CN107805255B - Furan [3, 2-b ] pyridine-2 (1H) -ketone compound, preparation method and medical application - Google Patents

Abstract

The invention belongs to the field of medicines, and particularly relates to aromatic benzofuran [3, 2-b ]]Pyridine-2 (1H) -ketone compounds, pharmaceutically acceptable salts and isotopic labels thereof, pharmaceutical compositions containing the same and application of the compounds in treating diseases related to protein kinase activity, such as cancer, inflammation and the like.

Description

Furan[3,2-b]pyridin-2(1H)-one compound, preparation method and medicinal use

technical field

The invention belongs to the field of medicine, and in particular relates to a class of furo[3,2-b]pyridin-2(1H)-one compounds, pharmaceutically acceptable salts thereof, a pharmaceutical combination comprising the above substances, and a drug combination for treatment and protein kinase activity Use in related diseases such as cancer, inflammation and the like.

Background technique

As the population grows and ages, as well as factors such as smoking, obesity, and lack of exercise, the incidence of tumors increases year by year. Leukemia and lymphoma are malignant tumors that seriously affect the normal function of the hematopoietic system, with high incidence and poor prognosis. In 2015 global cancer statistics, leukemia accounted for 3.2% of deaths, while non-Hodgkin lymphoma, the main subtype of lymphoma, accounted for 2.7% of new cancers (Lindsey A. Torre, et al. CA CANCER J CLIN 2015;65:87-108). Current treatments for leukemia and lymphoma include chemotherapy and targeted therapy as well as homologous bone marrow transplantation. Homologous bone marrow transplantation is the most effective treatment for leukemia, but limited by the source of transplantation, only a few patients benefit from it. Chemotherapy is the most widely used treatment option, especially in underdeveloped areas, but its efficacy is poor and the side effects are large. With the development of pathology and molecular biology, targeting pathogenic factors or key signaling components inside and outside cancer cells has become a new direction for the treatment of leukemia and lymphoma. Although tyrosine kinase inhibitors (such as Imatinib, Ponatinib) and monoclonal antibody drugs (such as Rituximab, Alemtuzumab) have been used in the clinic, the development of new targeted inhibitors is urgently needed due to the defects of marketed drugs and the increase in incidence. with application.

Bruton's tyrosine kinase (Btk) is an important member of the non-receptor tyrosine kinase Tec family (whose main members include Btk, BMX(etk), Itk, Tec and Txk). Studies have shown that Btk plays a key role in the generation and development of B lymphocytes and in immune regulation. The expression of Btk runs through the entire developmental stage of B cells (except plasma cells) and is a key signal transduction factor in the B cell receptor (BCR) signaling pathway. Proliferation, differentiation, maturation, and play an important role in allergic and inflammatory responses. Sustained activation of Btk is a prerequisite for the development of chronic lymphocytic leukemia (CLL). In addition, abnormal BCR-Btk signaling promotes the survival of activated B cell subtypes, leading to the development of diffuse large B cell lymphoma (DLBCL). Ibrutinib is the only Btk inhibitor currently on the market and can be used for the treatment of many types of leukemia and lymphoma.

Phosphatidylinositol (PI) kinases are a unique class of lipid kinases that catalyze the phosphorylation and metabolism of phosphatidylinositol, which is involved in cell proliferation, survival, membrane trafficking, and cellular structural remodeling. The second messenger, thus phosphatidylinositol kinase, plays an important role in the cell. Based on the differences in structure, distribution and function, phosphatidylinositol 3-kinases (PI3K) are divided into three types: type I, type II and type III, among which type I PI3K is more deeply studied (α, β, delta and gamma). Studies have found that type I PI3K is involved in a variety of diseases. As an important signal transduction factor for immune cells, it also plays a pivotal role in leukemia and inflammation. In recent years, with the deepening of PI3K research, a large number of selective PI3K inhibitors have entered the clinic, and idelalisib is a selective PI3Kδ inhibitor, which was approved in 2014 for the treatment of multiple types of leukemia and lymphoma.

Although there are already Btk inhibitors and PI3K inhibitors on the market, but the varieties are single, there are many toxic and side effects, and drug resistance is prone to occur. The development of new inhibitors is of great significance.

SUMMARY OF THE INVENTION

The invention discloses a furo[3,2-b]pyridin-2(1H)-one compound with the structure of general formula (I) or a pharmaceutically acceptable salt thereof, which can be used to prepare and treat diseases related to protein kinase activity medicine.

The structure of general formula (1) is as follows

in,

Ring A is independently selected from aryl or heteroaryl, wherein heteroaryl contains at least one heteroatom selected from N, O, S;

R1 is selected from H, halogen, nitro, amino, acetamido, trifluoroacetamido; or R ₃ OCO(CH ₂ ) _m NH- or R ₃ SO ₂ NH-, wherein R ₃ is selected from hydrogen, C1～ C6 alkyl, m=2～3; or R ₄ (CH ₂ ) _n CONH-, wherein R ₄ is selected from acetoxy, hydroxyl, vinyl, dimethylamino, diethylamino, or nitrogen-containing saturated carbocyclic ring , n=0～1;

R2 is selected from hydrogen, halogen, C1-C3 alkyl, hydroxyl, C1-C3 alkoxy, nitro, amino, carboxyl or C1-C3 alkoxyacyl;

X is selected from CH or N.

In some embodiments, in Formula I, R ₂ is independently selected from hydrogen, methyl, hydroxyl, methoxy, nitro, amino, carboxyl, or ethoxyyl; Ring A is independently selected from phenyl, pyridine, pyridine azole, indole, piperidine. For example, Ring _A substituted with R is one of the following structures:

In some embodiments, the compound is selected from the following compounds:

According to another aspect of the present application, the present application provides a pharmaceutical composition comprising the compound described above in the present application, a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier.

According to another aspect of the present application, the present invention provides use of the above-mentioned compounds of the present application, pharmaceutically acceptable salts or prodrugs thereof, in the preparation of a medicament for inhibiting one or both of Btk and PI3K kinases.

According to yet another aspect of the present application, the present invention provides the above compounds, pharmaceutically acceptable salts or prodrugs thereof, for use in inhibiting one or both of Btk and PI3K kinases.

According to another aspect of the present application, the present invention provides a compound described herein, a pharmaceutically acceptable salt or prodrug thereof, in the manufacture of a treatment or prevention of a disease associated with protein kinase activity (eg, by inhibiting one of Btk and PI3K). or two kinases to treat or prevent).

According to yet another aspect of the present application, the present invention provides the compounds described herein, pharmaceutically acceptable salts or prodrugs thereof, for use in the treatment or prevention of diseases associated with protein kinase activity.

According to some embodiments of the present application, the present invention provides that the disease associated with protein kinase activity (eg, a disease treated or prevented by inhibiting one or both of Btk and PI3K kinases) may be tumors, such as leukemia, malignant Lymphoma, multiple myeloma, breast cancer. The disease associated with protein kinase activity described in the present invention may also be inflammation, such as rheumatoid arthritis, systemic lupus erythematosus.

Detailed ways

The appended claims of the invention set forth the novel features of the invention with particularity. Exemplary embodiments utilizing the principles of the present invention are set forth below. The features and advantages of the present invention may be better understood by reference to the following.

While preferred embodiments of the present application have been described herein, these embodiments are provided by way of example only. It should be understood that the variants of the embodiments of the present application described herein can also be used to implement the technical solutions of the present application. It will be understood by those of ordinary skill in the art that various modifications, changes and substitutions may occur without departing from the scope of the present application. It should be understood that the scope of protection for various aspects of this application is to be determined by the appended claims, and that methods and structures within the scope of these claims, as well as their equivalents, are within the scope of the claims of this application.

synthetic route

The synthetic method of the compound in this application includes but is not limited to the following reaction formula and reaction steps:

route one

route two

route three

Example 1

Synthesis of Intermediate 5-Bromo-2-Hydroxybenzoate Methyl

Methyl salicylate (S1) (15.2g, 0.1mol) was dissolved in 100ml of dichloromethane at room temperature, and 1M bromine/dichloromethane solution (170ml) was added dropwise to the reaction solution, and the reaction was carried out for 12 hours. The dichloromethane was removed, and the residue was poured into saturated sodium sulfite to precipitate a solid, which was dried, crystallized from anhydrous ethanol, and dried to obtain 22.65 g with a yield of 98%. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 3.98 (s, 3H), 6.90 (d, J=8.91 Hz, 1H), 7.55 (dd, J=8.91, 2.52 Hz, 1H), 7.97 (d, J =2.52Hz, 1H), 10.7(s, 1H).

Synthesis of Intermediate (4-bromo-2-carboxylic acid)phenoxyacetic acid (S4)

Methyl 5-bromo-2-hydroxybenzoate (22.6 g, 97.8 mmol) was dissolved in 200 ml of acetone, potassium carbonate (27 g, 0.195 mol) and a catalytic amount of KI were added, followed by ethyl bromoacetate (12.2 ml, 0.107 mol), react at reflux temperature for 6h, spin off most of the acetone, then pour into water to precipitate a solid, suction filtration to obtain a solid (4-bromo-2-carboxylate) ethyl phenoxyacetate, and go directly to the next step.

The product of the previous step (S3) was added to 100ml of ethanol, added to 1M aqueous sodium hydroxide solution (250ml), refluxed for 2h, ethanol was removed, the pH was adjusted to strong acidity with concentrated hydrochloric acid, a solid was precipitated, suction filtered, and dried 24.38 g of (4-bromo-2-carboxylic acid)phenoxyacetic acid (S4) was obtained, with a yield of 90%.

Synthesis of Intermediate 5-Bromo-3(2H)-benzofuranone (S5)

(4-Bromo-2-carboxylic acid)phenoxyacetic acid (S4) (37.4g, 0.136mol) was added to 110ml of acetic acid, 380ml of acetic anhydride and 37g of sodium acetate were added, and the reaction was carried out at 150°C for 6h, and the acetic anhydride was removed. , cooled, added water and stirred for 2h, extracted with ethyl acetate, concentrated, added 150ml of 1M hydrochloric acid, 250ml of methanol, reacted at 100°C for 2h, spin off methanol, precipitated a solid, suction filtered, and dried to obtain 27.17g of 5-bromo- 3(2H)-benzofuranone (S5), yield 93.8%. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 4.88 (s, 2H), 7.28 (d, J=8.76 Hz, 1H), 7.79 (d, J=2.01 Hz, 1H), 7.84 (dd, J=8.76 , 2.01Hz, 1H).

Synthesis of Intermediate 5-Bromo-3-(4-nitroaniline)benzofuran

5-Bromo-3(2H)-benzofuranone (S5) (1.3 g, 6.1 mmol) and p-nitroaniline (0.9 g, 6.1 mmol) were dissolved in 60 ml of toluene, and a catalytic amount of p-methyl monohydrate was added benzenesulfonic acid, and equipped with a water separator, refluxed for 4 hours, spun off toluene, added water and suction filtered, and dried to obtain 2.03 g of crude product with a yield of 100%. ¹ H-NMR (300 MHz, d ₆ -DMSO) δ 7.04 (d, J=9.21 Hz, 2H), 7.52 (dd, J=1.95, 8.73 Hz, 1H), 7.58 (d, J=8.73 Hz, 1H) ), 7.89(d, J=1.95Hz, 1H), 8.10(d, J=9.21Hz, 2H), 8.33(s, 1H), 9.19(s, 1H).

Synthesis of Intermediate 5-Bromo-3-(N-acetamido-4nitroaniline)benzofuran

5-Bromo-3-(4-nitroaniline)benzofuran (0.4g, 1.2mmol) was dissolved in 5ml of N,N-dimethylformamide, and 60% sodium hydrogen (86mg, 60%) was added under ice bath. 2.16 mmol), until no bubbles were generated, slowly added acetyl chloride (0.14 ml, 1.8 mmol) dropwise to it, the addition was completed, the reaction was carried out at room temperature for 1 h, poured into water, extracted with ethyl acetate, and separated by column chromatography to obtain 0.32 g of solid, Direct next step, yield 71%.

Synthesis of Intermediate 8-Bromo-1-(4-nitrobenzene)-benzofuro[3,2-b]pyridin-2(1H)-one

N,N-dimethylformamide (2.8ml, 36.6mmol) was added to the reaction flask, under ice bath, phosphorus oxychloride (3.4ml, 36.6mmol) was slowly added dropwise to it, and then dissolved in N,N -5-bromo-3-(N-acetamido-4 nitroaniline) benzofuran (6.85g, 18.3mmol) in dimethylformamide was added, moved to room temperature and reacted for 0.5h, heated to 95°C for reaction 6h, cooled, poured into water, extracted with ethyl acetate, column chromatography gave 2.5g, the yield was 35.5%. ¹ H-NMR (300 MHz, d ₆ -DMSO) δ 6.3 (d, J=1.74 Hz, 1H), 6.72 (d, J=9.87 Hz, 1H), 7.63 (dd, J=1.74, 8.91 Hz, 1H) ), 7.76(d, J=8.91Hz, 1H), 7.92(d, J=8.94Hz, 2H), 8.22(d, J=9.87Hz, 1H), 8.54(d, J=8.94Hz, 2H).

Synthesis of 8-(6-Methoxy-3-pyridine)-1-(4-nitrobenzene)-benzofuro[3,2-b]pyridin-2(1H)-one (BP-A10)

8-Bromo-1-(4-nitrobenzene)-benzofuro[3,2-b]pyridin-2(1H)-one (2.04 g, 5.3 mmol) in 25 ml of dioxane was added 2-Methoxy-5-pyridineboronic acid (0.892g, 5.8mmol), and 1.46g potassium carbonate, 80mg triphenylphosphine palladium chloride and 1ml water, react for 5h under nitrogen protection, then spin to remove the solvent, add water , extracted three times with ethyl acetate, concentrated, and obtained 1.7 g of the target compound by column chromatography, with a yield of 77.6%. ¹ H-NMR (300 MHz, d ₆ -DMSO) δ 3.76 (s, 3H), 6.24 (d, J=1.29 Hz, 1H), 6.60 (d, J=9.81 Hz, 1H), 6.74 (d, J =8.58Hz, 1H), 7.57(dd, J=2.55, 8.61Hz, 1H), 7.64(dd, J=1.62, 8.73Hz, 1H), 7.75(d, J=8.7Hz, 1H), 7.87(d , J=8.85Hz, 2H), 8.01 (d, J=2.22Hz, 1H), 8.11 (d, J=9.84Hz, 1H), 8.47 (d, J=8.85Hz, 2H).

Example 2

Synthesis of 1-(4-Aminobenzene)-8-(6-methoxy-3-pyridine)-benzofuro[3,2-b]pyridin-2(1H)-one (BP-A01)

0.21 g (0.51 mmol) of compound BP-A10 in a mixed solvent of ethanol-water (4:1) was added with 0.34 g (6.12 mmol) of iron powder, heated to reflux, and then 0.33 g (6.12 mmol) of iron powder was added. Ammonium chloride, reacted for 4 h, filtered, the filter cake was washed with methanol and ethyl acetate, the filtrate was concentrated, and 0.16 g of the target compound was obtained by column chromatography with a yield of 82%. ¹ H-NMR (300 MHz, d ₆ -DMSO) δ 3.76 (s, 3H), 5.47 (s, 2H), 6.36 (d, J=1.32 Hz, 1H), 6.51 (d, J=9.75 Hz, 1H) ), 6.73 (d, J=8.55Hz, 2H), 6.79 (d, J=8.55Hz, 1H), 7.04 (d, J=8.55Hz, 2H), 7.63 (dd, J=2.25, 8.52Hz, 1H) ), 7.9(d, J=9.75Hz, 1H), 8.05(d, J=2.25Hz, 1H).

Example 3

1-(4-Trifluoroacetamidobenzene)-8-(6-methoxy-3-pyridine)-benzofuro[3,2-b]pyridin-2(1H)-one (BP-A03)

0.1 g (0.261 mmol) of compound BP-A01 was dissolved in 10 ml of dichloromethane, and 0.056 ml of triethylamine was added. At room temperature, 0.054 ml (0.39 mmol) of trifluoroacetic anhydride was added, and the reaction was carried out for 2 h. 50 ml of dichloromethane was added, washed with saturated sodium bicarbonate, brine, and anhydrous sodium sulfate overnight, and 94 mg of the target compound was obtained by column chromatography with a yield of 75.2%. ¹ H-NMR (300MHz, d ₆ -DMSO) δ 3.84 (s, 3H), 6.16 (s, 1H), 6.65 (d, J=9.75Hz, 1H), 6.77 (d, J=8.55Hz, 1H) ), 7.60 (d, J=2.31Hz, 1H), 7.64 (d, J=8.25Hz, 2H), 7.72 (dd, J=1.53, 10.1Hz, 1H), 7.79 (d, J=8.73Hz, 1H) ), 7.96 (d, J=8.61Hz, 2H), 8.11 (d, J=2.07Hz, 1H), 8.15 (d, J=9.81Hz, 1H).

Example 4

Synthesis of 1-(4-Acrylamidobenzene)-8-(6-methoxy-3-pyridine)-benzofuro[3,2-b]pyridin-2(1H)-one (BP-A04)

Put 0.1 g (0.261 mmol) of compound BP-A01 in 5 ml of N,N-dimethylformamide, add 72 mg (0.52 mmol) of potassium carbonate, and slowly add acryloyl chloride (32 ul, 0.391 mmol) to it under ice bath ), then reacted for 1 h, added water, extracted with ethyl acetate, and obtained 72 mg of the target compound by column chromatography with a yield of 63%. ¹ H-NMR (300MHz, d ₆ -DMSO) δ 3.84 (s, 3H), 5.84 (dd, J=0.51, 9.57Hz, 1H), 6.22 (s, 1H), 6.35 (d, J=16.5Hz) , 1H), 6.53 (dd, J=10.17, 12.7Hz, 1H), 6.64 (d, J=9.81Hz, 1H), 6.8 (d, J=8.55Hz, 1H), 7.53 (d, J=8.49Hz) , 2H), 7.63 (dd, J=1.59, 8.64Hz, 1H), 7.72 (d, J=8.73Hz, 1H), 7.8 (d, J=8.79Hz, 1H), 7.94 (d, J=8.46, 2H), 8.11 (d, J=2.07Hz, 1H), 8.14 (d, J=9.63Hz, 1H), 10.51 (s, 1H).

Example 5

Synthesis of 1-(4-Chloroacetamidobenzene)-8-(6-methoxy-3-pyridine)-benzofuro[3,2-b]pyridin-2(1H)-one (BP-A05)

Put 0.2g (0.52mmol) of compound BP-A01 in 5ml of N,N-dimethylformamide, add 0.143g of potassium carbonate, slowly add chloroacetyl chloride to it under ice bath, react for 1h, add water, Extracted with ethyl acetate, washed with brine, concentrated, and obtained 0.2 g by column chromatography with a yield of 84%. ¹ H-NMR (300MHz, d ₆ -DMSO) δ 3.84(s, 3H), 4.33(s, 2H), 6.19(s, 1H), 6.62(d, J=9.96Hz, 1H), 6.8(d , J=8.64Hz, 1H), 7.53 (d, J=8.4Hz, 2H), 7.60 (dd, J=2.04, 8.55Hz, 1H), 7.71 (d, J=8.73Hz, 1H), 7.78 (d , J=8.61Hz, 2H), 7.85 (d, J=8.4, 2H), 8.11 (d, J=2.04Hz, 1H), 8.12 (d, J=9.87Hz, 1H), 10.64 (s, 1H) .

Example 6

1-(4-Dimethylaminoacetamidobenzene)-8-(6-methoxy-3-pyridine)-benzofuro[3,2-b]pyridin-2(1H)-one (BP-A09) Synthesis

0.24g (0.52mmol) of compound BP-A05 was dissolved in 5ml of N,N-dimethylformamide, 0.215g of potassium carbonate and dimethylamine hydrochloride (85mg) were added, and then reacted at 60°C for 2h, cooled , poured into water, extracted with ethyl acetate, washed with brine, concentrated, and obtained 0.21 g by column chromatography with a yield of 86.4%. ¹ H-NMR (300MHz, d ₆ -DMSO) δ 2.47(s, 6H), 3.30(s, 2H), 3.98(s, 3H), 6.32(s, 1H), 6.76(d, J=9.81Hz) , 1H), 6.91 (d, J=8.55Hz, 1H), 7.62 (d, J=8.34Hz, 2H), 7.75 (d, J=8.37Hz, 1H), 7.83 (d, J=8.85Hz, 1H) ), 7.9(d, J=8.7Hz, 2H), 8.11(d, J=8.34, 2H), 8.22(s, 1H), 8.25(d, J=9.81Hz, 1H), 10.23(s, 1H) .

Example 7

(4-(8-(6-Methoxy-3-pyridine)-2-oxo-benzofuro[3,2-b]pyridine-(1H))-1-anilino)ethyl acetate (BP -A07) synthesis

Put 0.2g (0.52mmol) of compound BP-A01 in 5ml of N,N-dimethylformamide, add 0.143g of potassium carbonate, slowly add ethyl chloroacetate to it under ice bath, react for 1h, add water , extracted with ethyl acetate, washed with brine, concentrated, and obtained 0.2 g by column chromatography with a yield of 82%. ¹ H-NMR (300 MHz, d ₆ -DMSO) δ 1.20 (t, J=7.05 Hz, 4H), 3.86 (s, 3H), 4.0 (d, J=5.16 Hz, 2H), 4.13 (q, J =7.05Hz, 3H), 6.4(s, 1H), 6.49(m, 1H), 6.58(d, J=9.72Hz, 1H), 6.80(d, J=7.08Hz, 2H), 6.86(d, J =8.58Hz, 1H), 7.20(d, J=8.37Hz, 2H), 7.64(d, J=8.85Hz, 1H), 7.73(m, 2H), 8.0(d, J=9.72Hz, 1H), 8.19(s, 1H).

Example 8

(4-(8-(6-Methoxy-3-pyridine)-2-oxo-benzofuro[3,2-b]pyridine-(1H))-1-anilino)acetic acid (BP-A08 )Synthesis

Put 50mg (0.106mmol) of compound BP-A07 in 2ml of methanol, add 2ml of 1M sodium hydroxide solution, at 65°C, until the raw material disappears, adjust the pH to about 4 with 1M hydrochloric acid, precipitate solid, suction filtration , was dried to 30mg, the yield was 64.2%. ¹ H-NMR (300MHz, d ₆ -DMSO) δ 3.86(s, 3H), 3.94(s, 2H), 6.37(s, 1H), 6.58(d, J=9.75Hz, 1H), 6.80(d , J=8.58Hz, 2H), 6.86 (d, J=8.67Hz, 1H), 7.18 (d, J=8.52Hz, 2H), 7.61 (d, J=8.61Hz, 1H), 7.72 (s, 2H) ), 8.0(d, J=9.75Hz, 1H), 8.20(s, 1H).

Example 9

Synthesis of Intermediate 8-Bromo-1-(4-aminobenzene)-benzofuro[3,2-b]pyridin-2(1H)-one

A mixed solvent of 1.26 g (3.1 mmol) of compound 8-bromo-1-(4-nitrobenzene)-benzofuro[3,2-b]pyridin-2(1H)-one in ethanol-water (4 : 1), add 0.43g (7.7mmol) of iron powder, heat to reflux, then add 0.42g of ammonium chloride, react for 3h, filter, the filter cake is washed with methanol and ethyl acetate, the filtrate is concentrated, and then column chromatography 0.9 g of the target substance was obtained with a yield of 81.8%. ¹ H-NMR (300 MHz, d ₆ -DMSO) δ 5.57 (s, 2H), 6.39 (d, J=1.95 Hz, 1H), 6.61 (d, J=9.81 Hz, 1H), 6.77 (d, J =8.58Hz, 2H), 7.07(d, J=8.58Hz, 2H), 7.58(dd, J=2.04, 8.85Hz, 2H), 7.78(d, J=8.85Hz, 1H), 8.08(d, J =9.81Hz, 1H).

Synthesis of Intermediate 8-Bromo-1-(4-acrylamidobenzene)-benzofuro[3,2-b]pyridin-2(1H)-one

0.93 g (2.62 mmol) of compound S12 was dissolved in 10 ml of N,N-dimethylformamide, 0.72 g of potassium carbonate was added, and acryloyl chloride (0.43 ml, 5.24 mmol) was slowly added thereto under ice bath, and then reacted After 1 h, water was added, extracted with ethyl acetate, and 0.8 g of the target compound was obtained by column chromatography with a yield of 74.7%.

Synthesis of 1-(4-Acrylamidobenzene)-8-(3-aminophenyl)-benzofuro[3,2-b]pyridin-2(1H)-one (BP-C07)

8-Bromo-1-(4-acrylamidobenzene)-benzofuro[3,2-b]pyridin-2(1H)-one (0.15 g, 0.36 mmol) in 15 ml of dioxane, Add 3-aminopyridineboronic acid (62 mg, 0.4 mmol), 55 mg of potassium carbonate, 70 mg of triphenylphosphine palladium chloride and 1 ml of water, react under nitrogen protection for 5 h, then spin off the solvent, add water, and extract with ethyl acetate three times , concentrated, and column chromatography gave 0.1 g of the target product, the yield was 66.6%. ¹ H-NMR (300 MHz, d ₆ -DMSO) δ 5.08 (s, 2H), 5.85 (d, J=10.2 Hz, 1H), 6.23 (s 1H), 6.35 (d, J=17 Hz), 6.51 ( m, 4H), 6.63 (d, J=9.6Hz, 1H), 6.97 (t, J=7.38Hz, 1H), 7.53 (d, J=8.28Hz, 2H), 7.62 (d, J=8.79Hz, 1H), 7.72 (d, J=8.58Hz, 1H), 7.94 (d, J=8.28Hz, 2H), 8.12 (d, J=9.84Hz, 1H), 10.55 (s, 1H).

Example 10

Synthesis of Intermediate 8-Bromo-1-(4-chloroacetamidobenzene)-benzofuro[3,2-b]pyridin-2(1H)-one

1.4 g (3.95 mmol) of compound S12 was dissolved in 20 ml of N,N-dimethylformamide, 1.1 g of potassium carbonate was added, and chloroacetyl chloride (0.36 ml, 4.7 mmol) was slowly added thereto under an ice bath, and then The reaction was carried out for 2 h, water was added, extracted with ethyl acetate, and concentrated to the next step.

Synthesis of Intermediate 8-Bromo-1-(4-N,N-Dimethylaminoacetamidobenzene)-benzofuro[3,2-b]pyridin-2(1H)-one

About 1.69 g (3.95 mmol) of 8-bromo-1-(4-chloroacetamidobenzene)-benzofuro[3,2-b]pyridin-2(1H)-one was dissolved in 20 ml of N,N-di To methylformamide, add 1.63g potassium carbonate, catalytic potassium iodide, 0.64g (7.9mmol) dimethylamine hydrochloride, react at 65°C for 2h, add water, extract with ethyl acetate, and obtain 1.61g by column chromatography The target product, the yield is 93%. ¹ H-NMR (300MHz, d ₆ -DMSO) δ 2.44 (s, 6H), 3.16 (s, 2H), 6.52 (d, J=1.83, 1H), 6.75 (d, J=9.78, 1H), 7.41 (d, J=8.73Hz, 2H), 7.41 (d, J=8.97Hz, 1H), 7.47 (dd, J=1.83, 8.97Hz, 1H), 7.80 (d, J=9.73, 1H), 7.93 (d, J=8.73Hz, 2H).

Synthesis of 1-(4-Dimethylaminoacetamidobenzene)-8-(4-indole)-benzofuro[3,2-b]pyridin-2(1H)-one (BP-E01)

8-Bromo-1-(4-N,N-dimethylaminoacetamidobenzene)-benzofuro[3,2-b]pyridin-2(1H)-one (0.12 g, 0.27 mmol) in 15 ml of In the dioxane, 4-indoleboronic acid pinacol ester (62 mg, 0.4 mmol) was added, as well as 75 mg of potassium carbonate, 70 mg of triphenylphosphine palladium chloride and 1 ml of water, reacted under nitrogen protection for 6 h, and then rotated Remove the solvent, add water, extract three times with ethyl acetate, concentrate, and obtain 70 mg of the target compound by column chromatography with a yield of 54.6%. ¹ H-NMR (300MHz, d ₆ -DMSO) δ 2.29(s, 6H), 3.11(s, 2H), 6.18(s, 1H), 6.62(d, J=9.78Hz, 1H), 6.63(s) , 1H), 6.92 (d, J=6.96Hz, 1H), 7.08 (t, J=7.47Hz, 1H), 7.29 (t, J=2.7Hz, 1H), 7.48 (d, J=8.73Hz, 2H) ), 7.72 (dd, J=1.62, 8.37Hz, 1H), 7.78 (d, J=8.67Hz, 1H), 7.95 (d, J=8.76Hz, 2H), 8.12 (d, J=9.78, 2H) , 9.93(s, 1H), 11.21(s, 1H).

Example 11

Synthesis of Intermediate 8-(6-Methoxy-3-pyridine)-1-(3-aminobenzene)-benzofuro[3,2-b]pyridin-2(1H)-one (S18)

The synthesis method is the same as that of BP-A01 in Example 1. ¹ H-NMR (300 MHz, d ₆ -DMSO) δ 3.84 (s, 3H), 6.3 (d, J=1.23 Hz, 1H), 6.67 (d, J=9.81 Hz, 1H), 6.82 (d, J =8.7Hz, 1H), 7.65(dd, J=2.585, 8.58Hz, 1H), 7.64(dd, J=1.71, 8.76Hz, 1H), 7.83(d, J=8.67Hz, 1H), 7.99(t , J=8.07Hz, 2H), 8.06 (d, J=2.19Hz, 1H), 8.12 (d, J=8.31Hz, 1H), 8.18 (d, J=9.81Hz, 1H), 8.5 (s, 1H) ), 8.54(m, 1H).

Synthesis of 8-(6-Methoxy-3-pyridine)-1-(3-acrylamidobenzene)-benzofuro[3,2-b]pyridin-2(1H)-one (BP-D02)

The synthesis method is the same as that of BP-A04 in Example 1. ¹ H-NMR (300 MHz, d ₆ -DMSO) δ 3.87 (s, 3H), 5.77 (d, J=9.66 Hz, 1H), 6.26 (d, J=16.32 Hz, 1H), 6.34 (s, 1H) ), 6.45 (dd, J=10.17, 12.7Hz, 1H), 6.65 (d, J=9.54Hz, 1H), 6.83 (d, J=8.52Hz, 1H), 7.31 (d, J=7.89Hz, 1H) ), 7.65(d, J=7.98Hz, 2H), 7.72(d, J=8.64Hz, 1H), 7.81(m, 2H), 7.97(s, 1H), 8.09(s, 1H), 8.15(d , J=9.51Hz, 1H), 10.45(s, 1H).

Example 12

8-(6-Methoxy-3-pyridine))-(6-methoxy-3-pyridine)-1-(3-chloroacetamidobenzene)-benzofuro[3,2-b]pyridine- Synthesis of 2(1H)-ketones

The synthesis method is the same as that of BP-A09 in Example 1. ¹ H-NMR (300 MHz, d ₆ -DMSO) δ 2.5 (brs, 4H), 3.14 (s, 2H), 3.59 (brs, 4H), 3.86 (s, 3H), 6.32 (s, 1H), 6.65 (d, J=9.9Hz, 1H), 6.84 (d, J=8.64Hz, 1H), 7.28 (d, J=7.62Hz, 1H), 7.68 (m, 3H), 7.81 (d, J=8.85Hz) , 1H), 7.88(d, J=7.65Hz, 1H), 7.93(s, 1H), 8.07(d, J=2.19Hz, 1H), 8.16(d, J=9.87Hz, 1H), 10.0(s , 1H).

Example 13

Synthesis of Intermediate 5-Bromo-2-hydroxynicotinic acid

2-Hydroxynicotinic acid (18.98g, 0.136mmol) was dissolved in acetic acid, liquid bromine (8.4ml, 0.163mmol) was added, the reaction was carried out at 80°C overnight, the acetic acid was removed, water was added, stirred for 1h, suction filtered and dried to obtain 22.7g of product, Yield 76.6%. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.25 (d, J=2.4 Hz, 1H), 8.34 (d, J=2.4 Hz 1H), 13.8 (brs, 1H).

Synthesis of intermediate 5-bromo-2-chloro-nicotinic acid methyl ester

Put 5-bromo-2-hydroxynicotinic acid (22.7g, 0.104mol) in 100ml of thionyl chloride, drop a drop of N,N-dimethylformamide, react under reflux for 12h, then spin to remove sulfoxide The sulfone was cooled, diluted with dichloromethane, methanol was slowly added to it under an ice bath, and then at room temperature for 2 h, the DCM was spun off, the pH was adjusted with saturated sodium bicarbonate, extracted with ethyl acetate, and concentrated by column chromatography to obtain 20 g, yield 76.9%.

Synthesis of Intermediate 5-Bromo-furo[2,3-b]pyridin-3(2H)-one

NaH (2.78 g, 69.46 mmol) was dissolved in ethylene glycol dimethyl ether, under ice bath, ethyl alcohol and ethyl acetate (6 ml, 63.4 mmol) was slowly added, and then dissolved in ethylene glycol dimethyl ether after 0.5 h at room temperature. 5-Bromo-2-chloro-nicotinic acid methyl ester of ether (7.54g, 30.2mmol) was added to it, overnight at 65°C, the solvent was removed, ethanol was added, and then 1M sodium hydroxide solution (75mmol) was added, at 80°C After the reaction for half an hour, the ethanol was removed, concentrated hydrochloric acid was added, the reaction was carried out at 80° C. for 2 hours, extracted with ethyl acetate, and concentrated by column chromatography to obtain 4.4 g with a yield of 68.7%. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 4.76 (s, 2H), 8.09 (d, J=8.46 Hz 1H), 8.56 (d, J=2.46 Hz 1H).

Synthesis of Intermediate 5-Bromo-3-(4-nitroanilino)-furo[2,3-b]pyridine

5-Bromo-furo[2,3-b]pyridin-3(2H)-one (4.3 g, 20.18 mmol) and p-nitroaniline (2.8 g, 20.18 mmol) in toluene were added a catalytic amount of p-toluene Sulfuric acid, refluxed for 6 h, spun off toluene, added water, suction filtered, and dried to obtain 6.2 g of the target product with a yield of 92%. ¹ H-NMR (300 MHz, d ₆ -DMSO) δ 7.06 (d, J=9.21 Hz, 2H), 8.12 (d, J=9.21 Hz, 2H), 8.4 (d, J=2.25 Hz, 1H), 8.43(s, 1H), 8.46(d, J=2.25Hz, 1H), 9.29(s, 1H).

Synthesis of Intermediate N-acetyl-N-(5-bromo-furo[2,3-b]pyridine-3)-4-nitroaniline

6.24g (18.68mmol) of 5-bromo-3-(4-nitroanilino)-furo[2,3-b]pyridine in DMF was slowly added sodium hydrogen (1.12g, 28mmol) under ice bath, When no bubbles were generated, slowly inject acetyl chloride (2 ml, 28 mmol) with a syringe, pour into water at room temperature for 1 h, and precipitate a solid, filter with suction, and dry it directly to the next step.

Synthesis of Intermediate 8-Bromo-1-(4-nitrobenzene)-furo[2,3-b:4,5-b']bipyridin-2(1H)-one

N,N-dimethylformamide (2.8ml, 36.6mmol) was added to the reaction flask, under ice bath, phosphorus oxychloride (3.4ml, 36.6mmol) was slowly added dropwise to it, and then dissolved in N,N -N-acetyl-N-(5-bromo-furo[2,3-b]pyridine-3)-4-nitroaniline (6.85 g, 18.3 mmol) in dimethylformamide was added and moved to room temperature Under reaction for 0.5h, the temperature was raised to 95°C for 6h, cooled, poured into water, extracted with ethyl acetate, and 2.5g was obtained by column chromatography with a yield of 35.5%. ¹ H-NMR (300MHz, d ₆ -DMSO) δ 6.75 (d, J=9.87Hz, 1H), 6.82 (d, J=2.19Hz, 1H), 7.86 (d, J=8.88Hz, 2H), 8.22 (d, J=9.87Hz, 1H), 8.49 (d, J=8.88Hz, 2H), 8.51 (d, J=2.19Hz, 1H).

Intermediate 1-(4-Nitrobenzene)-8-(6-methoxy-3-pyridine)-furo[2,3-b:4,5-b']dipyridin-2(1H)-one Synthesis

8-Bromo-1-(4-nitrobenzene)-furo[2,3-b:4,5-b']dipyridin-2(1H)-one (1.9 g, 4.92 mmol) in 25 ml of dipyridin In oxane, add 2-methoxy-5-pyridineboronic acid (0.75g, 4.92mmol), and 1.35g of potassium carbonate, 80mg of triphenylphosphine palladium chloride and 1ml of water, react under nitrogen protection for 5h, Then spin off the solvent, add water, extract three times with ethyl acetate, concentrate, and obtain 1.5 g of the target compound by column chromatography with a yield of 73.8%. Intermediate 1-(4-Aminobenzene)-8-(6-methoxy-3-pyridine)-furo[2,3-b:4,5-b']dipyridin-2(1H)-one synthesis

1-(4-Nitrobenzene)-8-(6-methoxy-3-pyridine)-furo[2,3-b:4,5-b']dipyridin-2(1H)-one ( 1.5g, 3.63mmol) in ethanol, add 5% Pd-C, pass hydrogen, reflux overnight, filter, wash the filter cake with methanol and ethyl acetate, concentrate to obtain 1.2g, yield 86%. ¹ H-NMR (300MHz, d ₆ -DMSO) δ 3.98(s, 3H), 5.55(s, 2H), 6.67(d, J=9.78Hz, 1H), 6.78(s, 1H), 6.79(d , J=9.0Hz, 2H), 6.91 (d, J=8.61Hz, 1H), 7.14 (d, J=9.0Hz, 2H), 7.79 (dd, J=2.52, 8.61Hz, 1H), 8.13 (d , J=9.78Hz, 1H), 8.17 (d, J=2.19Hz, 1H), 8.65 (d, J=2.22Hz, 1H).

Intermediate 1-(4-Chloroacetamidobenzene)-8-(6-methoxy-3-pyridine)-furo[2,3-b:4,5-b']dipyridine-2(1H)- Synthesis of Ketones

0.5 g (1.3 mmol) of 1-(4-aminobenzene)-8-(6-methoxy-3-pyridine)-furo[2,3-b:4,5-b']dipyridine-2 (1H)-ketone was dissolved in DMF, potassium carbonate (0.358 g, 2.6 mmol) was added, chloroacetyl chloride (0.113 ml, 1.43 mmol) was slowly added to it under ice bath, then 1 h at room temperature, poured into water, ethyl acetate Extraction and concentration go directly to the next step.

1-(4-(N-Piperazinyl)acetamidobenzene)-8-(6-methoxy-3-pyridine)-furo[2,3-b:4,5-b']dipyridine-2 Synthesis of (1H)-ketone (BP-G04)

0.25 g (0.54 mmol) of 1-(4-chloroacetamidobenzene)-8-(6-methoxy-3-pyridine)-furo[2,3-b:4,5-b']dipyridine -2(1H)-ketone was dissolved in 5ml of N,N-dimethylformamide, 0.373g potassium carbonate and piperazine (0.46g) were added, then reacted at 60°C for 2h, cooled, poured into water, ethyl acetate Extracted, washed with brine, concentrated, and obtained 70 mg by column chromatography. ¹ H-NMR (300 MHz, d ₆ -DMSO) δ 2.31 (brs, 4H), 2.49 (brs, 4H), 3.23 (s, 2H), 3.85 (s, 3H), 6.57 (s, 1H), 6.79 (d, J=9.87Hz, 1H), 6.83 (d, J=8.61Hz, 1H), 7.51 (d, J=8.58Hz, 2H), 7.68 (dd, J=2.22, 8.58Hz, 1H), 7.93 (d, J=8.61Hz, 2H), 8.13 (s, 1H), 8.15 (d, J=9.9Hz, 1H), 8.63 (d, J=1.92Hz, 1H), 10.11 (s, 1H).

Biological activity test

Part of the pharmacological tests and results of the compounds of the present invention are as follows:

1. MTT assay for K562 cell proliferation assay

K562 cells are lymphoblasts derived from a 53-year-old female chronic myeloid leukemia patient at the outbreak stage.

Test method: K562 breast cancer cells were cultured in RPMI1640 medium containing 10% fetal bovine serum, and cells in logarithmic growth phase were used for experiments. After culturing for 12 hours, add 100 μl/well of drug-containing medium, and the final concentration of the sample is 4×10-5mol/L, 2×10-5mol/L, 1×10-5mol/L, 5×10-6mol/L and 1×10-6mol/L, 3 replicate wells for each concentration, the same volume of culture medium was used instead of the test drug as the control group, 20μl/well MTT (concentration 5mg/ml) was added after culturing for 48 hours, and the culture was incubated for 4h Then, the plate was centrifuged, the supernatant was discarded, 150 μl/well of DMSO was added, and the absorbance (A) value of each well was measured at a wavelength of 492 nm with an enzyme label detector, and the inhibition rate of cell proliferation was calculated according to the formula: inhibition rate = (A value of control group -A value of experimental group)/(A value of control group-A value of blank group)×100%, and IC50 was calculated.

2. MTT assay to test the anti-proliferative activity of Raji cells

The Raji cell line is derived from Burkitt's lymphoma in the left maxilla of an 11-year-old black boy, and is also a commonly used cell line for research such as leukemia treatment. The test method of MTT method is the same as that of MCF-7 cells.

3. Btk enzyme activity test

According to the principle that ATP can phosphorylate Btk to form ADP, the ADP-GloTM kinase system can convert ADP into fluorescently labeled ATP belonging to ATP tyrosine kinase, so as to measure the activity of the kinase. The brief steps are: 1. Enzyme inhibition reaction, that is, adding the tested inhibitor to the kinase reaction solution containing the enzyme substrate, then adding ATP, and reacting for 60 mins; 2. Adding ADP-GloTM reagent to terminate the kinase reaction and remove the remaining 3. Incubate at room temperature for 40 minutes; 4. Add detection reagent and luciferase to convert ADP into fluorescently labeled ATP; 5. Incubate at room temperature for 30 mins; 6. Detect fluorescence and calculate inhibition rate.

Table 1 Cell activity and Btk enzyme activity of the compounds of the present invention

Using Ibrutinib as a positive control, the anti-proliferation experiments of K562 cells and Raji were performed on the synthetic furo[3,2-b]pyridin-2(1H)-ones. The results showed that most of the compounds showed good inhibitory activity against the two cell lines. In the Btk enzyme inhibition experiment with Ibrutinib as the control, most of the compounds have inhibitory effect on Btk. Therefore, the compounds can be used as Btk inhibitors for the treatment of leukemia or lymphoma.

4. PI3K-Akt signaling pathway inhibition test

PI3K kinase can cause a series of cascade reactions and activate the downstream Akt protein, which is manifested by phosphorylation at Ser473 of Akt protein. Therefore, the activity of PI3K kinase can be indirectly reflected by detecting the expression level of phosphorylated protein, that is, if the compound inhibits the activity of PI3K kinase, the protein expression of pAkt (Ser473) decreases. The inhibitory activity of selected compounds on Akt (Ser473) protein expression was determined.

The K562 cell line was selected, cultured in a 5% carbon dioxide environment, and 1 μM of the selected compound was added respectively. After 24 hours, the cells were collected as the β-actin internal reference protein, dissolved in lysis buffer, and the protein was extracted by Western blotting. Changes in protein content were detected by the method (Figure 1).

Description of drawings

Figure 1 shows the grayscale images of Akt protein and pAkt protein expression detected by Western blot. The change of protein content can be judged according to the depth of the color, so as to detect the inhibitory effect of the compound on the protein. Using BEZ235 as a positive control, the synthetic furo[3,2-b]pyridin-2(1H)-one compounds were used to inhibit the expression of Akt phosphorylation. The results of the study showed that all the tested compounds could significantly inhibit Akt phosphorylation.

Claims (7)

1. A compound of formula (1), a pharmaceutically acceptable salt thereof:

in, Ring A is independently selected from phenyl, pyridine, pyrazole, indole, piperidine; R1 is selected from nitro, amino, acetamido, trifluoroacetamido; or R ₃ OCO(CH ₂ ) _m NH- or R ₃ SO ₂ NH-, wherein R ₃ is selected from hydrogen, methyl, ethyl, m=2～3; or R ₄ (CH ₂ ) _n CONH-, wherein R ₄ is selected from acetoxy, hydroxyl, vinyl, dimethylamino, diethylamino,

n=0～1; R2 is selected from hydrogen, C1-C3 alkyl, hydroxyl, C1-C3 alkoxy, nitro, amino, carboxyl or C1-C3 alkoxyacyl; X is selected from CH or N. 2. The compound of claim 1, a pharmaceutically acceptable salt thereof; in, Ring A is selected from phenyl, pyridine, pyrazole, indole, piperidine; R1 is selected from nitro, amino, acetamido, trifluoroacetamido, vinylamido; or R ₃ OCOCH ₂ NH- or R ₃ SO ₂ NH-, wherein R ₃ is selected from hydrogen, methyl, and ethyl; or R ₄ CH ₂ CONH-, wherein R ₄ is selected from acetoxy, hydroxy, vinyl, dimethylamino, diethylamino,

R2 is selected from hydrogen, methyl, hydroxy, methoxy, nitro, amino, carboxyl or tert-butyloxyacyl. 3. A compound, a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: 1-(4-Nitrobenzene)-8-(6-methoxy-3-pyridine)-benzofuro[3,2-b]pyridin-2(1H)-one 1-(4-Aminobenzene)-8-(6-methoxy-3-pyridine)-benzofuro[3,2-b]pyridin-2(1H)-one 1-(4-Acetylaminobenzene)-8-(6-methoxy-3-pyridine)-benzofuro[3,2-b]pyridin-2(1H)-one 1-(4-Trifluoroacetamidobenzene)-8-(6-methoxy-3-pyridine)-benzofuro[3,2-b]pyridin-2(1H)-one 1-(4-Acrylamidobenzene)-8-(6-methoxy-3-pyridine)-benzofuro[3,2-b]pyridin-2(1H)-one 1-(4-Chloroacetamidobenzene)-8-(6-methoxy-3-pyridine)-benzofuro[3,2-b]pyridin-2(1H)-one 1-(4-Methanesulfonamidobenzene)-8-(6-methoxy-3-pyridine)-benzofuro[3,2-b]pyridin-2(1H)-one (4-(8-(6-Methoxy-3-pyridine)-2-oxo-benzofuro[3,2-b]pyridine-(1H))-1-anilino)ethyl acetate (4-(8-(6-Methoxy-3-pyridine)-2-oxo-benzofuro[3,2-b]pyridine-(1H))-1-anilino)acetic acid 1-(4-Dimethylaminoacetamidobenzene)-8-(6-methoxy-3-pyridine)-benzofuro[3,2-b]pyridin-2(1H)-one 1-(4-Diethylaminoacetamidobenzene)-8-(6-methoxy-3-pyridine)-benzofuro[3,2-b]pyridin-2(1H)-one 1-(4-(N-Morpholinyl)acetamidobenzene)-8-(6-methoxy-3-pyridine)-benzofuro[3,2-b]pyridin-2(1H)-one 1-(4-Methylaminoacetamidobenzene)-8-(6-methoxy-3-pyridine)-benzofuro[3,2-b]pyridin-2(1H)-one 1-(4-(N-Piperidinyl)acetamidobenzene)-8-(6-methoxy-3-pyridine)-benzofuro[3,2-b]pyridin-2(1H)-one 1-(4-(N-Piperazinyl)acetamidobenzene)-8-(6-methoxy-3-pyridine)-benzofuro[3,2-b]pyridin-2(1H)-one 1-(4-(N-Methylpiperazinyl)acetamidobenzene)-8-(6-methoxy-3-pyridine)-benzofuro[3,2-b]pyridine-2(1H)- ketone 1-(4-(N-pyrrolidinyl)acetamidobenzene)-8-(6-methoxy-3-pyridine)-benzofuro[3,2-b]pyridin-2(1H)-one 1-(4-Acetoxyacetamidobenzene)-8-(6-methoxy-3-pyridine)-benzofuro[3,2-b]pyridin-2(1H)-one 1-(4-Hydroxyacetamidobenzene)-8-(6-methoxy-3-pyridine)-benzofuro[3,2-b]pyridin-2(1H)-one 1-(4-Acetylaminobenzene)-8-(4-methoxyphenyl)-benzofuro[3,2-b]pyridin-2(1H)-one 1-(4-Acrylamidobenzene)-8-(4-methoxyphenyl)-benzofuro[3,2-b]pyridin-2(1H)-one 1-(4-Aminobenzene)-8-(3-pyridine)-benzofuro[3,2-b]pyridin-2(1H)-one 1-(4-Acrylamidobenzene)-8-(3-pyridine)-benzofuro[3,2-b]pyridin-2(1H)-one 1-(4-Aminobenzene)-8-(3-nitrobenzene)-benzofuro[3,2-b]pyridin-2(1H)-one 1-(4-Acrylamidobenzene)-8-(3-nitrobenzene)-benzofuro[3,2-b]pyridin-2(1H)-one 1-(4-Acrylamidobenzene)-8-(3-aminobenzene)-benzofuro[3,2-b]pyridin-2(1H)-one 1-(4-Acrylamidobenzene)-8-(4-hydroxybenzene)-benzofuro[3,2-b]pyridin-2(1H)-one 1-(Aminobenzene)-8-(4-carboxybenzene)-benzofuro[3,2-b]pyridin-2(1H)-one 1-(Acrylamidobenzene)-8-(4-carboxybenzene)-benzofuro[3,2-b]pyridin-2(1H)-one 1-(4-Dimethylaminoacetamidobenzene)-8-(4-indole)-benzofuro[3,2-b]pyridin-2(1H)-one 1-(4-Nitrobenzene)-8-(4-pyrazole)-benzofuro[3,2-b]pyridin-2(1H)-one 1-(4-Acrylamidobenzene)-8-(1-methyl-4-pyrazole)-benzofuro[3,2-b]pyridin-2(1H)-one 1-(3-Aminobenzene)-8-(6-methoxy-3-pyridine)-benzofuro[3,2-b]pyridin-2(1H)-one 1-(3-Acrylamidobenzene)-8-(6-methoxy-3-pyridine)-benzofuro[3,2-b]pyridin-2(1H)-one 1-(3-(N-Methylpiperazinyl)acetamidobenzene)-8-(6-methoxy-3-pyridine)-benzofuro[3,2-b]pyridine-2(1H)- ketone 1-(3-Dimethylaminoacetamidobenzene)-8-(6-methoxy-3-pyridine)-benzofuro[3,2-b]pyridin-2(1H)-one 1-(3-(N-Morpholinyl)acetamidobenzene)-8-(6-methoxy-3-pyridine)-benzofuro[3,2-b]pyridin-2(1H)-one (3-(8-(6-Methoxy-3-pyridine)-2-oxo-benzofuro[3,2-b]pyridine-(1H))-1-anilino)ethanamine 1-(4-Dimethylaminoacetamidobenzene)-8-(4-indole)-benzofuro[3,2-b]pyridin-2(1H)-one 1-(4-Dimethylaminoacetamidobenzene)-8-(3-pyridine)-benzofuro[3,2-b]pyridin-2(1H)-one 1-(4-Dimethylaminoacetamidobenzene)-8-(4-(N-tert-butoxycarbonyl)pyrrole)-benzofuro[3,2-b]pyridin-2(1H)-one 1-(4-Dimethylaminoacetamidobenzene)-8-(4-pyrrole)-benzofuro[3,2-b']pyridin-2(1H)-one 1-(4-Acrylamidobenzene)-8-(6-methoxy-3-pyridine)-furo[2,3-b:4,5-b']dipyridin-2(1H)-one 1-(4-Trifluoroacetamidobenzene)-8-(6-methoxy-3-pyridine)-furo[2,3-b:4,5-b']dipyridin-2(1H)-one 2-(Dimethylamino)-N-(4-(8-(6-methoxy-3-pyridine)-furo[2,3-b:4,5-b]dipyridine-2(1H)- Keto)-phenyl)acetamide 1-(4-(N-Piperazinyl)acetamidobenzene)-8-(6-methoxy-3-pyridine)-furo[2,3-b:4,5-b']dipyridine-2 (1H)-ketone 1-(4-(N-Piperidinyl)acetamidobenzene)-8-(6-methoxy-3-pyridine)-furo[2,3-b:4,5-b']dipyridine-2 (1H)-ketone. 4. A pharmaceutical combination comprising a compound of any one of claims 1-3, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 5. Use of a compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting one or both of Bruton's tyrosine kinase Btk and PI3K kinase. 6. Use of the compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment or prevention of a disease selected from at least one of cancer and inflammation. 7. The use according to claim 6, wherein the cancer is selected from at least one of leukemia, lymphoma, multiple myeloma, and breast cancer.

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