Imidazolo[1,2-b]pyridazine compounds, their preparation methods, and applications as PI3K inhibitors

Abstract

This invention discloses a class of 3-heterocyclic-6-arylbenzenesulfonamide-substituted imidazo[1,2-b]pyridazine compounds, which are compounds conforming to general formula (I) or their pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, or prodrugs. Furthermore, the inventors have established methods for preparing the corresponding compounds. These compounds are characterized by novel structures and simple preparation. Experimental studies have shown that the imidazo[1,2-b]pyridazine compounds of this invention exhibit significant inhibitory activity against various tumor cell types, including A549, SGC7901, and HeLa, at the cellular level. They hold promise for development into novel, highly effective, and economically and easily prepared PI3K inhibitors, with broad market application and development prospects.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, and particularly relates to imidazo[1,2-b]pyridazine compounds, their preparation methods, and the application of PI3K inhibitors. Background Technology

[0002] PI3K (phosphatidylinositol 3-kinase) is a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival, and intracellular transport. It is part of the PI3K / Akt / mTOR signaling pathway, which is crucial for regulating the cell cycle. PI3K activates phosphorylation and activates Akt, localizing it to the plasma membrane. Akt can have many downstream effects, such as activating cyclic-AMP response binding protein (CREB), inhibiting the tumor suppressor gene p27, and localizing FOXO (Forkhead Box O) in the cytoplasm.

[0003] Studies have shown that the PI3K pathway is mutated or amplified in various cancers, including breast cancer, gastric cancer, ovarian cancer, colorectal cancer, prostate cancer, glioblastoma, and endometrial cancer. Therefore, elevated PI3K signaling is considered a hallmark of cancer. Many PI3K pathway-targeted therapies have been tested in clinical trials for cancer treatment. Furthermore, diseases or conditions associated with PI3K signaling include metabolic disorders, neurodegenerative diseases, and inflammatory diseases.

[0004] Drugs targeting the PI3K protein are called PI3K inhibitors. Although progress has been made in the development of therapeutic PI3K inhibitors for cancer and immune dysregulation, many problems remain to be solved: some PI3K inhibitors exhibit drug resistance, fail to significantly improve patient survival with long-term use, or show serious toxicity. Nevertheless, due to the hallmark role of the PI3K pathway in cancer, the development of new PI3K inhibitors remains necessary. Therefore, the development of novel PI3K inhibitors is of great significance for improving efficacy, overcoming drug resistance, and expanding indications. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to provide imidazo[1,2-b]pyridazine compounds with novel structures, simple preparation and good effects, as well as their preparation methods and applications as PI3K inhibitors.

[0006] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0007] Imidazolo[1,2-b]pyridazine compounds are compounds that conform to general formula (I) or pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates or prodrugs thereof;

[0008]

[0009] In general formula (Ⅰ), A is a substituted phenyl group and B is a heterocycle;

[0010] The substituted phenyl group is one of the following substituents:

[0011]

[0012] The heterocycle is one of the following substituents:

[0013]

[0014] The above-mentioned imidazo[1,2-b]pyridazine compounds are one of the following compounds LYB1-LYB30.

[0015]

[0016]

[0017] Pharmaceutically acceptable salts include salts formed by compounds of general formula (I) with acids and metal ions; the acids are galactosic acid, D-glucuronic acid, glycerophosphate, hippuric acid, hydroxyethylsulfonic acid, lactobionic acid, maleic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, neopentanoic acid, terephthalic acid, thiocyanate, cholic acid, n-dodecyl sulfate, benzenesulfonic acid, citric acid, D-glucose, glycolic acid, lactic acid, malic acid, malonic acid, mandelic acid, phosphoric acid, propionic acid, hydrochloric acid, sulfuric acid, tartaric acid, succinic acid, formic acid, hydroiodic acid, and hydrobromide. Acids, methanesulfonic acid, nicotinic acid, nitric acid, orotic acid, oxalic acid, picric acid, L-pyroglutamic acid, saccharinic acid, salicylic acid, gentian acid, p-toluenesulfonic acid, valeric acid, palmitic acid, sebacic acid, stearic acid, lauric acid, acetic acid, adipic acid, carbonic acid, 4-benzenesulfonic acid, ethanedisulfonic acid, ethylsuccinic acid, fumaric acid, 3-hydroxynaphthalene-2-carboxylic acid, 1-hydroxynaphthalene-2-carboxylic acid, oleic acid, undecenoic acid, ascorbic acid, camphoric acid, camphorsulfonic acid, dichloroacetic acid, ethanesulfonic acid; metal ions are sodium ion, potassium ion, and calcium ion.

[0018] The application of the above-mentioned imidazo[1,2-b]pyridazine compounds in the preparation of PI3K inhibitors.

[0019] The application of the above-mentioned imidazo[1,2-b]pyridazine compounds in the preparation of drugs for treating PI3K-related diseases.

[0020] PI3K-related diseases include malignant tumors, diabetes, cardiovascular diseases, and neurological diseases; malignant tumors include lung adenocarcinoma (A549), gastric adenocarcinoma (SGC7901), cervical cancer (HeLa), liver cancer, bile duct cancer, colon cancer, and breast cancer.

[0021] The preparation of the above-mentioned imidazo[1,2-b]pyridazine compounds is carried out according to the following reaction route:

[0022]

[0023] The preparation method of the above-mentioned imidazo[1,2-b]pyridazine compounds includes the following steps:

[0024] <1> Compound (III) was prepared by reacting compound (II) with 4-bromoaniline;

[0025] <2> Compound (IV) was prepared by reacting compound (III) with pinacol diborate under anhydrous and oxygen-free conditions via the Miyaura reaction.

[0026] <3> Compound (VI) was prepared by reacting compound (V) with bromoacetaldehyde diethanol condensation;

[0027] <4> Compound (VII) was prepared by reacting compound (VI) with N-bromosuccinimide (NBS);

[0028] <5> Compound (VIII) was prepared by a Suzuki coupling reaction of compound (VII) with 1-methylpyrazole-4-boronic acid pinacol ester, 4-pyridineboronic acid pinacol ester, or 5-methylfuran-2-boronic acid pinacol ester under anaerobic conditions.

[0029] <6> Compound (I) was prepared by a Suzuki coupling reaction between compound (IV) and compound (VIII) under anaerobic conditions.

[0030] step <1> In this reaction, the acid-binding agent is pyridine, the reaction solvent is pyridine, tetrahydrofuran, and water, and the reaction temperature is room temperature.

[0031] step <2> In the reaction, the base is potassium acetate, the catalyst is [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride, the solvent is 1,4-dioxane, and the reaction temperature is 80℃~90℃.

[0032] step <3> In this reaction, the acid is hydrogen bromide, the solvent is 90% ethanol, and the reaction temperature is 100℃~110℃.

[0033] step <4> In this reaction, the acid is trifluoroacetic acid, the reaction solvent is chloroform and dichloromethane, and the reaction temperature is room temperature.

[0034] step <5> In the reaction, the base is potassium carbonate, the catalyst is tetra(triphenylphosphine)palladium, the reaction solvent is 1,4-dioxane and water, and the reaction temperature is 90℃~100℃;

[0035] step <6> In this reaction, the base is potassium carbonate, the catalyst is tetra(triphenylphosphine)palladium, the reaction solvent is 1,4-dioxane and water, and the reaction temperature is 95℃~105℃.

[0036] Through rational design, the inventors obtained a class of 3-heterocyclic-6-arylbenzenesulfonamide-substituted imidazo[1,2-b]pyridazine compounds, which are compounds conforming to general formula (I) or their pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates or prodrugs;

[0037]

[0038] Furthermore, the inventors have established a method for preparing the corresponding compounds. These compounds are characterized by novel structures and simple preparation. Experimental studies have shown that the imidazo[1,2-b]pyridazine compounds of this invention exhibit significant inhibitory activity against various tumor cell types, including A549, SGC7901, and HeLa, at the cellular level. They are expected to be developed into novel, highly efficient, and economically and easily prepared PI3K inhibitors, with broad market applications and development prospects. Detailed Implementation

[0039] The reaction route for the 3-heterocyclic-6-arylbenzenesulfonamide-substituted imidazo[1,2-b]pyridazine compounds of this invention is as follows. To further illustrate how this invention is implemented, specific examples are provided below. Unless otherwise specified, all raw materials used are commercially available products, and all methods used are known methods.

[0040]

[0041] Example 1. Preparation of intermediate compounds (IV-1 to 10) (Compound (IV) in the following examples were prepared in this manner).

[0042] When A is hour,

[0043] Intermediates (IV) were prepared according to the following route:

[0044]

[0045] in,

[0046] Preparation of compound IV-1

[0047] First, 4-bromoaniline (1 g, 5.81 mmol) was dissolved in 10 mL of pyridine in a reaction vessel. Compound II-1 (1.66 g, 8.72 mmol) was dissolved in 10 mL of pyridine and slowly added dropwise to the reaction vessel through a constant-pressure dropping funnel under ice bath conditions. After the addition was complete, the reaction vessel was transferred to room temperature and stirred overnight. The mixture was concentrated under reduced pressure to remove some of the pyridine, diluted with tetrahydrofuran:water (4:1, v / v), adjusted to pH 2.0 with hydrochloric acid, and separated by silica gel column chromatography to obtain III-1 (1.81 g, 5.55 mmol, 95%) as a yellowish-white solid.

[0048] III-1 (1.00 g, 3.07 mmol) was added sequentially to a side-supported reaction flask along with pinacol diboron ester (1.17 g, 4.60 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.22 g, 0.31 mmol), and potassium acetate (1.27 g, 9.20 mmol). The air in the reaction flask was replaced with nitrogen, and the solvent 1,4-dioxane was added rapidly. The mixture was placed in an oil bath at 85 °C for 8 h. After cooling to room temperature, ethyl acetate was added and the mixture was filtered through diatomaceous earth. The filtrate was washed with saturated brine, and the organic phase was concentrated under reduced pressure to obtain a brownish-yellow solid compound IV-1 (which was directly added to the next reaction as a raw material for the preparation of compounds LYB1, LYB11, and LYB21, with a yield of 100%).

[0049] Preparation of compound IV-2

[0050] First, 4-bromoaniline (1 g, 5.81 mmol) was dissolved in 10 mL of pyridine in a reaction vessel. Compound II-2 (1.7 g, 8.72 mmol) was dissolved in 10 mL of pyridine and slowly added dropwise to the reaction vessel through a constant-pressure dropping funnel under ice bath conditions. After the addition was complete, the reaction vessel was transferred to room temperature and stirred overnight. The mixture was concentrated under reduced pressure to remove some of the pyridine, diluted with tetrahydrofuran:water (4:1, v / v), adjusted to pH 2.0 with hydrochloric acid, and separated by silica gel column chromatography to obtain III-2 (1.82 g, 5.51 mmol, 95%) as a yellowish-white solid.

[0051] III-2 (1.00 g, 3.03 mmol) was added sequentially to a side-supported reaction flask along with pinacol diborate (1.15 g, 4.54 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.22 g, 0.31 mmol), and potassium acetate (1.27 g, 9.20 mmol). The air in the reaction flask was replaced with nitrogen, and the solvent 1,4-dioxane was added rapidly. The mixture was placed in an oil bath at 85 °C for 8 h. After cooling to room temperature, ethyl acetate was added and the mixture was filtered through diatomaceous earth. The filtrate was washed with saturated brine, and the organic phase was concentrated under reduced pressure to obtain a brown solid compound IV-2 (which was directly added to the next reaction as a raw material for the preparation of compounds LYB-2, LYB-12, and LYB-22, with a yield of 100%).

[0052] Preparation of compound IV-3

[0053] First, 4-bromoaniline (1 g, 5.81 mmol) was dissolved in 10 mL of pyridine in a reaction vessel. Compound II-3 (1.85 g, 8.72 mmol) was dissolved in 10 mL of pyridine and slowly added dropwise to the reaction vessel through a constant-pressure dropping funnel under ice bath conditions. After the addition was complete, the reaction vessel was transferred to room temperature and stirred overnight. The mixture was concentrated under reduced pressure to remove some of the pyridine, diluted with tetrahydrofuran:water (4:1, v / v), adjusted to pH 2.0 with hydrochloric acid, and separated by silica gel column chromatography to obtain III-3 (1.95 g, 5.51 mmol, 96%) as a yellowish-white solid.

[0054] III-3 (1.00 g, 2.87 mmol) was added sequentially to a side-supported reaction flask along with pinacol diborate (1.09 g, 4.31 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.21 g, 0.29 mmol), and potassium acetate (1.19 g, 8.62 mmol). The air in the reaction flask was replaced with nitrogen, and the solvent 1,4-dioxane was quickly added. The mixture was placed in an oil bath at 85 °C for 8 h. After cooling to room temperature, ethyl acetate was added and the mixture was filtered through diatomaceous earth. The filtrate was washed with saturated brine, and the organic phase was concentrated under reduced pressure to obtain a brown solid compound IV-3 (which was directly added to the next reaction as a raw material for the preparation of compounds LYB-3, LYB-13, and LYB-23, with a yield of 100%).

[0055] Preparation of compound IV-4

[0056] First, 4-bromoaniline (1 g, 5.81 mmol) was dissolved in 10 mL of pyridine in a reaction vessel. Compound II-4 (1.85 g, 8.72 mmol) was dissolved in 10 mL of pyridine and slowly added dropwise to the reaction vessel through a constant-pressure dropping funnel under ice bath conditions. After the addition was complete, the reaction vessel was transferred to room temperature and stirred overnight. The mixture was concentrated under reduced pressure to remove some of the pyridine, diluted with tetrahydrofuran:water (4:1, v / v), adjusted to pH 2.0 with hydrochloric acid, and separated by silica gel column chromatography to obtain III-4 (1.95 g, 5.51 mmol, 96%) as a yellowish-white solid.

[0057] III-4 (1.00 g, 2.87 mmol) was added sequentially to a side-supported reaction flask along with pinacol diborate (1.09 g, 4.31 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.21 g, 0.29 mmol), and potassium acetate (1.19 g, 8.62 mmol). The air in the reaction flask was replaced with nitrogen, and the solvent 1,4-dioxane was added rapidly. The mixture was placed in an oil bath at 85 °C for 8 h. After cooling to room temperature, ethyl acetate was added and the mixture was filtered through diatomaceous earth. The filtrate was washed with saturated brine, and the organic phase was concentrated under reduced pressure to obtain a brown solid compound IV-4 (which was directly added to the next reaction as a raw material for the preparation of compounds LYB-4, LYB-14, and LYB-24, with a yield of 100%).

[0058] Preparation of compound IV-5

[0059] First, 4-bromoaniline (1 g, 5.81 mmol) was dissolved in 10 mL of pyridine in a reaction vessel. Compound II-5 (2.1 g, 8.72 mmol) was dissolved in 10 mL of pyridine and slowly added dropwise to the reaction vessel through a constant-pressure dropping funnel under ice bath conditions. After the addition was complete, the reaction vessel was transferred to room temperature and stirred overnight. The mixture was concentrated under reduced pressure to remove some of the pyridine, diluted with tetrahydrofuran:water (4:1, v / v), adjusted to pH 2.0 with hydrochloric acid, and separated by silica gel column chromatography to obtain III-5 (2.1 g, 5.81 mmol, 94%) as a yellowish-white solid.

[0060] III-5 (1.00 g, 2.61 mmol) was added sequentially to a side-supported reaction flask along with pinacol diborate (1.00 g, 3.92 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.19 g, 0.26 mmol), and potassium acetate (1.08 g, 7.84 mmol). The air in the reaction flask was replaced with nitrogen, and the solvent 1,4-dioxane was added rapidly. The mixture was placed in an oil bath at 85 °C for 8 h. After cooling to room temperature, ethyl acetate was added and the mixture was filtered through diatomaceous earth. The filtrate was washed with saturated brine, and the organic phase was concentrated under reduced pressure to obtain a brown solid compound IV-5 (which was directly added to the next reaction as a raw material for the preparation of compounds LYB-5, LYB-15, and LYB-25, with a yield of 100%).

[0061] Preparation of compound IV-6

[0062] First, 4-bromoaniline (1 g, 5.81 mmol) was dissolved in 10 mL of pyridine in a reaction vessel. Compound II-6 (2.13 g, 8.72 mmol) was dissolved in 10 mL of pyridine and slowly added dropwise to the reaction vessel through a constant-pressure dropping funnel under ice bath conditions. After the addition was complete, the reaction vessel was transferred to room temperature and stirred overnight. The mixture was concentrated under reduced pressure to remove some of the pyridine, diluted with tetrahydrofuran:water (4:1, v / v), adjusted to pH 2.0 with hydrochloric acid, and separated by silica gel column chromatography to obtain III-6 (2.1 g, 5.52 mmol, 95%) as a yellowish-white solid.

[0063] III-6 (1.00 g, 2.63 mmol) was added sequentially to a side-supported reaction flask along with pinacol diborate (1.00 g, 3.95 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.19 g, 0.26 mmol), and potassium acetate (1.09 g, 7.89 mmol). The air in the reaction flask was replaced with nitrogen, and the solvent 1,4-dioxane was added rapidly. The mixture was placed in an oil bath at 85 °C for 8 h. After cooling to room temperature, ethyl acetate was added and the mixture was filtered through diatomaceous earth. The filtrate was washed with saturated brine, and the organic phase was concentrated under reduced pressure to obtain a brown solid compound IV-6 (which was directly added to the next reaction as a raw material for the preparation of compounds LYB-6, LYB-16, and LYB-26, with a yield of 100%).

[0064] Preparation of compound IV-7

[0065] First, 4-bromoaniline (1 g, 5.81 mmol) was dissolved in 10 mL of pyridine in a reaction vessel. Compound II-7 (1.8 g, 8.72 mmol) was dissolved in 10 mL of pyridine and slowly added dropwise to the reaction vessel through a constant-pressure dropping funnel under ice bath conditions. After the addition was complete, the reaction vessel was transferred to room temperature and stirred overnight. The mixture was concentrated under reduced pressure to remove some of the pyridine, diluted with tetrahydrofuran:water (4:1, v / v), adjusted to pH 2.0 with hydrochloric acid, and separated by silica gel column chromatography to obtain III-7 (1.95 g, 5.7 mmol, 98%) as a yellowish-white solid.

[0066] III-7 (1.00 g, 2.92 mmol) was added sequentially to a side-supported reaction flask along with pinacol diboron ester (1.11 g, 4.38 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.21 g, 0.29 mmol), and potassium acetate (1.21 g, 8.77 mmol). The air in the reaction flask was replaced with nitrogen, and the solvent 1,4-dioxane was added rapidly. The mixture was placed in an oil bath at 85 °C for 8 h. After cooling to room temperature, ethyl acetate was added and the mixture was filtered through diatomaceous earth. The filtrate was washed with saturated brine, and the organic phase was concentrated under reduced pressure to obtain a brown solid compound IV-7 (which was directly added to the next reaction as a raw material for the preparation of compounds LYB-7, LYB-17, and LYB-27, with a yield of 100%).

[0067] Preparation of compound IV-8

[0068] First, 4-bromoaniline (1 g, 5.81 mmol) was dissolved in 10 mL of pyridine in a reaction vessel. Compound II-8 (2.27 g, 8.72 mmol) was dissolved in 10 mL of pyridine and slowly added dropwise to the reaction vessel through a constant-pressure dropping funnel under ice bath conditions. After the addition was complete, the reaction vessel was transferred to room temperature and stirred overnight. The mixture was concentrated under reduced pressure to remove some of the pyridine, diluted with tetrahydrofuran:water (4:1, v / v), adjusted to pH 2.0 with hydrochloric acid, and separated by silica gel column chromatography to obtain III-8 (2.1 g, 5.3 mmol, 91%) as a yellowish-white solid.

[0069] III-8 (1.00 g, 2.52 mmol) was added sequentially to a side-supported reaction flask along with pinacol diboron ester (0.96 g, 3.79 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.18 g, 0.25 mmol), and potassium acetate (1.05 g, 7.57 mmol). The air in the reaction flask was replaced with nitrogen, and the solvent 1,4-dioxane was added rapidly. The mixture was placed in an oil bath at 85 °C for 8 h. After cooling to room temperature, ethyl acetate was added and the mixture was filtered through diatomaceous earth. The filtrate was washed with saturated brine, and the organic phase was concentrated under reduced pressure to obtain a brown solid compound IV-8 (which was directly added to the next reaction as a raw material for the preparation of compounds LYB-8, LYB-18, and LYB-28, with a yield of 100%).

[0070] Preparation of compound IV-9

[0071] First, 4-bromoaniline (1 g, 5.81 mmol) was dissolved in 10 mL of pyridine in a reaction vessel. Compound II-9 (1.93 g, 8.72 mmol) was dissolved in 10 mL of pyridine and slowly added dropwise to the reaction vessel through a constant-pressure dropping funnel under ice bath conditions. After the addition was complete, the reaction vessel was transferred to room temperature and stirred overnight. The mixture was concentrated under reduced pressure to remove some of the pyridine, diluted with tetrahydrofuran:water (4:1, v / v), adjusted to pH 2.0 with hydrochloric acid, and separated by silica gel column chromatography to obtain III-9 (2 g, 5.60 mmol, 96%) as a yellowish-white solid.

[0072] III-9 (1.00 g, 2.80 mmol) was added sequentially to a side-supported reaction flask along with pinacol diborate (1.07 g, 4.20 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.20 g, 0.27 mmol), and potassium acetate (1.16 g, 8.40 mmol). The air in the reaction flask was replaced with nitrogen, and the solvent 1,4-dioxane was added rapidly. The mixture was placed in an oil bath at 85 °C for 8 h. After cooling to room temperature, ethyl acetate was added and the mixture was filtered through diatomaceous earth. The filtrate was washed with saturated brine, and the organic phase was concentrated under reduced pressure to obtain a brown solid compound IV-9 (which was directly added to the next reaction as a raw material for the preparation of compounds LYB-9, LYB-19, and LYB-29, with a yield of 100%).

[0073] Preparation of compound IV-10

[0074] First, 4-bromoaniline (1 g, 5.81 mmol) was dissolved in 10 mL of pyridine in a reaction vessel. Compound II-10 (2.01 g, 8.72 mmol) was dissolved in 10 mL of pyridine and slowly added dropwise to the reaction vessel through a constant-pressure dropping funnel under ice bath conditions. After the addition was complete, the reaction vessel was transferred to room temperature and stirred overnight. The mixture was concentrated under reduced pressure to remove some of the pyridine, diluted with tetrahydrofuran:water (4:1, v / v), adjusted to pH 2.0 with hydrochloric acid, and separated by silica gel column chromatography to obtain III-10 (2 g, 5.46 mmol, 94%) as a yellowish-white solid.

[0075] III-10 (1.00 g, 2.73 mmol) was added sequentially to a side-supported reaction flask along with pinacol diborate (1.04 g, 4.10 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.20 g, 0.27 mmol), and potassium acetate (1.13 g, 8.19 mmol). The air in the reaction flask was replaced with nitrogen, and the solvent 1,4-dioxane was added rapidly. The mixture was placed in an oil bath at 85 °C for 8 h. After cooling to room temperature, ethyl acetate was added and the mixture was filtered through diatomaceous earth. The filtrate was washed with saturated brine, and the organic phase was concentrated under reduced pressure to obtain a brownish-yellow solid compound IV-10 (which was directly added to the next reaction as a raw material for the preparation of compounds LYB-10, LYB-20, and LYB-30, with a yield of 100%).

[0076] Example 2. Preparation of intermediate compounds (VIII-1, VIII-2, VIII-3) (The compounds (VIII-1, VIII-2, VIII-3) in the following examples were prepared in the same manner).

[0077] When B is At that time, intermediates (VIII-1, VIII-2, VIII-3) were prepared according to the following route:

[0078]

[0079] in,

[0080] Preparation of compound (VIII-1)

[0081] Compound V (2 g, 15.44 mmol) was dissolved in 90% ethanol, and bromoacetaldehyde diethanol (2.79 ml, 18.53 mmol) and hydrobromic acid (5 ml) were added sequentially. The mixture was reacted at 103°C overnight. The mixture was washed with saturated sodium bicarbonate solution, extracted with ethyl acetate, and the solvent was removed by rotary evaporation to obtain compound VI (2.3 g, 97%), which was a yellowish-white solid.

[0082] Compound VI (2 g, 13.02 mmol) was dissolved in chloroform, and NBS (3.48 g, 19.54 mmol) and trifluoroacetic acid (2 ml) were added sequentially. The reaction was carried out at room temperature for 6 h. The reaction was quenched with saturated sodium bicarbonate solution, the organic phase was removed by rotary evaporation, the residue was extracted with ethyl acetate, and purified by silica gel column chromatography to give VII (3 g, 99%) as a yellowish-white solid.

[0083] Compound VII (1 g, 4.30 mmol), 1-methylpyrazole-4-boronic acid pinacol ester (0.99 g, 4.73 mmol), tetrakis(triphenylphosphine)palladium (0.4 mg, 0.34 mmol), and potassium carbonate (1.78 g, 12.91 mmol) were sequentially added to a side-supported reaction flask. The air in the flask was purged with nitrogen, followed by the addition of 1,4-dioxane:water (8:2) to dissolve the compound. The reaction mixture was transferred to 95 °C and reacted for 12 h. After cooling to room temperature, ethyl acetate was added to dilute the reaction mixture. The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain a yellow-green solid VIII-1 (0.8 g, 80%). The spectral data are as follows:

[0084] 1 H NMR (500MHz, DMSO-d6) δ8.35(s,1H),8.19(d,J=9.4Hz,1H),8.13(s,1H),8.09(s,1H),7.28(d,J=9.4Hz,1H),3.95(s,3H).

[0085] Preparation of compound (VIII-2)

[0086] Compound VII was prepared using the same method as described above.

[0087] Compound VII (1 g, 4.30 mmol), pinacol 4-pyridineboronic acid (0.98 g, 4.73 mmol), tetrakis(triphenylphosphine)palladium (0.4 mg, 0.34 mmol), and potassium carbonate (1.78 g, 12.91 mmol) were sequentially added to a side-supported reaction flask. The air in the flask was purged with nitrogen, followed by the addition of 1,4-dioxane:water (8:2) to dissolve the compound. The mixture was then transferred to 100 °C and reacted for 12 h. After cooling to room temperature, ethyl acetate was added to dilute the reaction mixture. The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography to obtain a yellowish-white solid VIII-2 (0.6 g, 60%). The spectral data are as follows:

[0088] 1H NMR (600MHz, DMSO-d6) δ8.75–8.68(m,2H),8.60(s,1H),8.37(d,J=9.5Hz,1H),8.16–8.09(m,2H),7.54(d,J=9.5Hz,1H).

[0089] Preparation of compound (VIII-3)

[0090] Compound VII was prepared using the same method as described above.

[0091] Compound VII (1 g, 4.30 mmol), 5-methylfuran-2-borate pinacol ester (0.98 g, 4.73 mmol), tetrakis(triphenylphosphine)palladium (0.4 mg, 0.34 mmol), and potassium carbonate (1.78 g, 12.91 mmol) were sequentially added to a side-supported reaction flask. The air in the flask was purged with nitrogen, followed by the addition of 1,4-dioxane:water (8:2) to dissolve the compound. The mixture was then transferred to 95 °C and reacted for 12 h. After cooling to room temperature, ethyl acetate was added to dilute the reaction mixture. The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography to obtain a yellow solid VIII-3 (0.7 g, 69%). The spectral data are as follows:

[0092] 1 H NMR(600MHz,Chloroform-d)δ8.03(s,1H),7.85(dd,J=23.4,9.4Hz,1H),7.12(d,J=3 .2Hz, 1H), 6.99 (d, J = 9.3Hz, 1H), 6.11 (dd, J = 3.3, 1.3Hz, 1H), 2.35 (d, J = 1.1Hz, 3H).

[0093] Example 3. Preparation of 4-methyl-N-(4-(3-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)phenyl)benzenesulfonamide (LYB-1)

[0094] Compounds VI-1 (1.14 g, 3.05 mmol), VIII-1 (0.64 g, 2.75 mmol), tetrakis(triphenylphosphine)palladium (0.35 g, 0.31 mmol), and potassium carbonate (0.9 g, 6.5 mmol) were sequentially added to a side-supported reaction flask. The air in the flask was purged with nitrogen, followed by the addition of 1,4-dioxane:water (8:2) to dissolve the compounds. The reaction mixture was reacted at 100 °C for 16 h. The reaction mixture was diluted with ethyl acetate, filtered through diatomaceous earth, washed with saturated sodium chloride solution, and the organic phase was concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography to obtain a yellow solid, LYB-1. The spectral data are as follows:

[0095] 1H NMR (600MHz, DMSO-d6) δ10.67(s,1H),8.50(d,J=202.2Hz,1H),8.08(s,1H),8.19(d,J=4.8Hz,1H),8.18(s,1H),8.10(d,J=2.7Hz, 2H),8.08(s,1H),7.74(d,J=8.1Hz,2H),7.71(d,J=9.5Hz,1H),7.38(d,J=8.0Hz,2H),7.34–7.30(m,2H),3.99(s,3H),2.33(s,3H). 13 C NMR(151MHz,DMSO-d6)δ151.05,144.02,140.19,138.23,137.09,136.84,131.27,130.73,1 30.32,128.56,128.40,127.20,126.28,122.72,119.86,114.89,109.90,39.25,21.42.HRMS m / z 445.1444[M+H] + .

[0096] Example 4. Preparation of 4-fluoro-N-(4-(3-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)phenyl)benzenesulfonamide (LYB-2)

[0097] The title compound was synthesized using a method similar to that in Example 3. Its spectral data, as determined by analysis, are as follows:

[0098] 1 H NMR(600MHz,Chloroform-d)δ10.81(s,1H),8.55(s,1H),8.24(s,2H),8.16(d,J=8.3Hz,2H),7.96(dd,J=8.5,5.1Hz, 2H),7.76(d,J=9.5Hz,1H),7.64–7.52(m,2H),7.5(d,J=8.7Hz,2H),7.49(s,1H),7.38(d,J=8.4Hz,2H),4.04(s,3H). 13C NMR(151MHz, DMSO-d6)δ164.88(d,J=251.4Hz),150.97,139.94,136.87,136.34,131.33,131.08(d,J=12.1H z),130.23(d,J=9.7Hz),129.00,128.62,128.44,126.36,120.24,117.13(d,J=22.7Hz),114.87,39.26.HRMS m / z 449.1190[M+H] + .

[0099] Example 5.2 Preparation of 5-difluoro-N-(4-(3-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)phenyl)benzenesulfonamide (LYB-3)

[0100] The title compound was synthesized using a method similar to that in Example 3. Its spectral data, as determined by analysis, are as follows:

[0101] 1 H NMR (600MHz, DMSO-d6) δ11.20(s,1H),8.50(s,1H),8.20(d,J=10.7Hz,1H),8.19(s,1H),8.13(s,1H),8.11(d,J=6.8Hz,2H ),7.78–7.74(m,1H),7.72(d,J=9.5Hz,1H),7.61(m,1H),7.55(dt,J=9.1,4.7Hz,1H),7.35(d,J=8.3Hz,2H),3.99(s,3H). 13 C NMR (151MHz, DMSO-d6) δ136.85,131.33,128.70,128.40,126.32,119.90,117.47(d,J=26.6Hz),114.90,109.89,39.25.HRMS m / z 467.1194[M+H] + .

[0102] Example 6.2 Preparation of 4-difluoro-N-(4-(3-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)phenyl)benzenesulfonamide (LYB-4)

[0103] The title compound was synthesized using a method similar to that in Example 3. Its spectral data, as determined by analysis, are as follows:

[0104] 1H NMR (600MHz, DMSO-d6) δ11.12(s,1H),8.50(d,J=8.0Hz,1H),8.20(d,J=7.6Hz,1H),8.19(s,1H),8.12(d,J=8.1Hz,2H),8.11( s,1H).8.02(td,J=8.6,6.0Hz,1H),7.72(d,J=9.5Hz,1H),7.58(ddd,J=11.2,9.0,2.5Hz,1H),7.36–7.28(m,3H),4.00(s,3H).

[0105] 13 C NMR (151MHz, DMSO-d6) δ159.41 (d, J = 257.4Hz), 158.65, 150.97, 139.34, 138.25, 136.85, 133.04 (d, J = 11.0Hz), 131.32, 131.12, 128. 61(d,J=12.8Hz),128.41,126.31,124.29,122.74,119.81,114.89,113.04(d,J=20.7Hz),109.89,106.72(t,J=26.0Hz),39.25.HRMS m / z 467.1097[M+H] + .

[0106] Example 7. Preparation of 5-chloro-2,4-difluoro-N-(4-(3-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)phenyl)benzenesulfonamide (LYB-5)

[0107] The title compound was synthesized using a method similar to that in Example 3. Its spectral data, as determined by analysis, are as follows:

[0108] 1 H NMR (600MHz, DMSO-d6) δ11.24(s,1H),8.51(s,1H),8.21(d,J=10.3Hz,1H),8.21(s,1H),8.13(dd,J =12.9,6.9Hz,4H),7.87(t,J=9.4Hz,1H),7.74(d,J=9.5Hz,1H),7.36(d,J=8.5Hz,2H),4.00(s,3H). 13C NMR (151MHz, DMSO-d6) δ143.50,139.07,138.27,136.87,131.96,131.38,128.76,128.43,126.33,120.13,114.93,109.89,108.52,39.25.HRMS m / z 501.0704[M+H] + .

[0109] Example 8. Preparation of N-(4-(3-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)phenyl)-4-(trifluoromethyl)benzenesulfonamide (LYB-6)

[0110] The title compound was synthesized using a method similar to that in Example 3. Its spectral data, as determined by analysis, are as follows:

[0111] 1 H NMR (600MHz, DMSO-d6) δ11.00(s,1H),8.51(s,1H),8.20(s,1H),8.13(d,J=8.3Hz,2H),8.08(d,J=8.2Hz,2H),8.0 1(d,J=8.3Hz,2H),7.72(d,J=9.4Hz,1H),7.57(t,J=8.7Hz,1H),7.51(s,1H),7.36(d,J=8.3Hz,2H),4.00(s,3H). 13 C NMR (151MHz, DMSO-d6) δ150.93,143.84,139.49,136.90,131.41,128.72,128.49,128.16,127.24,120.47,114.92,39.25.HRMS m / z 499.1160[M+H] + .

[0112] Example 9. Preparation of 4-methoxy-N-(4-(3-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)phenyl)benzenesulfonamide (LYB-7)

[0113] The title compound was synthesized using a method similar to that in Example 3. Its spectral data, as determined by analysis, are as follows:

[0114] 1H NMR(600MHz,DMSO-d6)δ10.62(s,1H),8.48(s,1H),8.18(s,1H),8.16–8.14(m,2H),8.07(d,J=8.4Hz,2H), 7.82–7.78(m,2H),7.69(d,J=9.5Hz,1H),7.36–7.31(m,2H),7.10–7.07(m,2H),3.98(s,3H),3.78(s,3H). 13 C NMR(151MHz,DMSO-d6)δ163.05,151.05,140.32,136.87,131.53,129.40,128.54,119.80,114.99,56.09,39.25.HRMS m / z461.1381[M+H] + .

[0115] Example 10. Preparation of 4-trifluoromethoxy-N-(4-(3-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)phenyl)benzenesulfonamide (LYB-8)

[0116] The title compound was synthesized using a method similar to that in Example 3. Its spectral data, as determined by analysis, are as follows:

[0117] 1 H NMR (600MHz, DMSO-d6) δ10.88(s,1H),8.51(s,1H),8.21(d,J=10.3Hz,2H),8.14(d,J=2.1Hz,1H),8.12(d,J= 5.0Hz,2H),8.03–7.97(m,2H),7.74(d,J=9.6Hz,1H),7.62(d,J=8.4Hz,2H),7.38–7.33(m,2H),4.00(s,3H). 13 C NMR(151MHz,DMSO-d6)δ151.67,150.94,139.69,138.86,138.24,136.84,131.32,131.2 0,129.81,128.66,128.39,126.30,122.72,122.05,120.28,119.39,114.86,39.23.HRMS m / z 515.1112[M+H] + .

[0118] Example 11. Preparation of 1,4-nitro-N-(4-(3-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)phenyl)benzenesulfonamide (LYB-9)

[0119] The title compound was synthesized using a method similar to that in Example 3. Its spectral data, as determined by analysis, are as follows:

[0120] 1 H NMR(600MHz,DMSO-d6)δ11.05(s,1H),8.49(s,1H),8.41(d,J=8.5Hz,2H),8.22–8.15 (m,3H),8.14–8.05(m,4H),7.72(d,J=9.5Hz,1H),7.35(d,J=8.3Hz,2H),3.99(s,3H). 13 C NMR (126MHz, DMSO-d6) δ150.92,150.41,145.45,139.54,138.25,136.85,134.70,134.62,131.40,13 1.37,130.72,128.75,128.72,128.39,126.35,125.28,122.73,120.65,114.86,109.88,39.26.HRMS m / z 476.1139[M+H] + .

[0121] Example 12. Preparation of 2,4,5-trifluoro-N-(4-(3-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)phenyl)benzenesulfonamide (LYB-10)

[0122] The title compound was synthesized using a method similar to that in Example 3. Its spectral data, as determined by analysis, are as follows:

[0123] 1 H NMR (600MHz, DMSO-d6) δ11.24(s,1H),8.50(s,1H),8.20(d,J=9.8Hz,2H),8.14(s,1H),8.12(d,J=7.5Hz,2H), 8.07(q,J=8.4Hz,1H),7.89(td,J=10.0,5.8Hz,1H),7.73(d,J=9.5Hz,1H),7.35(d,J=8.3Hz,2H),3.99(s,3H). 13C NMR (126MHz, DMSO-d6) δ150.95, 139.07, 138.25, 136.84, 131.95 (d, J = 9.7Hz), 131.33 (d, J = 5.7Hz), 129.22 (d, J = 11.9 Hz),128.71,128.40,126.34,122.73,119.99,119.44(d,J=21.3Hz),114.88,109.90,110.82–107.34(m),39.26.HRMS m / z 485.1001[M+H] + .

[0124] Example 13. Preparation of 4-methyl-N-(4-(3-(pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl)phenyl)benzenesulfonamide (LYB-11)

[0125] Compounds VI-1 (1.14 g, 3.05 mmol), VIII-2 (0.63 g, 2.75 mmol), tetrakis(triphenylphosphine)palladium (0.35 mg, 0.31 mmol), and potassium carbonate (0.9 mg, 6.5 mmol) were sequentially added to a side-supported reaction flask. The air in the flask was purged with nitrogen, followed by the addition of 1,4-dioxane:water (8:2) to dissolve the compounds. The reaction mixture was reacted at 105 °C for 16 h. The reaction mixture was diluted with ethyl acetate, filtered through diatomaceous earth, washed with saturated sodium chloride solution, and the organic phase was concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography to obtain a yellowish-white solid, LYB-11. The spectral data are as follows:

[0126] 1 H NMR(600MHz,DMSO-d6)δ10.70(s,1H),8.74–8.70(m,2H),8.55(s,1H),8.31(d,J=9.6Hz,1H),8.28–8.24(m,2H),8 .10–8.04(m,2H),7.88(d,J=9.6Hz,1H),7.77–7.72(m,2H),7.38(d,J=8.2Hz,2H),7.35–7.31(m,2H),2.33(s,3H). 13 C NMR(151MHz,DMSO-d6)δ151.41,150.67,144.04,140.87,140.45,137.07,135.98,13 5.82,130.33,128.65,127.19,126.92,125.32,119.94,119.81,117.18,21.42.HRMS m / z 442.1330[M+H] + .

[0127] Example 14. Preparation of 4-fluoro-N-(4-(3-(pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl)phenyl)benzenesulfonamide (LYB-12)

[0128] The title compound was synthesized using a method similar to that in Example 13. Its spectral data, as determined by analysis, are as follows:

[0129] 1 H NMR(600MHz,DMSO-d6)δ9.07(s,1H),8.74–8.69(m,2H),8.55(s,1H),8.32(d,J=9.6Hz,1H),8.28–8.24(m ,2H),8.12–8.06(m,2H),7.95–7.91(m,2H),7.89(d,J=9.6Hz,1H),7.48–7.41(m,2H),7.38–7.30(m,2H). 13 C NMR(151MHz,DMSO-d6)δ164.89(d,J=251.9Hz),150.99(d,J=107.2Hz),140.20,136.31,135.96,135.82,131.14 (d,J=9.9Hz),130.63,130.24(d,J=9.7Hz),129.00,128.70,126.93,120.18,117.19(d,J=7.2Hz),117.06.HRMS m / z 446.1089[M+H] + .

[0130] Example 15.2 Preparation of 5-difluoro-N-(4-(3-(pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl)phenyl)benzenesulfonamide (LYB-13)

[0131] The title compound was synthesized using a method similar to that in Example 13. Its spectral data, as determined by analysis, are as follows:

[0132] 1 H NMR(600MHz,DMSO-d6)δ13.18(s,1H),8.73–8.70(m,2H),8.56(s,2H),8.32(d,J=9.6Hz,1H),8.15–8.08(m, 2H),8.02–7.97(m,2H),7.89(d,J=9.5Hz,1H),7.77(d,J=5.1Hz,1H),7.62–7.59(m,2H),7.38–7.33(m,2H). 13C NMR (126MHz, DMSO-d6) δ151.68,151.30,150.63,139.93,138.81,135.98,130.83,129.8 2,128.75,126.93,125.32,122.06,120.23,119.94,119.31(d,J=24.0Hz),117.16.HRMS m / z 464.0987[M+H] + .

[0133] Example 16.2 Preparation of 4-difluoro-N-(4-(3-(pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl)phenyl)benzenesulfonamide (LYB-14)

[0134] The title compound was synthesized using a method similar to that in Example 13. Its spectral data, as determined by analysis, are as follows:

[0135] 1 H NMR (600MHz, DMSO-d6) δ11.15(s,1H),8.73(d,2H),8.56(s,1H),8.32(d,J=9.5Hz,1H),8.27(d,J=5.0Hz,2H),8. 09(d,J=8.5Hz,2H),8.02(td,J=8.6,6.1Hz,1H),7.89(d,J=9.5Hz,1H),7.59–7.48(m,2H),7.33(d,J=8.5Hz,2H). 13 C NMR (126MHz, DMSO-d6) δ151.03(d,J=88.6Hz), 135.92(d,J=15.0Hz), 133.01(d,J=11.3Hz), 130.61,128.74,126.98,119.90(d,J=27.4Hz),117.21,112.94,106.82(d,J=25.5Hz).HRMS m / z464.0991[M+H] + .

[0136] Example 17. Preparation of 5-chloro-2,4-difluoro-N-(4-(3-(pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl)phenyl)benzenesulfonamide (LYB-15)

[0137] The title compound was synthesized using a method similar to that in Example 13. Its spectral data, as determined by analysis, are as follows:

[0138] 1H NMR(600MHz,DMSO-d6)δ11.26(s,1H),8.74–8.69(m,2H),8.55(s,1H),8.32(d,J=9.5Hz,1H), 8.28–8.24(m,2H),8.16–8.08(m,3H),7.88(s,1H),7.85(t,J=9.5Hz,1H),7.38–7.33(m,2H). 13 C NMR (126MHz, DMSO-d6) δ156.78 (d, J = 12.5Hz), 151.01 (d, J = 87.0Hz), 139.40, 135.93 (d, J = 12.7Hz), 134.71 (d, J = 1 0.1Hz),131.95,132.80–129.73(m),128.87(d,J=10.1Hz),126.99,125.36,120.09,119.99,117.24,108.53.HRMS m / z

[0139] 498.0600[M+H] + .

[0140] Example 18. Preparation of 4-trifluoromethyl-N-(4-(3-(pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl)phenyl)benzenesulfonamide (LYB-16)

[0141] The title compound was synthesized using a method similar to that in Example 13. Its spectral data, as determined by analysis, are as follows:

[0142] 1 H NMR(600MHz,DMSO-d6)δ11.01(s,1H),8.73–8.70(m,2H),8.56(s,1H),8.32(d,J=9.6Hz,1H),8.29–8.25(m,2H), 8.11(d,J=8.3Hz,2H),8.07(d,J=8.2Hz,2H),8.01(d,J=8.3Hz,2H),7.89(d,J=9.6Hz,1H),7.36(d,J=8.3Hz,2H). 13 C NMR(126MHz,DMSO-d6)δ151.27,150.63,143.84,139.79,135.90(d,J=12.3Hz),133.34,13 3.08,130.96,128.78,128.15,127.22(q,J=3.7Hz),126.96,120.41,120.00,117.16.HRMS m / z496.1047[M+H] + .

[0143] Example 19. Preparation of 4-methoxy-N-(4-(3-(pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl)phenyl)benzenesulfonamide (LYB-17)

[0144] The title compound was synthesized using a method similar to that in Example 13. Its spectral data, as determined by analysis, are as follows:

[0145] 1 H NMR (600MHz, DMSO-d6) δ10.63(s,1H),8.72(d,J=5.2Hz,2H),8.55(s,1H),8.31(d,J=9.6Hz,1H),8.26(d,J=5.2Hz,2H),8.0 7(d,J=8.3Hz,2H),7.88(d,J=9.6Hz,1H),7.80(d,J=8.6Hz,2H),7.33(d,J=8.3Hz,2H),7.10(d,J=8.7Hz,2H),3.79(s,3H). 13 C NMR(126MHz,DMSO-d6)δ163.06,151.41,150.65,140.86,140.56,135.88(d,J=24.2Hz),13 1.49,130.25,129.41,128.62,126.89,119.85(d,J=24.0Hz),117.17,115.02,56.10.HRMS m / z 458.1293[M+H] + .

[0146] Example 20. Preparation of 4-trifluoromethoxy-N-(4-(3-(pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl)phenyl)benzenesulfonamide (LYB-18)

[0147] The title compound was synthesized using a method similar to that in Example 13. Its spectral data, as determined by analysis, are as follows:

[0148] 1 H NMR (600MHz, DMSO-d6) δ10.89(s,1H),8.73–8.70(m,3H),8.56(s,1H),8.32(d,J=9.5Hz,1H),8.27(d,J=5.2H z,2H),8.13–8.07(m,2H),8.02–7.95(m,2H),7.89(d,J=9.6Hz,1H),7.61(d,J=8.4Hz,2H),7.38–7.32(m,2H). 13C NMR (126MHz, DMSO-d6) δ151.83–151.52(m),151.31,150.65,139.99,138.85,135.91(d,J=13.5Hz ),130.80,129.81,128.75,126.95,125.35,122.06,121.27,120.24,119.97,119.22,117.16.HRMS m / z512.0998[M+H] + .

[0149] Example 21. Preparation of 1,4-nitro-N-(4-(3-(pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl)phenyl)benzenesulfonamide (LYB-19)

[0150] The title compound was synthesized using a method similar to that in Example 13. Its spectral data, as determined by analysis, are as follows:

[0151] 1 H NMR(600MHz,DMSO-d6)δ10.36(s,1H),8.74–8.71(m,2H),8.55(s,1H),8.36–8.22(m,3H),8.05( d,J=8.4Hz,2H),7.89(d,J=9.6Hz,1H),7.51–7.46(m,2H),7.32–7.27(m,2H),6.59–6.55(m,2H). 13 C NMR (126MHz, DMSO-d6) δ153.54, 151.36, 150.66, 140.12, 136.25 (d, J = 3.1Hz), 130.67, 130. 29,130.21,129.27,128.71,128.49,126.93,120.18,119.98,119.31,117.24,117.06.HRMS m / z 473.1025[M+H] + .

[0152] Example 22. Preparation of 2,4,5-trifluoro-N-(4-(3-(pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl)phenyl)benzenesulfonamide (LYB-20)

[0153] The title compound was synthesized using a method similar to that in Example 13. Its spectral data, as determined by analysis, are as follows:

[0154] 1H NMR(600MHz,DMSO-d6)δ11.28(s,1H),8.84–8.66(m,2H),8.57(s,1H),8.36–8.22(m,3H),8. 09(dd,J=18.6,8.2Hz,3H),7.90(d,J=10.1Hz,1H),7.59–7.55(m,1H),7.35(d,J=8.3Hz,2H). 13 C NMR(126MHz,DMSO-d6)δ151.37,150.62,148.46–139.14(m),135.84,130.73,128.78 ,126.99,120.12–119.77(m),119.41(d,J=21.7Hz),117.21,110.53–107.57(m).HRMS m / z 482.0889[M+H] + .

[0155] Example 23. Preparation of 4-methyl-N-(4-(3-(5-methylfuran-2-yl)imidazo[1,2-b]pyridazin-6-yl)phenyl)benzenesulfonamide (LYB-21)

[0156] Compounds VI-1 (1.14 g, 3.05 mmol), VIII-3 (0.64 g, 2.75 mmol), tetrakis(triphenylphosphine)palladium (0.35 mg, 0.31 mmol), and potassium carbonate (0.9 mg, 6.5 mmol) were sequentially added to a side-supported reaction flask. The air in the flask was purged with nitrogen, followed by the addition of 1,4-dioxane:water (8:2) to dissolve the compounds. The reaction mixture was reacted at 95 °C for 16 h. The reaction mixture was diluted with ethyl acetate, filtered through diatomaceous earth, washed with saturated sodium chloride solution, and the organic phase was concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography to obtain a yellow solid, LYB-21. The spectral data are as follows:

[0157] 1 H NMR (600MHz, DMSO-d6) δ10.68(s,1H),8.22(d,J=9.6Hz,1H),8.05(d,J=9.3Hz,3H),7.75(t,J=7.7Hz,3H),7.37 (d,J=8.1Hz,2H),7.32(d,J=8.3Hz,2H),7.21(d,J=3.2Hz,1H),6.33(d,J=3.2Hz,1H),2.39(s,2H),2.32(s,3H). 13C NMR (126MHz, DMSO-d6) δ151.91,151.30,144.00,142.08,140.36,138.77,137.09,131.99,131.9 1,130.30,129.26,129.17,128.48,127.21,126.43,119.82,109.24,108.50,21.41,13.80.HRMS m / z445.1327[M+H] + .

[0158] Example 24. Preparation of 4-fluoro-N-(4-(3-(5-methylfuran-2-yl)imidazo[1,2-b]pyridazin-6-yl)phenyl)benzenesulfonamide (LYB-22)

[0159] The title compound was synthesized using a method similar to that in Example 23. Its spectral data, as determined by analysis, are as follows:

[0160] 1 H NMR (600MHz, DMSO-d6) δ10.77(s,1H),8.25(d,J=9.6Hz,1H),8.08(d,J=8.3Hz,2H),8.05(s,1H),7.92(dd,J=8.7,5.1Hz,2H), 7.79(d,J=9.5Hz,1H),7.43(t,J=8.6Hz,2H),7.32(d,J=8.3Hz,2H),7.23(d,J=3.2Hz,1H),6.35(d,J=3.1Hz,1H),2.40(s,3H). 13 C NMR(126MHz, DMSO-d6)δ164.90(d,J=252.0Hz),151.94,151.27,142.08,140.02,138.79,136.28(d,J=3.0Hz),131.99 ,131.91,130.25(d,J=9.5Hz),129.27,129.17,128.56,126.48,120.20,117.13(d,J=22.8Hz),109.26,108.51,13.81.

[0161] Example 25.2 Preparation of 5-difluoro-N-(4-(3-(5-methylfuran-2-yl)imidazo[1,2-b]pyridazin-6-yl)phenyl)benzenesulfonamide (LYB-23)

[0162] The title compound was synthesized using a method similar to that in Example 23. Its spectral data, as determined by analysis, are as follows:

[0163] 1 H NMR(600MHz,DMSO-d6)δ11.21(s,1H),8.34–8.22(m,1H),8.10(d,J=8.5Hz,2H),7.83– 7.74(m,2H),7.67–7.48(m,3H),7.35(d,J=8.6Hz,2H),6.37–6.34(m,1H),2.41(s,3H). 13 C NMR (126MHz, DMSO-d6) δ159.57–153.07(m),151.96,151.28,146.79,137.13,131.99,131.91,129.27,129.18,128.75–128. 53(m),127.83,123.73(d,J=114.8Hz),120.14,119.92(d,J=14.9Hz),118.89,117.60,117.38,109.31,108.53,14.54.HRMS m / z467.0980[M+H] + .

[0164] Example 26.2 Preparation of 4-difluoro-N-(4-(3-(5-methylfuran-2-yl)imidazo[1,2-b]pyridazin-6-yl)phenyl)benzenesulfonamide (LYB-24)

[0165] The title compound was synthesized using a method similar to that in Example 23. Its spectral data, as determined by analysis, are as follows:

[0166] 1 H NMR (600MHz, DMSO-d6) δ11.13(s,1H),8.26(d,J=9.5Hz,1H),8.09(d,J=8.3Hz,2H),8.06(s,1H),8.03(td,J=8.6,6.0Hz,1 H),7.80(d,J=9.5Hz,1H),7.64–7.54(m,2H),7.33(d,J=8.5Hz,2H),7.24(d,J=3.2Hz,1H),6.37–6.34(m,1H),2.41(s,3H). 13CNMR(126MHz,DMSO-d6)δ157.70(d,J=245.3Hz),151.96,151.27,146.78,142.07,139.51,137.13,133.95,133.17–132.35( m),127.83,124.81–122.45(m),119.82(d,J=8.9Hz),117.60,117.39,115.81,113.13,109.29,108.53,106.72,13.82.HRMS m / z 467.0982[M+H] + .

[0167] Example 27. Preparation of 5-chloro-2,4-difluoro-N-(4-(3-(5-methylfuran-2-yl)imidazo[1,2-b]pyridazin-6-yl)phenyl)benzenesulfonamide (LYB-25)

[0168] The title compound was synthesized using a method similar to that in Example 23. Its spectral data, as determined by analysis, are as follows:

[0169] 1 H NMR (600MHz, DMSO-d6) δ11.25(s,1H),8.27(d,J=9.5Hz,1H),8.13(dd,J=17.1,8.1Hz,3H),7.86(t,J=9.5Hz,1H),7 .81(d,J=9.4Hz,1H),7.63(s,1H),7.35(d,J=8.4Hz,2H),7.24(d,J=3.3Hz,1H),6.36(d,J=3.1Hz,1H),2.41(s,3H). 13 C NMR (126MHz, DMSO-d6) δ151.96,151.25,142.09,139.14,133.59,132.78,132.50(d,J=2.7Hz),131.95(d,J=9.8Hz),131 .17,129.22(d,J=11.7Hz),128.68,127.42–124.47(m),120.09,117.54–116.46(m),115.80,109.29,108.52,13.82.HRMS m / z 501.0601[M+H] + .

[0170] Example 28. Preparation of 4-trifluoromethyl-N-(4-(3-(5-methylfuran-2-yl)imidazo[1,2-b]pyridazin-6-yl)phenyl)benzenesulfonamide (LYB-26)

[0171] The title compound was synthesized using a method similar to that in Example 23. Its spectral data, as determined by analysis, are as follows:

[0172] 1 H NMR(600MHz,DMSO-d6)δ9.06(s,1H),8.87–8.54(m,2H),8.30(d,J=9.6Hz,1H),8.16(d,J=8.2Hz,2H),8.08(s,1H),7.9 8(d,J=8.1Hz,2H),7.87(d,J=9.6Hz,1H),7.53–7.31(m,2H),7.24(d,J=3.2Hz,1H),6.36(d,J=3.2Hz,1H),2.41(s,3H). 13 C NMR (126MHz, DMSO-d6) δ151.98,151.27,142.07,139.84,138.83,133.59,132.78,132.51(d,J=2.7Hz),131.91,13 1.30–130.53(m),129.82,129.23(d,J=11.8Hz),128.62,126.52,122.06,120.27,115.80,109.28,108.52,13.81.

[0173] Example 29. Preparation of 4-methoxy-N-(4-(3-(5-methylfuran-2-yl)imidazo[1,2-b]pyridazin-6-yl)phenyl)benzenesulfonamide (LYB-27)

[0174] The title compound was synthesized using a method similar to that in Example 23. Its spectral data, as determined by analysis, are as follows:

[0175] 1 H NMR (600MHz, DMSO-d6) δ10.62(d,J=5.7Hz,1H),8.22(d,J=9.6Hz,1H),8.07–8.03(m,2H),7.77(dq,J=21.2,6.7,5.2H z,3H),7.29(dd,J=31.0,8.3Hz,3H),7.21(s,1H),7.09(d,J=8.5Hz,2H),6.37–6.31(m,1H),3.78(s,3H),2.39(s,3H). 13C NMR (126MHz, DMSO-d6) δ163.05,151.92,151.32,142.07,140.46,138.76,131.53(d,J=5.7Hz),130.81,130.3 8,129.42,128.46,126.41,121.49,119.76,115.75,114.97(d,J=6.5Hz),109.24,108.50,56.09,13.79.HRMS m / z 461.1269[M+H] + .

[0176] Example 30. Preparation of 4-trifluoromethoxy-N-(4-(3-(5-methylfuran-2-yl)imidazo[1,2-b]pyridazin-6-yl)phenyl)benzenesulfonamide (LYB-28)

[0177] The title compound was synthesized using a method similar to that in Example 23. Its spectral data, as determined by analysis, are as follows:

[0178] 1 H NMR(600MHz,DMSO-d6)δ8.98(s,1H),8.29(dd,J=21.4,9.4Hz,3H),8.14–8.11(m,2H),8.00(s,1H),7.6 5–7.53(m,2H),7.44(dd,J=19.6,9.5Hz,3H),7.06(d,J=3.3Hz,1H),6.35(d,J=3.2Hz,1H),2.40(s,3H). 13 C NMR(126MHz,DMSO-d6)δ152.25(d,J=72.7Hz),148.07,147.44,141.27,139.84,1 38.81,135.11,133.59,132.77,132.50(d,J=2.8Hz),131.99,131.91,131.46,12 9.82,129.27,129.17,128.59(d,J=3.6Hz),128.36,122.05,121.54(d,J=6.9Hz) ,120.26,119.99,118.85,109.72,108.52(d,J=3.1Hz),13.80(d,J=2.4Hz).HRMS m / z 515.0998[M+H] + .

[0179] Example 31. Preparation of 1,4-nitro-N-(4-(3-(5-methylfuran-2-yl)imidazo[1,2-b]pyridazin-6-yl)phenyl)benzenesulfonamide (LYB-29)

[0180] The title compound was synthesized using a method similar to that in Example 23. Its spectral data, as determined by analysis, are as follows:

[0181] 1 H NMR (600MHz, DMSO-d6) δ11.05(s,1H),8.41(dd,J=7.7,5.6Hz,2H),8.27(d,J=9.5Hz,1H),8.10(dd,J=8.7,1.6Hz,3H) ,8.07(s,1H),7.80(d,J=9.6Hz,1H),7.35(d,J=8.6Hz,2H),7.23(d,J=3.2Hz,1H),6.35(d,J=3.4Hz,1H),2.41(s,3H). 13 C NMR (126MHz, DMSO-d6) δ151.96,151.19,150.44,145.26,142.06,139.44,132.73,131.30,128. 77,128.67,126.53,125.25(d,J=9.8Hz),122.98,120.61,115.76,109.26,108.50,13.81.HRMS m / z476.1020[M+H] + .

[0182] Example 32. Preparation of 2,4,5-trifluoro-N-(4-(3-(5-methylfuran-2-yl)imidazo[1,2-b]pyridazin-6-yl)phenyl)benzenesulfonamide (LYB-30)

[0183] The title compound was synthesized using a method similar to that in Example 23. Its spectral data, as determined by analysis, are as follows:

[0184] 1 H NMR (600MHz, DMSO-d6) δ11.26(s,1H),8.27(d,J=9.1Hz,1H),8.09(dd,J=18.9,6.6Hz,3H),7.89(td,J=10.0,5.9Hz,1H),7 .81(d,J=9.6Hz,1H),7.66–7.53(m,1H),7.36(d,J=8.4Hz,2H),7.24(d,J=3.2Hz,1H),6.36(d,J=3.2Hz,1H),2.41(s,3H). 13C NMR(126MHz, DMSO-d6)δ157.12–152.53(m),151.97,151.27,142.51–137.84(m),131.99,131.91,131.23–130.80(m),129. 26,129.17,128.65,126.52,121.51,119.94,119.56,119.39,115.92–115.67(m),109.39–108.69(m),108.51,13.81.HRMS m / z 485.0883[M+H] + .

[0185] Example 33 Cell-level activity test

[0186] The inhibitory rate of drugs on different tumor cells was detected by the MTT assay. Cells required for bioassessment were cultured in DMEM medium. All cell cultures were supplemented with 10% Australian fetal bovine serum and 5% penicillin and streptomycin. Cells were cultured at 37°C in a 5% CO2 incubator. Tumor cells in logarithmic growth phase were seeded into 96-well plates. Specifically, 1000 A549 cells were seeded per well; 1500 SGC7901 cells per well; and 1000 HeLa cells per well. 150 μl of cell culture medium was added to each well. For this MTT experiment, 1-2 replicates were used per group. The positive control drug Omipalisib and the test compound were dissolved in DMSO and diluted to a stock solution of 50 mM. An appropriate amount of the stock solution was diluted to 1 μM, and after 24 h of culture, the drugs were added, followed by 72 h of incubation. After 72 hours, remove the 96-well plate and add 15 μl of 5 μg / ml MTT solution to each well. Incubate at 37°C for 4 hours, then remove the MTT solution and add 150 μl of DMSO per well. Shake on a light-protected incubator for 10 minutes. Detect the OD value using a microplate reader at a wavelength of 490 nm. Calculate the inhibition rate using the following formula. The results are shown in the table.

[0187] Cell inhibition rate (%) = [1 - (OD value of experimental group - OD value of blank well) / (OD value of control group - OD value of blank well)] × 100%

[0188] Inhibition rates (%) of compounds LYB-1 to LYB-30 on various organelles at a concentration of 1 μM

[0189]

[0190]

Claims

1. Imidazolo[1,2-b]pyridazine compounds, characterized in that... Compounds that conform to general formula (Ⅰ) or their pharmaceutically acceptable salts; In general formula (Ⅰ), A is a substituted phenyl group and B is a heterocycle. The substituted phenyl group is one of the following substituents: The heterocycle is one of the following substituents:

2. The imidazo[1,2-b]pyridazine compound according to claim 1, characterized in that... It is one of the following compounds LYB1-LYB30.

3. The imidazo[1,2-b]pyridazine compound according to claim 1, characterized in that: The pharmaceutically acceptable salt is a salt formed by a compound of general formula (I) with an acid or metal ion; the acid is galactosic acid, D-glucuronic acid, glycerophosphate, hippuric acid, hydroxyethylsulfonic acid, lactobionic acid, maleic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, neopentanoic acid, terephthalic acid, cholic acid, dodecyl sulfate, benzenesulfonic acid, citric acid, D-glucose, glycolic acid, lactic acid, malic acid, malonic acid, mandelic acid, phosphoric acid, propionic acid, hydrochloric acid, sulfuric acid, tartaric acid, succinic acid, formic acid, hydroiodic acid, or hydrobromic acid. The following are listed: methanesulfonic acid, nicotinic acid, nitric acid, orotic acid, oxalic acid, picric acid, L-pyroglutamic acid, saccharinic acid, salicylic acid, gentian acid, p-toluenesulfonic acid, valeric acid, palmitic acid, sebacic acid, stearic acid, lauric acid, acetic acid, adipic acid, carbonic acid, 4-benzenesulfonic acid, ethanedisulfonic acid, ethylsuccinic acid, fumaric acid, 3-hydroxynaphthalene-2-carboxylic acid, 1-hydroxynaphthalene-2-carboxylic acid, oleic acid, undecenoic acid, ascorbic acid, camphoric acid, camphorsulfonic acid, dichloroacetic acid, and ethanesulfonic acid; the metal ions are sodium ions, potassium ions, and calcium ions.

4. The use of the imidazo[1,2-b]pyridazine compound of claim 1 in the preparation of PI3K inhibitors.

5. The use of the imidazo[1,2-b]pyridazine compound of claim 1 in the preparation of a medicament for treating PI3K-related diseases.

6. The application according to claim 5, characterized in that: The PI3K-related diseases include malignant tumors, diabetes, cardiovascular diseases, and nervous system diseases; the malignant tumors include lung adenocarcinoma, gastric adenocarcinoma, cervical cancer, liver cancer, bile duct cancer, colon cancer, and breast cancer.

7. The method for preparing the imidazo[1,2-b]pyridazine compound according to claim 1, characterized in that... The reaction proceeds along the following route:

8. The method for preparing the imidazo[1,2-b]pyridazine compound according to claim 7, characterized in that... Includes the following steps: <1> Compound (III) was prepared by reacting compound (II) with 4-bromoaniline; <2> Compound (IV) was prepared by reacting compound (III) with pinacol diborate under anhydrous and oxygen-free conditions via the Miyaura reaction. <3> Compound (VI) was prepared by reacting compound (V) with bromoacetaldehyde diethanol condensation; <4> Compound (VII) was prepared by reacting compound (VI) with N-bromosuccinimide; <5> Compound (VIII) was prepared by a Suzuki coupling reaction of compound (VII) with 1-methylpyrazole-4-boronic acid pinacol ester, 4-pyridineboronic acid pinacol ester, or 5-methylfuran-2-boronic acid pinacol ester under anaerobic conditions. <6> Compound (I) was prepared by a Suzuki coupling reaction between compound (IV) and compound (VIII) under anaerobic conditions.

9. The method for preparing the imidazo[1,2-b]pyridazine compound according to claim 8, characterized in that: step <1> In this reaction, the acid-binding agent is pyridine, the reaction solvent is pyridine, tetrahydrofuran, and water, and the reaction temperature is room temperature. step <2> In the reaction, the base is potassium acetate, the catalyst is [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride, the solvent is 1,4-dioxane, and the reaction temperature is 80℃~90℃; step <3> In this reaction, the acid is hydrogen bromide, the solvent is 90% ethanol, and the reaction temperature is 100℃~110℃. step <4> In this reaction, the acid is trifluoroacetic acid, the reaction solvent is chloroform and dichloromethane, and the reaction temperature is room temperature. step <5> In the reaction, the base is potassium carbonate, the catalyst is tetra(triphenylphosphine)palladium, the reaction solvent is 1,4-dioxane and water, and the reaction temperature is 90℃~100℃; step <6> In this reaction, the base is potassium carbonate, the catalyst is tetra(triphenylphosphine)palladium, the reaction solvent is 1,4-dioxane and water, and the reaction temperature is 95℃~105℃.

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