A class of 2-(2-(quinolin-4-yloxy)ethyl)pyridazine-3(2H)-one compounds, their preparation methods and applications

Abstract

This invention discloses a class of 2-(2-(quinolin-4-yloxy)ethyl)pyridazine-3(2H)-one compounds, their preparation methods, and applications. The structure of these compounds is shown in general formula (I). This invention also discloses that the above compounds have a significant inhibitory effect on interleukin-1 receptor-associated kinase 1 (IRAK1). These compounds can inhibit the proliferation of various tumor cells, including liver cancer, lung cancer, pancreatic cancer, gastric cancer, kidney cancer, colon cancer, esophageal cancer, glioblastoma, leukemia, multiple myeloma, and other solid tumors and hematological malignancies. This invention provides a new option for tumor treatment.

Description

Technical Field

[0001] This invention relates to compounds, their preparation methods and applications, and specifically to a class of 2-(2-(quinolin-4-yloxy)ethyl)pyridazine-3(2H)-one compounds, their preparation methods and applications, belonging to the field of biomedical technology. Background Technology

[0002] IRAK1 (interleukin-1 receptor-associated kinase 1) is a core regulator of IL-1 receptor (IL-1R) and Toll-like receptor (TLR) signaling, belonging to the serine / threonine kinase family. Its main function is to mediate innate immune responses and inflammatory reactions. In signaling pathways, IRAK1 forms a heterodimer with IRAK4 and is recruited to the IL-1R / TLR complex via the MyD88 aptamer, activating the downstream TRAF6 and TAK1 complexes, thereby triggering pathways such as NF-κB and MAPK (e.g., p38, ERK), and inducing the expression of pro-inflammatory factors (e.g., TNF-α, IL-6). Furthermore, IRAK1 also participates in regulating the cell cycle, apoptosis, and the formation of the tumor microenvironment.

[0003] Abnormal activation of IRAK1 is closely related to a variety of diseases. In inflammatory diseases, its overactivation can lead to autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. In tumors, the role of IRAK1 is particularly prominent: 1) Promoting tumor development and progression: Studies have found that IRAK1 is highly expressed in tumors such as colorectal cancer and esophageal squamous cell carcinoma, and its high expression is significantly associated with poor patient prognosis. IRAK1 promotes cell proliferation by activating the p38 / MYC pathway and enhances tumor cell survival by inhibiting apoptosis-related proteins (such as Bax); 2) Regulating the tumor microenvironment: IRAK1 can induce the secretion of inflammatory factors, recruit immunosuppressive cells (such as MDSCs and Tregs), and promote immune escape. Simultaneously, its mediated NF-κB signaling can enhance angiogenesis and tumor invasion.

[0004] IRAK1 plays a crucial role in tumorigenesis, development, and tumor microenvironment formation by regulating innate immune and inflammatory signaling pathways. Targeted therapy against IRAK1 offers a new direction for tumor prevention and treatment, but further research is needed on its specific mechanisms and clinical translational potential. IRAK1 and IRAK4 are both key kinases in the IL-1R / TLR signaling pathway, and their structures are similar. Existing inhibitors may lack specificity for IRAK4 or other related kinases (such as TAK1), leading to off-target effects, potentially interfering with normal immune responses or inflammatory regulation, and causing unnecessary side effects. The shortcomings of existing IRAK1 inhibitors mainly lie in insufficient selectivity, drug resistance, side effects, and the need for personalized treatment. Overcoming these bottlenecks through technological innovation and mechanistic research is necessary to promote their clinical translation in tumors and autoinflammatory diseases. Summary of the Invention

[0005] Objective of this invention: The objective of this invention is to provide a class of 2-(2-(quinolin-4-yloxy)ethyl)pyridazine-3(2H)-one compounds or pharmaceutically acceptable salts thereof that exhibit potent antitumor activity by inhibiting the kinase activity of IRAK1, thus providing novel compounds for the development of tumor drugs targeting abnormal IRAK1 activation. Another objective of this invention is to provide a method for preparing the above-mentioned 2-(2-(quinolin-4-yloxy)ethyl)pyridazine-3(2H)-one compounds or pharmaceutically acceptable salts thereof; yet another objective of this invention is to provide an application of the above-mentioned 2-(2-(quinolin-4-yloxy)ethyl)pyridazine-3(2H)-one compounds or pharmaceutically acceptable salts thereof.

[0006] Technical solution: The present invention provides a compound represented by general formula (I) and a pharmaceutically acceptable salt thereof.

[0007]

[0008] In the formula, R1 is selected from C1-C3 alkyl, unsubstituted or substituted five-membered aromatic heterocycle, unsubstituted or substituted six-membered aromatic ring or substituted fused ring;

[0009] R2 is selected from hydrogen, methoxy, ;

[0010] R3 is selected from hydrogen or methoxy;

[0011] R4 is selected from:

[0012] .

[0013] Furthermore, R1 is selected from C1-C3 alkyl groups, unsubstituted or substituted five-membered aromatic heterocycles, unsubstituted or substituted benzene rings, and unsubstituted or substituted benzo5-6-membered rings;

[0014] The five-membered aromatic heterocycle is an imidazole ring or a furan ring; the substituents in the substituted five-membered aromatic heterocycle are C1-C3 alkyl, piperidinyl, or N-BOC-piperidinyl.

[0015] The substituents in the substituted benzene ring are -CN, -NO2, or -CF3;

[0016] The benzo5-6 membered ring is a piper ring, a 1,4-benzodioxane ring, a benzopyrrole ring, or a benzimidazole ring; the substituents in the substituted benzo5-6 membered ring are C1-C3 alkyl groups.

[0017] Furthermore, R1 is selected from:

[0018]

[0019] R2 is selected from hydrogen, methoxy, ;

[0020] R3 is selected from hydrogen or methoxy;

[0021] R4 is selected from:

[0022]

[0023] R5 is selected from , , .

[0024] Furthermore,

[0025] When R1 is or hour,

[0026] R2 is selected from hydrogen, methoxy, ,

[0027] R3 is selected from hydrogen or methoxy.

[0028] R4 is selected from:

[0029]

[0030] When R1 is selected from the following groups:

[0031] -CH3,

[0032] R2 is ,

[0033] R3 is hydrogen.

[0034] R4 is ,

[0035] R5 is , , .

[0036] Furthermore, the compound is selected from any compound shown as formula (B1) to (B24):

[0037]

[0038] Furthermore, the pharmaceutically acceptable salt is an acid addition salt of a compound of general formula (I), wherein the acid used for salt formation includes inorganic acids and organic acids, wherein the inorganic acids include hydrochloric acid, sulfuric acid, and phosphoric acid, and the organic acids include acetic acid, propionic acid, butyric acid, maleic acid, trichloroacetic acid, p-toluenesulfonic acid, malic acid, methanesulfonic acid, malonic acid, cinnamic acid, citric acid, fumaric acid, camphoric acid, digluconic acid, aspartic acid, or tartaric acid.

[0039] On the other hand, the method for preparing the 2-(2-(quinolin-4-yloxy)ethyl)pyridazine-3(2H)-one compound or a pharmaceutically acceptable salt thereof according to the present invention includes the following steps:

[0040] Dissolve A and B in toluene, then add 0.3 equivalents of palladium acetate, 0.2 equivalents of S-phos, and 1.2 equivalents of cesium carbonate. Purge three times with argon gas, and react overnight at 120 °C. After the reaction is complete, purify the product using silica gel column chromatography to obtain the target product.

[0041] On the other hand, the present invention provides a pharmaceutical composition comprising a compound of general formula (I) or a pharmaceutically acceptable salt thereof or an isomer thereof, and a pharmaceutically acceptable carrier.

[0042] On the other hand, the present invention provides the use of a 2-(2-(quinolin-4-yloxy)ethyl)pyridazine-3(2H)-one compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of cancer or tumor and viral infection-related diseases, wherein the cancer or tumor-related diseases include a variety of solid tumors and hematologic malignancies such as liver cancer, lung cancer, pancreatic cancer, gastric cancer, kidney cancer, colon cancer, esophageal cancer, glioblastoma, leukemia, and multiple myeloma.

[0043] On the other hand, the target of the antitumor activity of the above-mentioned 2-(2-(quinolin-4-yloxy)ethyl)pyridazine-3(2H)-one compound or its pharmaceutically acceptable salt is interleukin-1 receptor-associated kinase 1 (IRAK1).

[0044] On the other hand, the present invention provides the use of the above-mentioned 2-(2-(quinolin-4-yloxy)ethyl)pyridazine-3(2H)-one compound or a pharmaceutically acceptable salt thereof in the preparation of an interleukin-1 receptor-associated kinase 1 inhibitor.

[0045] Unless otherwise specified, the terms used in this invention generally have the following meanings:

[0046] The term "heterocycle" includes saturated and unsaturated multi-component nitrogen-containing heterocycles, including but not limited to thiophene, furanylpyrazine, pyrrole, tetrahydropyrrole, imidazole, pyridine, pyrazine, etc.

[0047] The term "cyclic ring" includes aromatic cyclic rings and aliphatic cyclic rings, including but not limited to indole, indazole, benzo[a]heterocyclic rings, benzo[a]alicylic rings, etc.

[0048] The present invention also discloses a method for preparing compounds of general formula (I).

[0049] Beneficial effects:

[0050] IRAK1 gene abnormalities have been shown to be closely related to the occurrence and development of various tumors. It plays a crucial role in tumorigenesis, development, and tumor microenvironment formation primarily by regulating innate immune and inflammatory signaling pathways. IRAK1 and IRAK4 are both key kinases in the IL-1R / TLR signaling pathway, and their structures are similar. Currently, IRAK1-targeting inhibitors lack specificity for IRAK4 or other related kinases (such as TAK1), leading to off-target effects that may interfere with normal immune responses or inflammatory regulation, causing unnecessary side effects. Therefore, the IRAK1 inhibitor prepared in this invention can significantly inhibit the kinase activity of IRAK1, exhibiting broad-spectrum antitumor activity and good selectivity for IRAK4. Detailed Implementation

[0051] The present invention will be further described below. The following embodiments are only used to more clearly illustrate the technical solutions of the present invention and should not be construed as limiting the scope of protection of the present invention. Unless otherwise specified, the experimental methods in the following embodiments are conventional methods. Unless otherwise specified, the experimental materials used in the following embodiments were all purchased from conventional biochemical reagent stores. The present application will now be described in detail with reference to specific embodiments.

[0052] I. Synthesis of intermediates

[0053] Intermediate 1a:

[0054] 6-(4-Methyl-1H-imidazol-1-yl)pyridazin-3(2H)-one (1a):

[0055]

[0056] 4-Methyl-1H-imidazole (410 mg, 5.0 mmol) was dissolved in 30 mL of N,N-dimethylformamide (DMF), and sodium hydride (240 mg, 10.0 mmol) was slowly added at 0 °C. After stirring for 30 minutes, 3,6-dichloropyridazine (894 mg, 6.0 mmol) was added, and the reaction was continued at room temperature with stirring for 6 hours. After the reaction was completed by TLC monitoring, the reaction solution was slowly poured into ice water and extracted three times with ethyl acetate (EA). The organic phases were combined, and the solvent was removed by vacuum concentration to obtain the crude intermediate. Glacial acetic acid (20 mL) was then added to the crude product, and the mixture was heated at 120 °C with stirring overnight. After the reaction was completed, the system was cooled to room temperature, and the solvent was removed by vacuum concentration. The crude product was purified by rapid column chromatography to obtain the target compound 1a as a white solid (343 mg, 39% yield). 1 H NMR(400 MHz, DMSO-d6) δ 13.43 (s, 1H), 9.73 (d, J = 1.7 Hz, 1H), 8.09 (d, J =10.1 Hz, 1H), 7.94 (t, J = 1.5 Hz, 1H), 7.25 (d, J = 10.1 Hz, 1H), 2.34 (d, J= 1.2 Hz, 3H).

[0057] Intermediate 1b:

[0058] 3-(6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (1b):

[0059]

[0060] 3,6-Dichloropyridazine (745 mg, 5.0 mmol), 3-cyanobenzonic acid (1.1 g, 7.5 mmol), potassium carbonate (1.4 g, 10.0 mmol), and tetrakis(triphenylphosphine)palladium (288 mg, 0.25 mmol) were added sequentially to 20 mL of a 1,4-dioxane / water (4:1) mixed solvent, and the mixture was heated under reflux overnight under argon protection. After the reaction was complete, the mixture was poured into water and extracted with ethyl acetate (EA). The obtained crude intermediate was concentrated under vacuum to remove the solvent, and then 20 mL of glacial acetic acid was added. The mixture was heated at 120 °C with stirring overnight. After the reaction was complete, the system was cooled to room temperature, concentrated under vacuum to remove the solvent, and the crude product was purified by rapid column chromatography to give compound 1b. It was a white solid (413 mg, 42% yield). 1H NMR (400 MHz, DMSO-d6) δ 13.38 (s,1H), 8.32 (t, J = 1.7 Hz, 1H), 8.22-8.19 (m, 1H), 8.14 (d, J = 10.0 Hz, 1H),7.93-7.91 (m, 1H), 7.70 (t, J = 7.9 Hz, 1H), 7.05 (dd, J = 10.0, 1.5 Hz, 1H).

[0061] Intermediate 2a:

[0062] 2-(2-hydroxyethyl)-6-(4-methyl-1H-imidazol-1-yl)pyridazin-3(2H)-one (2a):

[0063]

[0064] Compound 1a (264 mg, 1.5 mmol), cesium carbonate (975 mg, 3.0 mmol), (2-bromoethoxy)-tert-butyldimethylsilane (394 mg, 1.65 mmol), and DMF (6 mL) were added to a reaction flask. The mixture was stirred at 50 °C for 4 hours, then poured into water and extracted with ethyl acetate. The organic phases were combined and concentrated. Tetrabutylammonium fluoride (TBAF, 2.0 mL, 1 M THF solution) and a THF / H₂O mixed solvent (9 mL, 2:1) were added to the residue, and the mixture was stirred at room temperature for 2 hours. The crude product was purified by rapid column chromatography to give compound 2a as a gray solid (152 mg, 46% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J = 1.4 Hz, 1H), 7.97 (d, J = 9.9 Hz, 1H), 7.46 (t, J =1.3 Hz, 1H), 7.18 (d, J = 9.9 Hz, 1H), 4.87 (t, J = 5.9 Hz, 1H), 4.11 (t, J =5.9 Hz, 2H), 3.76 (q, J = 5.9 Hz, 2H), 2.16 (d, J = 1.1 Hz, 3H).

[0065] Intermediate 2b:

[0066] 3-(1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridazine-3-yl)benzylnitrile (2b):

[0067]

[0068] Compound 2b was prepared from compound 1b and (2-bromoethoxy)-tert-butyldimethylsilane using the same general preparation method as compound 2a. It was a gray solid (52% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.36 (t, J =1.8 Hz, 1H), 8.27 – 8.21 (m, 1H), 8.13 (d, J = 9.7 Hz, 1H), 7.93 (dt, J =7.8, 1.4 Hz, 1H), 7.72 (t, J = 7.9 Hz, 1H), 7.09 (d, J = 9.7 Hz, 1H), 4.86 (t, J = 5.9 Hz, 1H), 4.23 (t, J = 5.9 Hz, 2H), 3.80 (q, J = 5.9 Hz, 2H).

[0069] Intermediate 3:

[0070] 7-(3-bromopropoxy)-4-chloroquinoline (3):

[0071]

[0072] 4-Chloro-7-hydroxyquinoline (5.4 g, 30.0 mmol), potassium carbonate (20.7 g, 150.0 mmol), 1,3-dibromopropane (20.1 g, 100.0 mmol), and DMF (200 mL) were added to a reaction flask. After stirring at 50 °C for 4 hours, the reaction solution was filtered through diatomaceous earth. The crude product was purified by rapid column chromatography to give compound 3. A brown solid (6.4 g, 71% yield) was obtained. ESI-MS m / z: 300.5 [M+H] + .

[0073] Intermediate 4a:

[0074] 3-((4-chloroquinoline-7-yl)oxy)-N,N-dimethylpropyl-1-amine (4a):

[0075]

[0076] Compound 3 (300 mg, 1.0 mmol), potassium carbonate (690 mg, 5.0 mmol), dimethylamine (54 mg, 1.2 mmol), and DMF (5 mL) were added to a reaction flask. After stirring at 60 °C for 6 hours, the reaction solution was filtered through diatomaceous earth. The crude product was purified by rapid column chromatography to give compound 4a. A pale yellow solid (171 mg, 65% yield) was obtained. ESI-MS m / z: 265.2 [M+H] + .

[0077] Intermediate 4b:

[0078] 4-(3-((4-chloroquinoline-7-yl)oxy)propyl)morpholine (4b):

[0079]

[0080] The target product 4b was prepared from compound 3 and morpholine using the same general preparation method as compound 4a. It was a gray solid (85% yield). ESI-MS m / z: 307.4 [M+H] + .

[0081] Intermediate 4c:

[0082] 4-Chloro-7-(3-(4-methylpiperazin-1-yl)propoxy)quinoline (4c):

[0083]

[0084] The target product 4c was prepared from compound 3 and N-methylpiperazine using the same general preparation method as compound 4a. It was a brown solid (76% yield). ESI-MS m / z: 320.2 [M+H] + .

[0085] Intermediate 4d:

[0086] 4-Chloro-7-(3-(4-isopropylpiperazin-1-yl)propoxy)quinoline (4d):

[0087]

[0088] The target product 4d was prepared from compound 3 and N-isopropylpiperazine using the same general preparation method as compound 4a. It was a brown solid (68% yield). ESI-MS m / z: 348.4 [M+H] + .

[0089] Intermediate 4e:

[0090] 4-(3-((4-chloroquinoline-7-yl)oxy)propyl)piperazine-1-carboxylic acid tert-butyl ester (4e):

[0091]

[0092] The target product 4e was prepared from compounds 3 and 1-tert-butyloxycarbonylpiperazine using the same general preparation method as compound 4a. It was a gray solid (80% yield). ESI-MS m / z: 406.4 [M+H] + .

[0093] Intermediate 5a:

[0094] 6-(benzo[d][1,3]dioxacyclopenten-5-yl)pyridazine-3(2H)-one (5a):

[0095]

[0096] 6-Chlorpyridazine-3(2H)-one (652 mg, 5.0 mmol), 3,4-methylenedioxyphenylboronic acid (996 mg, 6.0 mmol), cesium carbonate (3.26 g, 10.0 mmol), and palladium dichlorobis(diphenylphosphine)dichloride (183 mg, 0.25 mmol) were added sequentially to 30 mL of a 1,4-dioxane / water (4:1) mixed solvent. The mixture was heated under reflux overnight under argon protection. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth short column, and the crude product was purified by rapid column chromatography to give compound 5a as a gray solid (972 mg, 90% yield). 1 H NMR (400 MHz, DMSO-d6) δ 13.09 (s, 1H), 7.98 (d, J = 9.9 Hz, 1H), 7.41 – 7.37 (m, 2H), 6.98 (dd, J = 24.1, 9.0 Hz, 2H), 6.09 (s, 2H). 1 H NMR (400 MHz, DMSO-d6) δ 13.09 (s, 1H), 7.98 (d, J = 9.9 Hz,1H), 7.41 – 7.37 (m, 2H), 6.98 (dd, J = 24.1, 9.0 Hz, 2H), 6.09 (s, 2H).

[0097] Intermediate 5b:

[0098] 6-(2,3-dihydrobenzo[b][1,4]dioxane-6-yl)pyridazine-3(2H)-one (5b):

[0099]

[0100] The target product 5b was prepared using 6-chloropyridazine-3(2H)-one and 1,4-benzodioxane-6-boronic acid as starting materials, following the preparation method of compound 5a. It was a gray solid (72%). 1 H NMR (400 MHz, DMSO-d6) δ 13.07 (s, 1H), 7.97 (d, J = 9.9 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 6.94 (dd, J = 9.0, 3.7Hz, 2H), 4.29 (s, 4H).

[0101] Intermediate 5c:

[0102] 6-(1-Methyl-1H-indol-5-yl)pyridazin-3(2H)-one (5c):

[0103]

[0104] Starting from 6-chloropyridazine-3(2H)-one and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-indole, the target product 5c was prepared according to the preparation method of compound 5a. White solid (yield 70%). 1 H NMR (400 MHz, DMSO-d6) δ 13.05 (s, 1H), 8.08 (d, J = 9.9 Hz, 1H), 8.05 (d,J = 1.8 Hz, 1H), 7.70 (dd, J = 8.6, 1.8 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.39 (d, J = 3.1 Hz, 1H), 6.96 (d, J = 9.9 Hz, 1H), 6.51 (d, J = 3.0 Hz, 1H), 3.82 (s, 3H).

[0105] Intermediate 5d:

[0106] 6-(1-Methyl-1H-indazol-5-yl)pyridazin-3(2H)-one (5d):

[0107]

[0108] Starting from 6-chloropyridazine-3(2H)-one and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-indazole, the target product 5d was prepared according to the preparation method of compound 5a. White solid (yield 73%). 1 H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.26 (dd, J = 1.7, 0.8 Hz, 1H), 8.14 – 8.10 (m, 2H), 7.94 (dd, J = 8.9, 1.7 Hz, 1H), 7.74 (dt, J = 8.9, 0.9Hz, 1H), 7.00 (d, J = 9.9 Hz, 1H), 4.08 (s, 3H).

[0109] Intermediate 5e:

[0110] 6-(furan-3-yl)pyridazin-3(2H)-one (5e):

[0111]

[0112] The target product 5e was prepared by using 6-chloropyridazine-3(2H)-one and 3-furanboronic acid as starting materials, following the preparation method of compound 5a. It was a gray solid (yield 42%). 1 H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 7.88 –7.83 (m, 2H), 7.06 (d, J = 3.4 Hz, 1H), 6.98 (d, J = 9.9 Hz, 1H), 6.66 (dd, J= 3.5, 1.8 Hz, 1H).

[0113] Intermediate 5f:

[0114] 6-(1-Isopropyl-1H-pyrazol-4-yl)pyridazin-3(2H)-one (5f):

[0115]

[0116] Starting from 6-chloropyridazine-3(2H)-one and 1-isopropyl-1H-pyrazole-4-boronic acid, the target product 5f was prepared according to the method for compound 5a. White solid (yield 30%) 1H NMR (400 MHz, DMSO-d6) δ 12.88 (s,1H), 8.28 (s, 1H), 7.86 (s, 1H), 7.78 (dd, J = 9.8, 1.0 Hz, 1H), 6.93 (d, J =9.8 Hz, 1H), 4.53 (h, J = 6.6 Hz, 1H), 1.44 (d, J = 6.6 Hz, 6H).

[0117] 5g of intermediate:

[0118] tert-butyl 4-[4-(6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (5g):

[0119]

[0120] Starting from 6-chloropyridazine-3(2H)-one and tert-butyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate, 5 g of the target product was prepared according to the method for compound 5a. It was a gray solid (yield 45%). 1 H NMR (400 MHz, DMSO-d6) δ 12.89 (s, 1H), 8.32 (s,1H), 7.88 (s, 1H), 7.77 (d, J = 9.8 Hz, 1H), 6.93 (d, J = 9.8 Hz, 1H), 4.43 –4.35 (m, 1H), 4.04 (brs, 2H), 2.92 (brs, 2H), 2.05 – 1.99 (m, 2H), 1.84 –1.74 (m, 2H), 1.42 (s, 9H).

[0121] Intermediate 5h:

[0122] 6-[3-(trifluoromethyl)phenyl]pyridazine-3(2H)-one (5h):

[0123]

[0124] The target product 5h was prepared using 6-chloropyridazine-3(2H)-one and 3-trifluoromethylphenylboronic acid as starting materials, following the preparation method of compound 5a. It was a white solid (66% yield). 1H NMR (400 MHz, DMSO-d6) δ 13.34 (s, 1H), 8.21 – 8.15 (m, 3H), 7.81 (d, J = 7.8 Hz, 1H), 7.74 (t, J = 8.0 Hz, 1H), 7.04(d, J = 9.9 Hz, 1H).

[0125] Intermediate 5i:

[0126] 4-(6-oxo-1,6-dihydropyridazin-3-yl)benzylnitrile (5i):

[0127]

[0128] The target product 5i was prepared by using 6-chloropyridazine-3(2H)-one and 4-cyanobenzoic acid as starting materials, following the preparation method of compound 5a. It was a white solid (yield 80%). 1 H NMR (400 MHz, DMSO-d6) δ 13.41 (s, 1H), 8.12 (d, J = 10.0 Hz, 1H), 8.06 (m, J = 8.4 Hz, 2H), 7.96 (d, J = 8.5 Hz, 2H), 7.04 (d, J = 9.9 Hz, 1H).

[0129] Intermediate 5j:

[0130] 6-(3-Nitrophenyl)pyridazine-3(2H)-one (5j):

[0131]

[0132] The target product 5j was prepared by using 6-chloropyridazine-3(2H)-one and 3-nitrophenylboronic acid as starting materials, following the preparation method of compound 5a. It was a yellow solid (yield 51%). 1 H NMR (400 MHz, DMSO-d6) δ 13.42 (s, 1H), 8.65 (t, J = 2.0 Hz, 1H), 8.33 (dt, J = 7.9, 1.2 Hz, 1H), 8.31 – 8.27 (m, 1H), 8.19 (d, J = 9.9 Hz, 1H), 7.79 (t, J = 8.0 Hz, 1H), 7.06 (d, J = 9.9 Hz, 1H).

[0133] Intermediate 6a:

[0134] 6-(benzo[d][1,3]dioxolane-5-yl)-2-(2-hydroxyethyl)pyridazine-3(2H)-one (6a):

[0135]

[0136] Starting with compound 5a and (2-bromoethoxy)-tert-butyldimethylsilane, the target product 6a was prepared following the same method as compound 2a. A green oily substance (62% yield) was obtained. 1 H NMR (400 MHz, DMSO-d6) δ 7.97 (dd,J = 9.8, 1.1 Hz, 1H), 7.46 – 7.43 (m, 1H), 7.41 (ddd, J = 8.1, 1.9, 0.8 Hz,1H), 7.02 (dd, J = 8.1, 0.9 Hz, 1H), 6.99 (d, J = 9.6 Hz, 1H), 6.09 (s, 2H), 4.84 (t, J = 5.8 Hz, 1H), 4.18 (t, J = 6.0 Hz, 2H), 3.77 (q, J = 6.0 Hz, 2H).

[0137] Intermediate 6b:

[0138] 6-(2,3-Dihydrobenzo[b][1,4]dioxane-6-yl)-2-(2-hydroxyethyl)pyridazine-3(2H)-one (6b):

[0139]

[0140] Starting with compound 5b and (2-bromoethoxy)-tert-butyldimethylsilane, the target product 6b was prepared by referring to the preparation method of compound 2a. It was a green oily substance (yield 59%). 1 H NMR (400 MHz, DMSO-d6) δ 7.96 (dd,J = 9.8, 1.2 Hz, 1H), 7.39 (d, J = 2.2 Hz, 1H), 7.37 (dd, J = 8.4, 2.2 Hz,1H), 6.97 (t, J = 9.2 Hz, 2H), 4.83 (t, J = 5.8 Hz, 1H), 4.29 (s, 4H), 4.17 (t, J = 6.1 Hz, 2H), 3.76 (q, J = 6.0 Hz, 2H).

[0141] Intermediate 6c:

[0142] 2-(2-hydroxyethyl)-6-(1-methyl-1H-indol-5-yl)pyridazin-3(2H)-one (6c):

[0143]

[0144] Starting from compound 5c and (2-bromoethoxy)-tert-butyldimethylsilane, the target product 6c was prepared by following the same method as compound 2a. It was a gray solid (85% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J= 1.7 Hz, 1H), 8.06 (d, J = 9.7 Hz, 1H), 7.72 (dd, J = 8.6, 1.8 Hz, 1H), 7.53(d, J = 8.6 Hz, 1H), 7.39 (d, J = 3.1 Hz, 1H), 7.00 (d, J = 9.7 Hz, 1H), 6.53 (d, J = 3.0 Hz, 1H), 4.88 (t, J = 5.8 Hz, 1H), 4.23 (t, J = 6.1 Hz, 2H), 3.83– 3.79 (m, 5H).

[0145] Intermediate 6d:

[0146] 5-(4-cyanophenyl)furan-2-carboxaldehyde (6d):

[0147]

[0148] Starting from compound 5d and (2-bromoethoxy)-tert-butyldimethylsilane, the target product 6d was prepared by following the same method as compound 2a. It was a gray solid (72% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (t, J= 1.2 Hz, 1H), 8.15 (d, J = 0.9 Hz, 1H), 8.10 (d, J = 9.8 Hz, 1H), 7.97 (dd,J = 8.9, 1.7 Hz, 1H), 7.74 (d, J = 8.9 Hz, 1H), 7.04 (d, J = 9.7 Hz, 1H), 4.88 (t, J = 5.8 Hz, 1H), 4.23 (t, J = 6.1 Hz, 2H), 4.08 (s, 3H), 3.82 (q, J= 6.0 Hz, 2H).

[0149] Intermediate 6e:

[0150] 6-(furan-3-yl)-2-(2-hydroxyethyl)pyridazine-3(2H)-one (6e):

[0151]

[0152] Starting from compound 5e and (2-bromoethoxy)-tert-butyldimethylsilane, the target product 6e was prepared by referring to the preparation method of compound 2a. It was a white solid (67% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J= 7.2 Hz, 1H), 7.84 (s, 1H), 7.09 (d, J = 3.4 Hz, 1H), 7.02 (d, J = 9.7 Hz,1H), 6.66 (dd, J = 3.4, 1.8 Hz, 1H), 4.84 (t, J = 5.9 Hz, 1H), 4.16 (t, J =6.0 Hz, 2H), 3.75 (q, J = 6.0 Hz, 2H).

[0153] Intermediate 6f:

[0154] 2-(2-hydroxyethyl)-6-(1-isopropyl-1H-pyrazol-4-yl)pyridazin-3(2H)-one (6f):

[0155]

[0156] Starting from compound 5f and (2-bromoethoxy)-tert-butyldimethylsilane, the target product 6f was prepared by following the same method as compound 2a. It was a brown solid (61% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (s,1H), 7.89 (s, 1H), 7.78 (d, J = 9.6 Hz, 1H), 6.97 (d, J = 9.6 Hz, 1H), 4.83(t, J = 5.8 Hz, 1H), 4.53 (hept, J = 6.7 Hz, 1H), 4.13 (t, J = 6.2 Hz, 2H), 3.74 (q, J = 6.1 Hz, 2H), 1.44 (d, J = 6.7 Hz, 6H).

[0157] 6g of intermediate:

[0158] tert-butyl 4-[4-(1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (6g):

[0159]

[0160] Using 5 g of compound and (2-bromoethoxy)-tert-butyldimethylsilane as starting materials, 6 g of the target product was prepared according to the preparation method of compound 2a. The product was a gray solid (70% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (s,1H), 7.91 (s, 1H), 7.77 (d, J = 9.6 Hz, 1H), 6.98 (d, J = 9.6 Hz, 1H), 4.87 –4.81 (m, 1H), 4.44 – 4.36 (m, 1H), 4.13 (t, J = 6.2 Hz, 2H), 4.09 – 3.98 (m,2H), 3.74 (q, J = 6.0 Hz, 2H), 2.92 (brs, 2H), 2.06 – 1.99 (m, 2H), 1.84 –1.74 (m, 2H), 1.42 (s, 9H).

[0161] Intermediate 6h:

[0162] 2-(2-hydroxyethyl)-6-[3-(trifluoromethyl)phenyl]pyridazine-3(2H)-one (6h):

[0163]

[0164] Starting from compound 5h and (2-bromoethoxy)-tert-butyldimethylsilane, the target product 6h was prepared by following the preparation method of compound 2a. It was a gray solid (75% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.21 (dt, J= 4.0, 1.7 Hz, 2H), 8.16 (d, J = 9.7 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.75(t, J = 8.0 Hz, 1H), 7.08 (d, J = 9.8 Hz, 1H), 4.88 (s, 1H), 4.24 (t, J = 5.9Hz, 2H), 3.80 (t, J = 6.1 Hz, 2H).

[0165] Intermediate 6i:

[0166] 4-[1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridazine-3-yl]benzylnitrile (6i):

[0167]

[0168] Starting from compound 5i and (2-bromoethoxy)-tert-butyldimethylsilane, the target product 6i was prepared by referring to the preparation method of compound 2a. It was a gray solid (50% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.14 - 8.11(m, 1H), 8.11 - 8.06 (m, 2H), 7.99 -7.95 (m, 2H), 7.09 (dd, J = 9.8, 1.1 Hz,1H), 4.86 (t, J = 5.9 Hz, 1H), 4.23 (t, J = 5.9 Hz, 2H), 3.79 (q, J = 5.9 Hz, 2H).

[0169] Intermediate 6j:

[0170] 2-(2-hydroxyethyl)-6-(3-nitrophenyl)pyridazine-3(2H)-one (6j):

[0171]

[0172] Starting from compound 5j and (2-bromoethoxy)-tert-butyldimethylsilane, the target product 6j was prepared by referring to the preparation method of compound 2a. It was a gray solid (66% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.67 (t, J= 2.1 Hz, 1H), 8.35 (dt, J = 7.9, 1.3 Hz, 1H), 8.32 -8.27 (m, 1H), 8.18 (d, J= 9.8 Hz, 1H), 7.80 (t, J = 8.0 Hz, 1H), 7.10 (d, J = 9.7 Hz, 1H), 4.89 (t, J= 5.9 Hz, 1H), 4.25 (t, J = 5.9 Hz, 2H), 3.81 (q, J = 5.9 Hz, 2H).

[0173] Intermediate 6k:

[0174] 2-(2-hydroxyethyl)-6-methylpyridazine-3(2H)-one (6k):

[0175]

[0176] The target product 6k was prepared by using 6-methylpyridazine-3(2H)-one and (2-bromoethoxy)-tert-butyldimethylsilane as starting materials, following the preparation method of compound 2a. It was a gray solid (60% yield). 1 H NMR (400 MHz, DMSO-d6) δ7.31 (d, J = 9.4 Hz, 1H), 6.85 (d, J = 9.5 Hz, 1H), 4.80 (t, J = 5.8 Hz, 1H), 4.06 (t, J = 6.2 Hz, 2H), 3.67 (q, J = 6.1 Hz, 2H), 2.25 (s, 3H).

[0177] Intermediate 7:

[0178] tert-butyl 4-[4-(1-(2-((7-(3-morpholinopropoxy)quinolin-4-yl)oxy)ethyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (7):

[0179]

[0180] Starting from compounds 6g and 4b, the target product 7 was prepared following the method used for compound B1. It was a white solid (55% yield). ESI-MS m / z: 660.4 [M+H] + .

[0181] II. Synthesis of the final product

[0182] Example 1

[0183] Synthesis of 6-(4-methyl-1H-imidazol-1-yl)-2-(2-(quinolin-4-yloxy)ethyl)pyridazine-3(2H)-one (B1):

[0184]

[0185] 4-Chloroquinoline (1.2 mmol), compound 2a (1.0 mmol), cesium carbonate (1.2 mmol), palladium acetate (0.3 mmol), and S-Phos (0.2 mmol) were added sequentially to 30 mL of toluene solution. The mixture was heated at 90 °C for 16 hours under argon protection. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth short column, and the crude product was purified by rapid column chromatography to give compound B1 as a white solid (82% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J = 5.2 Hz, 1H), 8.22 (s, 1H), 8.03 (dd, J = 8.5, 1.4 Hz, 1H), 7.99 (d, J = 9.9 Hz, 1H), 7.92(d, J = 8.4 Hz, 1H), 7.71 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H), 7.45 (t, J = 7.6Hz, 1H), 7.37 (s, 1H), 7.24 (d, J = 9.9 Hz, 1H), 7.09 (d, J = 5.2 Hz, 1H),4.68 (q, J = 3.6, 2.1 Hz, 2H), 4.61 (t, J = 4.8 Hz, 2H), 2.14 (s, 3H). 13 C NMR(101 MHz, DMSO-d6) δ 160.77, 159.24, 151.89, 148.93, 139.23, 138.51, 134.97,132.69, 130.27, 128.89, 126.83, 126.12, 121.87, 121.04, 112.84, 102.08,66.14, 49.86, 13.89.

[0186] Example 2

[0187] Synthesis of 2-(2-((6,7-dimethoxyquinoline-4-yl)oxy)ethyl)-6-(4-methyl-1H-imidazol-1-yl)pyridazin-3(2H)-one (B2):

[0188]

[0189] Starting from compound 2a and 4-chloro-6,7-dimethoxyquinoline, the target product B2 was prepared according to the method for preparing compound B1. It was a white solid (64% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 5.2Hz, 1H), 8.23 ​​(d, J = 1.4 Hz, 1H), 7.99 (d, J = 9.9 Hz, 1H), 7.37 (t, J = 1.3Hz, 1H), 7.29 – 7.21 (m, 3H), 6.92 (d, J = 5.3 Hz, 1H), 4.60 (q, J = 3.0 Hz, 4H), 3.89 (s, 3H), 3.68 (s, 3H), 2.13 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ164.83, 159.48, 155.52, 150.71, 144.07, 138.37, 137.60, 134.87, 132.82,127.04, 115.48, 113.38, 101.91, 100.95, 100.53, 68.26, 56.77, 56.14, 50.07,13.00. HRMS (ESI) m / z calcd. for C 21 H 21 N5O4 [M+H] + 408.1666, found: 408.1666.

[0190] Example 3

[0191] Synthesis of 2-(2-((7-methoxyquinoline-4-yl)oxy)ethyl)-6-(4-methyl-1H-imidazol-1-yl)pyridazin-3(2H)-one (B3):

[0192]

[0193] 4-Chloro-7-methoxyquinoline (231 mg, 1.2 mmol), compound 2a (220 mg, 1.0 mmol), cesium carbonate (390 mg, 1.2 mmol), palladium acetate (67 mg, 0.3 mmol), and S-Phos (82 mg, 0.2 mmol) were sequentially added to 30 mL of toluene solution. The mixture was heated at 90 °C for 16 hours under argon protection. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth short column, and the crude product was purified by rapid column chromatography to give compound B3. A white solid (300 mg, 80% yield) was obtained. 1H NMR (400 MHz, Chloroform-d) δ 8.66 (d, J = 5.4 Hz, 1H), 8.00 (d, J = 9.2Hz, 1H), 7.91 (d, J = 1.5 Hz, 1H), 7.45 – 7.37 (m, 2H), 7.14 (d, J = 9.9 Hz,1H), 7.13 – 7.06 (m, 2H), 6.69 (d, J = 5.5 Hz, 1H), 4.73 (t, J = 5.2 Hz, 2H), 4.63 (t, J = 5.2 Hz, 2H), 3.93 (s, 3H), 2.28 (d, J = 1.1 Hz, 3H). 1 H NMR (400MHz, Chloroform-d) δ 8.66 (d, J = 5.4 Hz, 1H), 8.00 (d, J = 9.2 Hz, 1H), 7.91 (d, J = 1.5 Hz, 1H), 7.45 – 7.37 (m, 2H), 7.14 (d, J = 9.9 Hz, 1H), 7.13 –7.06 (m, 2H), 6.69 (d, J = 5.5 Hz, 1H), 4.73 (t, J = 5.2 Hz, 2H), 4.63 (t, J= 5.2 Hz, 2H), 3.93 (s, 3H), 2.28 (d, J = 1.1 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 167.15, 163.96, 159.39, 146.96, 142.09, 137.75, 134.68, 132.78, 127.09,124.82, 120.97, 115.13, 114.43, 102.06, 100.42, 68.60, 56.64, 49.55, 11.63.HRMS (ESI) m / z calcd. for C 20 H 19 N5O3 [M+H] + 378.1561, found: 378.1561.

[0194] Example 4

[0195] Synthesis of 3-[1-(2-((6,7-dimethoxyquinoline-4-yl)oxy)ethyl)-6-oxo-1,6-dihydropyridazine-3-yl]benzyl nitrile (B4):

[0196]

[0197] Starting from compounds 2a and 4a, the target product B4 was prepared by referring to the preparation method of compound B1. It was a white solid (yield 43%). 1 H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 5.3 Hz, 1H), 8.21 (d, J =1.4 Hz, 1H), 7.98 (d, J = 9.9 Hz, 1H), 7.89 (d, J = 9.1 Hz, 1H), 7.33 (t, J =1.3 Hz, 1H), 7.27 – 7.22 (m, 2H), 7.05 (dd, J = 9.1, 2.5 Hz, 1H), 6.94 (d, J= 5.3 Hz, 1H), 4.64 (t, J = 5.1 Hz, 2H), 4.57 (t, J = 5.0 Hz, 2H), 4.11 (t, J= 6.4 Hz, 2H), 2.37 (t, J = 7.1 Hz, 2H), 2.15 (s, 6H), 2.13 (s, 3H), 1.89 (p,J = 6.7 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 165.67, 162.13, 159.30, 148.32,144.11, 138.30, 137.67, 134.87, 132.76, 126.94, 124.50, 120.30, 115.36,113.36, 102.91, 101.80, 68.00, 66.13, 54.34, 49.57, 42.62, 24.06, 13.08. HRMS(ESI) m / z calcd. for C 24 H 28 N6O3 [M+H] + 449.2296, found: 449.2295.

[0198] Example 5

[0199] Synthesis of 2-(2-((7-(3-(4-isopropylpiperazin-1-yl)propoxy)quinoline-4-yl)oxy)ethyl)-6-(4-methyl-1H-imidazol-1-yl)pyridazin-3(2H)-one (B5):

[0200]

[0201] Starting with compounds 2a and 4d, the target product B5 was prepared by referring to the preparation method of compound B1. It was a gray solid (yield 53%). 1 H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.60 (s, 1H), 8.07 (d, J= 9.1 Hz, 1H), 8.01 (d, J = 9.9 Hz, 1H), 7.56 (s, 1H), 7.44 (s, 1H), 7.39 (d,J = 6.1 Hz, 1H), 7.32 (d, J = 9.3 Hz, 1H), 7.27 (d, J = 9.8 Hz, 1H), 4.89 (t,J = 5.0 Hz, 2H), 4.63 (t, J = 4.9 Hz, 2H), 4.23 (t, J = 6.1 Hz, 2H), 3.49-3.01 HRMS (ESI) m / z calcd.forC 29 H 37 N7O3 [M+H] + 532.3031, found: 532.3029.

[0202] Example 6

[0203] Synthesis of 6-(4-methyl-1H-imidazol-1-yl)-2-(2-((7-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-4-yl)oxy)ethyl)pyridazin-3(2H)-one (B6):

[0204]

[0205] Starting with compounds 2a and 4c, the target product B6 was prepared by referring to the preparation method of compound B1. It was a gray solid (yield 40%). 1H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 5.2 Hz, 1H), 8.20 (d, J =1.4 Hz, 1H), 7.97 (d, J = 9.9 Hz, 1H), 7.89 (d, J = 9.1 Hz, 1H), 7.32 (t, J =1.3 Hz, 1H), 7.26 (d, J = 2.5 Hz, 1H), 7.23 (d, J = 9.9 Hz, 1H), 7.05 (dd, J= 9.1, 2.5 Hz, 1H), 6.93 (d, J = 5.3 Hz, 1H), 4.64 (t, J = 5.1 Hz, 2H), 4.58(d, J = 4.5 Hz, 2H), 4.12 (t, J = 6.4 Hz, 2H), 2.46 - 2.18 (m, 10H), 2.14 (s,3H), 2.12 (s, 3H), 1.92 (q, J = 6.7 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ167.58, 163.07, 159.47, 146.84, 141.48, 137.19, 134.49, 132.80, 131.68,127.20, 125.09, 121.13, 115.52, 115.24, 102.20, 100.80, 68.77, 66.35, 49.59,23.68, 10.22. HRMS (ESI) m / z calcd. for C 27 H 33 N7O3 [M+H] + 504.2718, found: 504.2717.

[0206] Example 7

[0207] Synthesis of 6-(4-methyl-1H-imidazol-1-yl)-2-(2-((7-(3-(piperazin-1-yl)propoxy)quinolin-4-yl)oxy)ethyl)pyridazin-3(2H)-one (B7):

[0208]

[0209] Starting with compounds 2a and 4e, the target product B7M was prepared following the same method as compound B1. It was a white solid (53% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 5.3 Hz, 1H), 8.20 (d, J =1.4 Hz, 1H), 7.97 (d, J = 9.9 Hz, 1H), 7.89 (d, J = 9.1 Hz, 1H), 7.32 (t, J =1.3 Hz, 1H), 7.27 (d, J = 2.5 Hz, 1H), 7.23 (d, J = 9.9 Hz, 1H), 7.05 (dd, J= 9.2, 2.5 Hz, 1H), 6.94 (d, J = 5.3 Hz, 1H), 4.66 – 4.62 (m, 2H), 4.57 (t, J= 4.8 Hz, 2H), 4.13 (t, J = 6.3 Hz, 2H), 3.32–3.30 (m, 4H), 2.46 (t, J = 7.2Hz, 2H), 2.33 (t, J = 5.0 Hz, 4H), 2.12 (s, 3H), 1.93 (t, J = 6.9 Hz, 2H),1.39 (s, 9H).

[0210]

[0211] Compound B7M (295 mg, 0.5 mmol) was added to 15 mL of 2M EA-HCl solution and reacted at room temperature for 3 hours. After removing the solvent, a white solid B7 (232 mg, 95% yield) was obtained. 1 H NMR (400 MHz, DMSO-d6) δ 9.89 (s,1H), 9.53 (s, 1H), 9.09 (d, J = 6.7 Hz, 1H), 8.12 – 8.08 (m, 2H), 7.86 (s,1H), 7.67 (d, J = 2.4 Hz, 1H), 7.51 (d, J = 6.8 Hz, 1H), 7.42 (dd, J = 9.3,2.4 Hz, 1H), 7.37 (d, J = 9.9 Hz, 1H), 4.98 (t, J = 4.9 Hz, 2H), 4.67 (t, J =4.9 Hz, 2H), 4.31 (t, J = 5.9 Hz, 2H), 3.68 – 3.46 (m, 9H), 3.35 (d, J = 8.1Hz, 2H), 2.36 – 2.29 (m, 5H). 13C NMR (101 MHz, DMSO-d6) δ 167.36, 162.89,159.49, 146.36, 141.37, 137.19, 134.38, 132.73, 131.58, 127.30, 125.00,121.02, 115.42, 115.19, 102.22, 100.70, 68.72, 66.43, 53.22, 49.60, 48.16,23.31, 10.33. HRMS (ESI) m / z calcd. for C 26 H 31 N7O3 [M+H] + 490.2651, found: 490.2656.

[0212] Example 8

[0213] Synthesis of 6-(4-methyl-1H-imidazol-1-yl)-2-(2-((7-(3-morpholinopropoxy)quinolin-4-yl)oxy)ethyl)pyridazine-3(2H)-one (B8):

[0214]

[0215] Starting with compounds 2a and 4b, the target product B8 was prepared by referring to the preparation method of compound B1. It was a white solid (55% yield). 1 H NMR (400 MHz, Chloroform-d) δ 8.65 (d, J = 5.3 Hz, 1H), 7.99(d, J = 9.2 Hz, 1H), 7.91 (d, J = 1.4 Hz, 1H), 7.42 (d, J = 9.9 Hz, 1H), 7.33(d, J = 2.5 Hz, 1H), 7.14 (d, J = 9.9 Hz, 1H), 7.11 – 7.08 (m, 1H), 7.06 (dd,J = 9.2, 2.5 Hz, 1H), 6.65 (d, J = 5.3 Hz, 1H), 4.72 (t, J = 5.2 Hz, 2H),4.61 (t, J = 5.2 HRMS (ESI) m / z calcd.for C26 H 30 N6O4 [M+H] + 491.2401, found: 491.2403.

[0216] Example 9

[0217] Synthesis of 3-[1-(2-((7-methoxyquinoline-4-yl)oxy)ethyl)-6-oxo-1,6-dihydropyridazine-3-yl]benzyl nitrile (B9):

[0218]

[0219] Starting from compound 2b and 4-chloro-7-methoxyquinoline, the target product B9 was prepared according to the method for compound B1. It was a white solid (60% yield). 1 H NMR (400 MHz, Chloroform-d) δ 8.64 (d, J = 5.4Hz, 1H), 8.06 (t, J = 1.8 Hz, 1H), 7.99 (d, J = 9.2 Hz, 1H), 7.93 (dt, J =8.1, 1.5 Hz, 1H), 7.72 (dt, J = 7.8, 1.4 Hz, 1H), 7.66 (d, J = 9.7 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 7.10 (d, J = 9.7 Hz, 1H), 7.02 (dd, J = 9.2, 2.6 Hz, 1H), 6.67 (d, J = 5.4 Hz, 1H), 4.82 (t, J = 5.2Hz, 2H), 4.67 (t, J = 5.3 Hz, 2H), 3.92 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ167.62, 164.07, 159.63, 146.44, 142.36, 141.40, 135.63, 133.17, 131.11,130.59, 130.50, 130.36, 129.61, 124.79, 120.97, 118.82, 114.40, 112.49,102.10, 99.88, 68.95, 56.59, 50.00. HRMS (ESI) m / z calcd. for C 23 H 18 N4O3 [M+H]+ 399.1452, found: 399.1454.

[0220] Example 10

[0221] Synthesis of 3-[1-(2-((6,7-dimethoxyquinoline-4-yl)oxy)ethyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzyl nitrile (B10):

[0222]

[0223] Starting from compound 2b and 4-chloro-6,7-dimethoxyquinoline, the target product B10 was prepared according to the method for preparing compound B1. It was a white solid (61% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 5.2Hz, 1H), 8.27 (s, 1H), 8.15 (dd, J = 9.2, 4.6 Hz, 2H), 7.91 (d, J = 7.7 Hz,1H), 7.64 (t, J = 7.8 Hz, 1H), 7.25 (s, 1H), 7.16 (d, J = 11.0 Hz, 2H), 6.94 (d, J = 5.2 Hz, 1H), 4.69 (dd, J = 10.0, 4.6 Hz, 4H), 3.87 (s, 3H), 3.60 (s,3H). 13 C NMR (101 MHz, DMSO-d6) δ 165.62, 159.82, 155.91, 150.89, 143.35,142.44, 136.43, 135.62, 133.21, 131.17, 130.60, 130.46, 130.44, 129.64,118.80, 115.55, 112.46, 102.13, 100.62, 99.98, 68.68, 56.82, 56.16, 50.38.HRMS (ESI) m / z calcd. for C 24 H 20 N4O4 [M+H] + 429.1557, found: 429.1557.

[0224] Example 11

[0225] Synthesis of 3-[1-(2-((7-(3-(4-methylpiperazin-1-yl)propoxy)quinoline-4-yl)oxy)ethyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzyl nitrile (B11):

[0226]

[0227] Starting with compounds 2b and 4c, the target product B11 was prepared by referring to the preparation method of compound B1. It was a gray solid (50% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 5.2 Hz, 1H), 8.27 (t, J =1.8 Hz, 1H), 8.17 – 8.12 (m, 2H), 7.91 (dt, J = 7.8, 1.4 Hz, 1H), 7.86 (d, J= 9.1 Hz, 1H), 7.66 (t, J = 7.9 Hz, 1H), 7.23 (d, J = 2.5 Hz, 1H), 7.15 (d, J= 9.8 Hz, 1H), 6.98 (dd, J = 9.2, 2.5 Hz, 1H), 6.95 (d, J = 5.3 Hz, 1H), 4.69(s, 4H), 4.10 (t, J = 6.3 Hz, 2H), 2.51- 2.26 (m, 10H), 2.18 (s, 3H), 1.91(p, J = 6.7 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 160.70, 160.08, 159.61,152.32, 151.03, 142.17, 135.77, 133.19, 131.07, 130.66, 130.53, 130.25,129.71, 123.05, 118.91, 118.40, 115.53, 112.52, 108.29, 100.59, 66.47, 66.07,55.07, 54.75, 52.98, 50.59, 45.99, 26.49. HRMS (ESI) m / z calcd. for C 30 H 32 N6O3[M+H] + 525.2609, found: 525.2610.

[0228] Example 12

[0229] Synthesis of 3-[1-(2-((7-(3-morpholinopropoxy)quinolin-4-yl)oxy)ethyl)-6-oxo-1,6-dihydropyridazine-3-yl]benzyl nitrile (B12):

[0230]

[0231] Starting with compounds 2b and 4b, the target product B12 was prepared following the same method as compound B1. It was a grayish-white solid (80% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 5.2 Hz, 1H), 8.27 (t, J= 1.8 Hz, 1H), 8.20 – 8.10 (m, 2H), 7.92 (dt, J = 7.7, 1.3 Hz, 1H), 7.86 (d,J = 9.1 Hz, 1H), 7.67 (t, J = 7.9 Hz, 1H), 7.24 (d, J = 2.4 Hz, 1H), 7.15 (d,J = 9.8 Hz, 1H), 6.98 (dd, J = 9.1, 2.5 Hz, 1H), 6.95 (d, J = 5.3 Hz, 1H),4.69 (s, 4H), 4.11 (t, J = 6.3 Hz, 2H), 3.58 (t, J = 4.6 Hz, 4H), 2.45 (d, J= 7.1 Hz, 2H), 2.40 (d, J = 18.7 Hz, 4H), 1.92 (p, J = 6.7 Hz, 2H). 13 C NMR(101 MHz, DMSO-d6) δ 167.70, 163.03, 159.63, 146.71, 142.37, 141.36, 135.67,133.16, 131.11, 130.60, 130.50, 130.36, HRMS (ESI) m / z calcd. for C 29 H 29 N5O4 [M+H] + 512.2292, found: 512.2291.

[0232] Example 13

[0233] Synthesis of 6-methyl-2-(2-((7-(3-morpholinopropoxy)quinolin-4-yl)oxy)ethyl)pyridazine-3(2H)-one (B13):

[0234]

[0235] Starting with compounds 6k and 4b, the target product B13 was prepared by referring to the preparation method of compound B1. It was a white solid (70% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 5.2 Hz, 1H), 7.90 (d, J =9.1 Hz, 1H), 7.33 (d, J = 9.5 Hz, 1H), 7.28 (d, J = 2.5 Hz, 1H), 7.16 (dd, J= 9.1, 2.5 Hz, 1H), 6.92 (d, J = 3.7 Hz, 1H), 6.90 (s, 1H), 4.54 – 4.53 (m,4H), 4.14 (t, J = 6.3 Hz, 2H), 3.58 (t, J = 4.6 Hz, 4H), 2.45 (t, J = 7.2 Hz,2H), 2.37 (t, J = 4.7 Hz, 4H), 2.24 (s, 3H), 1.96 – 1.90 (m, 2H). 13 C NMR (101MHz, DMSO-d6) δ 161.46, 160.11, 159.59, 151.93, 150.10, 145.00, 134.55,129.65, 123.43, 118.67, 115.70, 107.81, 100.74, 66.45, 65.75, 64.39, 54.17,52.03, 49.75, 23.98, 20.64. HRMS (ESI) m / z calcd. for C 23 H 28 N4O4 [M+H] + 425.2183, found: 425.2184.

[0236] Example 14

[0237] Synthesis of 6-(benzo[d][1,3]dioxolane-5-yl)-2-(2-((7-(3-morpholinopropoxy)quinolin-4-yl)oxy)ethyl)pyridazine-3(2H)-one (B14):

[0238]

[0239] Starting with compounds 6a and 4b, the target product B14 was prepared following the preparation method of compound B1. It was a gray solid (54% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 5.2 Hz, 1H), 7.99 (d, J =9.8 Hz, 1H), 7.89 (d, J = 9.1 Hz, 1H), 7.40 – 7.35 (m, 2H), 7.26 (d, J = 2.5Hz, 1H), 7.07 – 6.97 (m, 3H), 6.94 (d, J = 5.3 Hz, 1H), 6.09 (s, 2H), 4.65(s, 4H), 4.12 (t, J = 6.3 Hz, 2H), 3.58 (t, J = 4.6 Hz, 4H), 2.45 (t, J = 7.2Hz, 2H), 2.38 (brs, 4H), 1.92 (p, J = 6.7 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6)δ 160.77, 160.11, 159.54, 152.34, 151.03, 148.83, 148.46, 143.74, 131.17,130.01, 128.84, 123.13, HRMS (ESI)m / z calcd. for C 29 H 30 N4O6 [M+H] + 531.2238, found: 531.2238.

[0240] Example 15

[0241] Synthesis of 6-(2,3-dihydrobenzo[b][1,4]dioxane-6-yl)-2-(2-((7-(3-morpholinopropoxy)quinolin-4-yl)oxy)ethyl)pyridazine-3(2H)-one (B15):

[0242]

[0243] Starting with compounds 6b and 4b, the target product B15 was prepared by referring to the preparation method of compound B1. It was a gray solid (yield 57%). 1 H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 5.3 Hz, 1H), 7.98 (d, J =9.8 Hz, 1H), 7.90 (d, J = 9.1 Hz, 1H), 7.37 (d, J = 2.2 Hz, 1H), 7.33 (dd, J= 8.5, 2.2 Hz, 1H), 7.26 (d, J = 2.5 Hz, 1H), 7.06 – 7.00 (m, 2H), 6.95 –6.91 (m, 2H), 4.64 (s, 4H), 4.29 (s, 4H), 4.12 (t, J = 6.3 Hz, 2H), 3.57 (t,J = 4.6 Hz, 4H), 2.44 (t, J = 7.2 Hz, 2H), 2.37 (t, J = 4.4 Hz, 4H), 1.92 (p,J = 6.7 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 160.79, 160.12, 159.55, 152.35,151.03, 145.09, 144.07, 143.65, 131.11, 130.01, 127.93, 123.16, 119.41,118.43, 117.85, 115.55, 114.98, 108.32, 100.53, 66.67, 66.46, 66.20, 64.75,64.53, 55.28, 53.83, 50.33, 26.19. HRMS (ESI) m / z calcd. for C 30 H 32 N4O6 [M+H] + 545.2395, found: 545.2392.

[0244] Example 16

[0245] Synthesis of 6-(1-methyl-1H-indol-5-yl)-2-(2-((7-(3-morpholinopropoxy)quinolin-4-yl)oxy)ethyl)pyridazine-3(2H)-one (B16):

[0246]

[0247] Starting with compounds 6c and 4b, the target product B16 was prepared following the preparation method of compound B1. It was a gray solid (yield 46%). 1 H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 5.2 Hz, 1H), 8.09 (d, J =9.8 Hz, 1H), 8.01 (d, J = 1.7 Hz, 1H), 7.95 (d, J = 9.1 Hz, 1H), 7.68 (dd, J= 8.6, 1.8 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.39 (d, J = 3.1 Hz, 1H), 7.26 (d, J = 2.5 Hz, 1H), 7.06 (d, J = 9.7 Hz, 1H), 6.99 (dd, J = 9.1, 2.5 Hz,1H), 6.95 (d, J = 5.3 Hz, 1H), 6.47 (d, J = 3.0 Hz, 1H), 4.68 (s, 4H), 4.10(t, J = 6.3 Hz, 2H), 3.82 (s, 3H), 3.57 (t, J = 4.6 Hz, 4H), 2.42 (t, J = 7.2Hz, 2H), 2.36 (t, J = 4.6 Hz, 4H), 1.90 (p, J = 6.7 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 160.84, 160.11, 159.59, 152.37, 151.04, 145.50, 137.31, 131.60,131.30, 129.98, 128.57, 125.85, 123.24, 119.51, 118.83, 118.43, 115.58,110.57, 108.31, 101.67, 100.54, 66.66, 66.45, 66.23, 55.27, 53.81, 50.36,33.07, 26.18. HRMS (ESI) m / z calcd. for C 31 H 33 N5O4 [M+H] + 540.2605, found: 540.2608.

[0248] Example 17

[0249] Synthesis of 6-(1-methyl-1H-indazol-5-yl)-2-(2-((7-(3-morpholinopropoxy)quinolin-4-yl)oxy)ethyl)pyridazine-3(2H)-one (B17):

[0250]

[0251] Starting with compounds 6d and 4b, the target product B17 was prepared following the preparation method of compound B1. It was a gray solid (yield 40%). 1 H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 5.2 Hz, 1H), 8.20 (d, J =1.6 Hz, 1H), 8.13 (d, J = 9.8 Hz, 1H), 8.10 (s, 1H), 7.93 (d, J = 1.7 Hz, 1H), 7.91 (d, J = 1.8 Hz, 1H), 7.71 (d, J = 8.9 Hz, 1H), 7.26 (d, J = 2.5 Hz,1H), 7.10 (d, J = 9.7 Hz, 1H), 7.01 – 6.92 (m, 2H), 4.69 (s, 4H), 4.12 – 4.08(m, 5H), 3.57 (t, J = 4.6 Hz, 4H), 2.43 (t, J = 7.2 Hz, 2H), 2.37 (brs, 4H), 1.91 (q, J = 6.8 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 167.80, 162.99, 159.58,146.65, 144.66, 141.29, 140.17, 133.69, 131.41, 130.21, 127.11, 125.00,124.18, 124.02, 120.92, 119.07, 115.26, 110.53, 102.14, 100.61, 69.01, 66.28,63.81, 53.69, 51.61, 49.88, 35.85, 23.22. HRMS (ESI) m / z calcd. for C 30 H 32 N6O4[M+H] + 541.2558, found: 541.2556.

[0252] Example 18

[0253] Synthesis of 6-(1-isopropyl-1H-pyrazol-4-yl)-2-(2-((7-(3-morpholinopropoxy)quinolin-4-yl)oxy)ethyl)pyridazine-3(2H)-one (B18):

[0254]

[0255] Starting with compounds 6f and 4b, the target product B18 was prepared following the same method as compound B1. It was a white solid (58% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 5.2 Hz, 1H), 8.19 (s,1H), 7.91 (d, J = 9.1 Hz, 1H), 7.86 (s, 1H), 7.79 (d, J = 9.6 Hz, 1H), 7.27(d, J = 2.5 Hz, 1H), 7.05 – 7.00 (m, 2H), 6.93 (d, J = 5.3 Hz, 1H), 4.64-4.58 (m, J = 2.8 Hz, 4H), 4.51 (hept, J = 6.7 Hz, 1H), 4.12 (t, J = 6.3 Hz,2H), 3.57 (t, J = 4.6 Hz, 4H), 2.44 (t, J = 7.2 Hz, 2H), 2.37 (t, J = 4.7 Hz, 4H), 1.92 (p, J = 6.7 Hz, 2H), 1.43 (s, 3H), 1.41 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 160.81, 160.11, 159.42, 152.35, 151.04, 140.18, 136.51, 131.73,130.20, 126.55, 123.24, 118.43, 117.87, 115.57, 108.27, 100.53, 66.66, 66.44,66.12, 55.27, 53.83, 49.98, 26.19, 23.01. HRMS (ESI) m / z calcd. for C 28 H 34 N6O4[M+H] + 519.2714, found: 519.2715.

[0256] Example 19

[0257] Synthesis of 2-(2-((7-(3-morpholinopropoxy)quinolin-4-yl)oxy)ethyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridazin-3(2H)-one (B19):

[0258]

[0259] Compound 7 (394 mg, 0.6 mmol) was added to 15 mL of 2 M hydrochloric acid / ethyl acetate solution and reacted at room temperature for 3 hours. After removing the solvent, a gray solid B19 (265 mg, 95% yield) was obtained. 1 H NMR (400 MHz, DMSO-d6) δ8.61 (d, J = 5.2 Hz, 1H), 8.18 (s, 1H), 7.90 (d, J = 9.1 Hz, 1H), 7.86 (s,1H), 7.79 (d, J = 9.7 Hz, 1H), 7.26 (d, J = 2.5 Hz, 1H), 7.06- 6.99 (m, 2H), 6.93 (d, J = 5.3 Hz, 1H), 4.64- 4.57 (m, 4H), 4.23- 4.16 (m, 1H), 4.12 (t, J= 6.3 Hz, 2H), 3.57 (t, J = 4.6 Hz, 4H), 3.04 (dt, J = 12.8, 3.3 Hz, 2H), 2.58 (td, J = 12.3, 2.4 Hz, 2H), 2.44 (t, J = 7.2 Hz, 2H), 2.38 – 2.36 (m,4H), 1.95 – 1.88 (m, 4H), 1.75 (qd, J = 12.0, 4.1 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 160.82, 160.11, 159.46, 152.35, 151.02, 139.95, 137.12, 131.74,130.27, 127.57, 123.21, 118.47, 118.19, 115.56, 108.27, 100.54, 66.63, 66.15,63.81, 55.87, 55.25, 53.80, 51.58, 42.49, 29.08, 26.17. HRMS (ESI) m / z calcd.for C 30 H 37 N7O4 [M+H] +560.2980, found: 560.2982.

[0260] Example 20

[0261] Synthesis of 2-(2-((7-(3-morpholinopropoxy)quinolin-4-yl)oxy)ethyl)-6-(1-(isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridazin-3(2H)-one (B20):

[0262]

[0263] Compound B19 (200 mg, 0.36 mmol), potassium carbonate (248 mg, 1.8 mmol), and 2-iodopropane (74 mg, 0.43 mmol) were added to 30 mL of acetonitrile solution. The mixture was heated at 80 °C for 12 hours under argon protection. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth short column, and the crude product was purified by rapid column chromatography to give compound B20, a grayish-white solid (yield 152 mg, 70%). 1 H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 5.2 Hz, 1H), 8.20 (s, 1H), 7.90 (d, J = 9.1 Hz, 1H), 7.85 (s, 1H), 7.78 (d, J = 9.7 Hz,1H), 7.26 (d, J = 2.5 Hz, 1H), 7.05- 6.98 (m, 2H), 6.93 (d, J = 5.3 Hz, 1H), 4.63- 4.58 (m, 4H), 4.12 (t, J = 6.4 Hz, 2H), 4.10- 4.05 (m, 1H), 3.57 (t, J= 4.6 Hz, 4H), 2.86 (d, J = 11.1 Hz, 2H), 2.74 (p, J = 6.5 Hz, 1H), 2.44 (t,J = 7.2 Hz, 2H), 2.38- 2.36 (m, 4H), 2.25 (t, J = 11.5 Hz, 2H), 2.02 – 1.98(m, 2H), 1.94 – 1.83 (m, 4H), 0.98 (d, J = 6.5 Hz, 6H). 13C NMR (101 MHz, DMSO-d6) δ 167.60, 163.01, 159.51, 146.75, 141.51, 140.15, 137.10, 131.84,130.33, 127.52, 124.95, 121.03, 118.16, 115.24, 102.09, 100.85, 68.88, 66.38,63.79, 57.44, 55.99, 53.63, 51.55, 49.49, 46.93, 29.56, 23.20, 16.70. HRMS(ESI) m / z calcd. for C 33 H 43 N7O4 [M+H] + 602.3449, found: 602.3445.

[0264] Example 21

[0265] Synthesis of 6-(furan-3-yl)-2-(2-((7-(3-morpholinopropoxy)quinolin-4-yl)oxy)ethyl)pyridazine-3(2H)-one (B21):

[0266]

[0267] Starting with compounds 6e and 4b, the target product B21 was prepared following the same method as compound B1. It was a brown solid (43% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 5.3 Hz, 1H), 7.95 (d, J =9.1 Hz, 1H), 7.90 (d, J = 1.8 Hz, 1H), 7.88 (d, J = 9.8 Hz, 1H), 7.26 (d, J =2.5 Hz, 1H), 7.10- 7.06 (m, 2H), 7.03 (dd, J = 9.1, 2.5 Hz, 1H), 6.92 (d, J =5.3 Hz, 1H), 6.67 (dd, J = 3.5, 1.8 Hz, 1H), 4.64 (d, J = 4.8 Hz, 2H), 4.60(d, J = 4.8 Hz, 2H), 4.13 (t, J = 6.4 Hz, 2H), 3.58 (t, J = 4.6 Hz, 4H), 2.44(t, J = 7.2 Hz, 2H), 2.38 (brs, 4H), 1.92 (t, J = 6.9 Hz, 2H). 13 C NMR (101MHz, DMSO-d6) δ 167.80, 163.08, 159.38, 148.89, 146.72, 145.20, 141.30,137.47, 130.39, 130.35, 125.16, 120.95, 115.30, 112.63, 110.46, 102.13,100.61, 69.04, 66.34, 63.82, 53.71, 51.62, 49.88, 23.24. HRMS (ESI) m / zcalcd. for C 26 H 28 N4O5 [M+H] + 477.2132, found: 477.2130.

[0268] Example 22

[0269] Synthesis of 4-[1-(2-((7-(3-morpholinopropoxy)quinolin-4-yl)oxy)ethyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzyl nitrile (B22):

[0270]

[0271] Starting with compounds 6i and 4b, the target product B22 was prepared by referring to the preparation method of compound B1. It was a white solid (63% yield).1 H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 5.2 Hz, 1H), 8.13 (d, J =9.8 Hz, 1H), 8.01 (d, J = 8.5 Hz, 2H), 7.93 (d, J = 8.4 Hz, 2H), 7.84 (d, J =9.1 Hz, 1H), 7.24 (d, J = 2.5 Hz, 1H), 7.15 (d, J = 9.7 Hz, 1H), 6.99 (dd, J= 9.1, 2.5 Hz, 1H), 6.94 (d, J = 5.3 Hz, 1H), 4.69 (d, J = 4.5 Hz, 4H), 4.11(t, J = 6.4 Hz, 2H), 3.58 (t, J = 4.6 Hz, 4H), 2.44 (t, J = 7.2 Hz, 2H), 2.37(t, J = 4.6 Hz, 4H), 1.92 (p, J = 6.6 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ167.66, 163.02, 159.62, 146.72, 142.55, 141.36, 138.71, 133.19, 131.20,130.31, 126.78, 124.92, 120.99, 118.99, 115.23, 112.18, 102.19, 100.72,68.93, 66.38, 63.81, 53.69, 51.61, 50.15, 23.24. HRMS (ESI) m / z calcd. forC 29 H 29 N5O4 [M+H] + 512.2292, found: 512.2292.

[0272] Example 23

[0273] Synthesis of 2-(2-((7-(3-morpholinopropoxy)quinolin-4-yl)oxy)ethyl)-6-(3-(trifluoromethyl)phenyl)pyridazine-3(2H)-one (B23):

[0274]

[0275] Starting with compounds 6h and 4b, the target product B23 was prepared following the preparation method of compound B1. It was a white solid (52% yield).1 H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 5.3 Hz, 1H), 8.19- 8.11(m, 3H), 7.86 (d, J = 9.1 Hz, 1H), 7.81 (dd, J = 7.8, 1.9 Hz, 1H), 7.71 (t, J= 7.8 Hz, 1H), 7.25 (d, J = 2.5 Hz, 1H), 7.14 (d, J = 9.8 Hz, 1H), 6.95- 6.91(m, 2H), 4.73 - 4.65 (m, 4H), 4.11 (t, J = 6.4 Hz, 2H), 3.57 (t, J = 4.6 Hz,4H), 2.43 (t, J = 7.2 Hz, 2H), 2.36 (t, J = 4.7 Hz, 4H), 1.91 (p, J = 6.6 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 160.72, 160.06, 159.64, 152.32, 151.02,142.62, 135.70, 131.26, 130.49, 130.36, 130.22, 130.20 (q, J = 31.8 Hz), 126.25 (q, J = 3.5 Hz), 124.46 (q, J = 272.5 Hz), 122.99, 122.49 (q, J = 4.0Hz), 118.30, 115.51, 108.27, 100.53, 66.65, 66.41, 66.05, 55.25, 53.81,50.77, 26.15. HRMS (ESI) m / z calcd. for C 29 H 29 F3N4O4 [M+H] + 555.2214, found: 555.2215.

[0276] Example 24

[0277] Synthesis of 2-(2-((7-(3-morpholinopropoxy)quinolin-4-yl)oxy)ethyl)-6-(3-nitrophenyl)pyridazine-3(2H)-one (B24):

[0278]

[0279] Starting with compounds 6j and 4b, the target product B24 was prepared following the same method as compound B1. It was a pale yellow solid (59% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.61 - 8.58 (m, 2H), 8.29 - 8.24 (m,2H), 8.18 (d, J = 9.8 Hz, 1H), 7.86 (d, J = 9.1 Hz, 1H), 7.75 (t, J = 8.1 Hz,1H), 7.21 (d, J = 2.5 Hz, 1H), 7.15 (d, J = 9.8 Hz, 1H), 6.96- 6.92 (m, 2H),4.73- 4.66 (m, 4H), 4.09 (t, J = 6.4 Hz, 2H), 3.57 (t, J = 4.6 Hz, 4H), 2.43(t, J = 7.2 Hz, 2H), 2.37 (t, J = 4.6 Hz, 4H), 1.90 (p, J = 6.6 Hz, 2H). 13 CNMR (101 MHz, DMSO-d6) δ 160.69, 160.02, 159.61, 152.27, 151.00, 148.69,141.97, 136.19, 132.36, 131.13, 130.88, 130.26, HRMS (ESI) m / z calcd. for C 28 H 29 N5O6 [M+H] + 532.2191, found: 531.2190.

[0280] III. Biological Evaluation Experiment:

[0281] (1) In vitro enzyme activity assay of IRAK1:

[0282] 1) Prepare 2×ATP / substrate solution and 2×kinase solution using kinase reaction buffer.

[0283] 2) Use an Echo 655 to transfer 40 nL of the compound dilution to a 384-well detection plate; after centrifugation, add 2 μL of 2× kinase solution to the plate, centrifuge at 1000 rpm for 1 minute, and then incubate at 25°C for 10 minutes.

[0284] 3) Add 2 μL of 2× substrate and ATP solution to the 384-well plate, centrifuge at 1000 rpm for 1 minute, and then incubate at 25°C for 60 minutes.

[0285] 4) Add 4 μL of ADP-Glo ​​reagent to the 384-well plate, centrifuge at 1000 rpm for 1 minute, and then incubate at 25°C for 40 minutes.

[0286] 5) Add 8 μL of kinase detection reagent to the 384-well plate, centrifuge at 1000 rpm for 1 minute, and then incubate at 25°C for 40 minutes.

[0287] 6) Use the BMG instrument to read the chemiluminescence signal. Calculate the IC50 values ​​of each compound for enzyme activity using the GraphPad Prism analysis software. 50 value.

[0288] Table 1. Inhibitory activity of the compounds of the present invention against IRAK1 kinase

[0289]

[0290] The experimental results show that the compounds of this invention exhibit inhibitory activity against IRAK1 kinase, as illustrated in Table 1, where the IC50 values ​​of each compound are shown. 50 Classified according to the instructions:

[0291] “A” indicates IC 50 The measured value is less than or equal to 50 nM;

[0292] “B” indicates IC 50 The measured value is less than or equal to 500 nM and greater than 50 nM;

[0293] “C” represents IC 50 Measured values ​​are less than or equal to 5 μM and greater than 500 nM;

[0294] "-" indicates IC 50 Undetermined value.

Claims

1. A class of 2-(2-(quinolin-4-yloxy)ethyl)pyridazin-3(2H)-one compounds or pharmaceutically acceptable salts thereof, characterized in that, The compound has a structure as shown in general formula (I): wherein R1is selected from the group consisting of: , , , , , , , , , , ; R2is selected from ; R3 is hydrogen; R4is selected from , , , , ; R5is selected from , .

2. The 2-(2-(quinolin-4-yloxy)ethyl)pyridazin-3(2H)-one compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, when R1is or when R1is R2is selected from , R3 is hydrogen, R4is selected from , , , , ; when R1 is selected from the following groups: , , , , , , , , ， R2 is , R3 is hydrogen, R4 is , R5 is , .

3. The 2-(2-(quinolin-4-yloxy)ethyl)pyridazine-3(2H)-one compound or pharmaceutically acceptable salt thereof according to claim 1, characterized by, The pharmaceutically acceptable salt is an acid addition salt of the compound of general formula (I), wherein the acid used for salt formation is an inorganic acid selected from hydrochloric acid, sulfuric acid, phosphoric acid, or an organic acid selected from acetic acid, propionic acid, butyric acid, maleic acid, trichloroacetic acid, p-toluenesulfonic acid, malic acid, methanesulfonic acid, malonic acid, cinnamic acid, citric acid, fumaric acid, camphoric acid, digluconic acid, aspartic acid or tartaric acid.

4. A process for preparing the 2-(2-(quinolin-4-yloxy)ethyl)pyridazin-3(2H)-one compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized by, The preparation process is as follows: wherein R1, R2 and R3 are the same as defined in claim 1.

5. The preparation method according to claim 4, characterized in that, Compound A and compound B are dissolved in toluene for reaction.

6. A pharmaceutical composition comprising a compound of the formula: ###0005### or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier. The pharmaceutical composition comprises the compound or the pharmaceutically acceptable salt thereof according to any one of claims 1-3, and a pharmaceutically acceptable carrier.

7. Use of the 2-(2-(quinolin-4-yloxy)ethyl)pyridazin-3(2H)-one compound or the pharmaceutically acceptable salt thereof according to any one of claims 1-3 in the preparation of a medicament for preventing or treating a tumor selected from liver cancer, lung cancer, pancreatic cancer, gastric cancer, renal cancer, colon cancer, esophageal cancer, glioblastoma, leukemia, multiple myeloma, and a disease related to viral infection.

8. Use according to claim 7, characterized in that, The disease is an interleukin-1 receptor-associated kinase 1 related disease.

9. Use of the 2-(2-(quinolin-4-yloxy)ethyl)pyridazin-3(2H)-one compound or the pharmaceutically acceptable salt thereof according to any one of claims 1-3 in the preparation of an interleukin-1 receptor-associated kinase 1 inhibitor.

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