CN107805255B

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

Info

Publication number: CN107805255B
Application number: CN201710879128.3A
Authority: CN
Inventors: 向华; 刘林义; 石冰玉; 黄阿丽; 蔡学融; 王向前
Original assignee: China Pharmaceutical University
Current assignee: China Pharmaceutical University
Priority date: 2017-09-22
Filing date: 2017-09-22
Publication date: 2020-06-16
Anticipated expiration: 2037-09-22
Also published as: CN107805255A

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 ] pyridine-2 (1H) -ketone compound, preparation method and medical application

Technical Field

The invention belongs to the field of medicines, and particularly relates to a furan [3, 2-b ] pyridine-2 (1H) -ketone compound, a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the furan [3, 2-b ] pyridine-2 (1H) -ketone compound and application of the furan [3, 2-b ] pyridine-2 (1H) -ketone compound in treating diseases related to protein kinase activity such as cancer, inflammation and the like.

Background

The incidence of tumors has increased year by year as the population grows and ages, as well as being influenced by factors such as smoking, obesity, and lack of exercise. Leukemias and lymphomas are malignant neoplastic diseases that severely affect the normal function of the hematopoietic system, with high incidence and poor prognosis. In the global CANCER statistics of 2015, cases died due to leukemia accounted for 3.2%, while the major subtype of lymphoma, Non-Hodgkin lymphoma (Non-Hodgkin lymphoma), reached 2.7% in newly developed CANCERs (LindseyA. Torre, et al. CA CANCER J CLIN 2015; 65: 87-108). Currently, therapeutic approaches for leukemia and lymphoma include chemotherapy and targeted therapies as well as homologous bone marrow transplantation. Allogeneic bone marrow transplantation is the most effective protocol for leukemia therapy, but is limited by the source of the transplant, from which only a few patients benefit. Chemotherapy is the most widely used treatment, particularly in less developed areas, but has poor efficacy and high toxic and side effects. With the development of pathology, molecular biology and the like, targeting of pathological factors or key signal components inside and outside cancer cells becomes a new direction for treating leukemia and lymphoma. Although tyrosine kinase inhibitors (such as Imatinib and Ponatinib) and monoclonal antibody drugs (such as Rituximab and Alemtuzumab) are applied to clinic, the development and application of novel targeted inhibitors are urgently needed due to the defects of the drugs on the market and the increase of morbidity.

Bruton's tyrosine kinase (Btk) is an important member of the non-receptor tyrosine kinase Tec family, the major members of which include Btk, BMX (etk), Itk, Tec, and Txk. Studies have shown that Btk plays a critical role in the generation and development of B lymphocytes and in immunoregulation. The expression of Btk is throughout the development stage of B cells (except plasma cells), and is a key signal transduction factor of the B Cell Receptor (BCR) signaling pathway, regulates the signaling pathway involved by B cells, not only determines the survival, proliferation, differentiation, maturation of B cells, but also plays an important role in allergic and inflammatory reactions. Continued activation of Btk is a prerequisite for the development of Chronic Lymphocytic Leukemia (CLL). Furthermore, BCR-Btk signaling abnormalities promote survival of activated B cell subtypes, leading to the development of Diffuse Large B Cell Lymphoma (DLBCL). Ibrutinib is currently the only Btk inhibitor on the market and is useful in the treatment of various types of leukemia and lymphoma.

Phosphatidylinositol 3 (PI 3-kinases, PI3K) are classified into three types, I, II and III, based on differences in structure, distribution and function, wherein PI3K type I has been intensively studied (α, δ and γ), it has been found that PI3K type I is involved in various diseases, as an important signal transduction factor of immune cells, and plays a role in addressing the same in leukemia and inflammation, in recent years, as PI3K is intensively studied, a large number of selective PI3K inhibitors come into the clinic, idelalisib is a selective PI3 δ 3K inhibitor, which was approved for the treatment of various types of leukemia and lymphomas in 2014.

Although Btk inhibitors and PI3K inhibitors are already on the market, the Btk inhibitors and the PI3K inhibitors are single in variety, have more toxic and side effects and are easy to generate drug resistance, and the development of novel inhibitors is of great significance.

Disclosure of Invention

The invention discloses a furan [3, 2-b ] pyridine-2 (1H) -ketone compound with a structure shown in a general formula (I) or a pharmaceutically acceptable salt thereof, which can be used for preparing a medicament for treating diseases related to the activity of protein kinase.

The structure of the general formula (1) is as follows

Wherein,

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 R₃OCO(CH₂)_mNH-or R₃SO₂NH-, in which R₃Selected from hydrogen and C1-C6 alkyl, wherein m is 2-3; or R₄(CH₂)_nCONH-wherein R₄Selected from acetoxy, hydroxyl, vinyl, dimethylamino, diethylamino or a nitrogen-containing saturated carbocyclic ring, wherein n is 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, R₂Independently selected from hydrogenMethyl, hydroxy, methoxy, nitro, amino, carboxyl or ethoxyacyl; ring a is independently selected from phenyl, pyridine, pyrazole, indole, piperidine. For example, containing R₂Substituted ring a 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, there is provided a pharmaceutical composition comprising a compound described herein above, a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier.

According to another aspect of the present application, there is provided the use of a compound described herein above, a pharmaceutically acceptable salt or prodrug thereof, in the manufacture of a medicament for inhibiting one or both of Btk and PI3K kinase.

According to a further aspect of the application, the present invention provides the above compound, a pharmaceutically acceptable salt or prodrug thereof, for use in inhibiting one or both of Btk and PI3K kinase.

According to another aspect of the present application, there is provided the use of a compound described herein, a pharmaceutically acceptable salt or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of a disease associated with protein kinase activity (e.g. by inhibition of one or both of Btk and PI 3K).

According to a further aspect of the present application, the present invention provides a compound described herein, a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment or prevention of a disease associated with protein kinase activity.

According to some embodiments of the present application, the disease associated with protein kinase activity (e.g., a disease treated or prevented by inhibiting one or both of Btk and PI3K) provided herein can be a tumor, e.g., leukemia, malignant lymphoma, multiple myeloma, breast cancer. The diseases related to the activity of the protein kinase can also be inflammations, such as rheumatoid arthritis and systemic lupus erythematosus.

Detailed Description

The claims hereof set forth the features of the invention believed to be novel. The following sets forth illustrative embodiments in which the principles of the invention may be employed. The features and advantages of the present invention may be better understood by reference to the following.

Although preferred embodiments of the present application are described herein, these embodiments are provided by way of example only. It is to be understood that variations of the embodiments of the present application described herein may also be used to practice the teachings of the present application. Those of ordinary skill in the art will appreciate that various modifications, changes, and substitutions can be made without departing from the scope of the present application. It should be understood that the scope of the various aspects of the application is defined by the claims and that methods and structures within the scope of these claims and their equivalents are intended to be covered by the claims.

Synthetic route

Methods for the synthesis of compounds of the present application include, but are not limited to, the following equations and reaction steps:

route one

Route two

Route three

Example 1

Synthesis of intermediate methyl 5-bromo-2-hydroxybenzoate

Methyl salicylate (S1) (15.2g, 0.1mol) was added dropwise to 100ml of dichloromethane at room temperature to the reaction mixture, 1M bromine/dichloromethane solution (170ml) was added dropwise thereto, the reaction was allowed to react for 12 hours, dichloromethane was removed by rotation, and then the residue was poured into saturated sodium sulfite to precipitate a solid, which was dried, crystallized from absolute ethanol, and dried to give 22.65g, yield 98%.¹H-NMR(300MHz，CDCl₃)δ3.98(s，3H)，6.90(d，J＝8.91Hz，1H)，7.55(dd，J＝8.91，2.52Hz，1H)，7.97(d，J＝2.52Hz，1H)，10.7(s，1H).

Synthesis of intermediate (4-bromo-2-formic acid) phenoxyacetic acid (S4)

Adding 5-bromo-2-hydroxybenzoic acid methyl ester (22.6g, 97.8mmol) into 200ml of acetone, adding potassium carbonate (27g, 0.195mol) and catalytic amount of KI, then adding ethyl bromoacetate (12.2ml, 0.107mol), reacting at reflux temperature for 6h, removing most of acetone, then pouring into water, precipitating solid, and performing suction filtration to obtain solid (4-bromo-2-methyl formate) ethyl phenoxyacetate, and directly performing the next step.

Adding the product (S3) in the last step into 100ml of ethanol, adding 1M aqueous solution (250ml) of sodium hydroxide, refluxing for 2h, removing ethanol, adjusting pH to strong acidity with concentrated hydrochloric acid, separating out solid, filtering, and drying to obtain 24.38g of (4-bromo-2-formic acid) phenoxyacetic acid (S4) with the yield of 90%.

Synthesis of intermediate 5-bromo-3 (2H) -benzofuranone (S5)

Adding (4-bromo-2-formic acid) phenoxyacetic acid (S4) (37.4g, 0.136mol) into 110ml acetic acid380ml of acetic anhydride and 37g of sodium acetate react at 150 ℃ for 6H, acetic anhydride is removed by rotation, the mixture is cooled, water is added for stirring for 2H, ethyl acetate is used for extraction, concentration is carried out, 150ml of 1M hydrochloric acid and 250ml of methanol are added for reaction at 100 ℃ for 2H, methanol is removed by rotation, solid is separated out, and the 5-bromo-3 (2H) -benzofuranone (S5) of 27.17g is obtained by suction filtration and drying, and the yield is 93.8%.¹H-NMR(300MHz，CDCl₃)δ4.88(s，2H)，7.28(d，J＝8.76Hz，1H)，7.79(d，J＝2.01Hz，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) (1.3g, 6.1mmol) and p-nitroaniline (0.9g, 6.1mmol) are added into 60ml of toluene, a catalytic amount of p-toluenesulfonic acid monohydrate is added, a water separator is mounted, reflux reaction is carried out for 4 hours, toluene is removed by rotation, water is added, suction filtration is carried out, and a crude product of 2.03g is obtained after drying, wherein the yield is 100%.¹H-NMR(300MHz，d₆-DMSO)δ7.04(d，J＝9.21Hz，2H)，7.52(dd，J＝1.95，8.73Hz，1H)，7.58(d，J＝8.73Hz，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-4-nitroaniline) benzofuran

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

Synthesis of intermediate 8-bromo-1- (4-nitrophenyl) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

Adding N, N-dimethylformamide (2.8ml, 36.6mmol) into a reaction bottle, slowly dropwise adding phosphorus oxychloride (3.4ml, 36.6mmol) under ice bath, adding 5-bromo-3- (N-acetamido-4-nitroaniline) benzofuran (6.85g, 18.3mmol) dissolved in N, N-dimethylformamide, transferring to room temperature for reaction for 0.5h, heating to 95 ℃ for reaction for 6h, cooling, pouring into water, extracting with ethyl acetate,column chromatography gave 2.5g, yield 35.5%.¹H-NMR(300MHz，d₆-DMSO)δ6.3(d，J＝1.74Hz，1H)，6.72(d，J＝9.87Hz，1H)，7.63(dd，J＝1.74，8.91Hz，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-nitrophenyl) -benzofuran [3, 2-b ] pyridin-2 (1H) -one (BP-A10)

Reacting 8-bromo-1- (4-nitrobenzene) -benzofuran [3, 2-b]Pyridine-2 (1H) -ketone (2.04g, 5.3mmol) is added into 25ml dioxane, 2-methoxy-5-pyridine boric acid (0.892g, 5.8mmol) and 1.46g potassium carbonate, 80mg palladium chloride triphenylphosphine and 1ml water are added to react for 5H under the protection of nitrogen, then the solvent is removed, water is added, ethyl acetate is extracted for three times, concentration is carried out, column chromatography is carried out to obtain 1.7g of target compound, and the yield is 77.6%.¹H-NMR(300MHz，d₆-DMSO)δ3.76(s，3H)，6.24(d，J＝1.29Hz，1H)，6.60(d，J＝9.81Hz，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) -benzofuran [3, 2-b ] pyridin-2 (1H) -one (BP-A01)

0.21g (0.51mmol) of compound BP-A10 in a mixed solvent of ethanol and water (4: 1) is added with 0.34g (6.12mmol) of iron powder and heated to reflux, then 0.33g (6.12mmol) of ammonium chloride is added for reaction for 4h, filtration is carried out, a filter cake is washed by methanol and ethyl acetate, the filtrate is concentrated and column chromatography is carried out to obtain 0.16g of target substance, and the yield is 82%.¹H-NMR(300MHz，d₆-DMSO)δ3.76(s，3H)，5.47(s，2H)，6.36(d，J＝1.32Hz，1H)，6.51(d，J＝9.75Hz，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-trifluoroacetylaminobenzene) -8- (6-methoxy-3-pyridine) -benzofuran [3, 2-b ] pyridin-2 (1H) -one (BP-A03)

0.1g (0.261mmol) of the compound BP-A01 was added to 10ml of dichloromethane, 0.056ml of triethylamine was added thereto, 0.054ml (0.39mmol) of trifluoroacetic anhydride was added thereto at room temperature, reaction was carried out for 2 hours, 50ml of dichloromethane was added, saturated sodium bicarbonate was washed, brine was washed, anhydrous sodium sulfate was added overnight, and column chromatography was carried out to obtain 94mg of the objective compound with a yield of 75.2%.¹H-NMR(300MHz，d₆-DMSO)δ3.84(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) -benzofuran [3, 2-b ] pyridin-2 (1H) -one (BP-A04)

0.1g (0.261mmol) of the compound BP-A01 was added to 5ml of N, N-dimethylformamide, 72mg (0.52mmol) of potassium carbonate was added thereto, acryloyl chloride (32ul, 0.391mmol) was slowly added thereto under ice bath, followed by reaction for 1h, water was added, extraction was performed with ethyl acetate, and column chromatography gave 72mg of the objective compound in a yield of 63%.¹H-NMR(300MHz，d₆-DMSO)δ3.84(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) -benzofuran [3, 2-b ] pyridin-2 (1H) -one (BP-A05)

0.2g (0.52mmol) of the compound BP-A01 is added into 5ml of N, N-dimethylformamide, 0.143g of potassium carbonate is added, chloroacetyl chloride is slowly added into the mixture under ice bath, the mixture reacts for 1h, water is added, ethyl acetate is added for extraction, the mixture is washed by brine, the concentration is carried out, and the column chromatography is carried out to obtain 0.2g, wherein the yield is 84%.¹H-NMR(300MHz，d₆-DMSO)δ3.84(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

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

0.24g (0.52mmo1) of the compound BP-A05 was added to 5ml of N, N-dimethylformamide, and 0.215g of potassium carbonate and dimethylamine hydrochloride (85mg) were added, followed by reaction at 60 ℃ for 2 hours, cooling, pouring into water, extraction with ethyl acetate, brine washing, concentration, and column chromatography to obtain 0.21g, yield 86.4%.¹H-NMR(300MHz，d₆-DMSO)δ2.47(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

Synthesis of ethyl (4- (8- (6-methoxy-3-pyridine) -2-oxo-benzofuran [3, 2-b ] pyridine- (1H)) -1-anilino) acetate (BP-A07)

0.2g (0.52mmol) of the compound BP-A01 is added into 5ml of N, N-dimethylformamide, 0.143g of potassium carbonate is added, ethyl chloroacetate is slowly added into the dimethylformamide under ice bath for reaction for 1h, water is added, ethyl acetate is extracted, the mixture is washed by brine, the concentration is carried out, and the column chromatography is carried out to obtain 0.2g, wherein the yield is 82%.¹H-NMR(300MHz，d₆-DMSO)δ1.20(t，J＝7.05Hz，4H)，3.86(s，3H)，4.0(d，J＝5.16Hz，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

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

50mg (0.106mmol) of the compound BP-A07 was added to 2ml of methanol, 2ml of 1M sodium hydroxide solution was added thereto at 65 ℃ until the starting material disappeared, pH was adjusted to about 4 with 1M hydrochloric acid, and a solid was precipitated, filtered under suction, and dried to obtain 30mg, which was obtained in a yield of 64.2%.¹H-NMR(300MHz，d₆-DMSO)δ3.86(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-aminophenyl) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1.26g (3.1mmol) of the compound 8-bromo-1- (4-nitrophenyl) -benzofuran [3, 2-b]Pyridine-2 (1H) -ketone is added into a mixed solvent (4: 1) of ethanol and water, 0.43g (7.7mmol) of iron powder is heated to reflux, then 0.42g of ammonium chloride is added for reaction for 3 hours, the mixture is filtered, a filter cake is washed by methanol and ethyl acetate, the filtrate is concentrated and then subjected to column chromatography to obtain 0.9g of a target substance, and the yield is 81.8%.¹H-NMR(300MHz，d₆-DMSO)δ5.57(s，2H)，6.39(d，J＝1.95Hz，1H)，6.61(d，J＝9.81Hz，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-acrylamido-benzene) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

0.93g (2.62mmol) of compound S12 was added to 10ml of N, N-dimethylformamide, 0.72g of potassium carbonate was added thereto, acryloyl chloride (0.43ml, 5.24mmol) was slowly added thereto under ice bath, followed by reaction for 1 hour, addition of water, extraction with ethyl acetate, and column chromatography to give 0.8g of the objective compound with a yield of 74.7%.

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

Reacting 8-bromo-1- (4-acrylamido-benzene) -benzofuran [3, 2-b]Pyridine-2 (1H) -ketone (0.15g, 0.36mmol) is added into 15ml dioxane, 3-aminopyridineboronic acid (62mg, 0.4mmol) and 55mg potassium carbonate, 70mg palladium chloride triphenylphosphine and 1ml water are added for reaction for 5 hours under the protection of nitrogen, then the solvent is removed by rotation, water is added, ethyl acetate is extracted for three times, concentration and column chromatography are carried out to obtain 0.1g of target product, and the yield is 66.6%.¹H-NMR(300MHz，d₆-DMSO)δ5.08(s，2H)，5.85(d，J＝10.2Hz，1H)，6.23(s 1H)，6.35(d，J＝17Hz)，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) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1.4g (3.95mmol) of compound S12 in 20ml of N, N-dimethylformamide were added with 1.1g of potassium carbonate, to which chloroacetyl chloride (0.36ml, 4.7mmol) was slowly added under ice bath, followed by reaction for 2h, addition of water, extraction with ethyl acetate, and concentration directly next step.

Synthesis of intermediate 8-bromo-1- (4-N, N-dimethylaminoacetamidobenzene) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

About 1.69g (3.95mmol) of 8-bromo-1- (4-chloroacetamidobenzene) -benzofuran [3, 2-b]Pyridine-2 (1H) -ketone was added to 20ml of N, N-dimethylformamide, and 1.63g of potassium carbonate, a catalytic amount of potassium iodide, 0.64g (7.9mmol) of dimethylamine hydrochloride were reacted at 65 ℃ for 2 hours, followed by addition of water, extraction with ethyl acetate, and column chromatography to give 1.61g of the objective substance with a yield of 93%.¹H-NMR(300MHz，d₆-DMSO)δ2.44(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) -benzofuran [3, 2-b ] pyridin-2 (1H) -one (BP-E01)

Reacting 8-bromo-1- (4-N, N-dimethylaminoacetamidobenzene) -benzofuran [3, 2-b]Pyridine-2 (1H) -one (0.12g, 0.27mmol) was added to 15ml dioxane 4-indoleboronic acid pinacol ester (62mg, 0.4mmol), and 75mg potassium carbonate, 70mg palladium triphenylphosphine chloride and 1ml water, reacted under nitrogen for 6H, then the solvent was removed, water was added, and ethyl acetate was extractedTaking the mixture for three times, concentrating, and carrying out column chromatography to obtain a target substance 70mg with the yield of 54.6%.¹H-NMR(300MHz，d₆-DMSO)δ2.29(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) -benzofuran [3, 2-b ] pyridin-2 (1H) -one (S18)

The synthesis was the same as BP-A01 in example 1.¹H-NMR(300MHz，d₆-DMSO)δ3.84(s，3H)，6.3(d，J＝1.23Hz，1H)，6.67(d，J＝9.81Hz，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-acrylamido-benzene) -benzofuran [3, 2-b ] pyridin-2 (1H) -one (BP-D02)

The synthesis was the same as BP-A04 in example 1.¹H-NMR(300MHz，d₆-DMSO)δ3.87(s，3H)，5.77(d，J＝9.66Hz，1H)，6.26(d，J＝16.32Hz，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

Synthesis of 8- (6-methoxy-3-pyridine)) - (6-methoxy-3-pyridine) -1- (3-chloroacetamidobenzene) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

The synthesis was the same as BP-A09 in example 1.¹H-NMR(300MHz，d₆-DMSO)δ2.5(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

Adding 2-hydroxynicotinic acid (18.98g, 0.136mmol) into acetic acid, adding liquid bromine (8.4ml, 0.163mmol), reacting at 80 ℃ overnight, removing acetic acid by spinning, adding water, stirring for 1h, filtering and drying to obtain 22.7g of product, wherein the yield is 76.6%.¹H-NMR(300MHz，CDCl₃)δ8.25(d，J＝2.4Hz，1H)，8.34(d，J＝2.4Hz 1H)，13.8(brs，1H).

Synthesis of intermediate 5-bromo-2-chloro-methyl nicotinate

Adding 5-bromo-2-hydroxynicotinic acid (22.7g, 0.104mol) into 100ml of thionyl chloride dropwise, reacting for 12h under reflux, then removing thionyl chloride by rotation, cooling, diluting with dichloromethane, slowly adding methanol into the solution under ice bath, then removing DCM at room temperature for 2h by rotation, adjusting pH with saturated sodium bicarbonate, extracting with ethyl acetate, and performing concentrated column chromatography to obtain 20g, wherein the yield is 76.9%.

Synthesis of intermediate 5-bromo-furan [2, 3-b ] pyridin-3 (2H) -one

NaH (2.78g, 69.46mmol) was dissolved in ethylene glycol dimethyl ether, ethyl ethanoacetate (6ml, 63.4mmol) was slowly added thereto under ice bath, and then 5-bromo-2-carboxylic acid dissolved in ethylene glycol dimethyl ether was dissolved after 0.5h at room temperatureAdding chlorine-methyl nicotinate (7.54g, 30.2mmol), standing overnight at 65 deg.C, removing solvent, adding ethanol, adding 1M sodium hydroxide solution (75mmol), reacting at 80 deg.C for half an hour, removing ethanol, adding concentrated hydrochloric acid, reacting at 80 deg.C for 2 hr, extracting with ethyl acetate, concentrating, and performing column chromatography to obtain 4.4g with yield of 68.7%.¹H-NMR(300MHz，CDCl₃)δ4.76(s，2H)，8.09(d，J＝8.46Hz1H)，8.56(d，J＝2.46Hz 1H).

Synthesis of intermediate 5-bromo-3- (4-nitrophenylamino) -furan [2, 3-b ] pyridine

Reacting 5-bromo-furan [2, 3-b ]]Pyridine-3 (2H) -ketone (4.3g, 20.18mmol) and p-nitroaniline (2.8g, 20.18mmol) are added into toluene, catalytic amount of p-toluenesulfonic acid is added, the toluene is removed by rotation under reflux for 6H, water is added, and the target product is obtained by suction filtration and drying, wherein the yield is 6.2 g.¹H-NMR(300MHz，d₆-DMSO)δ7.06(d，J＝9.21Hz，2H)，8.12(d，J＝9.21Hz，2H)，8.4(d，J＝2.25Hz，1H)，8.43(s，1H)，8.46(d，J＝2.25Hz，1H)，9.29(s，1H).

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

6.24g (18.68mmol) of 5-bromo-3- (4-nitrophenylamino) -furan [2, 3-b ] pyridine in DMF was added slowly sodium hydrogen (1.12g, 28mmol) in ice bath until no bubbles were formed, then acetyl chloride (2ml, 28mmol) was pushed slowly with syringe, at room temperature for 1h, poured into water, the solid precipitated, filtered off with suction and dried directly to the next step.

Intermediate 8-bromo-1- (4-nitrophenyl) -furan [2, 3-b: synthesis of 4, 5-b' ] bipyridinyl-2 (1H) -one

N, N-dimethylformamide (2.8ml, 36.6mmol) was charged into a reaction flask, phosphorus oxychloride (3.4ml, 36.6mmol) was slowly added dropwise thereto under ice bath, and then N-acetyl-N- (5-bromo-furan [2, 3-b ] dissolved in N, N-dimethylformamide was added]Pyridine-3) -4-nitroaniline (6.85g, 18.3mmol) is added, the mixture is moved to room temperature for reaction for 0.5h, the temperature is increased to 95 ℃ for reaction for 6h, the mixture is cooled and poured into water, ethyl acetate is used for extraction, column chromatography is carried out to obtain 2.5g, and the yield is 35.5%.¹H-NMR(300MHz，d₆-DMSO)δ6.75(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-nitrophenyl) -8- (6-methoxy-3-pyridine) -furan [2, 3-b: synthesis of 4, 5-b' ] bipyridinyl-2 (1H) -one

Reacting 8-bromo-1- (4-nitrophenyl) -furan [2, 3-b: 4, 5-b' ] bipyridinyl-2 (1H) -one (1.9g, 4.92mmol) in 25ml dioxane was added 2-methoxy-5-pyridineboronic acid (0.75g, 4.92mmol), and 1.35g potassium carbonate, 80mg palladium triphenylphosphine chloride and 1ml water, reacted for 5H under nitrogen protection, then the solvent was removed by spinning, water was added, extracted three times with ethyl acetate, concentrated, and column chromatographed to give the desired compound 1.5g, 73.8% yield. Intermediate 1- (4-aminobenzene) -8- (6-methoxy-3-pyridine) -furan [2, 3-b: synthesis of 4, 5-b' ] bipyridinyl-2 (1H) -one

Reacting 1- (4-nitrobenzene) -8- (6-methoxy-3-pyridine) -furan [2, 3-b: 4, 5-b ″)]Dipyridin-2 (1H) -one (1.5g, 3.63mmol) was added to ethanol, 5% Pd-C was added, hydrogen was purged under reflux overnight, filtered, the filter cake was washed with MeOH/EtOAc and concentrated to give 1.2g, 86% yield.¹H-NMR(300MHz，d₆-DMSO)δ3.98(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) -furan [2, 3-b: synthesis of 4, 5-b' ] bipyridinyl-2 (1H) -one

0.5g (1.3mmol) of 1- (4-aminobenzene) -8- (6-methoxy-3-pyridine) -furan [2, 3-b: 4, 5-b' ] bipyridin-2 (1H) -one in DMF was added potassium carbonate (0.358g, 2.6mmol), and chloroacetyl chloride (0.113ml, 1.43mmol) was slowly added thereto under ice bath, followed by pouring into water at room temperature for 1H, extraction with ethyl acetate, and concentration directly next step.

1- (4- (N-piperazinyl) acetamidobenzene) -8- (6-methoxy-3-pyridine) -furan [2, 3-b: synthesis of 4, 5-b' ] bipyridin-2 (1H) -one (BP-G04)

0.25g (0.54mmol) of1- (4-chloroacetamidobenzene) -8- (6-methoxy-3-pyridine) -furan [2, 3-b: 4, 5-b ″)]Bipyridin-2 (1H) -one was dissolved in 5ml of N, N-dimethylformamide, and 0.373g of potassium carbonate and piperazine (0.46g) were added, followed by reaction at 60 ℃ for 2 hours, cooling, pouring into water, extraction with ethyl acetate, washing with brine, concentration, and column chromatography to obtain 70 mg.¹H-NMR(300MHz，d₆-DMSO)δ2.31(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 assay

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

MTT assay for K562 cell proliferation assay

The K562 cells are lymphoblast cells derived from a female patient with the age of 53 in the outbreak period of chronic myelogenous leukemia, belong to red leukemia cell strains, and are used for the fields of research on tumor and leukemia treatment, drug targets and the like.

The test method comprises the following steps: k562 breast cancer cells are cultured by RPMI1640 culture solution containing 10% fetal calf serum, cells in logarithmic growth phase are taken for experiment, the cell density is adjusted to be 2 × 104/mL, 100 μ L/well is inoculated in a 96-well plate, after 12 hours of culture, 100 μ L/well of drug-containing culture medium is added, the final concentration of a sample is 4 × 10-5mol/L, 2 × 10-5mol/L, 1 × 10-5mol/L, 5 × 10-6mol/L and 1 × 10-6mol/L, each concentration is 3 multiple wells, the test drug is replaced by the culture medium with the same volume as a control group, 20 μ L/well MTT (concentration is 5mg/mL) is added after 48 hours of continuous culture, after 4 hours of culture, the plate is centrifuged, supernatant is discarded, DMSO is added in 150 μ L/well, the absorbance (A) value of each well is measured at the wavelength of 492nm by an enzyme-labeling detector, the inhibition rate of cell proliferation was calculated according to the formula: the inhibition rate (control a value-experimental a value)/(control a value-blank a value) × 100%, and IC50 was calculated.

Experiment for testing anti-proliferative activity of Raji cells by MTT method

The Raji cell line was 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 studies on leukemia therapy and the like. The MTT method is the same as the MCF-7 cell.

Btk enzyme Activity assay

Based on the principle that ATP can phosphorylate Btk to form ADP, the ADP-GloTM kinase system can convert ADP generated into fluorescence labeled ATP belonging to ATP tyrosine kinase, thereby measuring the activity of the kinase. The method comprises the following steps: 1. enzyme inhibition reaction, namely adding a tested inhibitor into a kinase reaction solution containing an enzyme substrate, then adding ATP, and reacting for 60 mins; 2. adding ADP-GloTM reagent to stop kinase reaction and eliminate residual ATP; 3. incubation at room temperature for 40 minutes; 4. adding a detection reagent and a fluorescent enzyme to convert ADP into fluorescence labeled ATP; 5. incubating for 30mins at room temperature; 6. fluorescence was detected and inhibition was calculated.

TABLE cellular Activity and Btk enzymatic Activity of Compounds of the invention

K562 cell and Raji antiproliferative experiments were performed on synthetic furo [3, 2-b ] pyridin-2 (1H) -one compounds using Ibrutinib as a positive control. Research results show that most compounds show good inhibitory activity on two strains of cells. In Btk enzyme inhibition experiments with Ibrutinib as a control, most compounds have an inhibitory effect on Btk. Therefore, the compounds can be used as Btk inhibitors and used for treating leukemia or lymphoma.

PI3K-Akt signal pathway inhibition assay

PI3K kinase can cause a series of cascades and activation of downstream Akt proteins, manifested by phosphorylation of the Akt protein at the Ser473 site. Thus, the activity of PI3K kinase can be indirectly reflected by detecting the expression level of phosphorylated protein, i.e. if the compound inhibits the activity of PI3K kinase, the protein expression of pAkt (Ser473) is reduced, and according to the principle, the inhibitory activity of the selected compound on the expression of Akt (Ser473) protein is determined by Western blotting (Western blot).

Selecting K562 cell strain, culturing in 5% carbon dioxide environment, adding 1 μ M selected compounds, collecting cells after 24 hr to obtain β -actin reference protein, dissolving in lysis buffer solution, extracting protein, and detecting protein content change by Western blot method (FIG. 1).

Drawings

FIG. 1 is a gray scale diagram for detecting the expression of Akt protein and pAkt protein by Western blot method. The change of the protein content can be judged according to the shade of the color, so that the inhibition effect of the compound on the protein can be detected. Akt phosphorylation expression inhibition experiments are carried out on synthesized furan [3, 2-b ] pyridine-2 (1H) -ketone compounds by taking BEZ235 as a positive control. The research result shows that the tested compounds can obviously inhibit Akt phosphorylation.

Claims

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

wherein,

ring a is independently selected from phenyl, pyridine, pyrazole, indole, piperidine;

r1 is selected from nitro, amino, acetamido, trifluoroacetamido; or R₃OCO(CH₂)_mNH-or R₃SO₂NH-, in which R₃Selected from hydrogen, methyl and ethyl, wherein m is 2-3; or R₄(CH₂)_nCONH-wherein R₄Selected from acetoxy, hydroxy, vinyl, dimethylamino, diethylamino,

n＝0～1；

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

x is selected from CH or N.

2. A compound according to claim 1, a pharmaceutically acceptable salt thereof;

wherein,

ring A is selected from phenyl, pyridine, pyrazole, indole and piperidine;

r1 is selected from nitro, amino, acetamido, trifluoroacetamido and vinylamide; or R₃OCOCH₂NH-or R₃SO₂NH-, in which R₃Selected from hydrogen, methyl, ethyl; or R₄CH₂CONH-wherein R₄Selected from acetoxy, hydroxy, vinyl, dimethylamino, diethylamino,

R2 is selected from hydrogen, methyl, hydroxy, methoxy, nitro, amino, carboxy 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) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1- (4-Aminobenzene) -8- (6-methoxy-3-pyridine) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1- (4-Acylaminobenzene) -8- (6-methoxy-3-pyridine) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1- (4-trifluoroacetylaminobenzene) -8- (6-methoxy-3-pyridine) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1- (4-Acrylamidobenzene) -8- (6-methoxy-3-pyridine) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1- (4-Chloroacetamidobenzene) -8- (6-methoxy-3-pyridine) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1- (4-Methanesulphonylaminobenzene) -8- (6-methoxy-3-pyridine) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

(4- (8- (6-methoxy-3-pyridine) -2-oxo-benzofuran [3, 2-b ] pyridine- (1H)) -1-anilino) acetic acid ethyl ester

(4- (8- (6-methoxy-3-pyridine) -2-oxo-benzofuran [3, 2-b ] pyridine- (1H)) -1-anilino) acetic acid

1- (4-dimethylaminoacetamidobenzene) -8- (6-methoxy-3-pyridine) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1- (4-diethylaminoacetamidobenzene) -8- (6-methoxy-3-pyridine) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1- (4- (N-morpholinyl) acetamidobenzene) -8- (6-methoxy-3-pyridine) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1- (4-Methylacetoaminobenzene) -8- (6-methoxy-3-pyridine) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1- (4- (N-piperidinyl) acetamidobenzene) -8- (6-methoxy-3-pyridine) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1- (4- (N-piperazinyl) acetamidobenzene) -8- (6-methoxy-3-pyridine) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1- (4- (N-methylpiperazino) acetamidobenzene) -8- (6-methoxy-3-pyridine) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1- (4- (N-pyrrolidinyl) acetamidobenzene) -8- (6-methoxy-3-pyridine) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1- (4-acetoxyacetamidobenzene) -8- (6-methoxy-3-pyridine) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1- (4-Hydroxyacetamidophenyl) -8- (6-methoxy-3-pyridine) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1- (4-Acylaminobenzene) -8- (4-methoxyphenyl) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1- (4-Acrylamidobenzene) -8- (4-methoxyphenyl) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1- (4-Aminobenzene) -8- (3-pyridine) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1- (4-Acrylamidobenzene) -8- (3-pyridine) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1- (4-aminobenzene) -8- (3-nitrophenyl) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1- (4-Acrylamidobenzene) -8- (3-nitrophenyl) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1- (4-Acrylamidobenzene) -8- (3-aminophenyl) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1- (4-Acrylamidobenzene) -8- (4-hydroxybenzene) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1- (aminobenzene) -8- (4-carboxyphenyl) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1- (Acrylamidobenzene) -8- (4-carboxyphenyl) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1- (4-dimethylaminoacetamidobenzene) -8- (4-indole) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1- (4-Nitrobenzene) -8- (4-pyrazole) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1- (4-Acrylamidobenzene) -8- (1-methyl-4-pyrazole) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1- (3-Aminobenzene) -8- (6-methoxy-3-pyridine) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1- (3-Acrylamidobenzene) -8- (6-methoxy-3-pyridine) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1- (3- (N-methylpiperazino) acetamidobenzene) -8- (6-methoxy-3-pyridine) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1- (3-dimethylaminoacetamidobenzene) -8- (6-methoxy-3-pyridine) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1- (3- (N-morpholinyl) acetamidobenzene) -8- (6-methoxy-3-pyridine) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

(3- (8- (6-methoxy-3-pyridine) -2-oxo-benzofuran [3, 2-b ] pyridine- (1H)) -1-anilino) ethylamine

1- (4-dimethylaminoacetamidobenzene) -8- (3-pyridine) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1- (4-dimethylaminoacetamidobenzene) -8- (4- (N-tert-butoxycarbonyl) pyrrole) -benzofuran [3, 2-b ] pyridin-2 (1H) -one

1- (4-Dimethylaminoacetamidobenzene) -8- (4-pyrrole) -benzofuran [3, 2-b' ] pyridin-2 (1H) -one

1- (4-acrylamidobenzene) -8- (6-methoxy-3-pyridine) -furan [2, 3-b: 4, 5-b' ] bipyridinyl-2 (1H) -ones

1- (4-trifluoroacetylaminobenzene) -8- (6-methoxy-3-pyridine) -furan [2, 3-b: 4, 5-b' ] bipyridinyl-2 (1H) -ones

2- (dimethylamino) -N- (4- (8- (6-methoxy-3-pyridine) -furan [2, 3-b: 4, 5-b ] bipyridin-2 (1H) -one) -phenyl) acetamide

1- (4- (N-piperazinyl) acetamidobenzene) -8- (6-methoxy-3-pyridine) -furan [2, 3-b: 4, 5-b' ] bipyridinyl-2 (1H) -ones

1- (4- (N-piperidinyl) acetamidobenzene) -8- (6-methoxy-3-pyridine) -furan [2, 3-b: 4, 5-b' ] bipyridinyl-2 (1H) -one.

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 to 3, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting one or both of bruton's tyrosine kinase Btk and PI3K kinase.

6. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a disease selected from at least one of cancer, 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.