1]). + ) was obtained.

[0202] Step 2: Compound (11a) (0.05 g, 0.21 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (52.42 mg, 0.25 mmol), sodium carbonate (44.96 mg, 0.42 mmol), and Pd(dppf)Cl2 (10.24 mg, 0.014 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), combined with the organic phase, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PE:EA = 3:1) to obtain the target compound 11((2-(4-(butylamino)phthalazine-1-yl)-5-(trifluoromethyl)phenol) (0.025 g, yield: 32.61%, LCMS m / z = 362.2 [M+1]). + ) was obtained.

[0203] Example 12: (R)-2-(4-((1-(pyridine-2-yl)ethyl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol

[0204] [ka]

[0205] Step 1: Compound (1c) (0.10 g, 0.50 mmol), (R)-1-(pyridine-2-yl)ethane-1-amine (67.52 mg, 0.55 mmol), and Na2CO3 (0.11 g, 1.00 mmol) were dissolved in dry DMF (2 mL). This mixture was placed in a sealed tube, heated to 120°C, and allowed to react overnight. After confirming the completion of raw material conversion by TLC, the reaction mixture was added to water (20 ml), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PE:EA = 3:1) to obtain the target compound (12a) ((R)-4-chloro-N-(1-(pyridine-2-yl)ethyl)phthalazine-1-amine) (0.06 g, yield: 41.94%, LCMS m / z = 285.2 [M+1]). + ) was obtained.

[0206] Step 2: Compound (12a) (0.06 g, 0.21 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (52.07 mg, 0.25 mmol), sodium carbonate (44.67 mg, 0.42 mmol), and Pd(dppf)Cl2 (15.36 mg, 0.021 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), combined with the organic phase, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PE:EA = 3:1) to obtain the target compound 12((R)-2-(4-((1-(pyridine-2-yl)ethyl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol) (0.025 g, yield: 28.91%, LCMS m / z = 411.2 [M+1]). + ) was obtained.

[0207] Example 13: Synthesis of (S)-2-(4-((1-(pyridine-2-yl)ethyl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol

[0208] [ka]

[0209] Step 1: Compound (1c) (0.10 g, 0.50 mmol), (S)-1-(pyridine-2-yl)ethane-1-amine (67.52 mg, 0.55 mmol), and Na2CO3 (0.11 g, 1.00 mmol) were dissolved in dry DMF (2 mL). This mixture was placed in a sealed tube, heated to 120°C, and allowed to react overnight. After confirming that the raw material conversion was complete using TLC, the reaction mixture was added to water (20 ml), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PE:EA = 3:1) to obtain the target compound (13a) ((S)-4-chloro-N-(1-(pyridine-2-yl)ethyl)phthalazine-1-amine) (0.05 g, yield: 34.95%, LCMS m / z = 285.2 [M+1]). + ) was obtained.

[0210] Step 2: Compound (13a) (0.05 g, 0.17 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (43.39 mg, 0.21 mmol), sodium carbonate (38.22 mg, 0.35 mmol), and Pd(dppf)Cl2 (15.36 mg, 0.021 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), combined with the organic phase, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PE:EA = 3:1) to obtain the target compound 13((S)-2-(4-((1-(pyridine-2-yl)ethyl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol) (0.02 g, yield: 27.75%, LCMS m / z = 411.2 [M+1]). + ) was obtained.

[0211] Example 14: Synthesis of 2-(5-{[(3R)-1-methylpiperidine-3-yl]amino}pyrido[2,3-d]pyridazin-8-yl)-5-(trifluoromethyl)phenol

[0212] [ka]

[0213] Step 1: The compound furan[3,4-b]pyridine-5,7-dione (14a) (3.0 g, 20.12 mmol) and N2H4·H2O (3.02 g, 60.36 mmol) were dissolved in acetic acid (50 mL) and heated to 120 °C and refluxed overnight. After confirming the completion of the reaction by TLC, the reaction solution was concentrated directly to dryness, water (50 mL) was added to disperse the solid, and the mixture was filtered. The filtered cake was vacuum-dried and then vacuum-dried overnight to obtain the target compound (14b) (6,7-dihydropyrido[2,3-d]pyridazine-5,8-dione) (2.30 g, yield: 70.07%, LCMS m / z = 164.2 [M+1]). + ) was obtained.

[0214] Step 2: Compound (14b) (2.30 g, 14.10 mmol) was dissolved in POCl3 (20 mL) and heated to 100°C and reacted overnight. After confirming the completion of the reaction by TLC, the reaction solution was directly concentrated, and after removing the POCl3, the crude oily product was slowly added to ice water (50 mL) and stirred thoroughly. The aqueous solution was adjusted to pH=8 using 2N sodium hydroxide, extracted with ethyl acetate (30 mL x 3), the organic phase was combined, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PE:EA=10:1) to obtain the target compound (14c) (5,8-dichloropyrido[2,3-d]pyridazine) (1.25 g, yield: 44.33%, LCMS m / z = 200.2 [M+1]). + ) was obtained.

[0215] Step 3: Compound (14c) (0.20 g, 1.00 mmol), (R)-1-methylpiperidine-3-amine (0.14 g, 1.20 mmol), and Na2CO3 (0.21 g, 1.99 mmol) were dissolved in dry DMF (3 mL). This mixture was placed in a sealed tube, heated to 120°C, and allowed to react overnight. After confirming the completion of raw material conversion by TLC, the reaction mixture was added to water (20 ml), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound (14d)((3R)-N-(8-chloropyrido[2,3-d]pyridazin-5-yl)-1-methylpiperidine-3-amine) (0.13 g, yield: 46.80%, LCMS m / z = 278.2 [M+1]). + They obtained the following results.

[0216] Step 4: Compound (14d) (0.05 g, 0.18 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (44.00 mg, 0.22 mmol), sodium carbonate (29.15 mg, 0.27 mmol), and Pd(dppf)Cl2 (19.75 mg, 0.027 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), combined with the organic phase, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound 14 (2-(5-{[(3R)-1-methylpiperidine-3-yl]amino}pyrido[2,3-d]pyridazin-8-yl)-5-(trifluoromethyl)phenol) (0.022 g, yield: 30.30%, LCMS m / z = 404.4 [M+1]). + They obtained the following results.

[0217] Example 15: Synthesis of 2-(8-{[(3R)-1-methylpiperidine-3-yl]amino}pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol

[0218] [ka]

[0219] Step 1: Compound (14c) (0.20 g, 1.00 mmol), (R)-1-methylpiperidine-3-amine (0.14 g, 1.20 mmol), and Na2CO3 (0.21 g, 1.99 mmol) were dissolved in dry DMF (3 mL). This mixture was placed in a sealed tube, heated to 120°C, and allowed to react overnight. After confirming that the raw material conversion was complete using TLC, the reaction mixture was added to water (20 ml), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound (15d)((3R)-N-(5-chloropyrido[2,3-d]pyridazin-8-yl)-1-methylpiperidine-3-amine) (0.04 g, yield: 14.40%, LCMS m / z = 278.2 [M+1]). + ) was obtained.

[0220] Step 2: Compound (15d) (0.04 g, 0.14 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (35.00 mg, 0.17 mmol), sodium carbonate (22.10 mg, 0.21 mmol), and Pd(dppf)Cl2 (19.75 mg, 0.027 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), combined with the organic phase, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound 15 (2-(8-{[(3R)-1-methylpiperidine-3-yl]amino}pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol) (0.015 g, yield: 26.56%, LCMS m / z = 404.4 [M+1]). + They obtained the following results.

[0221] Example 16: Synthesis of 2-(7-fluoro-4-{[(3R)-1-methylpiperidine-3-yl]amino}phthalazine-1-yl)-5-(trifluoromethyl)phenol

[0222] [ka]

[0223] Step 1: Compound 5-fluoroisobenzofuran-1,3-dione (16a) (5.0 g, 30.10 mmol) and N2H4·H2O (7.53 g, 150.50 mmol) were dissolved in acetic acid (50 mL) and heated to 120 °C and refluxed overnight. After confirming the completion of the reaction by TLC, the reaction solution was concentrated directly to dryness, water (50 mL) was added to disperse the solid, and the mixture was filtered. The filtered cake was vacuum-dried and then vacuum-dried overnight to obtain the target compound (16b) (6-fluoro-2,3-dihydrophthalazine-1,4-dione) (5.40 g, yield: 99.59%, LCMS m / z = 181.1 [M+1]). + ) was obtained.

[0224] Step 2: Compound (16b) (5.40 g, 29.98 mmol) was dissolved in POCl3 (30 mL) and heated to 100°C and reacted overnight. After confirming the completion of the reaction by TLC, the reaction solution was directly concentrated, and after removing the POCl3, the crude oily product was slowly added to ice water (50 mL), stirred thoroughly, and the pH was adjusted to 8 with 2N sodium hydroxide aqueous solution. Extraction was performed with ethyl acetate (50 mL x 3), the organic phase was combined, washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PE:EA = 5:1) to obtain the target compound (16c) (1,4-dichloro-6-fluorophthalazine) (4.83 g, yield: 74.23%, LCMS m / z = 217.0 [M+1]). + ) was obtained.

[0225] Step 3: Compound (16c) (0.20 g, 0.92 mmol), (R)-1-methylpiperidine-3-amine (0.14 g, 1.20 mmol), and Na2CO3 (0.21 g, 1.99 mmol) were dissolved in dry DMF (3 mL). This mixture was placed in a sealed tube, heated to 120°C, and allowed to react overnight. After confirming the completion of raw material conversion by TLC, the reaction mixture was added to water (20 ml), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound (16d)((R)-4-chloro-6-fluoro-N-(1-methylpiperidine-3-yl)phthalazine-1-amine) (0.05 g, yield: 18.41%, LCMS m / z = 295.2 [M+1]). + They obtained the following results.

[0226] Step 4: Compound (16d) (0.05 g, 0.17 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (44.00 mg, 0.22 mmol), sodium carbonate (29.15 mg, 0.27 mmol), and Pd(dppf)Cl2 (19.75 mg, 0.027 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), combined with the organic phase, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound 16((R)-2-(7-fluoro-4-((1-methylpiperidine-3-yl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol) (0.01 g, yield: 14.02%, LCMS m / z = 421.4 [M+1]). + They obtained the following results.

[0227] Example 17: Synthesis of (R)-2-(1-((1-methylpiperidine-3-yl)amino)pyridine[3,4-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol

[0228] [ka]

[0229] Step 1: Compound furan[3,4-c]pyridine-1,3-dione (17a) (3.0 g, 20.12 mmol) and N2H4·H2O (3.02 g, 60.36 mmol) were dissolved in acetic acid (50 mL) and heated to 120 °C and refluxed overnight. After confirming the completion of the reaction by TLC, the reaction solution was concentrated directly to dryness, water (50 mL) was added to disperse the solid, and the mixture was filtered. The filtered cake was vacuum-dried and then vacuum-dried overnight to obtain the target compound (17b) (2,3-dihydropyrido[3,4-d]pyridazine-1,4-dione) (2.10 g, yield: 63.97%, LCMS m / z = 164.2 [M+1]). + ) was obtained.

[0230] Step 2: Compound (17b) (2.10 g, 12.87 mmol) was dissolved in POCl3 (20 mL) and heated to 100°C and reacted overnight. After confirming the completion of the reaction by TLC, the reaction solution was directly concentrated, and after removing the POCl3, the crude oily product was slowly added to ice water (50 mL), stirred thoroughly, and the pH was adjusted to 8 with 2N sodium hydroxide aqueous solution. Extraction was performed with ethyl acetate (30 mL x 3), the organic phase was combined, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PE:EA = 10:1) to obtain the target compound (17c) (1,4-dichloropyrido[3,4-d]pyridazine) (0.92 g, yield: 32.63%, LCMS m / z = 200.2 [M+1]). + ) was obtained.

[0231] Step 3: Compound (17c) (0.20 g, 1.00 mmol), (R)-1-methylpiperidine-3-amine (0.14 g, 1.20 mmol), and Na2CO3 (0.21 g, 1.99 mmol) were dissolved in dry DMF (3 mL). This mixture was placed in a sealed tube, heated to 120°C, and allowed to react overnight. After confirming the completion of raw material conversion by TLC, the reaction mixture was added to water (20 ml), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound (17d)((R)-4-chloro-N-(1-methylpiperidine-3-yl)pyrido[3,4-d]pyridazine-1-amine) (0.11 g, yield: 39.60%, LCMS m / z = 278.2 [M+1]). + They obtained the following results.

[0232] Step 4: Compound (17d) (0.05 g, 0.18 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (44.00 mg, 0.22 mmol), sodium carbonate (29.15 mg, 0.27 mmol), and Pd(dppf)Cl2 (19.75 mg, 0.027 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), combined with the organic phase, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound 17((R)-2-(1-((1-methylpiperidine-3-yl)amino)pyridine[3,4-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol) (0.01 g, yield: 13.77%, LCMS m / z = 404.4 [M+1]). + They obtained the following results.

[0233] Example 18: Synthesis of 2-(4-((trans)-4-(dimethylamino)cyclohexyl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol

[0234] [ka]

[0235] Step 1: Compound (1c) (0.20 g, 1.00 mmol), (trans)-N 1 ,N 1 -Dimethylcyclohexane-1,4-diamine (0.14 g, 1.00 mmol) and Na2CO3 (0.21 g, 1.99 mmol) were dissolved in dry DMF (3 mL). This mixture was placed in a sealed tube and heated to 120 °C, and reacted overnight. After confirming that the raw material conversion was complete by TLC, the reaction mixture was added to water (20 mL), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH = 10:1) to obtain the target compound (18b)(trans)-N 1 -(4-chlorophthalazine-1-yl)-N 4 ,N 4 -Dimethylcyclohexane-1,4-diamine (0.04g, yield: 13.15%, LCMS m / z = 305.2 [M+1]) + ) was obtained.

[0236] Step 2: Compound (18b) (0.04 g, 0.13 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (35.00 mg, 0.17 mmol), sodium carbonate (22.10 mg, 0.21 mmol), and Pd(dppf)Cl2 (19.75 mg, 0.027 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), combined with the organic phase, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound 18 2-(4-((trans)-4-(dimethylamino)cyclohexyl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol (0.012 g, yield: 21.46%, LCMS m / z = 431.5 [M+1]). + They obtained the following results.

[0237] Example 19: Synthesis of 2-(4-((cis)-4-(dimethylamino)cyclohexyl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol

[0238] [ka]

[0239] Step 1: Compound (1c) (0.20 g, 1.00 mmol), (cis)-N 1 ,N 1-Dimethylcyclohexane-1,4-diamine (0.14 g, 1.00 mmol) and Na2CO3 (0.21 g, 1.99 mmol) were dissolved in dry DMF (3 mL). This mixture was placed in a sealed tube and heated to 120 °C, and reacted overnight. After confirming that the raw material conversion was complete by TLC, the reaction mixture was added to water (20 mL), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH = 10:1) to obtain the target compound (19b)(cis)-N 1 -(4-chlorophthalazine-1-yl)-N 4 ,N 4 -Dimethylcyclohexane-1,4-diamine (0.05g, yield: 16.45%, LCMS m / z = 305.2 [M+1]) + ) was obtained.

[0240] Step 2: Compound (19b) (0.05 g, 0.13 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (35.00 mg, 0.17 mmol), sodium carbonate (22.10 mg, 0.21 mmol), and Pd(dppf)Cl2 (19.75 mg, 0.027 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), combined with the organic phase, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound 19: 2-(4-((cis)-4-(dimethylamino)cyclohexyl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol (0.020 g, yield: 35.78%, LCMS m / z = 431.5 [M+1]). + They obtained the following results.

[0241] Example 20: Synthesis of 2-(4-((2-hydroxy-2-methylpropyl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol

[0242] [ka]

[0243] Step 1: Compound (1c) (0.20 g, 1.00 mmol), 1-amino-2-methylpropan-2-ol (0.14 g, 1.00 mmol), and Na2CO3 (0.21 g, 1.99 mmol) were dissolved in dry DMF (3 mL). This mixture was placed in a sealed tube, heated to 120°C, and allowed to react overnight. After confirming the completion of raw material conversion by TLC, the reaction mixture was added to water (20 ml), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound (20b) 1-((4-chlorophthalazine-1-yl)amino)-2-methylpropan-2-ol (0.05 g, yield: 19.92%, LCMS m / z = 252.1 [M+1]). + ) was obtained.

[0244] Step 2: Compound (20b) (0.05 g, 0.20 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (50.00 mg, 0.24 mmol), sodium carbonate (42.40 mg, 0.40 mmol), and Pd(dppf)Cl2 (19.75 mg, 0.027 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), combined with the organic phase, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound 20: 2-(4-((2-hydroxy-2-methylpropyl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol (0.01 g, yield: 11.60%, LCMS m / z = 378.4 [M+1]). + They obtained the following results.

[0245] Example 21: Synthesis of 2-(4-((2-morpholinylethyl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol

[0246] [ka]

[0247] Step 1: Compound (1c) (0.20 g, 1.00 mmol), 2-morpholinyl ether-1-amine (0.12 g, 1.00 mmol), and Na2CO3 (0.21 g, 1.99 mmol) were dissolved in dry DMF (3 mL). This mixture was placed in a sealed tube, heated to 120°C, and allowed to react overnight. After confirming that the raw material conversion was complete using TLC, the reaction mixture was added to water (20 ml), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound (21b) 4-chloro-N-(2-morpholinylethyl)phthalazine-1-amine (0.05 g, yield: 17.12%, LCMS m / z = 293.1 [M+1]). + ) was obtained.

[0248] Step 2: Compound (21b) (0.05 g, 0.17 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (42.00 mg, 0.20 mmol), sodium carbonate (42.40 mg, 0.40 mmol), and Pd(dppf)Cl2 (19.75 mg, 0.027 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), combined with the organic phase, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound 21: 2-(4-((2-morpholinylethyl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol (0.01 g, yield: 11.60%, LCMS m / z = 419.4 [M+1]). + They obtained the following results.

[0249] Example 22: Synthesis of (R)-2-(4-(piperidine-3-ylamino)phthalazine-1-yl)-5-(trifluoromethyl)phenol

[0250] [ka]

[0251] Step 1: Compound (1c) (0.20 g, 1.00 mmol), t-butyl(R)-3-aminopiperidine-1-carboxylate (0.20 g, 1.00 mmol), and Na2CO3 (0.21 g, 1.99 mmol) were dissolved in dry DMF (10 mL). This mixture was placed in a 50 mL necked flask and heated to 120 °C and allowed to react overnight. After confirming the completion of raw material conversion by TLC, the reaction mixture was added to water (20 ml), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (EA:PE = 1:1) to obtain the target compound (22a) (t-butyl(R)-3-((4-chlorophthalazine-1-yl)amino)piperidine-1-carboxylate) (0.22 g, yield: 60.34%, LCMS m / z = 363.2 [M+1]). + They obtained the following results.

[0252] Step 2: Compound (22a) (0.22 g, 0.61 mmol) was dissolved in dichloromethane (10 mL), added to trifluoroacetic acid (2 mL), and reacted overnight at room temperature. After confirming completion of the reaction by TLC, the reaction mixture was directly concentrated to remove the trifluoroacetic acid, the pH was adjusted to 8 using 2N sodium hydroxide aqueous solution, extracted with ethyl acetate (30 mL x 3), the organic phase was combined, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to obtain the target compound (22b) ((R)-4-chloro-N-(piperidine-3-yl)phthalazine-1-amine) (0.11 g, yield: 69.05%, LCMS m / z = 263.2 [M+1]). + ) was obtained.

[0253] Step 3: Compound (22b) (0.05 g, 0.19 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (44.00 mg, 0.22 mmol), sodium carbonate (29.15 mg, 0.27 mmol), and Pd(dppf)Cl2 (19.75 mg, 0.027 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), combined with the organic phase, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound 22((R)-2-(4-(piperidine-3-ylamino)phthalazine-1-yl)-5-(trifluoromethyl)phenol) (0.03 g, yield: 40.59%, LCMS m / z = 389.2 [M+1]). + They obtained the following results.

[0254] Example 23: Synthesis of (R)-2-(4-((1-ethylpiperidine-3-yl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol

[0255] [ka]

[0256] Step 1: Compound (22) (0.02 g, 0.051 mmol) and a solution of acetaldehyde in tetrahydrofuran (0.20 mL, 5.0 M) were dissolved in dry tetrahydrofuran (5 mL). Two drops of acetic acid were added dropwise, and this mixture was placed in a 50 mL necked flask. After stirring at room temperature for 1 hour, NaBH(OAc)3 was added and the mixture was reacted for a further 3 hours. After confirming the completion of the reaction by TLC, the reaction mixture was added to water (20 ml), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound (23)((R)-2-(4-((1-ethylpiperidine-3-yl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol) (0.01 g, yield: 46.63%, LCMS m / z = 417.4 [M+1]). + ) was obtained.

[0257] Example 24: (R)-2-(4-((1-methylpyrrolidine-3-yl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol

[0258] [ka]

[0259] Step 1: Compound (1c) (0.20 g, 1.00 mmol), (R)-1-methylpyrrolidine-3-amine (0.11 g, 1.1 mmol), and Na2CO3 (0.21 g, 2.0 mmol) were dissolved in dry DMF (2 mL). This mixture was placed in a sealed tube, heated to 120°C, and allowed to react overnight. After confirming that the raw material conversion was complete using TLC, the reaction mixture was added to water (20 ml), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound (24a) ((R)-4-chloro-N-(1-methylpyrrolidine-3-yl)phthalazine-1-amine) (0.06 g, yield: 21.6%, LCMS m / z = 263.4 [M+1]). + ) was obtained.

[0260] Step 2: At room temperature, compound (24a) (27 mg, 0.10 mmol), 2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (0.045 g, 0.217 mmol), sodium carbonate (42 mg, 0.40 mmol), and Pd(dppf)Cl2 (5 mg, 0.007 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1). The mixture was purged with nitrogen three times and heated to 110°C for 16 hours. After rotating the reaction mixture until dry, it was separated by silica gel column chromatography (DCM:CH3OH=10:1) to obtain compound 24((R)-2-(4-((1-methylpyrrolidine-3-yl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol) (30 mg, yield: 71.24%, LCMS m / z = 389.4 [M+1]). + ) was obtained.

[0261] Example 25: (R)-2-(4-((1-ethylpyrrolidine-3-yl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol

[0262] [ka]

[0263] Step 1: Compound (1c) (0.20 g, 1.00 mmol), (R)-1-ethylpyrrolidine-3-amine (0.14 g, 1.1 mmol), and Na2CO3 (0.21 g, 2.0 mmol) were dissolved in dry DMF (2 mL). This mixture was placed in a sealed tube, heated to 120 °C, and allowed to react overnight. After confirming that the raw material conversion was complete using TLC, the reaction mixture was added to water (20 ml), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound (25a) ((R)-4-chloro-N-(1-ethylpyrrolidine-3-yl)phthalazine-1-amine) (0.10 g, yield: 36.23%, LCMS m / z = 277.4 [M+1]). + ) was obtained.

[0264] Step 2: At room temperature, compound (25a) (28 mg, 0.10 mmol), 2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (0.045 g, 0.217 mmol), sodium carbonate (42 mg, 0.40 mmol), and Pd(dppf)Cl2 (5 mg, 0.007 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1). The mixture was purged with nitrogen three times and heated to 110°C for 16 hours. After rotating the reaction mixture until dry, it was separated by silica gel column chromatography (DCM:CH3OH=10:1) to obtain compound 25((R)-2-(4-((1-ethylpyrrolidine-3-yl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol) (20 mg, yield: 49.75%, LCMS m / z = 403.4 [M+1]). + ) was obtained.

[0265] Example 27: (R)-2-(4-(((1-ethylpyrrolidine-2-yl)methyl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol

[0266] [ka]

[0267] Step 1: Compound (1c) (0.20 g, 1.00 mmol), (R)-(1-ethylpyrrolidine-2-yl)methylamine (0.11 g, 1.1 mmol), and Na2CO3 (0.21 g, 2.0 mmol) were dissolved in dry DMF (2 mL). This mixture was placed in a sealed tube, heated to 120 °C, and allowed to react overnight. After confirming that the raw material conversion was complete using TLC, the reaction mixture was added to water (20 ml), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound (27a) ((R)-4-chloro-N-((1-ethylpyrrolidine-2-yl)methyl)phthalazine-1-amine) (0.08 g, yield: 27.5%, LCMS m / z = 291.4 [M+1]). + ) was obtained.

[0268] Step 2: At room temperature, compound (27a) (30 mg, 0.10 mmol), 2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (0.045 g, 0.217 mmol), sodium carbonate (42 mg, 0.40 mmol), and Pd(dppf)Cl2 (5 mg, 0.007 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1). The mixture was purged with nitrogen three times and heated to 110°C for 16 hours. After rotating the reaction mixture until dry, it was separated by silica gel column chromatography (DCM:CH3OH=10:1) to obtain compound 27((R)-2-(4-(((1-ethylpyrrolidine-2-yl)methyl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol) (10 mg, yield: 23.98%, LCMS m / z = 417.4 [M+1]). + ) was obtained.

[0269] Example 29: Synthesis of (R)-2-(4-((6,7-dihydro-5H-cyclopentan[b]pyridine-5-yl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol

[0270] [ka]

[0271] Step 1: Compound (1c) (0.20 g, 1.00 mmol), (R)-6,7-dihydro-5H-cyclopentane[b]pyridine-5-amine (0.13 g, 1.00 mmol), and Na2CO3 (0.21 g, 1.99 mmol) were dissolved in dry DMF (3 mL). This mixture was placed in a sealed tube and heated to 120 °C, where it was allowed to react overnight. After confirming the completion of raw material conversion by TLC, the reaction mixture was added to water (20 ml), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound (29b)(R)-4-chloro-N-(6,7-dihydro-5H-cyclopentan[b]pyridine-5-yl)phthalazine-1-amine (0.06 g, yield: 20.27%, LCMS m / z = 297.8 [M+1]). + ) was obtained.

[0272] Step 2: Compound (29b) (0.06 g, 0.20 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (50.00 mg, 0.24 mmol), sodium carbonate (42.40 mg, 0.40 mmol), and Pd(dppf)Cl2 (19.75 mg, 0.027 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), combined with the organic phase, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound 29 (R)-2-(4-((6,7-dihydro-5H-cyclopentane[b]pyridine-5-yl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol (0.01 g, yield: 11.84%, LCMS m / z = 423.5 [M+1]). + They obtained the following results.

[0273] Example 30: Synthesis of (S)-2-(4-((6,7-dihydro-5H-cyclopentan[b]pyridine-5-yl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol

[0274] [ka]

[0275] Step 1: Compound (1c) (0.20 g, 1.00 mmol), (S)-6,7-dihydro-5H-cyclopentane[b]pyridine-5-amine (0.13 g, 1.00 mmol), and Na2CO3 (0.21 g, 1.99 mmol) were dissolved in dry DMF (3 mL). This mixture was placed in a sealed tube, heated to 120 °C, and allowed to react overnight. After confirming the completion of raw material conversion by TLC, the reaction mixture was added to water (20 ml), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound (30b)(S)-4-chloro-N-(6,7-dihydro-5H-cyclopentan[b]pyridine-5-yl)phthalazine-1-amine (0.05 g, yield: 16.83%, LCMS m / z = 297.8 [M+1]). + ) was obtained.

[0276] Step 2: Compound (30b) (0.06 g, 0.17 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (42.00 mg, 0.20 mmol), sodium carbonate (42.40 mg, 0.40 mmol), and Pd(dppf)Cl2 (19.75 mg, 0.027 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), combined with the organic phase, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound 30(S)-2-(4-((6,7-dihydro-5H-cyclopentane[b]pyridine-5-yl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol (0.01 g, yield: 13.94%, LCMS m / z = 423.5[M+1]). + They obtained the following results.

[0277] Example 31: (R)-2-(4-((1-methylpiperidine-3-yl)amino)phthalazine-1-yl)phenol

[0278] [ka]

[0279] Step 1: At room temperature, compound (1d) (50 mg, 0.18 mmol), (2-hydroxyphenyl)boric acid (50 mg, 0.36 mmol), sodium carbonate (60 mg, 0.57 mmol), and Pd(dppf)Cl2 (5 mg, 0.007 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1). The mixture was purged with nitrogen three times and heated to 110°C for 16 hours. After rotating the reaction mixture until dry, it was separated by silica gel column chromatography (DCM:CH3OH=10:1) to obtain compound 31((R)-2-(4-((1-methylpiperidine-3-yl)amino)phthalazine-1-yl)phenol) (20 mg, yield: 33.23%, LCMS m / z = 335.4 [M+1]). + ) was obtained.

[0280] Example 32: (R)-1-(3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)phthalazine-1-yl)amino)piperidine-1-yl)ethane-1-one [ka]

[0281] Step 1: Compound (22b) (0.01 g, 0.038 mmol) and triethylamine (77.03 mg, 0.76 mmol) were dissolved in dichloromethane (5 mL), acetyl chloride (29.88 mg, 0.038 mmol) was added dropwise, and the mixture was reacted at room temperature for 0.5 hours. After confirming the completion of the reaction by TLC, the reaction mixture was added to water (20 ml), stirred thoroughly, extracted with DCM (20 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (EA:PE = 1:3) to obtain the target compound (32a)((R)-1-(3-((4-chlorophthalazine-1-yl)amino)piperidine-1-yl)ethane-1-one) (0.06 g, yield: 51.72%, LCMS m / z = 305.2 [M+1]). + ) was obtained.

[0282] Step 2: Compound (32a) (0.05 g, 0.16 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (44.00 mg, 0.22 mmol), sodium carbonate (29.15 mg, 0.27 mmol), and Pd(dppf)Cl2 (19.75 mg, 0.027 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), combined with the organic phase, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound 32((R)-1-(3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)phthalazine-1-yl)amino)piperidine-1-yl)ethane-1-one) (0.02 g, yield: 28.32%, LCMS m / z = 431.2 [M+1]). + They obtained the following results.

[0283] Example 33: Synthesis of isomer 1 and isomer 2 of 2-(4-((-3-hydroxycyclohexyl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol

[0284] [ka]

[0285] Step 1: Compound (1c) (0.28 g, 1.39 mmol), 3-aminocyclohexanol (0.16 g, 1.39 mmol), and Na2CO3 (0.44 g, 4.17 mmol) were dissolved in dry DMAc (2.5 mL). This mixture was placed in a sealed tube, heated to 120°C, and allowed to react overnight. After confirming that the raw material conversion was complete using TLC, the reaction mixture was added to water (20 ml), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound (33a) 3-((4-chlorophthalazine-1-yl)amino)cyclohexane-1-ol (0.35 g, yield: 90.66%, LCMS m / z = 278.2 [M+1]). + ) was obtained.

[0286] Step 2: Compound (33a) (0.05 g, 0.18 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (0.048 g, 0.23 mmol), sodium carbonate (0.057 g, 0.54 mmol), and Pd(dppf)Cl2 (15.00 mg, 0.02 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 16 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), combined with the organic phase, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=20:1) to obtain isomer 1 (compound 33) of compound (2-(4-((-3-hydroxycyclohexyl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol (developing agent DCM:CH3OH=10:1, Rf=0.2, 15 mg, yield: 20.66%, LC-MS m / z = 404.5 [M+1]). + ) and isomer 2 (compound 34) (developing agent DCM:CH3OH = 10:1, Rf = 0.3, 15 mg, yield: 20.66%, LCMS m / z = 404.5 [M+1]) + ) was obtained.

[0287] Example 35: Synthesis of 2-(4-((1-methylpiperidine-4-yl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol

[0288] [ka]

[0289] Step 1: Compound (1c) (0.20 g, 1.00 mmol), 1-methylpiperidine-4-amine (0.12 g, 1.00 mmol), and Na2CO3 (0.21 g, 1.99 mmol) were dissolved in dry DMF (3 mL). This mixture was placed in a sealed tube, heated to 120°C, and allowed to react overnight. After confirming that the raw material conversion was complete using TLC, the reaction mixture was added to water (20 ml), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound (35b) 4-chloro-N-(1-methylpiperidine-4-yl)phthalazine-1-amine (0.06 g, yield: 21.73%, LCMS m / z = 277.2 [M+1]). + ) was obtained.

[0290] Step 2: Compound (35b) (0.03 g, 0.21 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (25.00 mg, 0.24 mmol), sodium carbonate (21.20 mg, 0.20 mmol), and Pd(dppf)Cl2 (19.75 mg, 0.027 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), combined with the organic phase, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound 35: 2-(4-((1-methylpiperidine-4-yl)amino)phthalazine-1-yl)-5-(trifluoromethyl)phenol (0.02 g, yield: 23.69%, LCMS m / z = 403.3 [M+1]). + They obtained the following results.

[0291] Example 36: Synthesis of (R)-2-(1-methyl-7-((1-methylpiperidine-3-yl)amino)-1H-imidazole[4,5-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol

[0292] [ka]

[0293] Step 1: Compound 1H-imidazole-4,5-dicarboxylate dimethyl (36a) (3.0 g, 16.29 mmol), methyl iodide (3.47 g, 24.43 mmol), and potassium carbonate (3.38 g, 24.43 mmol) were dissolved in DMF (20 mL) and heated to 60°C for 3 hours. After confirming completion of the reaction by TLC, the reaction mixture was added to water (50 mL), extracted with ethyl acetate (30 mL x 3), the organic phase was combined, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound (36b) (1-methyl-1H-imidazole-4,5-dicarboxylate dimethyl) (0.80 g, yield: 24.78%, LCMS m / z = 199.2 [M+1]). + They obtained the following results.

[0294] Step 2: Compound 1-methyl-1H-imidazole-4,5-dicarboxylate dimethyl (36b) (0.8g, 4.04 mmol) and N2H4·H2O (0.61g, 12.12 mmol) were dissolved in acetic acid (5 mL), heated to 120°C, and refluxed overnight. After confirming the completion of the reaction by TLC, the reaction mixture was concentrated directly to dryness, water (30 mL) was added to disperse the solid, and the mixture was filtered. The filtered cake was vacuum-dried and then vacuum-dried overnight to obtain the target compound (36c) (1-methyl-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione) (0.40 g, yield: 59.59%, LCMS m / z = 167.2 [M+1]). + ) was obtained.

[0295] Step 3: Compound (36c) (0.40 g, 2.41 mmol) was dissolved in POCl3 (10 mL) and heated to 100°C and reacted overnight. After confirming the completion of the reaction by TLC, the reaction solution was directly concentrated, and after removing the POCl3, the crude oily product was slowly added to ice water (50 mL), stirred thoroughly, and the pH was adjusted to 8 with 2N sodium hydroxide aqueous solution. Extraction was performed with ethyl acetate (30 mL x 3), the organic phase was combined, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PE:EA = 5:1) to obtain the target compound (36d) (4,7-dichloro-1-methyl-1H-imidazo[4,5-d]pyridazine) (0.40 g, yield: 81.75%, LCMS m / z = 203.2 [M+1]). + ) was obtained.

[0296] Step 4: Compound (36d) (0.40 g, 1.97 mmol), (R)-1-methylpiperidine-3-amine (0.27 g, 2.36 mmol), and Na2CO3 (0.21 g, 1.97 mmol) were dissolved in dry DMF (5 mL). This mixture was placed in a sealed tube, heated to 120 °C, and allowed to react overnight. After confirming the completion of raw material conversion by TLC, the reaction mixture was added to water (20 ml), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound (36e)((R)-4-chloro-1-methyl-N-(1-methylpiperidine-3-yl)-1H-imidazo[4,5-d]pyridazine-7-amine) (0.05 g, yield: 9.04%, LCMS m / z = 281.2 [M+1]). + They obtained the following results.

[0297] Step 5: Compound (36e) (0.04 g, 0.14 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (35.00 mg, 0.17 mmol), sodium carbonate (22.10 mg, 0.22 mmol), and Pd(dppf)Cl2 (19.75 mg, 0.027 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), combined with the organic phase, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound 36((R)-2-(1-methyl-7-((1-methylpiperidine-3-yl)amino)-1H-imidazole[4,5-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol) (0.020 g, yield: 35.15%, LCMS m / z = 407.4 [M+1]). + They obtained the following results.

[0298] Example 37: Synthesis of (R)-2-(1-methyl-4-((1-methylpiperidine-3-yl)amino)-1H-imidazole[4,5-d]pyridazin-7-yl)-5-(trifluoromethyl)phenol

[0299] [ka]

[0300] Step 1: Compound (36d) (0.40 g, 1.97 mmol), (R)-1-methylpiperidine-3-amine (0.27 g, 2.36 mmol), and Na2CO3 (0.21 g, 1.97 mmol) were dissolved in dry DMF (5 mL). This mixture was placed in a sealed tube, heated to 120 °C, and allowed to react overnight. After confirming that the raw material conversion was complete using TLC, the reaction mixture was added to water (20 ml), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound (37a) ((R)-7-chloro-1-methyl-N-(1-methylpiperidine-3-yl)-1H-imidazo[4,5-d]pyridazine-4-amine) (0.10 g, yield: 18.08%, LCMS m / z = 281.2 [M+1]). + They obtained the following results.

[0301] Step 2: Compound (37a) (0.05 g, 0.18 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (44.00 mg, 0.22 mmol), sodium carbonate (22.10 mg, 0.22 mmol), and Pd(dppf)Cl2 (19.75 mg, 0.027 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), combined with the organic phase, washed with saturated saline solution (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound 37((R)-2-(1-methyl-4-((1-methylpiperidine-3-yl)amino)-1H-imidazole[4,5-d]pyridazin-7-yl)-5-(trifluoromethyl)phenol) (0.030 g, yield: 41.04%, LCMS m / z = 407.4 [M+1]). + They obtained the following results.

[0302] Example 38: Synthesis of (R)-2-(4-((1-methylpiperidine-3-yl)amino)-7-(trifluoromethyl)phthalazine-1-yl)-5-(trifluoromethyl)phenol

[0303] [ka]

[0304] Step 1: Compound 4-(trifluoromethyl)phthalic acid (38a) (2.0 g, 8.54 mmol) was dissolved in 15 ml of thionyl chloride, 2 drops of dry DMF were added dropwise, and the mixture was reacted under reflux with heating for 2 hours. The reaction mixture was concentrated to dryness, dissolved repeatedly in toluene (20 mL), concentrated to dryness, the residue was dissolved in acetic acid (30 mL), N2H4·H2O (1.85 g, 37.00 mmol) was added, and the mixture was heated to 120°C and refluxed overnight. After directly concentrating the reaction mixture to dryness, water (20 ml) was added to disperse the solid, filtered, and the filtered cake was vacuum-dried. The target compound 38b (6-(trifluoromethyl)-2,3-dihydrophthalazine-1,4-dione) (0.70 g, yield: 35.61%, LCMS m / z = 231.2 [M+1]) was obtained. + ) was obtained.

[0305] Step 2: Compound (38b) (0.70 g, 3.04 mmol) was dissolved in POCl3 (10 mL), heated to 100°C, and reacted overnight. After confirming the completion of the reaction by TLC, the reaction solution was directly concentrated, and after removing the POCl3, the crude oily product was slowly added to ice water (50 mL), stirred thoroughly, and the pH was adjusted to 8 with 2N sodium hydroxide aqueous solution. Extraction was performed with ethyl acetate (10 mL x 3), the organic phase was combined, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PE:EA = 10:1) to obtain the target compound (38c) (1,4-dichloro-6-(trifluoromethyl)phthalazine) (0.52 g, yield: 64.02%, LCMS m / z = 267.2 [M+1]). + ) was obtained.

[0306] Step 3: Compound (38c) (0.22g, 0.82 mmol), (R)-1-methylpiperidine-3-amine (0.12g, 1.04 mmol), and Na2CO3 (0.20g, 1.89 mmol) were dissolved in dry DMF (2 mL). This mixture was placed in a sealed tube and heated to 120°C, where it was allowed to react overnight. After confirming that the starting material conversion was complete by TLC, the reaction mixture was added to water (20 mL), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain a mixture of target compounds (38d) and (39d) (0.15 g, yield: 52.81%, LCMS m / z = 345.2 [M+1]). + ) was obtained.

[0307] Step 4: A mixture of compounds (38d) and (39d) (0.10 g, 0.29 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (0.074 g, 0.357 mmol), sodium carbonate (0.058 g, 0.55 mmol), and Pd(dppf)Cl2 (20.00 mg, 0.027 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), combined with the organic phase, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by PTLC (DCM:CH3OH=10:1) to obtain the target compound 38((R)-2-(4-((1-methylpiperidine-3-yl)amino)-7-(trifluoromethyl)phthalazine-1-yl)-5-(trifluoromethyl)phenol) (0.01 g, yield: 7.33%, LCMS m / z = 471.4 [M+1]). + ) was obtained.

[0308] Example 39: Synthesis of (R)-2-(4-((1-methylpiperidine-3-yl)amino)-6-(trifluoromethyl)phthalazine-1-yl)-5-(trifluoromethyl)phenol

[0309] [ka]

[0310] Step 1: Compound (38c) (0.22g, 0.82 mmol), (R)-1-methylpiperidine-3-amine (0.12g, 1.04 mmol), and Na2CO3 (0.20g, 1.89 mmol) were dissolved in dry DMF (2 mL). This mixture was placed in a sealed tube and heated to 120°C, where it was allowed to react overnight. After confirming that the starting material conversion was complete by TLC, the reaction mixture was added to water (20 mL), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain a mixture of target compounds (38d) and (39d) (0.15 g, yield: 52.81%, LCMS m / z = 345.2 [M+1]). + ) was obtained.

[0311] Step 2: A mixture of compounds (38d) and (39d) (0.10 g, 0.29 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (0.074 g, 0.357 mmol), sodium carbonate (0.058 g, 0.55 mmol), and Pd(dppf)Cl2 (20.00 mg, 0.027 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), combined with the organic phase, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by PTLC (DCM:CH3OH=10:1) to obtain the target compound 39(R)-2-(4-((1-methylpiperidine-3-yl)amino)-6-(trifluoromethyl)phthalazine-1-yl)-5-(trifluoromethyl)phenol) (0.007 g, yield: 5.13%, LCMS m / z = 471.4 [M+1]). + ) was obtained.

[0312] Example 40: Synthesis of (R)-5-methyl-2-(4-((1-methylpiperidine-3-yl)amino)phthalazine-1-yl)phenol

[0313] [ka]

[0314] Step: Compound (1d) (0.05 g, 0.18 mmol), (2-hydroxy-4-methylphenyl)boric acid (40.77 mg, 0.27 mmol), sodium carbonate (42.40 mg, 0.40 mmol), and Pd(dppf)Cl2 (19.75 mg, 0.027 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), combined with the organic phase, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound 40(R)-5-methyl-2-(4-((1-methylpiperidine-3-yl)amino)phthalazine-1-yl)phenol (0.02 g, yield: 23.69%, LCMS m / z = 348.3 [M+1]). + They obtained the following results.

[0315] Example 41: Synthesis of (R)-2-(4-((1-methylpiperidine-3-yl)amino)phthalazine-1-yl)-5-(trifluoromethoxy)phenol

[0316] [ka]

[0317] Step: Compound (1d) (0.05 g, 0.18 mmol), (2-hydroxy-4-(trifluoromethoxy)phenyl)boric acid (59.94 mg, 0.27 mmol), sodium carbonate (42.40 mg, 0.40 mmol), and Pd(dppf)Cl2 (19.75 mg, 0.027 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), combined with the organic phase, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound 41(R)-2-(4-((1-methylpiperidine-3-yl)amino)phthalazine-1-yl)-5-(trifluoromethoxy)phenol (0.02 g, yield: 26.52%, LCMS m / z = 419.2[M+1]). + They obtained the following results.

[0318] Example 43: (R)-(1-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-((1-methylpiperidine-3-yl)amino)phthalazine-6-yl)dimethylphosphine oxide

[0319] [ka]

[0320] Step 1: Compound (43a) (1.0 g, 4.44 mmol) and N2H4·H2O (2.5 g, 41.1 mmol, 80% wt) were dissolved in acetic acid (20 mL) and heated to 120 °C and refluxed overnight. After confirming the completion of the reaction by TLC, the reaction mixture was filtered directly, washed with water (20 mL x 3), and the filtration cake was vacuum-dried and then vacuum-dried to obtain the target compound 43b (6-bromophthalazine-1,4-diol) (1.0 g, yield: 94.34%, LCMS m / z = 241.1 [M+1]). + ) was obtained.

[0321] Step 2: Compound (43b) (0.70 g, 2.9 mmol) was dissolved in POCl3 (4 mL), heated to 110°C, and allowed to react overnight. After confirming completion of the reaction by TLC, the reaction solution was concentrated to one-tenth of its volume, then slowly added dropwise to ice water (20 mL), stirred thoroughly, adjusted the pH to 8 with 2N sodium hydroxide aqueous solution, extracted with ethyl acetate (10 mL x 3), combined the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PE:EA = 20:1) to obtain the target compound 43c (6-bromo-1,4-dichlorophthalazine) (0.61 g, yield: 75.68%, LCMS m / z = 277.0 [M+1]). + ) was obtained.

[0322] Step 3: Compound (43c) (0.60 g, 2.16 mmol), (R)-1-methylpiperidine-3-amine (0.25 g, 2.16 mmol), and Na2CO3 (0.43 g, 4.00 mmol) were dissolved in dry DMF (4 mL). This mixture was placed in a sealed tube, heated to 120°C, and allowed to react overnight. After confirming the completion of raw material conversion by TLC, the reaction mixture was added to water (20 ml), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound (43d) ((R)-7-bromo-4-chloro-N-(1-methylpiperidine-3-yl)phthalazine-1-amine) (0.50 g, yield: 65.09%, LCMS m / z = 355.1 [M+1]). + ) was obtained.

[0323] Step 4: At room temperature, compound (43d) (0.40 g, 1.12 mmol), dimethylphosphine oxide (87.4 mg, 1.12 mmol), palladium acetate (25 mg, 0.11 mmol), Xantphos (92 mg, 0.16 mmol), and anhydrous potassium phosphate (467 mg, 2.2 mmol) were added to dry DMF (6 mL), and the mixture was purged with argon three times. The mixture was heated to 150 °C and reacted for 3 hours. After the reaction mixture was rotated and evaporated to dryness, it was separated by silica gel column chromatography (DCM:CH3OH=10:1) to obtain compound 43e((R)-(1-chloro-4-((1-methylpiperazine-3-yl)amino)phthalazine-6-yl)dimethylphosphine oxide) (32 mg, yield: 7.7%, LCMS m / z = 353.2 [M+1]). + ) and compound 43f(R)-4-chloro-1-((1-methylpiperazine-3-yl)amino)phthalazine-6-yl)dimethylphosphine oxide) (30 mg, yield: 7.6%, LCMS m / z = 353.2 [M+1]) + ) was obtained.

[0324] Step 5: Compound (43e) (30 mg, 0.08 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (35 mg, 0.17 mmol), sodium carbonate (26 mg, 0.24 mmol), and Pd(dppf)Cl2 (5 mg, 0.007 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 16 hours. After the reaction mixture was rotated and evaporated until dry, it was separated by silica gel column chromatography (DCM:CH3OH=10:1) to obtain compound 43((R)-(1-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-((1-methylpiperidine-3-yl)amino)phthalazine-6-yl)dimethylphosphine oxide) (0.01g, yield: 24.59%, LCMS m / z = 479.6 [M+1]). + ) was obtained.

[0325] Example 44: Synthesis of (R)-5-fluoro-2-(4-((1-methylpiperidine-3-yl)amino)phthalazine-1-yl)phenol

[0326] [ka]

[0327] Step: Compound (1d) (0.05 g, 0.18 mmol), (4-fluoro-2-hydroxyphenyl)boric acid (41.85 mg, 0.27 mmol), sodium carbonate (42.40 mg, 0.40 mmol), and Pd(dppf)Cl2 (19.75 mg, 0.027 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), combined with the organic phase, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound 44(R)-5-fluoro-2-(4-((1-methylpiperidine-3-yl)amino)phthalazine-1-yl)phenol (0.02 g, yield: 31.54%, LCMS m / z = 353.2 [M+1]). + They obtained the following results.

[0328] Example 45: (R)-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)-1-((1-methylpiperidine-3-yl)amino)phthalazine-6-yl)dimethylphosphine oxide

[0329] [ka]

[0330] Step 1: Compound (43f) (30 mg, 0.08 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (35 mg, 0.17 mmol), sodium carbonate (26 mg, 0.24 mmol), and Pd(dppf)Cl2 (5 mg, 0.007 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 16 hours. After the reaction mixture was rotated and evaporated until dry, it was separated by silica gel column chromatography (DCM:CH3OH=10:1) to obtain the compound 45(R)-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)-1-((1-methylpiperidine-3-yl)amino)phthalazine-6-yl)dimethylphosphine oxide (0.01g, yield: 24.59%, LCMS m / z = 479.6 [M+1]). + ) was obtained.

[0331] Example 46: Synthesis of (R)-4-fluoro-2-(4-((1-methylpiperidine-3-yl)amino)phthalazine-1-yl)phenol

[0332] [ka]

[0333] Step: Compound (1d) (0.05 g, 0.18 mmol), (5-fluoro-2-hydroxyphenyl)boric acid (41.85 mg, 0.27 mmol), sodium carbonate (42.40 mg, 0.40 mmol), and Pd(dppf)Cl2 (19.75 mg, 0.027 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), combined with the organic phase, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound 46(R)-4-fluoro-2-(4-((1-methylpiperidine-3-yl)amino)phthalazine-1-yl)phenol (0.012 g, yield: 18.93%, LCMS m / z = 353.2 [M+1]). + They obtained the following results.

[0334] Example 47: Synthesis of ((R)-4-methyl-2-(4-((1-methylpiperidine-3-yl)amino)phthalazine-1-yl)phenol

[0335] [ka]

[0336] Step: Compound (1d) (0.05 g, 0.18 mmol), (2-hydroxy-5-methylphenyl)boric acid (40.77 mg, 0.27 mmol), sodium carbonate (42.40 mg, 0.40 mmol), and Pd(dppf)Cl2 (19.75 mg, 0.027 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), combined with the organic phase, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound 47(R)-4-methyl-2-(4-((1-methylpiperidine-3-yl)amino)phthalazine-1-yl)phenol (0.015 g, yield: 23%, LCMS m / z = 349.2[M+1]). + They obtained the following results.

[0337] Example 48: 2-(3-methyl-8-{[(3R)-1-methylpiperidine-3-yl]amino}pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol and

[0338] Example 49: 2-(3-methyl-5-{[(3R)-1-methylpiperidine-3-yl]amino}pyrido[2,3-d]pyridazin-8-yl)-5-(trifluoromethyl)phenol

[0339] [ka]

[0340] Step 1: Compound (48a) (3-methyl-5H,7H-flu[3,4-b]pyridine-5,7-dione) (1.0 g, 6.13 mmol) and N2H4·H2O (2.5 g, 41.1 mmol, 80% wt) were dissolved in acetic acid (20 mL), heated to 110 °C, and refluxed overnight. After confirming completion of the reaction by TLC, the reaction mixture was filtered directly, washed with water (20 mL x 3), and the filter cake was vacuum-dried and then vacuum-dried to obtain the target compound 48b (3-methylpyrido[2,3-d]pyridazine-5,8-diol) (1.0 g, yield: 92.08%, LCMS m / z = 177.1 [M+1]). + ) was obtained.

[0341] Step 2: Compound (48b) (1.0 g, 5.6 mmol) was dissolved in POCl3 (5 mL), heated to 110°C, and allowed to react overnight. After confirming completion of the reaction by TLC, the reaction solution was concentrated to one-tenth of its volume, then slowly added dropwise to ice water (20 mL), stirred thoroughly, adjusted the pH to 8 with 2N sodium hydroxide aqueous solution, extracted with ethyl acetate (10 mL x 3), combined the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PE:EA = 20:1) to obtain the target compound 48c (5,8-dichloro-3-methylpyrido[2,3-d]pyridazine) (0.70 g, yield: 58.66%, LCMS m / z = 214.2 [M+1]). + ) was obtained.

[0342] Step 3: Compound (48c) (0.46 g, 2.16 mmol), (R)-1-methylpiperidine-3-amine (0.25 g, 2.16 mmol), and Na2CO3 (0.43 g, 4.00 mmol) were dissolved in dry DMF (4 mL). This mixture was placed in a sealed tube, heated to 120°C, and allowed to react overnight. After confirming the completion of raw material conversion by TLC, the reaction mixture was added to water (20 ml), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound 48d((R)-5-chloro-3-methyl-N-(1-methylpiperidine-3-yl)pyrido[2,3-d]pyridazine-8-amine) (0.20 g, yield: 31.73%, LCMS m / z = 292.2 [M+1]). + ) and compound 48e(3R)-N-(8-chloro-3-methylpyrido[2,3-d]pyridazin-5-yl)-1-methylpiperidine-3-amine (50 mg, yield: 7.95%, LCMS m / z = 292.2 [M+1]) + ) was obtained.

[0343] Step 4: Compound (48d) (200 mg, 0.69 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (280 mg, 1.38 mmol), sodium carbonate (220 mg, 2.07 mmol), and Pd(dppf)Cl2 (50 mg, 0.07 mmol) were added to 10 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 16 hours. After the reaction mixture was rotated and evaporated until dry, it was separated by silica gel column chromatography (DCM:CH3OH=10:1) to obtain compound 48 (2-(3-methyl-8-{[(3R)-1-methylpiperidine-3-yl]amino}pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol) (0.10 g, yield: 34.72%, LCMS m / z = 418.6 [M+1]). + ) was obtained.

[0344] Step 5: Compound (48e) (25 mg, 0.086 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (35 mg, 0.17 mmol), sodium carbonate (28 mg, 0.26 mmol), and Pd(dppf)Cl2 (5 mg, 0.007 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 16 hours. After the reaction mixture was rotated and evaporated until dry, it was separated by silica gel column chromatography (DCM:CH3OH=10:1) to obtain compound 49 (2-(3-methyl-5-{[(3R)-1-methylpiperidine-3-yl]amino}pyrido[2,3-d]pyridazin-8-yl)-5-(trifluoromethyl)phenol) (20 mg, yield: 55.71%, LCMS m / z = 418.6 [M+1]). + ) was obtained.

[0345] Example 50: (R)-2-(3-ethyl-8-((1-methylpiperidine-3-yl)amino)pyridine[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol, and

[0346] Example 51: (R)-2-(3-ethyl-5-((1-methylpiperidine-3-yl)amino)pyridine[2,3-d]pyridazin-8-yl)-5-(trifluoromethyl)phenol

[0347] [ka]

[0348] Step 1: Compound (50a) 3-ethylfurfural[3,4-b]pyrididine-5,7-dione (1.0 g, 5.64 mmol) and N2H4·H2O (2.5 g, 41.1 mmol, 80% wt) were dissolved in acetic acid (20 mL), heated to 110 °C, and refluxed overnight. After confirming completion of the reaction by TLC, the reaction mixture was filtered directly, washed with water (20 mL x 3), and the filtration cake was vacuum-dried and then vacuum-dried to obtain the target compound 50b (3-ethylpyridine[2,3-d]pyridazine-5,8-diol) (0.8 g, yield: 74.26%, LCMS m / z = 192.2 [M+1]). + ) was obtained.

[0349] Step 2: Compound (50b) (0.8g, 4.2 mmol) was dissolved in POCl3 (5mL), heated to 110°C, and allowed to react overnight. After confirming completion of the reaction by TLC, the reaction solution was concentrated to one-tenth of its volume, then slowly added dropwise to ice water (20mL), stirred thoroughly, adjusted to pH=8 with 2N sodium hydroxide aqueous solution, extracted with ethyl acetate (10mL x 3), combined with the organic phase, washed with saturated brine (10mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PE:EA=20:1) to obtain the target compound 50c (5,8-dichloro-3-ethylpyrido[2,3-d]pyridazine) (0.70g, yield: 73.09%, LCMS m / z = 228.1 [M+1]). + ) was obtained.

[0350] Step 3: Compound (50c) (0.46 g, 2.01 mmol), (R)-1-methylpiperidine-3-amine (0.25 g, 2.16 mmol), and Na2CO3 (0.43 g, 4.00 mmol) were dissolved in dry DMF (4 mL). This mixture was placed in a sealed tube, heated to 120°C, and allowed to react overnight. After confirming the completion of raw material conversion by TLC, the reaction mixture was added to water (20 ml), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound 50d((R)-5-chloro-3-ethyl-N-(1-methylpiperidine-3-yl)pyrido[2,3-d]pyridazine-8-amine) (0.20 g, yield: 32.51%, LCMS m / z = 306.2 [M+1]). + ) and compound 50e(R)-8-chloro-3-ethyl-N-(1-methylpiperidine-3-yl)pyrido[2,3-d]pyridazine-5-amine (100 mg, yield: 16.25%, LCMS m / z = 305.4 [M+1]) + ) was obtained.

[0351] Step 4: Compound (50d) (100 mg, 0.326 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (280 mg, 1.38 mmol), sodium carbonate (220 mg, 2.07 mmol), and Pd(dppf)Cl2 (50 mg, 0.07 mmol) were added to 10 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 16 hours. After the reaction mixture was rotated and evaporated until dry, it was separated by silica gel column chromatography (DCM:CH3OH=10:1) to obtain compound 50((R)-2-(3-ethyl-8-((1-methylpiperidine-3-yl)amino)pyridine[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol) (0.05g, yield: 35.56%, LCMS m / z = 432.6 [M+1]). + ) was obtained.

[0352] Step 5: Compound (50e) (100 mg, 0.326 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (35 mg, 0.17 mmol), sodium carbonate (28 mg, 0.26 mmol), and Pd(dppf)Cl2 (5 mg, 0.007 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 16 hours. After the reaction mixture was rotated and evaporated until dry, it was separated by silica gel column chromatography (DCM:CH3OH=10:1) to obtain compound 51 ((R)-2-(3-ethyl-5-((1-methylpiperidine-3-yl)amino)pyridine[2,3-d]pyridazin-8-yl)-5-(trifluoromethyl)phenol) (0.1g, yield: 71.17%, LCMS m / z = 432.6 [M+1]). + ) was obtained.

[0353] Example 52: (R)-2-(2-methyl-8-((1-methylpiperidine-3-yl)amino)pyridine[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol, and

[0354] Example 53: (R)-2-(2-methyl-5-((1-methylpiperidine-3-yl)amino)pyridine[2,3-d]pyridazin-8-yl)-5-(trifluoromethyl)phenol

[0355] [ka]

[0356] Step 1: Compound (52a) (2-methylfurfural[3,4-b]pyrididine-5,7-dione) (1.0 g, 6.13 mmol) and N2H4·H2O (2.5 g, 41.1 mmol, 80% wt) were dissolved in acetic acid (20 mL), heated to 110 °C, and refluxed overnight. After confirming completion of the reaction by TLC, the reaction mixture was filtered directly, washed with water (20 mL x 3), and the filtration cake was vacuum-dried and then vacuum-dried to obtain the target compound 52b (2-methylpyridine[2,3-d]pyridazine-5,8-diol) (1.0 g, yield: 92.08%, LCMS m / z = 177.1 [M+1]). + ) was obtained.

[0357] Step 2: Compound (52b) (1.0 g, 5.6 mmol) was dissolved in POCl3 (5 mL), heated to 110°C, and reacted overnight. After confirming completion of the reaction by TLC, the reaction solution was concentrated to one-tenth of its volume, then slowly added dropwise to ice water (20 mL), stirred thoroughly, adjusted the pH to 8 with 2N sodium hydroxide aqueous solution, extracted with ethyl acetate (10 mL x 3), combined the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PE:EA = 20:1) to obtain the target compound 52c (5,8-dichloro-2-methylpyrido[2,3-d]pyridazine) (0.70 g, yield: 58.66%, LCMS m / z = 214.2 [M+1]). + ) was obtained.

[0358] Step 3: Compound (52c) (0.46 g, 2.16 mmol), (R)-1-methylpiperidine-3-amine (0.25 g, 2.16 mmol), and Na2CO3 (0.43 g, 4.00 mmol) were dissolved in dry DMF (4 mL). This mixture was placed in a sealed tube, heated to 120°C, and allowed to react overnight. After confirming the completion of raw material conversion by TLC, the reaction mixture was added to water (20 ml), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound 52d((R)-5-chloro-2-methyl-N-(1-methylpiperidine-3-yl)pyrido[2,3-d]pyridazine-8-amine) (0.10 g, yield: 15.90%, LCMS m / z = 292.4 [M+1]). + ) and compound 52e ((R)-8-chloro-2-methyl-N-(1-methylpiperidine-3-yl)pyrido[2,3-d]pyridazine-5-amine) (0.10 g, yield: 15.90%, LCMS m / z = 292.4 [M+1]) + ) was obtained.

[0359] Step 4: Compound (52d) (100 mg, 0.34 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (280 mg, 1.38 mmol), sodium carbonate (220 mg, 2.07 mmol), and Pd(dppf)Cl2 (50 mg, 0.07 mmol) were added to 10 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 16 hours. After the reaction mixture was rotated and evaporated until dry, it was separated by silica gel column chromatography (DCM:CH3OH=10:1) to obtain compound 52((R)-2-(2-methyl-8-((1-methylpiperidine-3-yl)amino)pyridine[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol) (25 mg, yield: 17.63%, LCMS m / z = 418.6 [M+1]). + ) was obtained.

[0360] Step 5: Compound (52e) (100 mg, 0.34 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (35 mg, 0.17 mmol), sodium carbonate (28 mg, 0.26 mmol), and Pd(dppf)Cl2 (5 mg, 0.007 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 16 hours. After the reaction mixture was rotated and evaporated until dry, it was separated by silica gel column chromatography (DCM:CH3OH=10:1) to obtain compound 53 ((R)-2-(2-methyl-5-((1-methylpiperidine-3-yl)amino)pyridine[2,3-d]pyridazin-8-yl)-5-(trifluoromethyl)phenol) (20 mg, yield: 14.10%, LCMS m / z = 418.6 [M+1]). + ) was obtained.

[0361] Example 54: (R)-2-(4-((1-methylpiperidine-3-yl)amino)thieno[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol

[0362] [ka]

[0363] Step 1: Compound (54a) (3,4-thiophene dicarboxylic acid anhydride) (180 mg, 1.16 mmol) and N2H4·H2O (0.6 mL, 9.88 mmol, 80% wt) were dissolved in acetic acid (10 mL), heated to 110 °C, and refluxed overnight. After confirming the completion of the reaction by TLC, the reaction mixture was filtered directly, washed with water (10 mL x 3), and the filtration cake was vacuum-dried and then vacuum-dried to obtain the target compound 54b (thieno[3,4-d]pyridazine-1,4-diol) (150 mg, yield: 76.89%, LCMS m / z = 169.1 [M+1]). + ) was obtained.

[0364] Step 2: Compound (54b) (150 mg, 0.89 mmol) was dissolved in POCl3 (3 mL), heated to 110°C, and allowed to react overnight. After confirming completion of the reaction by TLC, the reaction solution was concentrated to one-tenth of its volume, then slowly added dropwise to ice water (10 mL), stirred thoroughly, adjusted to pH=8 with 2N sodium hydroxide aqueous solution, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PE:EA = 20:1) to obtain the target compound 54c (1,4-dichlorothieno[3,4-d]pyridazine) (76 mg, yield: 41.64%, LCMS m / z = 205.0 [M+1]). + ) was obtained.

[0365] Step 3: Compound (54c) (70 mg, 0.34 mmol), (R)-1-methylpiperidine-3-amine (40 mg, 0.35 mmol), and Na2CO3 (74 mg, 0.70 mmol) were dissolved in dry DMF (3 mL). This mixture was placed in a sealed tube, heated to 120°C, and allowed to react overnight. After confirming the completion of raw material conversion by TLC, the reaction mixture was added to water (10 ml), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound 54d((R)-4-chloro-N-(1-methylpyridine-3-yl)thieno[3,4-d]pyridazine-1-amine) (50 mg, yield: 52.00%, LCMS m / z = 283.1 [M+1]). + ) was obtained.

[0366] Step 4: Compound (54d) (50 mg, 0.18 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (74 mg, 0.36 mmol), sodium carbonate (60 mg, 0.57 mmol), and Pd(dppf)Cl2 (5 mg, 0.007 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 16 hours. After the reaction mixture was rotated and evaporated until dry, it was separated by silica gel column chromatography (DCM:CH3OH=10:1) to identify compound 54((R)-2-(4-((1-methylpiperidine-3-yl)amino)thieno[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol) (20 mg, yield: 27.2%, LCMS m / z = 409.4 [M+1]). + ) was obtained.

[0367] Example 55: (R)-5-fluoro-2-(3-methyl-8-((1-methylpiperidine-3-yl)amino)pyrido[2,3-d]pyridazin-5-yl)phenol

[0368] [ka]

[0369] Step 1: At room temperature, compound (48d) (30 mg, 0.10 mmol), 5-fluoro-2-(tetramethyl-1,3,2-dioxaboran-2-yl)phenol (86 mg, 0.36 mmol), sodium carbonate (42 mg, 0.40 mmol), and Pd(dppf)Cl2 (5 mg, 0.007 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 16 hours. After the reaction mixture was rotated and evaporated until dry, it was separated by silica gel column chromatography (DCM:CH3OH=10:1) to obtain compound 55((R)-5-fluoro-2-(3-methyl-8-((1-methylpiperidine-3-yl)amino)pyrido[2,3-d]pyridazin-5-yl)phenol) (20 mg, yield: 45.36%, LCMS m / z = 368.6 [M+1]).+ ) was obtained.

[0370] Example 56: (R)-2-(3-methyl-8-((1-methylpiperidine-3-yl)amino)pyrido[2,3-d]pyridazin-5-yl)phenol

[0371] [ka]

[0372] Step 1: At room temperature, compound (48d) (30 mg, 0.10 mmol), 5-fluoro-2-(tetramethyl-1,3,2-dioxaboran-2-yl)phenol (79 mg, 0.36 mmol), sodium carbonate (42 mg, 0.40 mmol), and Pd(dppf)Cl2 (5 mg, 0.007 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 16 hours. After the reaction mixture was rotated and evaporated until dry, it was separated by silica gel column chromatography (DCM:CH3OH=10:1) to obtain compound 56((R)-2-(3-methyl-8-((1-methylpiperidine-3-yl)amino)pyrido[2,3-d]pyridazin-5-yl)phenol) (30 mg, yield: 71.55%, LCMS m / z = 350.6 [M+1]). + ) was obtained.

[0373] Example 60: 5-Methyl-2-(3-methyl-8-{[(3R)-1-methylpiperidine-3-yl]amino}pyrido[2,3-d]pyridazine-5-yl)phenol

[0374] [ka]

[0375] Step 1: At room temperature, compound (48d) (30 mg, 0.10 mmol), 5-methyl-2-(tetramethyl-1,3,2-dioxaboran-2-yl)phenol (47 mg, 0.20 mmol), sodium carbonate (42 mg, 0.40 mmol), and Pd(dppf)Cl2 (5 mg, 0.007 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 16 hours. After the reaction mixture was rotated and evaporated until dry, it was separated by silica gel column chromatography (DCM:CH3OH=10:1) to obtain compound 60 (5-methyl-2-(3-methyl-8-{[(3R)-1-methylpiperidine-3-yl]amino}pyrido[2,3-d]pyridazin-5-yl)phenol) (10 mg, yield: 27.51%, LCMS m / z = 364.6 [M+1]). + ) was obtained.

[0376] Example 61: 2-(3-methyl-8-{[(3R)-1-methylpiperidine-3-yl]amino}pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethoxy)phenol

[0377] [ka]

[0378] Step 1: At room temperature, compound (48d) (30 mg, 0.10 mmol), 5-trifluoromethoxy-2-(tetramethyl-1,3,2-dioxaboran-2-yl)phenol (61 mg, 0.20 mmol), sodium carbonate (42 mg, 0.40 mmol), and Pd(dppf)Cl2 (5 mg, 0.007 mmol) were added to 5 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 16 hours. After the reaction mixture was rotated and evaporated until dry, it was separated by silica gel column chromatography (DCM:CH3OH=10:1) to obtain compound 61(2-(3-methyl-8-{[(3R)-1-methylpiperidine-3-yl]amino}pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethoxy)phenol) (20 mg, yield: 46.14%, LCMS m / z = 434.6 [M+1]). + ) was obtained.

[0379] Example 62: ((R)-2-(1-methyl-7-((1-methylpiperidine-3-yl)amino)-1H-pyrazole[3,4-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol), and,

[0380] Example 63: ((R)-2-(1-methyl-4-((1-methylpiperidine-3-yl)amino)-1H-pyrazole[3,4-d]pyridazin-7-yl)-5-(trifluoromethyl)phenol)

[0381] [ka]

[0382] Step 1: Compound (62a) (10.0 g, 69.84 mmol), DMAP (0.14 g, 1.25 mmol), and triethylamine (9.19 g, 90.79 mmol) were dissolved in dry tetrahydrofuran (100 mL) in an ice bath. To this mixture, a tetrahydrofuran solution (50 mL) of 2-chloro-2-oxyethyl acetate (11.44 g, 83.81 mmol) was slowly added dropwise. After the addition was complete, the mixture was allowed to rise naturally to room temperature and reacted for 1 hour. After confirming that the starting material (62a) had been completely consumed by TLC, the salt produced in the reaction mixture was filtered, and the filtrate was added back to the reaction flask. 1-methylhydrazine-1-carboxylate t-butyl (12.25 g, 83.81 mmol) was added, and after the addition was complete, the mixture was allowed to react at room temperature for a further 2 hours. The reaction solution was concentrated directly to dryness to obtain a yellow solid. This solid was recrystallized with methanol / water (100 mL, v / v=1:1), and then vacuum-dried to obtain the target compound 62b ((Z / E mixed)-2-(2-(t-butoxycarbonyl)-2-methylhydrazino)methylene)-3-diethyl oxosuccinate) (19.2 g, yield: 79.83%).

[0383] Step 2: Starting material (62b) (19.2 g, 55.75 mmol) was dispersed in ethyl acetate (60 ml), HCl / dioxane solution (200 ml) was added, and this mixed solution was heated to 50°C and reacted for 3 hours. The mixture was concentrated to dryness, redissolved in ethyl acetate (200 ml), the pH was adjusted to >7 using 2N sodium carbonate aqueous solution, liquid-liquid separation was performed, the organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PE:EA = 5:1) to obtain the target compound 62c (1-methyl-1H-pyrazole-4,5-dicarboxylate diethyl) (10.2 g, yield: 80.87%, LCMS m / z = 227.2 [M+1]+).

[0384] Step 3: Compound 1-methyl-1H-pyrazole-4,5-dicarboxylate diethyl (62c) (0.8g, 4.04 mmol) and N2H4·H2O (0.61g, 12.12 mmol) were dissolved in acetic acid (5 mL), heated to 120°C, and refluxed overnight. After confirming the completion of the reaction by TLC, the reaction solution was concentrated directly to dryness, water (30 mL) was added to disperse the solid, and the mixture was filtered. The filtered cake was vacuum-dried and then vacuum-dried overnight to obtain the target compound 62d (1-methyl-1H-pyrazolo[3,4-d]pyridazine-4,7-diol) (0.40 g, yield: 59.59%, LCMS m / z = 167.2 [M+1]). + ) was obtained.

[0385] Step 4: Compound 62d (0.40 g, 2.41 mmol) was dissolved in POCl3 (10 mL) and heated to 100°C and reacted overnight. After confirming the completion of the reaction by TLC, the reaction solution was directly concentrated, and after removing the POCl3, the crude oily product was slowly added to ice water (50 mL), stirred thoroughly, and the pH was adjusted to 8 with 2N sodium hydroxide aqueous solution. Extraction was performed with ethyl acetate (30 mL x 3), the organic phase was combined, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (PE:EA = 5:1) to obtain the target compound (62e) (4,7-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyridazine) (0.40 g, yield: 81.75%, LCMS m / z = 203.2 [M+1]). + ) was obtained.

[0386] Step 5: Compound (62e) (0.40 g, 1.97 mmol), (R)-1-methylpiperidine-3-amine (0.27 g, 2.36 mmol), and Na2CO3 (0.21 g, 1.97 mmol) were dissolved in dry DMF (5 mL). This mixture was placed in a sealed tube, heated to 120°C, and allowed to react overnight. After confirming the completion of raw material conversion by TLC, the reaction mixture was added to water (20 ml), stirred thoroughly, extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain the target compound (a mixture of 62f and 63f) (((R)-4-chloro-1-methyl-N-(1-methylpiperidine-3-yl)-1H-pyrazolo[3,4-d]pyridazin-7-amine, (R)-7-chloro-1-methyl-N-(1-methylpiperidine-3-yl)-1H-pyrazolo[3,4-d]pyridazin-4-amine) (0.31 g, yield: 56.04%, LCMS m / z = 281.2 [M+1]). + They obtained the following results.

[0387] Step 6: Compound (a mixture of 62f and 63f) (0.31 g, 1.10 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (350.00 mg, 1.72 mmol), sodium carbonate (220.10 mg, 2.22 mmol), and Pd(dppf)Cl2 (90.75 mg, 0.13 mmol) were added to 30 mL of a mixed solvent of dioxane and water (v / v=4:1), nitrogen purging was performed three times, and the mixture was heated to 110°C and reacted for 3 hours. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL x 3), combined with the organic phase, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was separated by column chromatography (DCM:CH3OH=10:1) to obtain a mixture of the target compounds (a mixture of 62 and 63). Next, the target compound 62 ((R)-2-(1-methyl-7-((1-methylpiperidine-3-yl)amino)-1H-pyrazole[3,4-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol) (0.04 g, yield: 8.91%, LCMS m / z = 407.4 [M+1]) was separated by pre-HPLC preparative fractionation. + ), target compound 63((R)-2-(1-methyl-4-((1-methylpiperidine-3-yl)amino)-1H-pyrazole[3,4-d]pyridazin-7-yl)-5-(trifluoromethyl)phenol) (0.16g, yield: 35.66%, LCMS m / z = 407.4 [M+1]) + ) was obtained.

[0388] Examples 26 and 28 were the same as Example 25, except that the amine in Step 1 was replaced with a commercially available corresponding starting amine.

[0389] Examples 57-59 were similar to Example 36, except that the imidazole dicarboxylate in Step 2 was replaced with a commercially available corresponding raw material, and in Step 5, it was replaced with a desired boric acid or boric acid ester.

[0390] Examples 64-75 were the same as Example 62, except that the amine in step 5 was replaced with a desired commercially available amine, and in step 6, it was replaced with a desired boric acid or boric acid ester.

[0391] Examples 76-88 were the same as Example 36, except that the amine in step 4 was replaced with a desired commercially available amine, and in step 5, it was replaced with a desired boric acid or boric acid ester.

[0392] Table 1. Characterization data of example compounds

[0393] [Table 1-1]

[0394] [Table 1-2]

[0395] [Table 1-3]

[0396] [Table 1-4]

[0397] [Table 1-5]

[0398] [Table 1-6]

[0399] [Table 1-7]

[0400] [Table 1-8]

[0401] Table 1-9

[0402] Table 1-10

[0403] Table 1-11

[0404] Table 1-12

[0405] Table 1-13

[0406] Table 1-14

[0407] Table 1-15

[0408] Table 1-16

[0409] Table 1-17

[0410] Table 1-18

[0411] Table 1-19

[0412] Table 1-20

[0413] Table 1-21

[0414] Table 1-22

[0415] Table 1-23

[0416] Table 1-24

[0417] Table 1-25

[0418] Table 1-26

[0419] Table 1-27

[0420] Table 1-28

[0421] Table 1-29

[0422] Table 1-30

[0423] Table 1-31

[0424] Table 1-32

[0425] Table 1-33

[0426] Table 1-34

[0427] Table 1-35

[0428] Table 1-36

[0429] Table 1-37

[0430] Table 1-38

[0431] [Table 1-39]

[0432] Example 89: Pyroptosis test The in vitro activity of the above compounds was demonstrated in the following assay. In vitro activity screening was performed using THP-1 human monocytic cells (THP-1) to inhibit the NLRP3 inflammasome as a target using small molecule compounds. Phorbol ester (PMA) was used to induce differentiation of THP-1 cells into macrophages, and lipopolysaccharide (LPS) was used to induce macrophage M1 polarization, releasing cytokines such as TNF-α and IL-6, thereby creating a typical inflammation model.

[0433] 1. Experimental materials RPMI Medium 1640 was purchased from Gibco, penicillin and streptomycin from Hyclone, lipopolysaccharide (LPS), phorbol ester (PMA), and nigericin from MedChemExpress (MCE), thiazole blue (MTT) from Beijing Suolaibao Technology Co., Ltd., and sodium dodecyl sulfate (SDS) from Biofroxx.

[0434] 2.THP-1 cell culture THP-1 cells were cultured in a cell incubator at 37°C and 5% CO2 using 1640 medium + 10% FBS + 1% penicillin / streptomycin medium.

[0435] 3. THP-1 pyroptosis test THP-1 cells in the logarithmic growth phase were collected and 1 × 10⁻⁶ cells were taken. 6 Prepare a cell suspension at 1 cell / mL, add PMA to bring the final concentration in the cell suspension to 300 ng / mL, then add 1 × 10⁻⁶ 5Cells were inoculated into 96-well plates at a rate of one cell per well and cultured for 24 hours in a cell incubator at 37°C and 5% CO2 to induce differentiation of the cells into macrophages.

[0436] The following day, LPS was added to stimulate the cells and induce the production of an inflammation model. Specifically, the original culture medium was removed from the well plate, 100 μL of 1640 medium containing 2 μg / mL of LPS was added to each well, and the 96-well plate was then cultured for 3-4 hours in a cell incubator at 37°C and 5% CO2 to create the inflammation model. Each 96-well plate contained a drug-treated group, an inflammation model group, a normal cell group (containing only cells and 1640 medium), and a blank control group (containing only medium, without cells). After the LPS stimulation was complete, the target compound was diluted in 1640 medium to the corresponding concentration (0.004-40 μM), and 50 μL was added to each corresponding well of the 96-well plate, with three duplicate wells for each sample concentration. After adding 50 μL of 1640 medium to the inflammation model group and the normal cell group, the 96-well plate was cultured for 30 minutes in a cell incubator at 37°C and 5% CO2. After culturing, 50 μL of 1640 medium containing 40 μM nigericin, which can activate the NLRP3 inflammasome in cells and induce pyroptosis, was added to each of the drug-treated and inflammation model groups. 50 μL of 1640 medium was added to the normal cell group. In a 200 μL system using a 96-well plate, the final concentrations of each drug ranged from 0.001 to 10 μM, with the final concentration of nigericin being 10 μM. After adding nigericin, the 96-well plates were incubated in a 37°C, 5% CO2 cell incubator for 3-4 hours. After incubation, 20 μL of MTT solution (5 mg / mL) was added per well, and the plates were incubated in a 37°C, 5% CO2 cell incubator for 1.5 hours. Then, 50 μL of 20% SDS solution (containing 0.1% hydrochloric acid) was added per well, and the 96-well plates were incubated overnight in a 37°C, 5% CO2 cell incubator. On the third day, absorbance was detected at a wavelength of 562 nm using a microplate reader. The drug-induced cell pyroptosis protection rate was then calculated using the following formula. Cellular pyroptosis protection rate = [(X-C0) / (C-C0)] × 100% Here, C, C0, and X represent the mean absorbance values ​​of the normal cell group, the blank control group, and the drug-treated group, respectively. Finally, cell viability curves were fitted using Graphpad Prism 5.0 software to calculate the EC50 values ​​of compounds that inhibit pyroptosis by the NLRP3 inflammasome.

[0437] Table 2 EC50 values ​​of each compound in the in vitro assay 1

[0438] [Table 2-1]

[0439] [Table 2-2]

[0440] [Table 2-3]

[0441] For the EC50 value, "+" indicates that the EC50 value is greater than 1 μM, "++" indicates that the EC50 value is greater than 500 nM and less than or equal to 1 μM, "+++" indicates that the EC50 value is greater than 100 nM and less than or equal to 500 nM, "++++" indicates that the EC50 value is greater than 20 nM and less than or equal to 100 nM, and "+++++" indicates that the EC50 value is less than 20 nM.

Claims

1. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (Here, n is 0, m is selected from integers between 1 and 2. p is selected from 1 or 2. X １ and X ２ Each is independently selected from NH, CH, or N. X ５ It is independently selected from CH or N, X ３ and X ４ Each of them is independently C, R １ is selected from hydrogen, C １～６ alkyl, C １～６ alkoxy, halogen, and hydroxy, wherein the C １～６ alkyl or C １～６ alkoxy is optionally substituted by one or more halogens, and where m R １ are the same as or different from each other R ３ is hydrogen, C １～６ Alkyl, C １～６ Alkoxy, C ３～６ Selected from cycloalkyl or halogen, the C １～６ Alkyl, C １～６ Alkoxy, or C ３～６ Cycloalkyls are composed of one or more halogens or C １～３ It is optionally substituted with alkyl groups, where p R groups ３ They are either identical or different from each other. A is a single bond or C １～３ It is an alkylene chain, R ４ These include pyrrolyl, piperidyl, morpholinil, tetrahydropyranil, 【Chemistry 2】 or 【Transformation 3】 Selected from, The aforementioned pyrrolyl, piperidyl, morpholinyl, tetrahydropyranil, 【Chemistry 4】 or 【Transformation 5】 is one or more C １～３ It is optionally substituted with alkyl or =O, The compound of formula (I) has the following structure: 【Transformation 6】 【Transformation 7】 and 【Transformation 8】 (Excluding...)

2. R １ C １～３ Alkyl, C １～３ Selected from alkoxy, hydroxy, or halogen, C １～３ Alkyl, or C １～３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the alkoxy is optionally substituted with 1 to 3 fluorine atoms.

3. R １ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from trifluoromethyl, methyl, fluorine, hydroxy, or trifluoromethoxy.

4. R １ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from trifluoromethyl, methyl, or hydroxy.

5. R ３ is hydrogen, C １～３ Alkyl, C ３～６ Cycloalkyl, C １～３ Selected from alkoxy or halogen, C １～３ Alkyl, C １～３ Alkoxy, or C ３～６ Cycloalkyl groups consist of 1 to 3 halogens or C １～３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, optionally substituted with an alkyl group.

6. R ３ C １～３ Alkyl, C １～３ Alkoxy, or C ３～６ Selected from cycloalkyl, the C １～３ Alkyl, C １～３ Alkoxy, or C ３～６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the cycloalkyl group is optionally substituted with 1 to 3 fluorine or methyl groups.

7. R ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from hydrogen, methyl, methoxy, cyclopropyl, ethyl, fluorine, or trifluoromethyl.

8. R ３ is a compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from hydrogen, methyl, or methoxy.

9. A is a single bond, -CH ２ -, - (CH ３ )CH-, or -CH ２ CH ２ - The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

10. R ４ teeth, 【Chemistry 9】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

11. The compound is the compound according to claim 1 or a pharmaceutically acceptable salt thereof, having the structure represented by formula (II). 【Chemistry 10】 (Here, n, X １ , X ２ , X ３ , X ４ , X ５ , R ３ , R ４ , and A are the same as the definitions in claim 1, R １１ This is selected from trifluoromethyl, methyl, trifluoromethoxy, or fluorine. R ２ It is selected from hydroxyl, R ５ , R ６ , and R ７ Each of these is independently selected from hydrogen.

12. The compound is the compound according to claim 11 or a pharmaceutically acceptable salt thereof, having a structure represented by formula (IVd), formula (V), or formula (VI). 【Chemistry 11】 (Here, R １１ , R ３ , R ４ , and A are defined as in Claim 11.

13. The following compounds or their pharmaceutically acceptable salts. 【Chemistry 12】 【Chemistry 13】

14. A method for preparing the compound described in claim 11 or a pharmaceutically acceptable salt thereof, Compound A0' in POCl ３ Dissolve in , heat, and allow to react overnight. After the reaction is complete, concentrate the reaction solution directly and POCl ３ Step 1 involves removing the oily crude product, slowly adding it dropwise to ice water, extracting it with ethyl acetate, and separating it by column chromatography to obtain the target compound A1'. Compound A1', the corresponding amine, and Na ２ CO ３ Step 2 involves dissolving in dry DMF, placing this mixture in a sealed tube and heating it, allowing it to react overnight, and after the raw material conversion is complete, adding the reaction solution to water, extracting with ethyl acetate, and separating by column chromatography to obtain the target compound A2'. Compound A2', boric acid, sodium carbonate, and Pd(dppf)Cl ２ A preparation method comprising: step 3, adding to a mixed solvent of dioxane and water, purging with nitrogen three times, heating and reacting for 3 hours, adding the reaction solution to water, extracting with ethyl acetate, and separating by column chromatography to obtain the target compound II. 【Chemistry 14】

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable auxiliary material.

16. The pharmaceutical composition according to claim 15 for use in the treatment of NLRP3-mediated disorders.

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