2-(2-(quinoline-4-yloxy) ethyl) pyridazine-3 (2H)-ketone compound as well as preparation method and application thereof

Abstract

The invention discloses a 2-(2-(quinoline-4-yloxy) ethyl) pyridazine-3 (2H)-ketone compound as well as a preparation method and application thereof. The structure of the compound is shown as a general formula (I). The invention also discloses an obvious inhibition effect of the compound on interleukin-1 receptor-associated kinase 1 (IRAK1), and the compound can inhibit 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 hematoma. The invention provides a new choice for tumor treatment.

Description

TECHNICAL FIELD

[0001] The present application relates to compounds and methods for their preparation and use, in particular, to a class of 2-(2-(quinolin-4-yloxy)ethyl)pyridazin-3(2H)-one compounds and methods for their preparation and use, belonging to the field of biological medicine. BACKGROUND

[0002] IRAK1 (Interleukin-1 receptor-associated kinase 1) is a key 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 response and inflammatory response. In the signaling pathway, IRAK1 forms a heterodimer with IRAK4, recruits to the IL-1R / TLR complex through the MyD88 adaptor protein, activates the downstream TRAF6 and TAK1 complex, and then triggers the NF-κB, MAPK (such as p38, ERK) pathway, inducing the expression of pro-inflammatory factors (such as TNF-α, IL-6). In addition, IRAK1 is also involved in the regulation of cell cycle, apoptosis and the formation of 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, systemic lupus erythematosus. In tumors, the role of IRAK1 is particularly prominent: 1) promoting tumor occurrence and development: studies have found that IRAK1 is highly expressed in colorectal cancer, esophageal squamous cell carcinoma and other tumors, and its high expression is significantly associated with poor prognosis of patients, 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 tumor microenvironment: IRAK1 can induce the secretion of inflammatory factors, recruit immunosuppressive cells (such as MDSCs, Tregs), and promote immune escape. At the same time, the NF-κB signal mediated by it can enhance angiogenesis and tumor invasion.

[0004] IRAK1 plays a key role in tumor occurrence, development and microenvironment formation by regulating innate immune and inflammatory signaling pathways. Targeted therapy against IRAK1 provides a new direction for tumor prevention and treatment, but further research is needed to understand its specific mechanisms and clinical translation potential. IRAK1 and IRAK4 belong to the key kinases of IL-1R / TLR signaling pathway, and their structures are similar. The existing inhibitors may lack specificity for IRAK4 or other related kinases (such as TAK1), leading to off-target effects, which may interfere with normal immune response or inflammation regulation, and cause unnecessary side effects. The main defects of existing IRAK1 inhibitors are lack of selectivity, drug resistance, side effects and individualized treatment needs, etc. Technical innovation and mechanism research are needed to break through these bottlenecks and promote the clinical translation of IRAK1 inhibitors in tumors and autoimmune diseases. SUMMARY

[0005] The present application aims to provide a kind of 2-(2-(quinoline-4-yloxy)ethyl) pyridazine-3 (2H)-ketone compound or its pharmaceutically acceptable salt, inhibit IRAK1 The kinase activity of strong anti-tumor activity is played, and it provides new compound for IRAK1 Abnormal activation of tumor drug development.The another purpose of the present application is to provide a kind of above-mentioned 2-(2-(quinoline-4-yloxy)ethyl) pyridazine-3 (2H)-ketone compound or its pharmaceutically acceptable salt preparation method;The another purpose of the present application is to provide a kind of above-mentioned 2-(2-(quinoline-4-yloxy)ethyl) pyridazine-3 (2H)-ketone compound or its pharmaceutically acceptable salt application.

[0006] Technical scheme: the present application provides a kind of compound and its pharmaceutically acceptable salt shown in general formula (I).

[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 annelated ring;

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

[0010] R3 is selected from hydrogen or methoxy;

[0011] R4 is selected from: .

[0012] Further, R1 is selected from C1-C3 alkyl, unsubstituted or substituted five-membered aromatic heterocycle, unsubstituted or substituted benzene ring, unsubstituted or substituted benzene 5-6-membered ring;

[0013] Five-membered aromatic heterocycle is imidazole ring or furan ring;Substituted five-membered aromatic heterocycle substituent is C1-C3 alkyl, piperidyl or N-BOC-piperidyl;

[0014] Substituted benzene ring substituent is-CN, -NO2 or-CF3;

[0015] Benzene 5-6-membered ring is pepper ring, 1,4-benzodioxane, benzopyrrole ring, benzimidazole ring;Substituted benzene 5-6-membered ring substituent is C1-C3 alkyl.

[0016] Further, R1 is selected from:

[0017] R2 is selected from hydrogen, methoxy, ;

[0018] R3is selected from hydrogen or methoxy;

[0019] R4is selected from:

[0020] R5is selected from , , .

[0021] Further,

[0022] when R1is or ,

[0023] R2is selected from hydrogen, methoxy, ,

[0024] R3is selected from hydrogen or methoxy,

[0025] R4is selected from:

[0026] when R1is selected from the group consisting of:

[0027] -CH3,

[0028] R2is ,

[0029] R3is hydrogen,

[0030] R4is ,

[0031] R5is , , .

[0032] Further, the compound is selected from any one of the compounds as shown in formula (B1) to formula (B24):

[0033]

[0034] Further, the pharmaceutically acceptable salt is an acid addition salt of the compound of general formula (I), wherein the acid used for salt formation includes inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and organic acids such as 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.

[0035] In another aspect, the present application provides a method for preparing the 2-(2-(quinolin-4-yloxy)ethyl)pyridazin-3(2H)-one compound or the pharmaceutically acceptable salt thereof, comprising the following steps:

[0036] A and B are dissolved in toluene, 0.3 equivalent of palladium acetate, 0.2 equivalent of S-phos and 1.2 equivalent of cesium carbonate are added. The reaction is replaced with argon for three times, and the reaction is carried out at 120°C overnight. After the reaction is completed, the target product is obtained by silica gel column purification.

[0037] In another aspect, the present application provides a pharmaceutical composition comprising the compound of general formula (I) or the pharmaceutically acceptable salt thereof or the isomer thereof, and a pharmaceutically acceptable carrier.

[0038] In another aspect, the present application provides the use of the 2-(2-(quinolin-4-yloxy)ethyl)pyridazin-3(2H)-one compound or the pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating cancer or tumor related diseases and viral infection related diseases, wherein the cancer or tumor related diseases include liver cancer, lung cancer, pancreatic cancer, gastric cancer, renal cancer, colon cancer, esophageal cancer, glioblastoma, leukemia, multiple myeloma and various solid tumors and hematological tumors.

[0039] In another aspect, the target point of the 2-(2-(quinolin-4-yloxy)ethyl)pyridazin-3(2H)-one compound or the pharmaceutically acceptable salt thereof for exerting anti-tumor activity is interleukin-1 receptor associated kinase 1 (IRAK1).

[0040] In another aspect, the present application provides the use of the 2-(2-(quinolin-4-yloxy)ethyl)pyridazin-3(2H)-one compound or the pharmaceutically acceptable salt thereof in the preparation of an interleukin-1 receptor associated kinase 1 inhibitor.

[0041] In the present application, the terms have the following meanings unless otherwise specified:

[0042] The term "heterocycle" includes saturated and unsaturated polynuclear nitrogen-containing heterocycles, including but not limited to thiophene, furan pyrazine, pyrrole, tetrahydropyrrole, imidazole, pyridine, pyrazine, etc.

[0043] The term "fused ring" includes aromatic fused rings and aliphatic fused rings, including but not limited to indole, indazole, benzo-heterocycle, benzo-aliphatic ring, etc.

[0044] The present application also discloses a preparation method of the compound of general formula (I).

[0045] Advantages:

[0046] IRAK1 gene abnormalities have been proved to be closely related to the occurrence and development of various tumors, and it mainly regulates the innate immune and inflammatory signaling pathways, and plays a key role in tumor occurrence, development and microenvironment formation. IRAK1 and IRAK4 belong to the key kinases of IL-1R / TLR signaling pathway, and the two have similar structures. At present, the targeting inhibitor of IRAK1 lacks specificity for IRAK4 or other related kinases (such as TAK1), resulting in off-target effects, which may interfere with normal immune response or inflammation regulation, and cause unnecessary side effects. Therefore, the IRAK1 inhibitor prepared by the present application can significantly inhibit the kinase activity of IRAK1, has broad-spectrum anti-tumor activity and has good selectivity for IRAK4. DETAILED DESCRIPTION

[0047] The present application will be further described below. The following examples are only used to more clearly illustrate the technical solutions of the present application, and cannot be used to limit the protection scope of the present application. In the following examples, the experimental methods are all conventional methods unless otherwise specified. In the following examples, the experimental materials are all purchased from conventional biochemical reagent stores unless otherwise specified. The present application will be described in detail below in combination with specific examples.

[0048] I. Synthesis of intermediates

[0049] Intermediate 1a:

[0050] 6-(4-methyl-1H-imidazol-1-yl)pyridazin-3(2H)-one (1a):

[0051] To a solution of 4-methyl-1H-imidazole (410 mg, 5.0 mmol) in 30 mL of N,N- dimethylformamide (DMF) was added sodium hydride (240 mg, 10.0 mmol) slowly at 0 °C. After stirring for 30 min, 3,6-dichloropyridazine (894 mg, 6.0 mmol) was added and the reaction was stirred at room temperature for 6 h. After the reaction was completed by TLC, the reaction mixture was poured into ice water and extracted with ethyl acetate (EA) three times. The organic phase was combined and concentrated under vacuum to remove the solvent to give the crude intermediate. Then, glacial acetic acid (20 mL) was added to the crude product and the mixture was heated and stirred at 120 °C overnight. After the reaction was completed, the system was cooled to room temperature and concentrated under vacuum to remove the solvent. The crude product was purified by flash column chromatography to give the target compound 1a. White solid (343 mg, yield 39%). 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).

[0052] Intermediate 1b:

[0053] 3-(6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (1b):

[0054] To a solution of 4-methyl-1H-imidazole (410 mg, 5.0 mmol) in 30 mL of N,N- dimethylformamide (DMF) was added sodium hydride (240 mg, 10.0 mmol) slowly at 0 °C. After stirring for 30 min, 3,6-dichloropyridazine (894 mg, 6.0 mmol) was added and the reaction was stirred at room temperature for 6 h. After the reaction was completed by TLC, the reaction mixture was poured into ice water and extracted with ethyl acetate (EA) three times. The organic phase was combined and concentrated under vacuum to remove the solvent to give the crude intermediate. Then, glacial acetic acid (20 mL) was added to the crude product and the mixture was heated and stirred at 120 °C overnight. After the reaction was completed, the system was cooled to room temperature and concentrated under vacuum to remove the solvent. The crude product was purified by flash column chromatography to give the target compound 1a. White solid (343 mg, yield 39%). 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).

[0055] Intermediate 2a:

[0056] 2-(2-hydroxyethyl)-6-(4-methyl-1H-imidazol-1-yl)pyridaz-3(2H)-one (2a):

[0057] 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 into a reaction vial. The mixture was stirred at 50 °C for 4 h, then poured into water and extracted with ethyl acetate. The organic phases were combined and concentrated. To the residue was added tetrabutylammonium fluoride (TBAF, 2.0 mL, 1 M in THF) and a mixture of THF / H2O (9 mL, 2:1) and stirred at room temperature for 2 h. Compound 2a was obtained after purification by flash column chromatography 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).

[0058] Intermediate 2b:

[0059] 3-(1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (2b):

[0060] Compound 2b was obtained by referring to the general preparation method of compound 2a, using compound 1b and (2-bromoethoxy)-tert-butyldimethylsilane as raw materials. Gray solid (yield 52%). 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).

[0061] Intermediate 3:

[0062] 7-(3-bromopropoxy)-4-chloroquinoline (3):

[0063] 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 into a reaction flask. After stirring at 50 °C for 4 h, the reaction solution was filtered through celite, and the crude product was purified by flash column chromatography to give compound 3. Brown solid (6.4 g, yield 71%). ESI-MS m / z: 300.5 [M+H] + .

[0064] Intermediate 4a:

[0065] 3-((4-chloroquinolin-7-yl)oxy)-N,N-dimethylpropan-1-amine (4a):

[0066] 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 into a reaction flask. After stirring at 60 °C for 6 h, the reaction solution was filtered through celite, and the crude product was purified by flash column chromatography to give compound 4a. Light yellow solid (171 mg, yield 65%). ESI-MS m / z: 265.2 [M+H] + .

[0067] Intermediate 4b:

[0068] 4-(3-((4-chloroquinolin-7-yl)oxy)propyl)morpholine (4b):

[0069] The target product 4b was prepared from compound 3 and morpholine according to the general preparation method of compound 4a. Grey solid (yield 85%). ESI-MS m / z: 307.4 [M+H] + .

[0070] Intermediate 4c:

[0071] 4-chloro-7-(3-(4-methylpiperazin-1-yl)propoxy)quinoline (4c):

[0072] The target product 4c was prepared from compound 3 and N-methylpiperazine according to the general preparation method of compound 4a. Brown solid (yield 76%). ESI-MS m / z: 320.2 [M+H] + .

[0073] Intermediate 4d:

[0074] 4-chloro-7-(3-(4-isopropylpiperazin-1-yl)propoxy)quinoline (4d):

[0075] The target product 4d was prepared from compound 3 and N-isopropylpiperazine according to the general preparation method of compound 4a. Brown solid (yield 68%). ESI-MS m / z: 348.4 [M+H] + .

[0076] Intermediate 4e:

[0077] 4-(3-((4-chloroquinolin-7-yl)oxy)propyl)piperazine-1-carboxylic acid tert-butyl ester (4e):

[0078] The target product 4e was prepared from compound 3 and 1-tert-butoxycarbonylpiperazine according to the general preparation method of compound 4a. Grey solid (yield 80%). ESI-MS m / z: 406.4 [M+H] + .

[0079] Intermediate 5a:

[0080] 6-(benzo[d][l,3]dioxol-5-yl)pyridazin-3(2H)-one (5a):

[0081] To a mixture of 30 mL of 1,4-dioxane / water (4:1) was added 6-chloropyridazin-3(2H)-one (652 mg, 5.0 mmol), 3,4-methylenedioxybenzeneboronic acid (996 mg, 6.0 mmol), cesium carbonate (3.26 g, 10.0 mmol) and dichlorobis(diphenylphosphino)palladium (183 mg, 0.25 mmol) sequentially. The mixture was heated to reflux under argon overnight. After the reaction was completed, the reaction mixture was filtered through a short plug of celite and the crude product was purified by flash column chromatography to give compound 5a. 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).

[0082] Intermediate 5b:

[0083] 6-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)pyridazin-3(2H)-one (5b):

[0084] The target product 5b was prepared according to the procedure described for compound 5a using 6-chloropyridazin-3(2H)-one and l,4-benzodioxane-6-boronic acid as starting materials. 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, 3.7 Hz, 2H), 4.29 (s, 4H).

[0085] Intermediate 5c:

[0086] 6-(l-methyl-lH-indol-5-yl)pyridazine-3(2H)-one (5c):

[0087] The title compound 5c was prepared from 6-chloropyridazin-3(2H)-one and l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indole following the procedure described for the preparation of compound 5a. White solid (yield 70%). 1 HNMR (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).

[0088] Intermediate 5d:

[0089] 6-(l-methyl-lH-indazol-5-yl)pyridazin-3(2H)-one (5d):

[0090] The title compound 5d was prepared from 6-chloropyridazin-3(2H)-one and l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazole following the procedure described for the preparation of compound 5a. White solid (yield 73%). 1 HNMR (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, 0.9 Hz,1H), 7.00 (d, J = 9.9 Hz, 1H), 4.08 (s, 3H).

[0091] Intermediate 5e:

[0092] 6-(furan-3-yl)pyridazin-3(2H)-one (5e):

[0093] The title compound 5e was prepared according to the procedure described for compound 5a using 6-chloropyridazin-3(2H)-one and 3-furanboronic acid as starting materials. Grey 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).

[0094] Intermediate 5f:

[0095] 6-(1-isopropyl-1H-pyrazol-4-yl)pyridazin-3(2H)-one (5f):

[0096] The title compound 5f was prepared according to the procedure described for compound 5a using 6-chloropyridazin-3(2H)-one and 1-isopropyl-1H-pyrazol-4-boronic acid as starting materials. White solid (yield 30%) 1 H 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).

[0097] Intermediate 5g:

[0098] tert-butyl 4-[4-(6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (5g):

[0099] The title compound 5g was prepared according to the procedure described for compound 5a using 6-chloropyridazin-3(2H)-one and tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate as starting materials. Grey solid (yield 45%). 1H 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).

[0100] Intermediate 5h:

[0101] 6-[3-(trifluoromethyl)phenyl]pyridazin-3(2H)-one (5h):

[0102] The title compound 5h was prepared from 6-chloropyridazin-3(2H)-one and 3- trifluoromethylbenzeneboronic acid according to the procedure described for compound 5a. White solid (yield 66%). 1 H 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).

[0103] Intermediate 5i:

[0104] 4-(6-oxo-l,6-dihydropyridazin-3-yl)benzonitrile (5i):

[0105] The title compound 5i was prepared from 6-chloropyridazin-3(2H)-one and 4- cyanobenzeneboronic acid according to the procedure described for compound 5a. 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).

[0106] Intermediate 5j:

[0107] 6-(3-nitrophenyl)pyridazin-3(2H)-one (5j):

[0108] The title compound 5j was prepared according to the procedure described for compound 5a using 6-chloropyridazin-3(2H)-one and 3-nitrophenylboronic acid as starting materials. 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).

[0109] Intermediate 6a:

[0110] 6-(benzo[d][l,3]dioxol-5-yl)-2-(2-hydroxyethyl)pyridazin-3(2H)-one (6a):

[0111] The title compound 6a was prepared according to the procedure described for compound 2a using compound 5a and (2-bromoethoxy)-tert-butyldimethylsilane as starting materials. Green oil (yield 62%) 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).

[0112] Intermediate 6b:

[0113] 6-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-2-(2-hydroxyethyl)pyridazin-3(2H)-one (6b):

[0114] The title compound 6b was prepared according to the procedure described for compound 2a using compound 5b and (2-bromoethoxy)-tert-butyldimethylsilane as starting materials. Green oil (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).

[0115] Intermediate 6c:

[0116] 2-(2-Hydroxyethyl)-6-(l-methyl-lH-indol-5-yl)pyridazin-3(2H)-one (6c):

[0117] The title compound 6c was prepared according to the procedure described for compound 2a using compound 5c and (2-bromoethoxy)-tert-butyldimethylsilane as starting materials. Grey solid (yield 85%). 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).

[0118] Intermediate 6d:

[0119] 5-(4-Cyanophenyl)furan-2-carbaldehyde (6d):

[0120] The title compound 6d was prepared from compound 5d and (2-bromoethoxy)-tert- butyldimethylsilane following the procedure described for compound 2a. Gray solid (yield 72%). 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).

[0121] Intermediate 6e:

[0122] 6-(Furan-3-yl)-2-(2-hydroxyethyl)pyridazin-3(2H)-one (6e):

[0123] The title compound 6e was prepared from compound 5e and (2-bromoethoxy)-tert- butyldimethylsilane following the procedure described for compound 2a. White solid (yield 67%). 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).

[0124] Intermediate 6f:

[0125] 2-(2-Hydroxyethyl)-6-(l-isopropyl-lH-pyrazol-4-yl)pyridazin-3(2H)-one (6f):

[0126] The title compound 6f was prepared according to the procedure described for compound 2a using compound 5f and (2-bromoethoxy)-tert-butyldimethylsilane as starting materials. Brown solid (yield 61%). 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).

[0127] Intermediate 6g:

[0128] Tert-butyl 4-[4-(1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrazol-1- yl]piperidine-1-carboxylate (6g):

[0129] The title compound 6g was prepared according to the procedure described for compound 2a using compound 5g and (2-bromoethoxy)-tert-butyldimethylsilane as starting materials. Grey solid (yield 70%). 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).

[0130] Intermediate 6h:

[0131] 2-(2-Hydroxyethyl)-6-[3-(trifluoromethyl)phenyl]pyridazin-3(2H)-one (6h):

[0132] The title compound 6h was prepared according to the procedure described for compound 2a using compound 5h and (2-bromoethoxy)-tert-butyldimethylsilane as starting materials. Grey 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 = 5.9 Hz, 2H), 3.80 (t, J = 6.1 Hz, 2H).

[0133] Intermediate 6i:

[0134] 4-[1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzonitrile (6i):

[0135] The title compound 6i was prepared according to the procedure described for compound 2a using compound 5i and (2-bromoethoxy)-tert-butyldimethylsilane as starting materials. Grey 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).

[0136] Intermediate 6j:

[0137] 2-(2-hydroxyethyl)-6-(3-nitrophenyl)pyridazin-3(2H)-one (6j):

[0138] The title compound 6j was prepared according to the procedure described for compound 2a using compound 5j and (2-bromoethoxy)-tert-butyldimethylsilane as starting materials. Grey solid (66% yield). 1H 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).

[0139] Intermediate 6k:

[0140] 2-(2-Hydroxyethyl)-6-methylpyridazin-3(2H)-one (6k):

[0141] The target product 6k was prepared by referring to the preparation method of compound 2a, with 6-methylpyridazin-3(2H)-one and (2-bromoethoxy)-tert-butyldimethylsilane as starting materials. Grey solid (yield 60%). 1 H NMR (400 MHz, DMSO-d6) δ 7.31 (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).

[0142] Intermediate 7:

[0143] 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):

[0144] The target product 7 was prepared by referring to the preparation method of compound B1, with compound 6g and 4b as starting materials. White solid (yield 55%). ESI-MS m / z: 660.4 [M+H] + .

[0145] II. Synthesis of final product

[0146] Example 1

[0147] 6-(4-methyl-lH-imidazol-l-yl)-2-(2-(quinolin-4-yloxy)ethyl)pyridaz-3(2H)-one (B1) was synthesized:

[0148] To a solution of 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) in 30 mL of toluene was added. The mixture was heated at 90 °C under argon for 16 h. After the reaction was completed, the reaction mixture was filtered through a short plug of celite and the crude product was purified by flash column chromatography to give compound B1 as a white solid (yield 82%). 1 H 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 = 7.6 Hz, 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.

[0149] Example 2

[0150] 2-(2-((6,7-dimethoxyquinolin-4-yl)oxy)ethyl)-6-(4-methyl-lH-imidazol-l-yl)pyridaz-3(2H)-one (B2) was synthesized:

[0151] The target product B2 was prepared according to the preparation method of compound B1 using compound 2a and 4-chloro-6,7-dimethoxyquinoline as starting materials. White solid (yield 64%). 1 H 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.

[0152] Example 3

[0153] Synthesis of 2-(2-((7-methoxyquinolin-4-yl)oxy)ethyl)-6-(4-methyl-1H-imidazol-1-yl)pyridaz-3(2H)-one (B3):

[0154] 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 added into 30 mL of toluene successively. The mixture was heated at 90 °C for 16 hours under argon protection. After the reaction was completed, the reaction mixture was filtered through a short column of celite, and the crude product was purified by flash column chromatography to obtain compound B3. White solid (300 mg, yield 80%).1 H NMR (400 MHz, 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). 1 H NMR (400 MHz, 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.

[0155] Example 4

[0156] 3-[1-(2-((6,7-dimethoxyquinolin-4-yl)oxy)ethyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzonitrile (B4) was synthesized:

[0157] The target product B4 was prepared according to the preparation method of compound Bl, using compound 2a and 4a as starting materials. 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.

[0158] Example 5

[0159] 2-(2-((7-(3-(4-Isopropylpiperazin-1-yl)propoxy)quinolin-4-yl)oxy)ethyl)-6-(4- methyl-1H-imidazol-1-yl)pyridazin-3(2H)-one (B5)

[0160] The target product B5 was prepared according to the preparation method of compound B1, taking compound 2a and 4d as starting materials. 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 (m, 10H), 2.81 (d, J = 7.4 Hz, 2H), 2.17 (s, 3H), 2.08 (q, J = 7.0 Hz, 2H), 1.24 (d, J = 6.5 Hz, 6H), 1.20-1.16 (m, 1H). HRMS (ESI) m / z calcd. for C 29 H 37 N7O3 [M+H] + 532.3031, found: 532.3029.

[0161] Example 6

[0162] 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)

[0163] The target product B6 was prepared according to the preparation method of compound B1, taking compound 2a and 4c as starting materials. 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.

[0164] Example 7

[0165] Synthesis of 6-(4-methyl-lH-imidazol-l-yl)-2-(2-((7-(3-(piperazin-l-yl)propoxy)quinolin-4-yl)oxy)ethyl)pyridazin-3(2H)-one (B7):

[0166] The target product B7M was prepared by using compound 2a and 4e as starting materials, and referring to the preparation method of compound B1. White solid (yield 53%). 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).

[0167] Compound B7M (295 mg, 0.5 mmol) was added to 15 mL 2M EA-HCl solution and reacted at room temperature for 3 hours. After removing the solvent, white solid B7 (232 mg, yield 95%) 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.

[0168] Example 8

[0169] Synthesis of 6-(4-methyl-lH-imidazol-l-yl)-2-(2-((7-(3-morpholinopropoxy)quinolin-4- yl)oxy)ethyl)pyridazin-3(2H)-one (B8):

[0170] The target product B8 was prepared by using compound 2a and 4b as starting materials, according to the preparation method of compound Bl. White solid (yield 55%). 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 Hz, 2H), 4.15 (t, J = 6.3 Hz, 2H), 3.75 (s, 4H), 2.68 – 2.43(m, 6H), 2.28 (d, J = 1.1 Hz, 3H), 2.07 – 2.00 (m, 2H). HRMS (ESI) m / z calcd.for C 26H 30 N6O4 [M+H] + 491.2401, found: 491.2403.

[0171] Example 9

[0172] Synthesis of 3-[1-(2-((7-methoxyquinolin-4-yl)oxy)ethyl)-6-oxo-1,6-dihydropyridazin-3- yl]benzonitrile (B9):

[0173] The target product B9 was prepared according to the preparation method of compound Bl, using compound 2b and 4-chloro-7-methoxyquinoline as starting materials. White solid (yield 60%). 1 H NMR (400 MHz, Chloroform-d) δ 8.64 (d, J = 5.4 Hz, 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 = 5.2 Hz, 2H), 4.67 (t, J = 5.3 Hz, 2H), 3.92 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 167.62, 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.

[0174] Example 10

[0175] Synthesis of 3-[1-(2-((6,7-dimethoxyquinolin-4-yl)oxy)ethyl)-6-oxo-1,6- dihydropyridazin-3-yl]benzonitrile (B10):

[0176] The target product B10 was prepared according to the procedure for the preparation of compound Bl, using compound 2b and 4-chloro-6,7-dimethoxyquinoline as starting materials. White solid (yield 61%). 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 5.2 Hz, 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.

[0177] Example 11

[0178] Synthesis of 3-[1-(2-((7-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-4- yl)oxy)ethyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzonitrile (B11):

[0179] The title compound B11 was prepared according to the procedure described for the preparation of compound Bl using compound 2b and 4c as starting materials. Off-white solid (yield 50%). 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.

[0180] Example 12

[0181] Synthesis of 3-[1-(2-((7-(3-morpholinopropoxy)quinolin-4-yl)oxy)ethyl)-6-oxo-1,6- dihydro pyridazin-3-yl]benzonitrile (B12):

[0182] The title compound B12 was prepared according to the procedure described for the preparation of compound Bl using compound 2b and 4b as starting materials. Off-white solid (yield 80%). 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, 129.63, 124.94, 120.96, 117.40,114.51, 112.51, 102.19, 100.72, 68.96, 66.36, 63.81, 53.70, 51.61, 50.00,23.24. HRMS (ESI) m / z calcd. for C 29 H 29 N5O4 [M+H] + 512.2292, found: 512.2291.

[0183] Example 13

[0184] Synthesis of 6-methyl-2-(2-((7-(3-morpholinopropoxy)quinolin-4-yl)oxy)ethyl)pyridaz- in-3(2H)-one (B13):

[0185] The target product B13 was prepared according to the procedure for the preparation of compound B1 using compound 6k and 4b as starting materials. White solid (yield 70%). 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.

[0186] Example 14

[0187] Synthesis of 6-(benzo[d][l,3]dioxol-5-yl)-2-(2-((7-(3-morpholinopropoxy)quinolin-4- yl)oxy)ethyl)pyridazin-3(2H)-one (B14):

[0188] The target product B14 was prepared according to the procedure for the preparation of compound B1 using compound 6a and 4b as starting materials. Grey solid (yield 54%). 1H 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, 120.62, 118.43, 115.55, 108.88, 108.31, 106.26, 101.99, 100.55, 66.63, 66.45, 66.15, 55.26, 53.80, 50.28, 26.15. HRMS (ESI) m / z calcd. for C 29 H 30 N4O6 [M+H] + 531.2238, found: 531.2238.

[0189] Example 15

[0190] Synthesis of 6-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-2-(2-((7-(3-morpholinopropoxy)quinolin-4-yl)oxy)ethyl)pyridazin-3(2H)-one (B15):

[0191] The target product B15 was prepared according to the preparation method of compound Bl, using compound 6b and 4b as starting materials. Gray solid (yield 57%). 1H 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.

[0192] Example 16

[0193] Synthesis of 6-(l-methyl-lH-indol-5-yl)-2-(2-((7-(3-morpholinopropoxy)quinolin-4- yl)oxy)ethyl)pyridazin-3(2H)-one (B16):

[0194] The target product B16 was prepared according to the preparation method of compound Bl, using compound 6c and 4b as starting materials. Gray solid (yield 46%). 1H 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.

[0195] Example 17

[0196] Synthesis of 6-(l-methyl-lH-indazol-5-yl)-2-(2-((7-(3-morpholinopropoxy)quinolin-4-yl)oxy)ethyl)pyridazin-3(2H)-one (B17):

[0197] The title compound B17 was prepared using the similar procedure as described for compound Bl starting from compound 6d and 4b. The product was obtained as a gray solid (40% yield). 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.

[0198] Example 18

[0199] Synthesis of 6-(l-isopropyl-lH-pyrazol-4-yl)-2-(2-((7-(3-morpholinopropoxy)quinolin-4-yl)oxy)ethyl)pyridazin-3(2H)-one (B18):

[0200] The title compound B18 was prepared using the similar procedure as described for compound B1 starting from compound 6f and 4b. 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.

[0201] Example 19

[0202] 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):

[0203] Compound 7 (394 mg, 0.6 mmol) was added to 15 mL of 2M hydrochloric acid in ethyl acetate solution and reacted at room temperature for 3 hours. After removing the solvent, a gray solid B19 (265 mg, yield 95%) was obtained. 1 H NMR (400 MHz, DMSO-d6) δ 8.61 (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.

[0204] Example 20

[0205] 2-(2-((7-(3-morpholinopropoxy)quinolin-4-yl)oxy)ethyl)-6-(1-(isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridazin-3(2H)-one (B20)

[0206] Compound B19 (200 mg, 0.36 mmol), potassium carbonate (248 mg, 1.8 mmol) and 2-iodopropane (74 mg, 0.43 mmol) were added into 30 mL acetonitrile. The mixture was heated at 80 °C under argon protection for 12 hours. After the reaction was completed, the reaction mixture was filtered through a short column of celite and the crude product was purified by flash column chromatography to give compound B20. Off-white solid (yield 152 mg, yield 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.

[0207] Example 21

[0208] Synthesis of 6-(furan-3-yl)-2-(2-((7-(3-morpholinopropoxy)quinolin-4-yl)oxy)ethyl)pyridaz- in-3(2H)-one (B21):

[0209] The target product B21 was prepared according to the procedure for preparing compound Bl, using compound 6e and 4b as starting materials. Brown solid (yield 43%). 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 / z calcd. for C 26 H 28 N4O5 [M+H] + 477.2132, found: 477.2130.

[0210] Example 22

[0211] Synthesis of 4-[1-(2-((7-(3-morpholinopropoxy)quinolin-4-yl)oxy)ethyl)-6-oxo-1,6- dihydro pyridazin-3-yl]benzonitrile (B22):

[0212] The target product B22 was prepared according to the procedure for the preparation of compound Bl using compound 6i and 4b as starting materials. White solid (yield 63%). 1H 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) δ 167.66, 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. for C 29 H 29 N5O4 [M+H] + 512.2292, found: 512.2292.

[0213] Example 23

[0214] Synthesis of 2-(2-((7-(3-morpholinopropoxy)quinolin-4-yl)oxy)ethyl)-6-(3- (trifluoromethyl)phenyl)pyridazin-3(2H)-one (B23):

[0215] The target product B23 was prepared according to the procedure for the preparation of compound Bl using compound 6h and 4b as starting materials. White solid (yield 52%). 1H 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.

[0216] Example 24

[0217] Synthesis of 2-(2-((7-(3-morpholinopropoxy)quinolin-4-yl)oxy)ethyl)-6-(3- nitrophenyl)pyridazin-3(2H)-one (B24):

[0218] The target product B24 was prepared by using compound 6j and 4b as starting materials, and referring to the preparation method of compound B1. Light yellow solid (yield 59%). 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, 124.21, 123.02, 120.45,118.36, 115.51, 108.18, 100.55, 66.65, 66.41, 66.04, 55.26, 53.80, 50.83,26.15. HRMS (ESI) m / z calcd. for C 28 H 29 N5O6 [M+H] + 532.2191, found: 531.2190.

[0219] Three, biological evaluation experiment:

[0220] (1) IRAK1 in vitro enzyme activity determination:

[0221] 1) Prepare 2x ATP / substrate solution and 2x kinase solution using kinase reaction buffer.

[0222] 2) ) 40 nL of compound dilution was transferred to a 384-well assay plate using Echo 655; after centrifugation, 2 μL of 2x kinase solution was added to the plate, centrifuged at 1000 rpm for 1 min, and then incubated at 25°C for 10 min.

[0223] 3) ) 2 μL of 2x substrate and ATP solution was added to the 384-well assay plate, centrifuged at 1000 rpm for 1 min, and then incubated at 25°C for 60 min.

[0224] 4) ) 4 μL of ADP-Glo reagent was added to the 384-well assay plate, centrifuged at 1000 rpm for 1 min, and then incubated at 25°C for 40 min.

[0225] 5) ) 8 μL of kinase detection reagent was added to the 384-well assay plate, centrifuged at 1000 rpm for 1 min, and then incubated at 25°C for 40 min.

[0226] 6) Chemiluminescence signal was read using a BMG instrument. The IC 50 values of each compound on enzyme activity were calculated using analysis software GraphPad Prism.

[0227] Table 1, Inhibitory activity of the compounds of the present application on IRAK1 kinase

[0228]

[0229] From the experimental results, it can be seen that the example compounds of the present application have inhibitory activity on IRAK1 kinase, and the results are shown in Table 1, wherein the IC 50 According to the instructions, classify:

[0230] "A" indicates that the IC 50 determination value is less than or equal to 50 nM;

[0231] "B" indicates that the IC 50 determination value is less than or equal to 500 nM and greater than 50 nM;

[0232] "C" indicates that the IC 50 determination value is less than or equal to 5 μM and greater than 500 nM;

[0233] "-" indicates that the IC 50 determination value is not measured.

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 structure is shown in general formula (I): wherein R1is selected from the group consisting of C1-C3 alkyl, unsubstituted or substituted five-membered aromatic heterocycle, unsubstituted or substituted phenyl ring, unsubstituted or substituted benzo 5-6 membered ring; The five-membered aromatic heterocycle is an imidazole ring or a furan ring; the substituent in the substituted five-membered aromatic heterocycle is C1-C3 alkyl, piperidyl or N-BOC-piperidyl; The substituent in the substituted benzene ring is -CN, -NO2 or -CF3; The benzene 5-6-membered ring is a piperonyl ring, a 1,4-benzodioxane ring, a benzopyrrole ring or a benzimidazole ring; the substituent in the substituted benzene 5-6-membered ring is C1-C3 alkyl; R2is selected from hydrogen, methoxy, ; R3 is selected from hydrogen or methoxy; R4is selected from , , , , , ; when R1is or when R1is R2is selected from hydrogen, methoxy, , R3 is selected from hydrogen or methoxy, R4is selected from , , , , , ; when R1 is selected from the following groups: -CH3, , , , , , , , , , R2 is , R3 is hydrogen, R4 is , R5 is , or .

2. 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 or an organic acid, the inorganic acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, and the organic acid is 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.

3. 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: 。 4. The production method according to claim 3, characterized by, Compound A and compound B are dissolved in toluene for reaction.

5. A pharmaceutical composition comprising a compound of the formula: ###00006### or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier. A pharmaceutical composition comprising a compound of any one of claims 1-2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

6. Use of a 2-(2-(quinolin-4-yloxy)ethyl)pyridazin-3(2H)-one compound of any one of claims 1-2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention or treatment of a tumor selected from the group consisting of liver cancer, lung cancer, pancreatic cancer, gastric cancer, renal cancer, colon cancer, esophageal cancer, glioblastoma, leukemia, multiple myeloma, and a disease associated with viral infection.

7. Use according to claim 6, characterized in that, The disease is an interleukin-1 receptor-associated kinase 1 related disease.

8. Use of a 2-(2-(quinolin-4-yloxy)ethyl)pyridazin-3(2H)-one compound of any one of claims 1-2, or a pharmaceutically acceptable salt thereof, for the manufacture of an interleukin-1 receptor-associated kinase 1 inhibitor.

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