Compounds containing a pyrazolo[3,4-d]pyrimidine structure, and methods of making and uses thereof

Abstract

The present application relates to the field of medicinal chemistry, disclose a kind of pyrazolo [3, 4-d] pyrimidine derivatives with BTK / JAK3 inhibitory activity and preparation method and purposes thereof. The present application also discloses a composition containing the pyrazolo [3, 4-d] pyrimidine derivative with BTK / JAK3 inhibitory activity or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier, and its application in preparing BTK / JAK3 inhibitor. The compound of the present application can be used for treating inflammation and tumor, including rheumatoid arthritis and B-cell lymphoma.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a class of BTK and JAK3 kinase inhibitors containing pyrazolo[3,4-d]pyrimidine structures, their preparation methods, and pharmaceutical compositions containing these compounds and their use in the preparation of drugs for treating autoimmune diseases such as rheumatoid arthritis or B-cell lymphoma or B-cell malignancies. Technical Background

[0002] Rheumatoid arthritis (RA) is a chronic autoimmune disease of unknown etiology, mainly characterized by inflammatory synovitis. Its main pathological features are inflammatory cell infiltration of synovial tissue, pannus formation, and progressive destruction of articular cartilage and bone, ultimately leading to joint deformity or even loss of function.

[0003] JAK (Janus Kinase) is a non-receptor tyrosine kinase comprising four subtypes: JAK1, JAK2, JAK3, and TYK2. Several JAK inhibitors are currently on the market, such as tofacitinib, ruxolitinib, baricitinib, abrocitinib, delgocitinib, and filgotinib. Currently, Ritlecitinib (PF-06651600), a selective JAK3 inhibitor developed by Pfizer, is undergoing regulatory review in Japan, the United States, and the European Union for the treatment of alopecia areata. Tofacitinib was launched in 2012 for the treatment of moderate to severe rheumatoid arthritis and was approved in 2017 for the treatment of psoriatic arthritis. However, tofacitinib has serious side effects such as infection and anemia. This is mainly because tofacitinib is a pan-JAK inhibitor; while it inhibits JAK1 and JAK3 to produce a therapeutic effect, it also causes anemia due to the inhibition of JAK2 activity. Therefore, selective JAK1 or JAK3 inhibitors should be developed for the treatment of rheumatoid arthritis. Since JAK1 can form dimers or polymers with JAK2 or TYK2 in addition to forming dimers with JAK3, it can also cause side effects. Therefore, the side effects caused by selectively inhibiting JAK3 may be less than those caused by inhibiting JAK1.

[0004] BTK (Bruton's tyrosine kinase) is a member of the TEC family, belonging to the non-receptor tyrosine kinase family. It is primarily expressed in B cells, myeloid cells, mast cells, and platelets, but not in T cells and NK cells. BTK plays a crucial role in the BCR signaling pathway, and is also involved in the transduction of many other signaling pathways. Aberrant activation of B cells can lead to B-cell lymphoma and autoimmune diseases. Currently, five BTK inhibitors are on the market, including ibrutinib, acalabrutinib, zanubrutinib, orelabrutinib, and tirabrutinib.

[0005] Literature reports that the combined use of the BTK inhibitor LFM-A13 and the JAK3 inhibitor JANEX-1 is far more effective in treating graft-versus-host disease (GVHD) than the use of LFM-A13, JANEX-1, or methotrexate alone. Furthermore, the JAK3 selective inhibitor Ritlecitinib (PF-06651600) has shown good anti-RA efficacy in clinical practice. This is attributed not only to JAK3 inhibition but also to the inhibition of TEC family kinases such as BTK. Therefore, the inventors believe that simultaneous inhibition of BTK and JAK3 has a synergistic effect in treating autoimmune diseases such as RA. However, those skilled in the art will combine existing BTK and JAK3 inhibitors, but compounds with excellent BTK and JAK3 inhibitory activity cannot be readily obtained using existing technology. Summary of the Invention

[0006] This invention provides a class of compounds containing a pyrazolo[3,4-d]pyrimidine structure that can simultaneously inhibit BTK and JAK3. Furthermore, this invention also provides specific methods for preparing these compounds and their pharmaceutical applications as BTK and JAK3 kinase inhibitors.

[0007] Specifically, this invention provides a class of compounds containing a pyrazolo[3,4-d]pyrimidine structure as shown in general formula (I) and their pharmaceutically acceptable salts:

[0008]

[0009] (I)

[0010] Where: X 1 X 2 Each can independently represent O or CH2;

[0011] R 1 represent: , , , , , where R 2 Representing H, F, Cl, Br, I, C1-C6 alkyl, CF3, OH, C1-C6 alkoxy, OCF3, CN, NO2, -NH2, C1-C6 alkylamine, -NHCH3, -N(CH3)2, -N(C2H5)2, -CH(CH3CN), -NHCOCH3, etc. , , , , , , , or R 2 It can be monosubstituted, disubstituted, or trisubstituted; Y 1 Y 2 , representing N or CR 3 R 3 Z represents H, F, Cl, Br, I, CH3, CF3, OH, OCH3, OCF3, or CN; Z represents O, S, or NR. 4 R 4 Represents H, CH3, C2H5, or cyclopropyl;

[0012] Preferably, in general formula (I), X 1 Represents CH2 or O; X 2 Represents O;

[0013] Preferably, in general formula (Ⅰ), R 1 represent , , , , , , , where R 5 Represents H, F, Cl, CH3, t-Bu, CF3, CN, OH, OCH3, OCF3, -NH2, -NHCH3, -N(CH3)2, -N(C2H5)2, -NHCOCH3 , , , , , or R 5 It can be mono-substituted, di-substituted, or tri-substituted.

[0014] Furthermore, R 5 Preferred representatives include H, F, Cl, CF3, OCH3, CN, -NHCH3, and -N(CH3)2. , , or R 5 It can be mono-substituted, di-substituted, or tri-substituted.

[0015] More preferably, the compounds containing pyrazolo[3,4-d]pyrimidine structure of the present invention are I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I- 10. I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22 and I-23.

[0016] More preferably, the compounds of the present invention containing a pyrazolo[3,4-d]pyrimidine structure are selected from the following compounds:

[0017]

[0018] Ⅰ-1 Ⅰ-2 Ⅰ-3

[0019]

[0020] Ⅰ-4 Ⅰ-5 Ⅰ-6

[0021]

[0022] Ⅰ-7 Ⅰ-8 Ⅰ-9

[0023]

[0024] I-10 I-11 I-12

[0025]

[0026] I-13 I-14 I-15

[0027]

[0028] I-16 I-17 I-18

[0029]

[0030] I-19 I-20 I-21

[0031]

[0032] I-22 I-23

[0033] Pharmaceutically acceptable salts of the compounds of the present invention are acid addition salts of compounds of general formula (I), wherein the acid used for salt formation is: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or ferulic acid.

[0034] When X 2 When O is represented, the compounds of general formula (I) of this invention can be prepared by the following methods:

[0035]

[0036] (III) (IV) (V) (VI)

[0037]

[0038] (I)

[0039] Among them, R 1 X 1 The definition is the same as described above.

[0040] Compound (V) was prepared by a Suzuki coupling reaction of compound (III) and compound (IV), using a solvent selected from toluene and N2. The solvent used is N-dimethylformamide (DMF), ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, acetonitrile, acetone, water, or a mixture of any two solvents, preferably ethylene glycol dimethyl ether; the base used is selected from sodium ethoxide, sodium acetate, potassium acetate, potassium phosphate, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, or triethylamine, preferably sodium carbonate or potassium carbonate; the catalyst used is selected from tetratetra(triphenylphosphine)palladium (Pd(PPh3)4), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (Pd(dppf)Cl2), bis(triphenylphosphine)palladium dichloride (Pd(PPh3)2Cl2), palladium acetate (Pd(OAc)2), or (1,1'-bis(diphenylphosphine)ferrocene)nickel dichloride (NiCl2(dppf)), preferably Pd(dppf)Cl2; the reaction temperature is selected from room temperature to 120 °C, preferably 70~100 °C.

[0041] Compound (VI) is prepared from compound (V) by removing the tert-butyloxycarbonyl (Boc) protecting group. The reagents used are selected from trifluoroacetic acid, concentrated hydrochloric acid, hydrogen chloride / ethyl acetate solution or hydrogen chloride / methanol solution, preferably trifluoroacetic acid or hydrogen chloride / ethyl acetate solution; the reaction solvents are selected from acetone, dichloromethane, ethyl acetate, 1,4-dioxane or acetonitrile, preferably ethyl acetate or dichloromethane.

[0042] Compound (I) is prepared by reacting compound (VI) with acryloyl chloride. The acid-binding agent used is selected from triethylamine, pyridine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, potassium carbonate or sodium carbonate, preferably triethylamine; the solvent used is selected from dichloromethane, tetrahydrofuran, 1,4-dioxane, ethyl acetate, acetone, toluene or DMF, preferably dichloromethane.

[0043] Compound (I) can also be prepared by reacting compound (VI) with acrylic acid in the presence of a condensing agent selected from N,N'-carbonyldiimidazole (CDI), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) / 1-hydroxybenzotriazole (HOBt) or dicyclohexylcarbodiimide (DCC) / 4-dimethylaminopyridine (DMAP), preferably EDCI / HOBt.

[0044] When X 1 For O, X 2 When the form is CH2, the preparation method of the target compound is the same as described above.

[0045] Intermediate (IV) can be prepared by the following methods:

[0046]

[0047] (IX) (X) (XI) (IV)

[0048] Where R 1 X 1 The definition is the same as described above.

[0049] Compound IX is dissolved in DMF, and bromination with N-bromosuccinimide (NBS) yields 7-bromo-2,3-dihydrobenzofuran-4-amine (X).

[0050] Compound X and pinacol diboronic acid ester dissolved in 1,4-dioxane reacted in the presence of catalyst Pd(dppf)Cl2 and potassium acetate to give 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-2,3-dihydrobenzofuran-4-amine (XI).

[0051] Intermediate (IV) is prepared by reacting compound XI with the corresponding acyl chloride. The acid-binding agent used is selected from triethylamine, pyridine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, potassium carbonate or sodium carbonate, preferably N,N-diisopropylethylamine or triethylamine. The solvent used is selected from dichloromethane, tetrahydrofuran, 1,4-dioxane, ethyl acetate, acetone, toluene or DMF, preferably dichloromethane.

[0052] The present invention also discloses a pharmaceutical composition comprising a compound of the above general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The compound can be formulated into common pharmaceutical preparations, such as tablets, capsules, syrups, suspensions, and injections, by adding a pharmaceutically acceptable carrier, and can be supplemented with commonly used pharmaceutical excipients such as flavorings, sweeteners, liquid or solid fillers, or diluents.

[0053] The pharmaceutical compositions of the present invention can be administered via methods of administration well known to those skilled in the art, such as oral, rectal, sublingual, pulmonary, transdermal, iontophoresis, vaginal, and intranasal administration. The pharmaceutical compositions of the present invention are preferably administered parenterally, such as subcutaneously, intramuscularly, or intravenously. The dosage varies depending on the formulation, desired duration of action, and the patient's condition; the effective therapeutic dose required for actual treatment can be determined by a physician based on the specific circumstances (e.g., the patient's condition, weight, etc.). For a typical adult, the dosage of the pharmaceutical compositions of the present invention, calculated as compounds of general formula (I), can be 1 ng to 10 g per kg of adult body weight, such as 100 ng to 10 mg per kg of body weight.

[0054] The use of compounds of general formula (I) or their stereoisomers, hydrates, solvates, crystals, or pharmaceutically acceptable salts in the preparation of BTK and / or JAK3 inhibitor medicaments is also within the scope of protection of this invention. Accordingly, this invention also provides a treatment method comprising administering a therapeutically effective amount of a compound of general formula (I) or its stereoisomers, hydrates, solvates, crystals, or pharmaceutically acceptable salts of this invention to a subject requiring inhibition of BTK and / or JAK3 activity.

[0055] Preferably, the present invention provides the use of the compound of general formula (I) of the present invention or its stereoisomers, hydrates, solvates, crystals or pharmaceutically acceptable salts in the preparation of a dual-target inhibitor of BTK and JAK3.

[0056] Furthermore, the BTK and JAK3 inhibitors are used to treat autoimmune diseases and B-cell malignancies. Preferably, the autoimmune diseases include rheumatoid arthritis, psoriasis, and alopecia areata, and the B-cell malignancies include B-cell lymphoma. Accordingly, the present invention also provides a method for treating autoimmune diseases or B-cell malignancies, comprising administering to a subject suffering from an autoimmune disease or B-cell malignancy a therapeutically effective amount of the compound of general formula (I) of the present invention or its stereoisomers, hydrates, solvates, crystals, or pharmaceutically acceptable salts.

[0057] The beneficial effect of this invention lies in providing a novel method for preparing the pyrazolo[3,4-d]pyrimidine derivative shown in general formula (I). Pharmacological experiments show that compound (I) of this invention can produce good inhibitory effects on both BTK and JAK3 kinases, and can be used to prepare drugs for treating rheumatoid arthritis caused by overactivation of the BTK and JAK3 pathways. Detailed Implementation

[0058] The present application will now be described in detail with reference to specific embodiments.

[0059] Example 1

[0060] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,3-dihydrobenzofuran-4-yl)-6-methoxynicotinamide (I-1)

[0061] Synthesis of 7-bromo-2,3-dihydrobenzofuran-4-amine (X-1)

[0062] 2,3-Dihydrobenzofuran-4-amine IX-1 (5.00 g, 0.037 mol) was placed in a 150 mL three-necked flask, dissolved in 60 mL of DMF, and NBS (6.59 g, 0.037 mol) was added in portions at -40 °C, reacting for approximately 2 h. The reaction was quenched with 20 mL of saturated sodium bisulfite aqueous solution, and extracted with 80 mL of water and ethyl acetate (100 mL × 2). The organic phases were combined and washed with 50 mL × 2 of water and 50 mL × 2 of saturated sodium chloride aqueous solution, respectively. The solution was dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to give 6.67 g of a brown oily substance, with a yield of 84.2%. 1H NMR (400 MHz, DMSO-d6)δ (ppm): 6.91 (dd, J = 8.5, 2.4 Hz, 1H, ArH), 6.09 (dd, J = 8.6, 2.4 Hz, 1H, ArH), 4.54 (t, J = 8.7 Hz, 2H, CH2C H2 O), 3.03 (t, J = 8.8 Hz, 2H, C H2 CH2O).

[0063] Synthesis of 7-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-2,3-dihydrobenzofuran-4-amine (XI-1)

[0064] Compound X-1 (5.60 g, 0.026 mol), pinacol diboronate (8.25 g, 0.032 mol), potassium acetate (7.74 g, 0.079 mol), and Pd(dppf)Cl2 (950 mg, 0.0013 mol) were added to a 250 mL three-necked flask, followed by 80 mL of 1,4-dioxane. The mixture was stirred at 70 °C for 8 h under nitrogen protection. The mixture was filtered through diatomaceous earth, and the filtrate was washed with 150 mL of ethyl acetate and then with water (50 mL × 2) and saturated sodium chloride aqueous solution (50 mL × 2), respectively. The solution was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The mixture was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 10:1–2:1) to give 4.21 g of a pale yellow solid, yield: 62.0%. 1 H NMR (300 MHz, CDCl3) δ (ppm): 7.38 (d, J = 8.0 Hz, 1H, ArH), 6.21 (d, J = 8.0 Hz, 1H, ArH), 4.65 (t, J = 8.7 Hz, 2H, CH2C H2 O), 2.94 (t, J = 8.7 Hz, 2H, C H2 CH2O), 1.32 (s, 12H, 4CH3).

[0065] Synthesis of 6-methoxy-N-(7-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-2,3-dihydrobenzofuran-4-yl)nicotinamide (Ⅳ-1)

[0066] Add 345 mg (2.3 mmol) of 6-methoxynicotinic acid and 10 mL of anhydrous dichloromethane to a 50 mL round-bottom flask, add two drops of DMF, and then slowly add oxalyl chloride (197 μL, 4.6 mmol) dropwise under ice bath conditions. After the addition is complete, bring the mixture to room temperature and react for 30 minutes. Remove the solvent under reduced pressure, and dissolve the residue in anhydrous dichloromethane for later use (acyl chloride solution A).

[0067] Compound XI-1 (500 mg, 0.0019 mol) and triethylamine (530 μL, 0.0038 mol) were added to a 50 mL round-bottom flask. The above-mentioned acyl chloride solution A was slowly added dropwise under ice bath conditions. After the addition was complete, the reaction was allowed to proceed at room temperature for approximately 3 h. The reaction was quenched with saturated sodium carbonate aqueous solution, extracted with dichloromethane, and the combined organic phases were washed with water (20 mL × 2) and saturated sodium chloride aqueous solution (20 mL × 2), respectively. The mixture was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation of the filtrate. The filtrate was then slurried with petroleum ether:ethyl acetate in a 6:1 ratio. Filtering yielded 615 mg of an off-white solid, with a yield of 81.7%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 10.07(s, 1H, CONH), 8.77 (s, 1H, ArH), 8.20 (d, J = 8.6 Hz, 1H, ArH), 7.35 (d, J =8.1 Hz, 1H, ArH), 7.02 (d, J = 8.5 Hz, 1H, ArH), 6.94 (d, J = 8.6 Hz, 1H, ArH), 4.63-4.41 (m, 2H, OC H2 CH2), 3.93 (s, 3H, OCH3), 3.22-3.06 (m, 2H,C H2 CH2O), 1.26 (s, 12H, 4CH3).

[0068] Synthesis of (R)-3-(4-amino-3-(4-(6-methoxynicotinamide)-2,3-dihydrobenzofuran-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (V-1)

[0069] Compounds IV-1 (520 mg, 1.30 mmol), III (560 mg, 1.30 mmol), and Pd(dppf)Cl2 (48 mg, 0.065 mmol) were added to a 100 mL three-necked flask, where 1,4-dioxane was dissolved. A 2 mol / L sodium carbonate aqueous solution (1.3 mL, 2.60 mmol) was added, and the reaction was carried out at 70 °C for approximately 4 h under nitrogen protection. After cooling to room temperature, the mixture was filtered through diatomaceous earth, dissolved in 50 mL of ethyl acetate, and washed with water and saturated sodium chloride aqueous solution, respectively. The solution was dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate by vacuum distillation. The solution was purified by column chromatography (eluent: dichloromethane:methanol = 200:1–50:1) to give 440 mg of a white solid, in a yield of 57.7%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 10.17 (s, 1H, NHCO), 8.82 (s, 1H,ArH), 8.28-8.22 (m, 2H, ArH), 7.32 (d, J = 8.3 Hz, 1H, ArH), 7.23 (d, J = 8.4Hz, 1H, ArH), 6.97 (d, J = 8.7 Hz, 1H, ArH), 4.66 (m, 3H, CH2C H2 O, NC H 2CH), 4.19-4.00 (m, 1H, NCH2C) H ), 3.95 (s, 3H,OCH3), 3.88-3.73 (m, 1H, NC H 2CH), 3.69-3.61 (m, 1H, NC H 2CH2), 3.31 (t, J = 8.7 Hz, 2H, C H 2CH2O), 3.14-2.87 (m, 1H, NC) H 2CH2), 2.31-2.14 (m, 1H, NCH2CHC H 2), 2.13-2.05 (m, 1H, NCH2CHC H 2), 1.96-1.80 (m, 1H, NCH2C) H 2), 1.65-1.52 (m, 1H, NCH2C H 2), 1.34 (s, 9H).

[0070] Synthesis of (R)-N-(7-(4-amino-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,3-dihydrobenzofuran-4-yl)-6-methoxynicotinamide (VI-1)

[0071] Compound V-1 (400 mg, 0.68 mmol) and 10 mL of dichloromethane were added to a round-bottom flask and dissolved. 1 mL of ethyl acetate saturated with hydrogen chloride was added under ice bath conditions, and the reaction was carried out at room temperature for 1 h. The mixture was filtered to give 306 mg of a pale yellow solid, with a yield of 92.5%, which was directly added to the next step without purification.

[0072] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,3-dihydrobenzofuran-4-yl)-6-methoxynicotinamide (I-1)

[0073] Compound VI-1 (300 mg, 0.62 mmol) and 8 mL of dichloromethane were added to a 50 mL round-bottom flask and dissolved. Triethylamine (160 μL, 1.20 mmol) was added, and the mixture was stirred for 30 min. A diluted dichloromethane solution of acryloyl chloride (44 μL, 0.55 mmol) was added under ice bath conditions, and the reaction was continued for approximately 1 h. The mixture was quenched with 5 mL of saturated sodium carbonate aqueous solution, extracted with dichloromethane (15 mL × 2), and the organic phases were combined and washed with water (5 mL × 2) and saturated sodium chloride aqueous solution (5 mL × 2), respectively. The mixture was dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The solution was purified by column chromatography (eluent: dichloromethane: methanol = 200:1–30:1) to give 151 mg of a white solid, yield 45.1%. HPLC purity: 98.00%. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.16 (s, 1H, NH), 8.81 (s, 1H, ArH), 8.29-8.20 (m,2H, ArH), 7.31 (d, J = 8.3 Hz, 1H, ArH), 7.22 (d, J = 8.3 Hz, 1H, ArH), 6.98(d, J = 8.7 Hz, 1H, ArH), 6.92-6.70 (m, 1H, C H =CH2), 6.22-6.01 (m, 1H, CH=C H 2), 5.76-5.55 (m, 1H, CH=C H 2), 4.75-4.51 (m, 3.5H, OCH2 CH2, NC H 2CH, NCH2C H ), 4.31-4.17 (m, 1H, NC H 2CH), 4.13-4.02 (m, 0.5H, NCH2C H ), 3.96 (s, 3H, OCH3), 3.81-3.62 (m, 0.5H, NC H 2CH2) 3.30 (t, J = 8.5 Hz, 2H, C H2 CH2O), 3.27-3.16 (m, 1H, NC) H 2CH2), 3.04-2.91 (m, 0.5H, NC H 2CH2), 2.31-2.20 (m, 1H, NCH2CHCH2), 2.18-2.08 (m, 1H, NCH2CHC H 2), 2.01-1.89 (m, 1H, NCH2C H 2), 1.61 (m, 1H, NCH2C H 2)

[0074] Example 2

[0075] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,3-dihydrobenzofuran-4-yl)-4-(dimethylamino)benzamide (I-2)

[0076] Synthesis of 4-(dimethylamino)-N-(7-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-2,3-dihydrobenzofuran-4-yl)benzamide (Ⅳ-2)

[0077] Using 4-dimethylaminobenzoic acid (402 mg, 2.40 mmol) and compound XI-1 (530 mg, 2.00 mol) as raw materials, the same procedure as for compound IV-1 was followed to give 400 mg of yellow solid (IV-2), with a yield of 49.0%.

[0078] Synthesis of (R)-N-3-(4-amino-3-(4-(4-(dimethylamino)benzoylamino)-2,3-dihydrobenzofuran-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (V-2)

[0079] Using compounds IV-2 (0.40 g, 0.98 mmol) and III (415 mg, 0.94 mmol) as raw materials, the same procedure as compound V-1 was followed to obtain 128 mg of a pale yellow solid, with a yield of 21.82%. 1 H NMR (300 MHz, DMSO-d6) δ(ppm): 9.79 (s, 1H, CONH), 8.22 (s, 1H, ArH), 7.88 (d, J = 8.9 Hz, 2H, ArH), 7.28 (d, J = 8.3 Hz, 1H, ArH), 7.19 (d, J = 8.4 Hz, 1H, ArH), 6.78 (d, J =9.1 Hz, 2H, ArH), 4.78-4.59 (m, 3H, CH2C H2 O, NC H 2CH), 4.12-4.00 (m, 1H, NCH2C) H ), 3.98-3.73 (m, 2H, NC H 2CH, NC H 2CH2), 3.28 (t, J = 8.6 Hz, 2H, C H2 CH2O),3.01 (s, 6H, N(CH3)2), 2.28-2.16(m, 1H, NC H 2CH2), 2.11-2.03 (m, 1H, NCH2CHC H 2), 1.96-1.80 (m, 1H, NCH2CHC) H 2), 1.70-1.52 (m, 2H, NCH2C) H2 ), 1.36 (s, 9H, NBoc).

[0080] Synthesis of (R)-N-(7-(4-amino-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2,3-dihydrobenzofuran-4-yl)-4-(dimethylamino)benzamide (VI-2)

[0081] Using compound V-2 (100 mg, 0.17 mmol) as the starting material, the same procedure as compound VI-1 was followed to give 57 mg of a pale yellow solid, with a yield of 67.2%.

[0082] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2,3-dihydrobenzofuran-4-yl)-4-(dimethylamino)benzamide (I-2)

[0083] Using compound VI-2 (57 mg, 0.011 mmol) as the starting material, the procedure was the same as for compound I-1, yielding 11 mg of white solid in 18.1% yield. HPLC purity: 97.83%. 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 9.84 (s,1H, NHCO), 8.21 (s, 1H, ArH), 7.88 (d, J = 8.5 Hz, 2H, ArH), 7.27 (d, J = 8.3Hz, 1H, ArH), 7.18 (d, J = 8.4 Hz, 1H, ArH), 6.95-6.70 (m, 3H, ArH, C H =CH2),6.20-6.03 (m, 1H, CH=CH2), 5.81-.56 (m, 1H, CH=C H 2), 4.74-4.49 (m, 3H,CH2C H2 O, NC H 2CH), 4.31-4.15 (m, 1H, NCH2C H ), 4.13-3.95 (m, 1H, NC H 2CH), 3.32-3.12 (m, 4H, C H2 CH2O, NC H2 CH2), 3.00 (s, 6H, N(CH3)2), 2.30-2.22 (m, 1H,NCH2CHC H 2), 2.16-2.04 (m, 1H, NCH2CHC H 2), 1.95-1.85 (m, 1H, NCH2C H 2), 1.67-1.52 (m, 1H, NCH2C) H 2).

[0084] Example 3

[0085] Synthesis of (R)-N-(7-1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-4-fluorobenzamide (I-3)

[0086] Synthesis of 7-bromobenzo[d][1,3]dioxane-4-amine (X-2)

[0087] Benzo[d][1,3]dioxane-4-amine(IX-2) (1.24 g, 9.04 mmol) and DMF (30 mL) were mixed and dissolved by stirring. The mixture was cooled to -30 °C, and NBS (1.69 g, 9.50 mmol) was added in portions. After the addition was complete, the mixture was kept at this temperature for 1 hour. Water (60 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phase was washed successively with water (10 mL × 3) and saturated sodium chloride solution (10 mL × 3), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was separated by column chromatography (eluent: petroleum ether: ethyl acetate = 30:1-10:1) to give 1.01 g of white solid, yield 51.7%, mp 99-100 °C. 1 H-NMR (300 MHz, CDCl3) δ (ppm): 6.80 (d, J = 8.67 Hz, 1H, ArH), 6.23 (d, J = 8.67 Hz, 1H, ArH), 6.02 (s, 2H, OCH2O), 3.58 (s, 2H, NH2).

[0088] Synthesis of 7-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzo[d][1,3]dioxoboronyl-4-amine (XI-2)

[0089] Compound X-2 (3.14 g, 14.54 mmol), pinacol diborate (7.39 g, 29.07 mmol), Pd(dppf)Cl2 (0.53 g, 0.73 mmol), potassium acetate (4.28 g, 43.62 mmol), and 1,4-dioxane (25 mL) were mixed and reacted under N2 protection at 95 °C for 12 h. The mixture was filtered through diatomaceous earth, the solvent was removed by vacuum evaporation of the filtrate, and the residue was dissolved in ethyl acetate (20 mL). The solution was washed successively with water (10 mL × 3) and saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under vacuum. The residue was subjected to column chromatography (eluent: petroleum ether: dichloromethane = 10:1–5:1) to give 2.7 g of a white solid, yield 70.6%. mp 84–86 °C. 1 H-NMR (300 MHz, CDCl3) δ (ppm):7.09 (d, J = 8.16 Hz, 1H, ArH), 6.31 (d, J = 8.19 Hz, 1H, ArH), 5.99 (s, 2H,OCH2O), 3.71 (br, 2H, NH2), 1.34 (s, 12H, 4CH3).

[0090] Synthesis of 4-fluoro-N-(7-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzo[d][1,3]dioxoboronyl-4-yl)benzamide (Ⅳ-3)

[0091] 0.64 g (4.60 mmol) of 4-fluorobenzoic acid and 12 mL of anhydrous dichloromethane were added to a 50 mL round-bottom flask. Three drops of DMF were added, and then an anhydrous dichloromethane solution of oxaloyl chloride (645 μL, 7.60 mmol) was added dropwise under ice bath conditions. After the addition was complete, the mixture was stirred at room temperature. As the reaction proceeded, the solution changed from a white turbidity to a colorless and clear state. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 3:1) for approximately 30 minutes to indicate completion. The solvent was removed under reduced pressure, and the product was dissolved in 15 mL of anhydrous dichloromethane for later use (acyl chloride solution C).

[0092] Compound XI-2 (1.00 g, 3.80 mmol), 15 mL of anhydrous dichloromethane, and triethylamine (1.50 mL, 11.40 mmol) were added to a 50 mL round-bottom flask and stirred until dissolved. The above-mentioned acyl chloride solution C was added dropwise under ice bath conditions. After the addition was complete, the reaction was allowed to proceed at room temperature for 3.5 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 3:1) to ensure complete reaction of the starting material. The organic phase was washed with water (10 mL × 3) and saturated sodium chloride aqueous solution (10 mL × 3), respectively, and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a pale yellow solid. A slurry was prepared by mixing petroleum ether and ethyl acetate in an 8:1 ratio (1 g / 6 mL) to give 1.38 g of a white solid, with a yield of 94.3%. 1 HNMR (300 MHz, DMSO-d6) δ (ppm): 10.22 (s, 1H, NHCO), 8.06 (d, J = 5.5 Hz, 1H,ArH), 8.03 (d, J = 5.5 Hz, 1H, ArH), 7.42-7.34 (m, 2H, ArH), 7.07 (d, J = 8.3Hz, 1H, ArH), 7.02 (d, J = 8.3Hz, 1H, ArH), 6.07 (s, 2H, OCH2O), 1.29 (s,12H, 4CH3).

[0093] (R)-3-(4-amino-3-(7-(4-fluorobenzoylamino)benzo[d][1,3]dioxacyclopentan-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester -3) Synthesis

[0094] Compound IV-3 (1.27 g, 3.30 mmol), compound III (1.46 g, 3.67 mmol), 15 mL of 1,4-dioxane, 3 mL of 2 mol / L Na₂CO₃, and 0.12 g of Pd(dppf)Cl₂ (0.17 mmol) were added to a 50 mL three-necked flask. The mixture was reacted under nitrogen protection at 70 °C for 2 h, during which the yellow turbidity turned black. The reaction was monitored by TLC (dichloromethane:methanol = 30:1) to ensure complete reaction. The mixture was filtered through diatomaceous earth, and the solvent was removed by vacuum distillation of the filtrate. The filtrate was dissolved in dichloromethane (25 mL), washed with water (10 mL × 3), and saturated sodium chloride aqueous solution (10 mL × 3), and dried over anhydrous sodium sulfate. The solution was filtered, concentrated under reduced pressure, and purified by column chromatography (eluent: dichloromethane:methanol = 200:1-100:1-50:1-40:1) to give 1.52 g of a yellowish-brown solid, yield 80.0%. mp 176-178 ℃. 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 10.29 (s, 1H,NHCO), 8.23 ​​(s, 1H, ArH), 8.13-8.00 (m, 2H, ArH), 7.42-7.33 (m, 2H, ArH), 7.18 (d, J = 8.6 Hz, 1H, ArH), 7.03 (d, J = 8.5 Hz, 1H, ArH), 6.15 (s, 2H,OCH2O), 5.77 (s, 1H, NH), 4.81-4.63 (m, 1H, NC H 2CH), 4.35-4.10 (m, 1H, NCH2C) H ), 4.09-3.90 (m, 1H, NC H 2CH), 3.44-3.27 (m, 1H, NC H 2CH2), 3.17 (s, 1H,NH), 2.81-2.63 (m, 1H, NC H 2CH2), 2.24-2.07 (m, 2H, NCH2CHC H2 ), 1.85-1.67 (m, 1H, NCH2C) H2 ), 1.65-1.48 (m, 1H, NCH2C H2 ), 1.32 (s, 9H, NBoc).

[0095] Synthesis of (R)-N-(7-(4-amino-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-4-fluorobenzamide (VI-3)

[0096] compound -3 (1.40 g, 2.43 mmol) was dissolved in 5 mL of anhydrous dichloromethane. Approximately 2.5 mL of ethyl acetate solution saturated with hydrogen chloride was added under ice bath conditions. A large amount of solid precipitated immediately. After the addition was complete, the ice bath was removed. The reaction was stirred at room temperature for approximately 2 h. TLC (dichloromethane:methanol = 20:1) was used to monitor the reaction until complete. The mixture was filtered, the filter cake was washed with ethyl acetate, and dried under vacuum to give 1.13 g of an off-white solid, yielding 97.8%.

[0097] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-4-fluorobenzamide (I-3)

[0098] Compound VI-3 (1.10 g, 2.31 mmol) was added to 5 mL of dichloromethane, followed by Et3N (498 μL, 5.56 mmol). The compound gradually dissolved, and the reaction solution became a clear, yellowish-brown color. After stirring at room temperature for 0.5 h, a solution of acryloyl chloride (127 μL, 2.08 mmol) in 1 mL of dichloromethane was slowly added dropwise under ice bath conditions. After the addition was complete, the mixture was stirred at room temperature for 2 h. The reaction was monitored for completeness by TLC (dichloromethane:isopropanol = 15:1). The solution was diluted with dichloromethane, washed with water (10 mL × 3), washed with saturated sodium chloride aqueous solution (10 mL × 3), and concentrated under reduced pressure to obtain the crude product. Column chromatography purification (eluent: dichloromethane:methanol = 100:1-75:1-50:1-40:1-35:1) yielded 450 mg of a white solid, with a yield of 40.9%. HPLC purity: 99.13%. mp 157-159 ℃. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 10.27 (s, 1H, NHCO), 8.24 (s,1H, ArH), 8.10-8.05 (m, 2H, ArH), 7.41-7.35 (m, 2H, ArH), 7.20 (d, J = 8.6Hz, 1H, ArH), 7.05 (d, J = 8.5 Hz, 1H, ArH), 6.81-6.76 (m, 1H, C H=CH2), 6.16(s, 2H, OCH2O), 6.09-5.96 (m, 1H, CH=C H 2), 5.91 (s, 2H, NH2), 5.87-5.63 (m,1H, CH=C H 2), 4.77-4.65 (m, 1H, NC H 2CH), 4.59-4.52 (m, 0.5H, NCH2C H ), 4.30-4.17(m, 1H, NC H 2CH), 4.12-4.05 (m, 0.5H, NCH2C H ), 3.73-3.66 (m, 0.5H, NC H 2CH2),3.26-3.15 (m, 1H, NC H 2CH2), 3.02-2.92 (m, 0.5H, NC H 2CH2), 2.31-2.22 (m, 1H,NCH2CHC H 2), 2.16-2.08 (m, 1H, NCH2CHC H 2), 1.97-1.89 (m, 1H, NCH2C H 2), 1.67-1.54(m, 1H, NCH2C H 2). 13C NMR (101 MHz, DMSO-d6) δ (ppm): 165.19 (d, J = 250.3 Hz),165.05, 163.44, 158.54, 156.18, 154.16, 146.36, 141.49, 138.84, 131.06 (d, J = 9.2 Hz, 2C), 130.91 (d, J = 2.9 Hz), 128.78, 127.93, 122.56, 121.76,119.46, 115.96 (d, J = 21.9 Hz, 2C), 112.12, 102.16, 99.09, 53.39 (0.5C),52.63 (0.5C), 49.72 (0.5C), 46.17 (0.5C), 45.62 (0.5C), 42.05 (0.5C), 30.09(0.5C), 29.98 (0.5C), 25.39 (0.5C), 23.86 (0.5C). HRMS (ESI): m / z [M+Na] + .Calcd for C 27 H 24 FN7NaO4: 552.1772; Found:552.1762.

[0099] Example 4

[0100] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-4-cyanobenzamide (I-4)

[0101] Synthesis of 4-cyano-N-(7-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzo[d][1,3]dioxoboronyl-4-yl)benzamide (Ⅳ-4)

[0102] Using 4-cyanobenzoic acid (0.67 g, 4.56 mmol) and compound XI-2 (1.00 g, 3.80 mmol) as raw materials, the same procedure as for compound IV-3 was followed to give 1.47 g of a pale yellow solid, with a yield of 99.1%. 1H NMR (300 MHz, CDCl3) δ(ppm): 8.24 (s, 1H, NHCO), 7.98 (d, J = 8.1 Hz, 2H, ArH), 7.85-7.74 (m, 4H,ArH), 6.08 (s, 2H, OCH2O), 1.37 (s, 12H, 4CH3).

[0103] Synthesis of (R)-3-(4-amino-3-(7-(4-cyanobenzoylamino)benzo[d][1,3]dioxacyclopentan-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (V-4)

[0104] Using compounds IV-4 (1.45 g, 3.72 mmol) and III (1.65 g, 3.72 mmol) as starting materials, the same procedure as for the synthesis of compound V-3 was followed to give 1.49 g of a yellow solid, yielding 68.1%. mp 159–161 °C. 1 HNMR (300 MHz, DMSO-d6) δ (ppm): 10.54 (s, 1H, NHCO), 8.23 ​​(s, 1H, ArH), 8.13 (d, J = 8.2 Hz, 2H, ArH), 8.04 (d, J = 8.3 Hz, 2H, ArH), 7.20 (d, J = 8.6 Hz,1H, ArH), 7.04 (d, J = 8.6 Hz, 1H, ArH), 6.15 (s, 2H, OCH2O), 5.77 (s, 2H,NH2), 4.74-4.60 (m, 1H, NC H 2CH), 4.10-3.95 (m, 1H, NCH2C H ), 3.91-3.75 (m, 1H,NC H 2CH), 3.19-3.14 (m, 1H, NC H 2CH2), 3.09-2.88 (m, 1H, NC H 2CH2), 2.24-2.15 (m,1H, NCH2CHC H 2), 2.12-2.02 (m, 1H, NCH2CHC H 2), 2.00-1.82 (m, 1H, NCH2C H 2), 1.60-1.51 (m, 1H, NCH2C H2), 1.32 (s, 9H, NBoc).

[0105] Synthesis of (R)-N-(7-(4-amino-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-4-cyanobenzamide (VI-4)

[0106] Using compound V-4 (1.44 g, 0.0025 mol) as the starting material, the same procedure as for compound VI-3 was followed to give 1.18 g of a pale yellow solid, with a yield of 99.15%.

[0107] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-4-cyanobenzamide (I-4)

[0108] Using compound VI-4 (1.18 g, 2.44 mmol) as the starting material, the same synthesis as compound I-3 was performed to give 470 mg of white solid, yield 35.9%. HPLC purity: 99.13%. mp 180-182 ℃. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 10.53 (s, 1H, NHCO), 8.24 (s, 1H, ArH), 8.14 (d, J = 8.4Hz, 2H, ArH), 8.04 (d, J = 8.4 Hz, 2H, ArH), 7.22 (d, J = 8.6 Hz, 1H, ArH),7.06 (d, J = 8.6 Hz, 1H, ArH), 6.89-6.79 (m, 1H, C H =CH2), 6.17 (s, 2H, OCH2O),6.14-6.05 (m, 1H, CH=C H 2), 5.75-5.57 (m, 1H, CH=C H 2), 4.75-4.67 (m, 1H,NC H 2CH), 4.58-4.55 (m, 0.5H, NCH2C H ), 4.38-4.24 (m, 1H, NC H 2CH), 4.13-4.01 (m,0.5H, NCH2C H ), 3.76-3.64 (m, 0.5H, NCH 2CH2), 3.26-3.15 (m, 1H, NC H 2CH2), 3.03-2.94 (m, 0.5H, NC H 2CH2), 2.31-2.20 (m, 1H, NCH2CHC H 2), 2.17-2.08 (m, 1H,NCH2CHC H 2), 1.99-1.89 (m, 1H, NCH2C H 2), 1.68-1.53 ​​(m, 1H, NCH2C H 2). 13 C NMR (101MHz, DMSO) δ (ppm): 165.04, 164.27, 158.53, 156.18, 154.17, 146.44, 141.49,138.79, 138.46, 132.98, 129.16, 128.80, 127.88, 122.62, 121.32, 119.30,118.77, 114.55, 112.36, 102.25, 99.09, 53.39 (0.5C), 52.63 (0.5C), 49.71(0.5C), 46.17 (0.5C), 45.62 (0.5C), 42.05 (0.5C), 30.09 (0.5C), 29.87 (0.5C), 25.39 (0.5C), 23.85 (0.5C). HRMS (ESI): m / z [M+Na] + Calculated for C 28 H 24 N8NaO4:559.1818; Found: 559.1801.

[0109] Example 5

[0110] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-3-(dimethylamino)benzamide (I-5)

[0111] Synthesis of 3-dimethylamino-N-(7-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzo[d][1,3]dioxoboronyl-4-yl)benzamide (Ⅳ-5)

[0112] Using compound 3-dimethylaminobenzoic acid (0.60 g, 3.64 mmol) and compound XI-2 (0.80 g, 3.00 mmol) as raw materials, the same procedure as for compound IV-3 was followed to give 0.92 g of a pale yellow solid, with a yield of 74.8%. 1 HNMR (300MHz, DMSO-d6) δ (ppm): 9.60 (s, 1H, NHCO), 7.71 (d, J = 8.3 Hz, 2H, ArH), 7.03 (d, J = 8.6 Hz, 2H, ArH), 6.85 (d, J = 8.5 Hz, 1H, ArH), 6.42 (d, J =8.4 Hz, 1H, ArH), 5.97 (s, 2H, OCH2O), 3.13 (s, 6H, N(CH3)2).1.32(s, 12H,4CH3).

[0113] Synthesis of (R)-3-(4-amino-3-(7-(3-(dimethylamino)benzoylamino)benzo[d][1,3]dioxacyclopentan-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (V-5)

[0114] Using compounds IV-5 (0.71 g, 1.73 mmol) and III (0.73 g, 1.64 mmol) as starting materials, the same procedure as for the synthesis of compound V-3 was followed to give 0.82 g of a yellow solid, with a yield of 83.2%. 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 9.76 (s, 1H, NHCO), 8.23 ​​(s, 1H, ArH), 7.87 (d, J = 8.4 Hz, 2H, ArH), 7.19 (d, J = 8.6 Hz, 1H, ArH), 7.01 (d, J = 8.6 Hz, 1H, ArH), 6.58(d, J = 8.5 Hz, 2H, ArH), 6.13 (s, 2H, OCH2O), 5.68 (s, 2H, NH2), 4.73-4.61(m, 1H, NC H 2CH), 4.23-3.89 (m, 1H, NCH2C H ), 3.90-3.67 (m, 1H, NC H 2CH), 3.13(s, 6H, N(CH3)2), 3.09-2.86 (m, 2H, NCH 2CH2), 2.27-2.13 (m, 1H, NCH2CHC H 2), 2.12-2.04 (m, 1H, NCH2CHC) H 2), 1.62-1.49 (m, 2H, NCH2C H 2), 1.30 (s, 9H, NBoc).

[0115] Synthesis of (R)-N-(7-(4-amino-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-3-(dimethylamino)benzamide (VI-5)

[0116] Using compound V-5 (0.60 g, 1.00 mmol) as the starting material, the same procedure as for compound VI-3 was followed to give 0.42 g of a pale yellow solid, with a yield of 84.0%.

[0117] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-3-(dimethylamino)benzamide (I-5)

[0118] Using compound VI-5 (0.37 g, 0.74 mmol) as the starting material, the same synthesis as compound I-3 was performed to give 45 mg of a white solid, yield 11.0%. HPLC purity: 99.15%. mp 168-170 ℃. 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 10.12 (s, 1H, NHCO), 8.24 (s, 1H, ArH), 7.36-7.24 (m, 3H,ArH), 7.17 (d, J = 8.6 Hz, 1H, ArH), 7.04 (d, J = 8.6 Hz, 1H, ArH), 6.94 (d,J = 9.3 Hz, 1H, ArH), 6.90-6.70 (m, 1H, C H =CH2), 6.15 (s, 2H, OCH2O), 6.13-6.04 (m, 1H, CH=C H 2), 5.76-5.58 (m, 1H, CH=C H 2), 4.78-4.65 (m, 1H, NC H2CH),4.63-4.51 (m, 0.5H, NCH2C H ), 4.34-4.16 (m, 1H, NC H 2CH), 4.17-4.01 (m, 0.5H,NCH2C H ), 3.80-3.56 (m, 0.5H, NC H 2CH2), 3.27-3.11 (m, 1H, NC H 2CH2), 2.99 (s, 6H,N(CH3)2), 2.98-2.91 (m, 0.5H, C H 2CH2), 2.36-2.18 (m, 1H, NCH2CHC H 2), 2.20-2.04 (m, 1H, NCH2CHC) H 2), 2.01-1.88 (m, 1H, NCH2C H 2), 1.72-1.52 (m, 1H, NCH2C H 2). 13 CNMR (75 MHz, DMSO-d6) δ 166.11, 165.06, 158.58, 156.22, 154.19, 150.81,146.35, 141.55, 135.15, 138.99, 129.44, 128.85, 128.05, 127.87, 122.54,122.07, 119.66, 115.94, 112.01, 111.84, 102.15, 99.15, 60.28 (0.5C), 53.45(0.5C), 52.70 (0.5C), 49.75 (0.5C), 46.21 (0.5C), 45.74 (0.5C), 40.65, 30.07(0.5C), 29.93 (0.5C), 25.46 (0.5C), 23.92 (0.5C).

[0119] Example 6

[0120] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-2-(dimethylamino)benzamide (I-6)

[0121] Synthesis of 2-dimethylamino-N-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzo[d][1,3]dioxoboronyl-4-yl)benzamide (Ⅳ-6)

[0122] Using compound 2-dimethylaminobenzoic acid (0.53 g, 3.19 mmol) and compound XI-2 (0.70 g, 2.66 mmol) as raw materials, the same procedure as for compound IV-3 was followed to give 0.86 g of a pale yellow solid, with a yield of 78.8%. 1 H NMR(300 MHz, DMSO-d6) δ (ppm): 10.18 (s, 1H, NHCO), 8.07 (d, J = 7.8 Hz, 1H,ArH), 7.96 (d, J = 8.7 Hz, 1H, ArH), 7.58 (d, J = 8.7 Hz, 1H, ArH), 7.52 (d,J = 6.8 Hz, 1H, ArH), 7.32 (d, J = 7.4 Hz, 1H, ArH), 7.04 (d, J = 8.7 Hz, 1H,ArH), 6.21 (s, 2H, OCH2O), 1.35 (s, 12H, 4CH3).

[0123] Synthesis of (R)-3-(4-amino-3-(7-(2-(dimethylamino)benzoylamino)benzo[d][1,3]dioxacyclopentan-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (V-6)

[0124] Using compounds IV-6 (0.85 g, 2.10 mmol) and III (0.84 g, 1.88 mmol) as starting materials, the same procedure as that for compound V-3 was followed to obtain 444 mg of a yellow solid, with a yield of 39.3%. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 10.10 (s, 1H, NHCO), 8.24 (s, 1H, ArH), 8.11 (d, J = 7.8Hz, 1H, ArH), 8.01 (d, J = 8.7 Hz, 1H, ArH), 7.59 (d, J = 6.9 Hz, 1H, ArH), 7.52 (d, J = 6.8 Hz, 1H, ArH), 7.42 (d, J = 8.1 Hz, 1H, ArH), 6.98 (d, J = 8.7Hz, 1H, ArH), 6.21 (s, 2H, OCH2O), 4.78-4.56 (m, 1H, NC H 2CH), 4.35-4.22 (m,2H, NC H 2C H ), 3.57-3.31 (m, 1H, NC H 2CH2), 3.39 (s, 6H, N(CH3)2) 3.17-2.99 (m,1H, NC H 2CH2), 2.29-2.09 (m, 1H, NCH2CHC H 2), 2.16-2.02 (m, 1H, NCH2CHC H 2), 1.98-1.85 (m, 1H, NCH2C H 2), 1.66-1.43 (m, 1H, NCH2C H 2), 1.33 (s, 9H, NBoc).

[0125] Synthesis of (R)-N-(7-(4-amino-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-2-(dimethylamino)benzamide (VI-6)

[0126] Using compound V-6 (0.41 g, 0.68 mmol) as the starting material, the same procedure as for compound VI-3 was followed to give 300 mg of a pale yellow solid, with a yield of 88.2%.

[0127] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-2-(dimethylamino)benzamide (I-6)

[0128] Using compound VI-6 (0.30 g, 0.60 mmol) as the starting material, the same synthesis procedure as for compound I-3 was followed to give 63 mg of a white solid, yielding 19.0%. HPLC purity: 95.38%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm):13.09 (s, 1H, NHCO), 8.23 ​​(s, 1H, ArH), 8.08 (dd, J = 7.8, 1.7 Hz, 1H, ArH), 7.97 (d, J = 8.7 Hz, 1H, ArH), 7.60 (t, J = 6.8 Hz, 1H, ArH), 7.53 (d, J =8.1 Hz, 1H, ArH), 7.33 (t, J = 7.4 Hz, 1H, ArH), 7.05 (d, J = 8.7 Hz, 1H, ArH), 6.91-6.82 (m, 1H, C H =CH2), 6.22 (s, 2H, OCH2O), 6.12 (m, 1H, CH=C H 2), 5.76-5.57 (m, 1H, CH=C) H 2), 4.75-4.67 (m, 1H, NC H 2CH), 4.64-4.55 (m, 0.5H,NCH2C H ), 4.30-4.20 m, 1H, NC H 2CH), 4.14-4.03 (m, 0.5H, NCH2C H ), 3.75-3.57 (m, 0.5H, NC H 2CH2), 3.26-3.16 (m, 1H, NC H 2CH2), 3.02-2.91 (m, 0.5H, NC H 2CH2), 2.80(s, 6H, N(CH3)2), 2.32-2.22 (m, 1H, NCH2CHC H 2), 2.17-2.08 (m, 1H, NCH2CHC H 2), 1.97-1.87 (m, 1H, NCH2C) H 2), 1.66-1.51 (m, 1H, NCH2C H 2). 13C NMR (101 MHz, DMSO-d6) δ (ppm): 165.03, 163.97, 158.53, 156.16, 154.14, 152.87, 145.73, 138.98,138.03, 133.37, 130.96, 128.85, 127.88, 127.25, 125.24, 123.36, 123.09,122.14, 115.06, 110.69, 102.62, 99.05, 53.38 (0.5C), 52.61 (0.5C), 49.72(0.5C), 46.18(0.5C), 45.60 (0.5C), 45.42, 42.03(0.5C), 30.00 (0.5C), 29.90(0.5C), 25.41 (0.5C), 23.88 (0.5C).

[0129] Example 7

[0130] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-4-morpholinobenzamide (I-7)

[0131] Synthesis of 4-morpholino-N-(7-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzo[d][1,3]-dioxoboronyl-4-yl)benzamide (Ⅳ-7)

[0132] Using 4-morpholinobenzoic acid (0.75 g, 3.64 mmol) and compound XI-2 (0.80 g, 3.04 mmol) as starting materials, the same procedure as for compound IV-3 was followed to give 1.37 g of a pale yellow solid, with a yield of 99.7%. 1 H NMR (400 MHz, CDCl3)δ (ppm): 7.84 (m, 4H, ArH), 6.91 (d, J = 8.4 Hz, 2H, ArH), 6.06 (s, 2H,OCH2O), 3.92-3.82 (m, 4H, N(C H2 CH2)2O), 3.34-3.23 (m, 4H, N(CH2C H2 O)2), 1.35(s, 12H, 4CH3).

[0133] Synthesis of (R)-3-(4-amino-3-(7-(4-morpholinobenzoylamino)benzo[d][1,3]dioxacyclopentan-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (V-7)

[0134] Using compounds IV-7 (1.27 g, 2.81 mmol) and III (1.00 g, 2.26 mmol) as starting materials, the same procedure as for the synthesis of compound V-3 was followed to give 374 mg of yellow solid, with a yield of 25.8%. 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 9.91 (s, 1H, NHCO), 8.23 ​​(s, 1H, ArH), 7.90 (d, J = 8.7 Hz, 2H, ArH), 7.18 (d, J = 8.6 Hz, 1H, ArH), 7.01 (m, 3H, ArH), 6.13 (s, 2H,OCH2O), 5.75 (s, 2H, NH2), 4.71-4.61 (m, 1H, NC H 2CH), 4.19-4.01 (m, 1H, NCH2C) H ), 3.98-3.87 (m, 1H, NC H 2CH), 3.76-3.72 (m, 4H, N(C H2 CH2)2O), 3.38-3.37 (m, 1H, NC) H 2CH2), 3.27-3.23 (m, 4H, N(CH2C H2)2 O), 3.05-2.92 (m, 1H, NC H 2CH2),2.24-2.16 (m, 1H, NCH2CHC H 2), 2.11-2.04 (m, 1H, NCH2CHC H 2), 1.97-1.87 (m, 1H, NCH2C) H 2), 1.59-1.51 (m, 1H, NCH2C H 2), 1.28 (s, 9H, NBoc).

[0135] Synthesis of (R)-N-(7-(4-amino-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-4-morpholinobenzamide (VI-7)

[0136] Using compound V-7 (0.37 g, 0.58 mmol) as the starting material, the same procedure as that for the synthesis of compound VI-3 was followed to obtain 0.26 g of white solid, with a yield of 82.7%.

[0137] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-4-morpholinobenzamide (I-7)

[0138] Using compound VI-7 (250 mg, 0.46 mmol) as the starting material, the same synthesis procedure as for compound I-3 was followed to give 80 mg of a white solid, with a yield of 29.1%. HPLC purity: 97.79%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm):9.90 (s, 1H, NHCO), 8.23 ​​(s, 1H, ArH), 7.92 (s 1H, ArH), 7.91 (d, J = 6.8 Hz,1H, ArH), 7.20 (d, J = 8.6 Hz, 1H, ArH), 7.06-7.01 (m, 3H, ArH), 6.85-6.73(m, 1H, C H =CH2), 6.14 (s, 2H, OCH2O), 6.11-6.06 (m, 1H, CH=C H 2), 5.90 (s, 2H,NH2), 5.74-5.57 (m, 1H, CH=C H 2), 4.75-4.64 (m, 1H, NC H 2CH), 4.59-4.53 (m,0.5H, NCH2C H ), 4.29-4.18 (m, 1H, NC H 2CH), 4.11-4.04 (m, 0.5H, NCH2C H ), 3.80-3.74 (m, 4H, N(C H2 CH2)2O), 3.72-3.65 (m, 0.5H, NC H 2CH2), 3.32-3.21 (m, 4H, N(CH2C H 2)2O), 3.22-3.15 (m, 1H, NC H2CH2), 3.01-2.90 (m, 0.5H, NC H 2CH2), 2.32-2.20 (m, 1H, NCH2CHC H 2), 2.14-2.08 (m, 1H, NCH2CHC H 2), 1.96-1.88 (m, 1H, NCH2C) H 2), 1.65-1.52 (m, 1H, NCH2C H 2).

[0139] Example 8

[0140] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-4-(pyrrolidine-1-yl)benzamide (I-8)

[0141] Synthesis of 4-pyrrolidine-1-yl-N-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)benzo[d][1,3]dioxoborhecyclopentan-4-yl)benzamide (Ⅳ-8)

[0142] Using 4-(pyrrolidone-1-yl)benzoic acid (0.61 g, 3.19 mmol) and compound XI-2 (0.70 g, 2.66 mmol) as starting materials, the same procedure as for compound IV-3 was followed to give 1.13 g of a pale yellow solid, with a yield of 97.4%. 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 9.68 (s, 1H, NHCO), 7.83 (d, J = 8.5 Hz, 2H, ArH), 7.02 (s,2H, ArH), 6.56 (d, J = 8.9 Hz, 2H, ArH), 6.03 (s, 2H, OCH2O), 3.31-3.26 (m,4H, N(C H2 CH2)2), 1.98-1.94 (m, 4H, N(CH2C H2 )2), 1.27 (s, 12H, 4CH3).

[0143] Synthesis of (R)-3-(4-amino-3-(7-(4-(pyrrolidin-1-yl)benzoylamino)benzo[d][1,3]dioxacyclopentan-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (V-8)

[0144] Using compounds IV-8 (1.12 g, 2.54 mmol) and III (1.03 g, 2.32 mmol) as starting materials, the same procedure as for the synthesis of compound V-3 was followed to give 0.42 g of a yellow solid, with a yield of 28.9%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.73 (s, 1H, NHCO), 8.24 (s, 1H, ArH), 7.87 (d, J = 8.78Hz, 2H, ArH), 7.19 (d, J = 8.6 Hz, 1H, ArH), 7.01 (d, J = 8.6 Hz, 1H, ArH), 6.59 (d, J = 8.9 Hz, 2H, ArH), 6.12 (s, 2H, OCH2O), 5.64 (s, 2H, NH2), 4.70-4.65 (m, 1H, NC H 2CH), 4.17-4.02 (m, 1H, N CH2C H ), 3.87-3.78 (m, 1H, NC H 2CH), 3.57-3.56 (m, 0.5H, NC) H 2CH2), 3.35-3.29 (m, 4H, N(C H2 CH2)2), 3.06-3.01 (m, 0.5H, NC H 2CH2), 3.00-2.92 (m, 1H, NC H 2CH2), 2.65-2.39 (m, 1H, NCH2CHC H 2), 2.23-2.15 (m, 1H, NCH2CHC H 2), 2.12-2.07 (m, 1H, NCH2C H 2), 2.00-1.95 (m, 4H, N(CH2C H2 )2), 1.60-1.54 (m, 1H, NCH2C H 2), 1.34 (s, 9H, NBoc).

[0145] Synthesis of (R)-N-(7-(4-amino-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-4-(pyrrolidine-1-yl)benzamide (VI-8)

[0146] Using compound V-8 (0.378 g, 0.61 mmol) as the starting material, the same procedure as that for the synthesis of compound VI-3 was followed, yielding 0.27 g of a white solid with a yield of 84.1%.

[0147] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-4-(pyrrolidine-1-yl)benzamide (I-8)

[0148] Using compound VI-8 (254 mg, 0.48 mmol) as the starting material, the same synthesis procedure as for compound I-3 was followed to give 60 mg of a white solid, yield 21.5%. HPLC purity: 97.98%. 1 H NMR (300 MHz, DMSO-d6) δ (ppm):9.74 (s, 1H, NHCO), 8.23 ​​(s, 1H, ArH), 7.87 (d, J = 8.4 Hz, 2H, ArH), 7.20 (d, J = 8.5 Hz, 1H, ArH), 7.01 (d, J = 8.5 Hz, 1H, ArH), 6.94-6.68 (m, 1H, C H =CH2), 6.59 (d, J = 8.5 Hz, 2H, ArH), 6.20-6.03 (m, 3H, OCH2O, CH=C H 2), 5.77-5.56 (m, 1H, CH=C H 2), 4.79-4.62 (m, 1H, NC H 2CH), 4.62-4.69 (m, 0.5H, NCH2C H ), 4.34-4.15 (m, 1H, NC H 2CH), 4.14-4.00 (m, 0.5H, NCH2C H ), 3.75-3.65 (m, 0.5H,NC H 2CH2), 3.27-3.13 (m, 1H, NC H 2CH2), 3.41-3.28 (m, 4H, N(C H2 CH2)2), 3.04-2.88(m, 0.5H, NC H 2CH2), 2.35-2.19 (m, 1H, NCH2CHCH 2), 2.16-2.07 (m, 1H, NCH2CHC H 2), 2.03-1.87 (m, 4H, N(CH2C) H2 )2), 1.71-1.50 (m, 1H, NCH2C H 2), 1.31-1.19 (m, 1H, NCH2C) H 2).

[0149] Example 9

[0150] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-4-(1-cyano)ethylbenzamide (I-9)

[0151] Synthesis of 4-((1-cyano)ethyl)-N-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzo[d][1,3]-dioxoboronyl-4-yl)benzamide (Ⅳ-9)

[0152] Using 4-(1-cyano)ethylbenzoic acid (0.44 g, 2.53 mmol) and compound XI-2 (0.60 g, 2.28 mmol) as starting materials, the same procedure as for compound IV-3 was followed to give 0.71 g of a pale yellow solid, with a yield of 74.1%. 1 H NMR (400 MHz, CDCl3) δ (ppm): 10.50 (s, 1H, NHCO), 7.90-7.86 (m, 2H, ArH), 7.81 (d, J = 7.6Hz, 2H, ArH), 7.59 (d, J = 7.8 Hz, 1H, ArH), 7.53 (d, J = 7.7 Hz, 1H, ArH), 6.07 (s, 2H, OCH2O), 4.92 (q, J = 7.3 Hz, 1H, CH3C H CN), 1.71 (d, J = 6.0 Hz, 3H, CH3), 1.31 (s, 12H, 4CH3).

[0153] Synthesis of (R)-3-(4-amino-3-(7-(4-(((1-cyano)ethyl)benzoylamino)benzo[d][1,3]dioxacyclopentan-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (V-9)

[0154] Using compounds IV-9 (0.7 g, 1.67 mmol) and III (0.74 g, 1.67 mmol) as starting materials, the same procedure as for the synthesis of compound V-3 was followed to give 374 mg of yellow solid, with a yield of 36.7%.

[0155] Synthesis of (R)-N-(7-(4-amino-1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-4-((1-cyano)ethyl)benzamide (VI-9)

[0156] Using compound V-9 (0.37 g, 0.61 mmol) as the starting material, the same procedure as that for the synthesis of compound VI-3 was followed, yielding 0.31 g of a white solid with a yield of 99.7%.

[0157] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-4-((1-cyano)ethyl)benzamide (I-9)

[0158] Using compound VI-9 (300 mg, 0.59 mmol) as the starting material, the same synthesis procedure as for compound I-3 was followed to give 137 mg of a white solid, yielding 41.3%. HPLC purity: 98.28%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm):10.34 (s, 1H, CONH), 8.24 (s, 1H, ArH), 8.03 (s, 1H, ArH), 7.97 (d, J = 7.7Hz, 1H, ArH), 7.66 (d, J = 7.8 Hz, 1H, ArH), 7.59 (t, J = 7.7 Hz, 1H, ArH), 7.22 (d, J = 8.6 Hz, 1H, ArH), 7.06 (d, J = 8.5 Hz, 1H, ArH), 6.91-6.72 (m,1H,C H =CH2), 6.17 (s, 2H), 6.14-6.03 (m, 1H, CH=C H 2), 5.73-5.60 (m, 1H, CH=C H 2), 4.79-4.65 (m, 1H, NC H2CH), 4.60-4.46 (m, 0.5H, NCH2C H ), 4.44 (q, J = 7.2Hz, 1H, C H CN), 4.52-4.18 (m, 1H, NC H 2CH), 4.13-4.04 (m, 0.5H, NCH2C H ), 3.75-3.64 (m, 0.5H, NC H 2CH2), 3.27-3.17 (m, 1H, NC H 2CH2), 3.02-2.92 (m, 0.5H,NC H 2CH2), 2.34-2.21 (m, 1H, NCH2CHC H 2), 2.17-2.09 (m, 1H, NCH2CHC H 2), 1.96-1.88 (m, 1H, NCH2C) H 2), 1.63-1.53 ​​(m, 4H, C H3 NCH2C H 2). 13 C NMR (101 MHz, DMSO-d6) δ(ppm): 165.07, 165.04, 158.54, 156.18, 154.17, 146.38, 141.46, 138.89,138.46,135.19, 130.76, 129.70, 128.79,127.97, 127.88, 126.88, 122.56, 121.71,119.42, 112.15, 102.18, 99.09,53.40 (0.5C), 52.63 (0.5C), 49.72 (0.5C), 46.18(0.5C), 45.62 (0.5C), 30.30, 30.09 (0.5C), 29.86 (0.5C), 25.40 (0.5C), 23.86(0.5C), 21.04.

[0159] Example 10

[0160] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-4-fluoro-2-(trifluoromethyl)benzamide (I-10)

[0161] Synthesis of 4-fluoro-N-(7-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzo[d][1,3]dioxoboronyl-4-yl)-2-(trifluoromethyl)benzamide (Ⅳ-10)

[0162] Using 4-fluoro-2-(trifluoromethyl)benzoic acid (0.96 g, 4.60 mmol) and compound XI-2 (1.00 g, 3.80 mmol) as raw materials, the same procedure as for compound IV-3 was followed to give 0.98 g of a pale yellow solid, with a yield of 60.0%. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.48 (s, 1H, NHCO), 7.81-7.69 (m, 2H, ArH), 7.64 (td,J = 8.5, 2.6 Hz, 1H, ArH), 7.30 (d, J = 8.4 Hz, 1H, ArH), 7.07 (d, J = 8.4Hz, 1H, ArH), 6.07 (s, 2H, OCH2O), 1.29 (s, 12H, 4CH3).

[0163] Synthesis of (R)-3-(4-amino-3-(4-(4-fluoro-2-(trifluoromethyl)benzoylamino)benzo[d][1,3]dioxacyclopentan-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (V-10)

[0164] Using compounds IV-10 (0.80 g, 1.77 mmol) and III (0.75 g, 1.77 mmol) as starting materials, the same procedure as for the synthesis of compound V-3 was followed to obtain 1.06 g of yellow solid, with a yield of 93.1%. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 10.16 (s, 1H, NHCO), 8.77 (d, J = 2.8 Hz, 1H, ArH), 8.27 (dd, J = 8.7, 4.6 Hz, 1H, ArH), 8.22 (s, 1H, ArH), 8.02 (td, J = 8.7, 2.8 Hz,1H, ArH), 7.71 (d, J = 8.6 Hz, 1H, ArH), 7.06 (d, J = 8.6 Hz, 1H, ArH), 6.20(s, 2H, OCH2O), 5.75 (s, 2H, NH2), 4.73-4.60 (m, 1H, NC H 2CH), 4.20-3.95 (m, 1H, NCH2C) H ), 3.90-3.70 (m, 1H, NC H 2CH), 3.09-2.82 (m, 2H, NC H2 CH2), 2.29-2.12(m, 1H, NCH2CHC H 2), 2.11-2.01 (m, 1H, NCH2CHC H 2), 1.99-1.84 (m, 1H, NCH2C H 2), 1.60-1.50 (m, 1H, NCH2C) H 2), 1.34 (s, 9H, NBoc).

[0165] Synthesis of (R)-N-(7-(4-amino-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-4-fluoro-2-(trifluoromethyl)benzamide (VI-10)

[0166] Using compound V-10 (0.82 g, 1.27 mmol) as the starting material, the same procedure as that for the synthesis of compound VI-3 was followed to obtain 0.64 g of a pale yellow solid, with a yield of 92.8%.

[0167] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-4-fluoro-2-(trifluoromethyl)benzamide (I-10)

[0168] Using compound VI-10 (0.60 g, 1.10 mmol) as the starting material, the same synthesis procedure as for compound I-3 was followed to give 160 mg of a white solid, yielding 24.3%. HPLC purity: 98.30%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm):10.55 (s, 1H, ArH), 8.23 ​​(s, 1H, ArH), 7.81-7.79 (m, 1H, ArH), 7.77 (dd, J =6.2, 3.8 Hz, 1H, ArH), 7.67 (td, J = 8.4, 2.6 Hz, 1H, ArH), 7.43 (d, J = 8.7Hz, 1H, ArH), 7.05 (d, J = 8.6 Hz, 1H, ArH), 6.92-6.70 (m, 1H, C H =CH2), 6.17(s, 2H, OCH2O), 6.13-6.02 (m, 1H, CH=C H 2), 5.76-5.59 (m, 1H, CH=C H 2), 4.78-4.64 (m, 1H, NC H 2CH), 4.62-4.52 (m, 0.5H, NCH2C H ), 4.31-4.18 (m, 1H, NC H 2CH),4.15-4.07 (m, 0.5H, NCH2C H ), 3.78-3.60 (m, 0.5H, NC H 2CH2), 3.26-3.16 (m, 1H,NC H 2CH2), 3.02-2.92 (m, 0.5H, NC H 2CH2), 2.34-2.20 (m, 1H, NCH2CHC H 2), 2.18-2.06 (m, 1H, NCH2CHC) H 2), 2.00-1.88 (m, 1H, NCH2C H 2), 1.68-1.51 (m, 1H, NCH2C H 2).

[0169] Example 11

[0170] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-3-chloro-4-(trifluoromethyl)benzamide (I-11)

[0171] Synthesis of 3-chloro-N-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzo[d][1,3]dioxoboronyl-4-yl)-4-trifluoromethylbenzamide (Ⅳ-11)

[0172] Using 3-chloro-(4-trifluoromethyl)benzoic acid (0.82 g, 3.64 mmol) and compound XI-2 (0.8 g, 3.00 mmol) as raw materials, the same procedure as for compound IV-3 was followed to give 1.32 g of a pale yellow solid, with a yield of 93.8%.

[0173] Synthesis of (R)-3-(4-amino-3-(7-(3-chloro-4-(trifluoromethyl)benzoylamino)benzo[1,3]dioxacyclopentan-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (V-11)

[0174] Using compounds IV-11 (1.10 g, 2.34 mmol) and III (0.99 g, 2.23 mmol) as starting materials, the same procedure as for the synthesis of compound V-3 was followed to give 1.16 g of yellow solid, with a yield of 78.9%. 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 10.62 (s, 1H, NHCO), 8.42 (s, 1H, ArH), 8.27 (dd, J = 8.4,2.2 Hz, 1H, ArH), 8.22 (s, 1H, ArH), 7.93 (d, J = 8.4 Hz, 1H, ArH), 7.21 (d,J = 8.5 Hz, 1H, ArH), 7.05 (d, J = 8.6 Hz, 1H, ArH), 6.16 (s, 2H, OCH2O), 5.68 (s, 2H, NH2), 4.73-4.62 (m, 1H, NC H 2CH), 4.05-3.97 (m, 1H, NCH2C H ), 3.93-3.75 (m, 1H, NC H 2CH), 3.57-3.56 (m, 1H, NC H2CH2), 3.06-2.91 (m, 1H, NC H 2CH2),2.24-2.15 (m, 1H, NCH2CHC H 2), 2.12-2.02 (m, 1H, NCH2CHC H 2), 1.96-1.85 (m, 1H, NCH2C) H 2), 1.62-1.50 (m, 1H, NCH2C H 2), 1.34 (s, 9H, NBoc).

[0175] Synthesis of (R)-N-(7-(4-amino-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-3-chloro-(4-trifluoromethyl)benzamide (VI-11)

[0176] Using compound V-11 (1.11 g, 1.68 mmol) as the starting material, the same procedure as that for the synthesis of compound VI-3 was followed to obtain 0.86 g of brown solid, with a yield of 91.5%.

[0177] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-3-chloro-4-(trifluoromethyl)benzamide (I-11)

[0178] Using compound VI-11 (860 mg, 1.54 mmol) as the starting material, the same synthesis as compound I-3 was performed to give 422 mg of white solid, yield 44.6%. HPLC purity: 98.83%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm):10.62 (s, 1H, CONH), 8.43 (d, J = 2.1 Hz, 1H, ArH), 8.28 (dd, J = 8.4, 2.2Hz, 1H, ArH), 8.24 (s, 1H, ArH), 7.94 (d, J = 8.4 Hz, 1H, ArH), 7.23 (d, J =8.6 Hz, 1H, ArH), 7.07 (d, J = 8.5 Hz, 1H, ArH), 6.96-6.69 (m, 1H, C H=CH2),6.17 (s, 2H, OCH2O), 6.15-6.04 (m, 1H, CH=C H 2, 5.75-5.57 (m, 1H, CH=C H 2), 4.79-4.61 (m, 1H, NC) H 2CH), 4.61-4.50 (m, 0.5H, NCH2C H ), 4.32-4.17 (m, 1H,NC H 2CH), 4.13-4.05 (m, 0.5H, NCH2C H ), 3.79-3.59 (m, 0.5H, NC H 2CH2), 3.30-3.11(m, 1H, NC H 2CH2), 3.08-2.91 (m, 0.5H, NC H 2CH2), 2.36-2.22 (m, 1H, NCH2CHC H 2), 2.20-2.09 (m, 1H, NCH2CHC) H 2), 2.02-1.89 (m, 1H, NCH2C H 2), 1.64-1.57 (m, 1H, NCH2C) H 2).

[0179] Example 12

[0180] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-2,4-bis(trifluoromethyl)benzamide (I-12)

[0181] Synthesis of N-(7-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzo[d][1,3]dioxoboronyl-4-yl)-2,4-bis(trifluoromethyl)benzamide (Ⅳ-12)

[0182] Using 2,4-bis(trifluoromethyl)benzoic acid (0.94 g, 3.64 mmol) and compound XI-2 (0.80 g, 3.00 mmol) as raw materials, the same procedure as for compound IV-3 was followed to give 1.26 g of a pale yellow solid, with a yield of 83.4%. 1H NMR (300MHz, DMSO-d6) δ (ppm): 10.65 (s, 1H, NHCO), 8.18 (d, J = 7.2 Hz, 2H, ArH), 7.92 (d, J = 8.0 Hz, 1H, ArH), 7.36 (d, J = 8.4 Hz, 1H, ArH), 7.09 (d, J =8.4 Hz, 1H, ArH), 6.09 (s, 2H, OCH2O), 1.28 (s, 12H, 4CH3).

[0183] Synthesis of (R)-3-(4-amino-3-(7-(2,4-bis(trifluoromethyl)benzoylamino)benzo[1,3]dioxacyclopentan-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (V-12)

[0184] Using compounds IV-12 (1.17 g, 2.33 mmol) and III (0.98 g, 2.21 mmol) as starting materials, the same procedure as for the synthesis of compound V-3 was followed to give 1.24 g of yellow solid, with a yield of 80.9%.

[0185] Synthesis of (R)-N-(7-(4-amino-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-2,4-bis(trifluoromethyl)benzamide (VI-12)

[0186] Using compound V-12 (1.10 g, 1.59 mmol) as the starting material, the same procedure as that for the synthesis of compound VI-3 was followed to obtain 0.93 g of a pale yellow solid, with a yield of 98.6%.

[0187] Synthesis of (R)-N-(7-1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-2,4-bis(trifluoromethyl)benzamide (I-12)

[0188] Using compound VI-12 (0.93 g, 1.57 mmol) as the starting material, the same synthesis procedure as for compound I-3 was followed to give 410 mg of a white solid, with a yield of 40.3%. HPLC purity: 97.38%. 1H NMR (400 MHz, DMSO-d6) δ (ppm):10.71 (s, 1H, NHCO), 10.09 (s, 1H, ArH), 8.22 (s, 1H, ArH), 8.19 (s, 1H,ArH), 7.94 (d, J = 7.9 Hz, 1H, ArH), 7.48 (d, J = 8.6 Hz, 1H, ArH), 7.05 (d,J = 8.6 Hz, 1H, ArH), 6.91-6.79 (m, , 1H, C H =CH2), 6.17 (s, 2H, OCH2O), 6.12-6.05 (m, 1H, CH=C H 2), 5.89 (s, 2H, NH2), 5.74-5.58 (m, 1H, CH=C H 2), 4.75-4.65 (m, 1H, NC) H 2CH), 4.59-4.53 (m, 0.5H, NCH2C H ), 4.29-4.17 (m, 1H, NC H 2CH), 4.12-4.04 (m, 0.5H, NCH2C H ), 3.74-3.65 (m, 0.5H, NC H 2CH), 3.24-3.14 (m, 1H,NC H 2CH2), 2.99-2.93 (m, 0.5H, NC H 2CH2), 2.32-2.21 (m, 1H, NCH2CHC H 2), 2.16-2.08 (m, 1H, NCH2CHC) H 2), 1.98-1.89 (m, 1H, NCH2C H 2), 1.65-1.53 ​​(m, 1H, NCH2C H 2).

[0189] Example 13

[0190] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-5-fluoropyridinecarboxamide (I-13)

[0191] Synthesis of 5-fluoro-N-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzo[d][1,3]dioxoboronyl-4-yl)pyridinecarboxamide (Ⅳ-13)

[0192] Using 5-fluoro-2-pyridinecarboxylic acid (0.65 g, 4.60 mmol) and compound XI-2 (1.00 g, 3.80 mmol) as raw materials, the same procedure as for compound IV-3 was followed to give 1.04 g of a pale yellow solid, with a yield of 70.9%.

[0193] Synthesis of (R)-3-(4-amino-3-(7-(5-fluoropyridinylamino)benzo[1,3]dioxacyclopentan-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (V-13)

[0194] Using compounds IV-13 (0.8 g, 2.07 mmol) and III (0.87 g, 1.97 mmol) as starting materials, the same procedure as for the synthesis of compound V-3 was followed to give 1.06 g of yellow solid, with a yield of 93.4%. 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 10.16 (s, 1H, NHCO), 8.77 (d, J = 2.8 Hz, 1H, ArH), 8.27 (dd, J = 8.7, 4.6 Hz, 1H, ArH), 8.22 (s, 1H, ArH), 8.02 (td, J = 8.7, 2.8 Hz,1H, ArH), 7.71 (d, J = 8.6 Hz, 1H, ArH), 7.06 (d, J = 8.6 Hz, 1H, ArH), 6.20(s, 2H, OCH2O), 5.75 (s, 2H, NH2), 4.73-4.60 (m, 1H, NC H 2CH), 4.20-3.95 (m, 1H, NCH2C) H ), 3.90-3.70 (m, 1H, NC H 2CH), 3.09-2.82 (m, 2H, NC H 2CH2), 2.29-2.12(m, 1H, NCH2CHC H 2), 2.11-2.01 (m, 1H, NCH2CHC H 2), 1.99-1.84 (m, 1H, NCH2C H2), 1.60-1.50 (m, 1H, NCH2C) H 2), 1.34 (s, 9H, NBoc).

[0195] Synthesis of (R)-N-(7-(4-amino-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-5-fluoropyridinecarboxamide (VI-13)

[0196] Using compound V-13 (1.00 g, 1.73 mmol) as the starting material, the same procedure as that for the synthesis of compound VI-3 was followed to obtain 0.79 g of a pale yellow solid, with a yield of 96.1%.

[0197] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-5-fluoropyridinecarboxamide (I-13)

[0198] Using compound VI-13 (0.78 g, 1.64 mmol) as the starting material, the same synthesis procedure as for compound I-3 was followed to give 450 mg of a white solid, yield 51.7%. HPLC purity: 98.36%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm):10.52 (s, 1H, NHCO), 8.23 ​​(s, 1H, ArH), 8.13 (d, J = 8.26 Hz, 2H, ArH), 8.03(d, J = 8.4 Hz, 2H, ArH), 7.21 (d, J = 8.6 Hz, 1H, ArH), 7.05 (d, J = 8.6 Hz, 1H, ArH), 6.89-6.74 (m, 1H, C H =CH2), 6.16 (s, 2H, OCH2O), 6.13-6.03 (m, 1H, CH=C H 2), 5.91 (s, 2H, NH2), 5.75-5.57 (m, 1H, C H =CH2), 4.77-4.63 (m, 1H,NC H 2CH), 4.60-4.52 (m, 0.5H, NCH2C H ), 4.28-4.17 (m, 1H, NC H2CH), 4.11-4.05 (m,0.5H, NCH2C H ), 3.72-3.64 (m, 0.5H, NC H 2CH2), 3.26-3.15 (m, 1H, NC H 2CH2), 3.00-2.92 (m, 0.5H, NC H 2CH2), 2.32-2.20 (m, 1H, NCH2CHC H 2), 2.16-2.07 (m, 1H,NCH2CHC H 2), 1.96-1.89 (m, 1H, NCH2C H 2), 1.66-1.53 ​​(m, 1H, NCH2C H 2).

[0199] Example 14

[0200] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-6-methoxynicotinamide (I-14)

[0201] Synthesis of 6-methoxy-N-(7-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyl-2-yl)benzo[d][1,3]dioxoborhecyl-4-yl)nicotinamide (Ⅳ-14)

[0202] Using 6-methoxynicotinic acid (0.52 g, 3.60 mmol) and compound XI-2 (0.80 g, 3.00 mmol) as raw materials, the same procedure as for compound IV-3 was followed to give 0.78 g of a pale yellow solid, with a yield of 65.3%. 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 10.62 (s, 1H, NHCO), 8.15 (d, J = 7.2 Hz, 2H, ArH), 7.89 (d, J =8.0 Hz, 1H, ArH), 7.33 (d, J = 8.4 Hz, 1H, ArH), 7.06 (d, J = 8.4 Hz, 1H,ArH), 6.06 (s, 2H, OCH2O), 1.25 (s, 12H, 4CH3).

[0203] Synthesis of (R)-3-(4-amino-3-(7-(6-methoxynicotinamide)benzo[1,3]dioxacyclopentan-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (V-14)

[0204] Using compounds IV-14 (0.70 g, 1.76 mmol) and III (0.74 g, 1.67 mmol) as starting materials, the same procedure as for the synthesis of compound V-3 was followed to give 0.95 g of a yellow solid, with a yield of 96.7%. 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 10.28 (s, 1H, NHCO), 8.81 (d, J = 2.5 Hz, 1H, ArH), 8.26 (d, J = 3.0 Hz, 1H, ArH), 8.23 ​​(s, 1H, ArH), 7.19 (d, J = 8.6 Hz, 1H, ArH),7.03 (d, J = 8.5 Hz, 1H, ArH), 6.96 (d, J = 8.7 Hz, 1H, ArH), 6.15 (s, 2H,OCH2O), 5.68 (s, 2H, NH2), 4.72-4.61 (m, 1H, NC H 2CH), 4.22-4.08 (m, 0.5H,NCH2C H ), 3.94 (s, 3H, OCH3), 3.92-3.90 (m, 0.5H, NCH2C H ), 3.84-3.72 (m, 1H,NC H 2CH), 3.59-3.45 (m, 0.5H, NC H 2CH2), 3.18-3.15 (m, 0.5H, NC H 2CH2), 3.07-2.90 (m, 1H, NC) H 2CH2), 2.28-2.16 (m, 1H, NCH2CHC H 2), 2.12-2.02 (m, 1H, NCH2CHC H 2), 1.99-1.87 (m, 1H, NCH2C) H 2), 1.60-1.50 (m, 1H, NCH2C H 2), 1.34 (s, 9H, NBoc).

[0205] Synthesis of (R)-N-(7-(4-amino-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-6-methoxynicotinamide (VI-14)

[0206] Using compound V-14 (0.94 g, 1.60 mmol) as the starting material, the same procedure as that for the synthesis of compound VI-3 was followed to obtain 0.66 g of brown solid, with a yield of 84.4%.

[0207] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-6-methoxynicotinamide (I-14)

[0208] Using compound VI-14 (0.60 g, 1.23 mmol) as the starting material, the same synthesis procedure as for compound I-3 was followed to give 122 mg of a white solid, yielding 18.3%. HPLC purity: 96.38%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm):10.28 (s, 1H, NHCO), 8.82 (s, 1H, ArH), 8.30-8.22 (m, 2H, ArH), 7.21 (d, J =8.6 Hz, 1H, ArH), 7.05 (d, J = 8.6 Hz, 1H, ArH), 6.97 (d, J = 8.7 Hz, 1H, ArH), 6.93-6.69 (m, 1H, C H =CH2), 6.16 (s, 2H, OCH2O), 6.14-6.05 (m, 1H, CH=C H 2), 5.79-5.55 (m, 1H, CH=C H 2), 4.78-4.65 (m, 1H, NC H 2CH), 4.64-4.51 (m,0.5H, NCH2C H ), 4.34-4.16 (m, 1H, NC H 2CH), 4.17-3.99 (m, 0.5H, NCH2C H ), 3.95(s, 3H, OCH3), 3.77-3.64 (m,0.5H, NCH2C H2 ), 3.26-3.12 (m, 1H, NCH 2CH2), 3.08-2.93 (m, 0.5H, NCH2C H2 ), 2.31-2.23 (m, 1H, NCH2CHC H 2), 2.17-2.07 (s, 1H, NCH2CHC H2 ), 1.97-1.88 (m, 1H, NCH2C) H2 ), 1.69-1.51 (m, 1H, NCH2C H2 ).

[0209] Example 15

[0210] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-furan-2-carboxamide (I-15)

[0211] Synthesis of N-(7-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyl-2-yl)benzo[d][1,3]dioxoborhecyl-4-yl)furan-2-carboxamide (Ⅳ-15)

[0212] Using furan-2-carboxylic acid (0.51 g, 4.56 mmol) and compound XI-2 (1.00 g, 3.80 mmol) as raw materials, the same procedure as for compound IV-3 was followed to give 1.24 g of a pale yellow solid, with a yield of 91.4%. 1 H NMR (300 MHz, DMSO-d6)δ (ppm): 9.98 (s, 1H, NHCO), 7.96-7.92 (m, 1H, ArH), 7.35 (dd, J = 3.5, 0.8Hz, 1H, ArH), 7.06 (s, 2H, ArH), 6.70 (dd, J = 3.5, 1.7 Hz, 1H, ArH), 6.07(s, 2H, OCH2O), 1.29 (s, 12H, 4CH3).

[0213] Synthesis of (R)-3-(4-amino-3-(7-(furan-2-carboxyamino)benzo[d][1,3]dioxacyclopentan-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (V-15)

[0214] Using compounds IV-15 (1.14 g, 3.19 mmol) and III (1.35 g, 3.04 mmol) as starting materials, the same procedure as for the synthesis of compound V-3 was followed to give 1.43 g of yellow solid, with a yield of 86.0%.

[0215] Synthesis of (R)-N-(7-(4-amino-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-furan-2-carboxamide (VI-15)

[0216] Using compound V-15 (1.43 g, 2.61 mmol) as the starting material, the same procedure as that for the synthesis of compound VI-3 was followed to obtain 1.13 g of a pale yellow solid, with a yield of 96.8%.

[0217] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentane-4-yl)-furan-2-carboxamide (I-15)

[0218] Using compound VI-15 (1.13 g, 2.25 mmol) as the starting material, the same synthesis as compound I-3 was performed to give 238 mg of white solid, yield 22.2%. mp 158-160 ℃. HPLC purity: 97.79%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 10.05 (s, 1H, ArH), 8.24 (s, 1H, ArH), 7.96 (d, J = 1.8 Hz,1H, ArH), 7.38 (d, J = 7.5 Hz, 1H, ArH), 7.21 (d, J = 8.6 Hz, 1H, ArH), 7.04(d, J = 8.6 Hz, 1H, ArH), 6.92-6.76 (m, 1H, C H =CH2), 6.72 (dd, J = 3.5, 1.8Hz, 1H, ArH), 6.16 (s, 2H, OCH2O), 6.14 -6.04 (m, 1H, CH=C H 2), 5.75-5.58 (m, 1H, CH=C) H 2), 4.77-4.65 (m, 1H, NC H 2CH), 4.61-4.50 (m, 0.5H, NCH2CH ), 4.30-4.18 (m, 1H, NC) H 2CH), 4.10-4.03 (m, 0.5H, NCH2C H ), 3.74-3.60 (m, 0.5H, NC H 2CH2), 3.25-3.16 (m, 1H, NC) H 2CH2), 3.00-2.94 (m, 0.5H, NC H 2CH2), 2.33-2.21 (m, 1H,NCH2CHC H 2), 2.17-2.06 (m, 1H, NCH2CHC H 2), 1.97-1.88 (m, 1H, NCH2C H 2), 1.66-1.54 (m, 1H, NCH2C) H 2). 13 C NMR (101 MHz, DMSO-d6) δ (ppm): 165.04, 158.53, 156.36,156.17, 154.20, 147.62, 146.40, 146.36, 141.26, 138.86, 128.78, 127.88,122.60, 121.05, 119.14, 115.47, 112.62, 112.11, 102.22, 99.07, 52.61(0.5C),52.61(0.5C), 49.72 (0.5C), 46.17(0.5C), 45.62(0.5C), 42.05(0.5C), 30.08(0.5C), 29.98(0.5C), 25.39(0.5C), 23.85(0.5C).

[0219] Example 16

[0220] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)quinoline-2-carboxamide (I-16)

[0221] Synthesis of N-(7-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)benzo[d][1,3]dioxoborhexacyclopentan-4-yl)quinoline-2-carboxamide (Ⅳ-16)

[0222] Using quinoline-2-carboxylic acid (0.55 g, 3.19 mmol) and compound XI-2 (0.70 g, 2.66 mmol) as raw materials, the same procedure as for compound IV-3 was followed to give 0.92 g of a pale yellow solid, with a yield of 71.9%. 1 H NMR (300 MHz, DMSO-d6)δ (ppm): 10.37 (s, 1H, NHCO), 8.67 (d, J = 8.5 Hz, 1H, ArH), 8.27 (dd, J =8.5, 1.3 Hz, 1H, ArH), 8.19 (d, J = 8.5 Hz, 1H, ArH), 8.14 (dd, J = 8.3, 1.4Hz, 1H, ArH), 7.93 (td, J = 4.1, 3.2, 1.6 Hz, 2H, ArH), 7.81-7.76 (m, 1H,ArH), 7.72 (d, J = 8.4 Hz, 1H, ArH), 6.18 (s, 2H, OCH2O), 1.30 (s, 12H,4CH3).

[0223] Synthesis of (R)-3-(4-amino-3-(7-(quinoline-2-carboxamido)benzo[d][1,3]dioxacyclopentan-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (V-16)

[0224] Using compounds IV-16 (0.83 g, 1.72 mmol) and III (0.89 g, 2.00 mmol) as starting materials, the same procedure as that for compound V-3 was followed to give 384 mg of yellow solid, with a yield of 31.6%.

[0225] Synthesis of (R)-N-(7-(4-amino-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)quinoline-2-carboxamide (VI-16)

[0226] Using compound V-16 (0.38 g, 0.62 mmol) as the starting material, the same procedure as that for the synthesis of compound VI-3 was followed to obtain 0.31 g of a pale yellow solid, with a yield of 98.4%.

[0227] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)quinoline-2-carboxamide (I-16)

[0228] Using compound VI-16 (0.28 g, 0.55 mmol) as the starting material, the same synthesis procedure as for compound I-3 was followed to give 137 mg of a white solid, yield 49.0%. HPLC purity: 97.92%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm):10.42 (s, 1H, NHCO), 8.69 (d, J = 8.5 Hz, 1H, ArH), 8.31 (d, J = 8.5 Hz, 1H,ArH), 8.25 (s, 1H, ArH), 8.22 (d, J = 8.3 Hz, 1H, ArH), 8.16 (d, J = 8.2 Hz,1H, ArH), 7.94 (t, J = 7.7 Hz, 1H, ArH), 7.85 (d, J = 8.7 Hz, 1H, ArH), 7.79(t, J = 7.0 Hz, 1H, ArH), 7.11 (d, J = 8.6 Hz, 1H, ArH), 6.91-6.72 (m, 1H, C H =CH2), 6.27 (s, 2H, OCH2O), 6.20-6.05 (m, 1H, CH=C H 2), 5.77-5.58 (m, 1H, CH=C H 2), 4.78-4.65 (m, 1H, NC H 2CH), 4.62-4.54 (m, 0.5H, NCH2C H ), 4.31-4.19 (m, 1H, NC H 2CH), 4.13-4.00 (m, 0.5H, NCH2C H 2), 3.34-3.16 (m, 1H, NC H 2CH2), 3.02-2.92 (m, 1H, NC H 2CH2), 2.36-2.21 (m, 1H, NCH2CHC H 2), 2.17-2.08 (m, 1H,NCH2CHC H 2), 2.02-1.90 (m, 1H, NCH2C H 2), 1.66-1.53 ​​(m, 1H, NCH2C H 2).

[0229] Example 17

[0230] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-bicyclo[2.2.1]heptane-1-carboxamide (I-17)

[0231] Synthesis of N-(7-(4,4,5,5-tetramethyl-1,3,2-dioxoborheptan-2-yl)benzo[d][1,3]dioxoborheptan-4-yl)bicyclo[2.2.1]heptane-1-carboxamide (Ⅳ-17)

[0232] Using bicyclic [2.2.1]heptane-1-carboxylic acid (0.65 g, 4.61 mmol) and compound XI-2 (1.00 g, 3.80 mmol) as raw materials, the same procedure as for compound IV-3 was followed to give 1.39 g of a pale yellow solid, with a yield of 95.0%. 1 H NMR (300MHz, DMSO-d6) δ (ppm): 9.59 (s, 1H, ArH), 7.28 (d, J = 8.4 Hz, 1H, ArH), 7.00 (d, J = 8.4 Hz, 1H, ArH), 6.05 (s, 2H, OCH2O), 2.96-2.87 (m, 1H, (CH2)3C H ),2.60-2.54 (m, 1H, C(C H 2CH2)2), 2.25-2.16 (m, 1H, C(C H 2CH2)2), 1.67-1.58 (m, 2H,C(C H 2CH2)2), 1.57-1.45 (m, 2H, C(CH2C H 2)2), 1.44-1.36 (m, 2H, C(CH2C H 2)2), 1.35-1.29 (m, 2H, CHC H2 C), 1.27 (s, 12H, 4CH3).

[0233] Synthesis of (R)-3-(4-amino-3-(7-(bicyclo[2.2.1]heptane-1-carboxylammono)benzo[d][1,3]dioxacyclopentan-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (V-17)

[0234] Using compounds IV-17 (1.09 g, 2.80 mmol) and III (1.38 g, 3.10 mmol) as starting materials, the same procedure as for the synthesis of compound V-3 was followed to give 1.48 g of yellow solid, with a yield of 91.9%. 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 9.66 (s, 1H, NHCO), 8.21 (s, 1H, ArH), 7.42 (d, J = 8.7 Hz,1H, ArH), 6.95 (d, J = 8.7 Hz, 1H, ArH), 6.12 (s, 2H, OCH2O), 4.74-4.59 (m,1H, NC H 2CH), 4.18-3.72 (m, 1.5H, NC H 2CH, NCH2C H ), 3.04-2.89 (m, 1.5H, NCH2C H (CH2)3C H ), 2.64-2.55 (m, 1H, NC H 2CH2), 2.26-2.11 (m, 2H, C(C H2 CH2)2), 2.10-2.01(m, 1H, NC H 2CH2), 1.96-1.81 (m, 1H, NCH2CHC H 2), 1.70-1.61 (m, 1H, NCH2CHC H 2), 1.60-1.56 (m, 1H, NCH2C) H 2), 1.55-1.47 (m, 2H, C(C H2 CH2)2), 1.45-1.37 (m, 5H, C(CH2C H2 )2, NCH2C H 2), 1.33 (s, 9H, NBoc), 1.21-1.05 (m, 2H, CHC H2 C).

[0235] Synthesis of (R)-N-(7-(4-amino-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)bicyclo[2.2.1]heptane-1-carboxamide (VI-17)

[0236] Using compound V-17 (1.41 g, 2.46 mmol) as the starting material, the same procedure as for compound VI-3 was followed to give 1.08 g of a pale yellow solid, with a yield of 92.4%.

[0237] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)bicyclo[2.2.1]heptane-1-carboxamide (I-17)

[0238] Using compound VI-17 (1.00 g, 2.10 mmol) as the starting material, the same synthesis procedure as for compound I-3 was followed to give 557 mg of white solid, yield 55.8%. HPLC purity: 97.52%. mp 180-182 ℃. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.63 (s, 1H, NHCO), 8.22 (s, 1H, ArH), 7.43 (d, J = 8.7 Hz,1H, ArH), 6.97 (d, J = 8.6 Hz, 1H, ArH), 6.78-6.71 (m, 1H, C H =CH2), 6.18-6.01(m, 3H, CH=C H 2, OCH2O), 5.73-5.59 (m, 1H, CH=C H 2), 4.70-4.54 (m, 1H, NC H 2CH),4.59-4.50 (m, 0.5H, NCH2C H ), 4.30-4.16 (m, 1H, NC H 2CH), 4.15-4.01 (m, 0.5H,NCH2C H ), 3.72-3.63 (m. 0.5H, NC H 2CH2), 3.25-3.12 (m, 1H, NC H 2CH2), 3.01-2.91(m, 1H, NCH2CHC H 2), 2.63-2.54 (m, 1H, (CH2)3C H ), 2.29-2.19 (m, 2H, C(C H2 CH2)2),2.15-2.06 (m, 1H, NCH2CHC H2), 1.97-1.82 (m, 1.5H, NC H 2CH2, NCH2C H 2), 1.68-1.61 (m, 1H, NCH2C) H 2,), 1.59-1.14 (m, 8H, C(C H2 C H2 )2, CHC H2 C). 13 C NMR (101 MHz, DMSO-d6) δ 172.81, 165.03, 158.52, 156.14, 154.10, 146.01, 139.34,138.64,128.78, 127.88, 122.85, 122.56, 117.31, 110.85, 101.97, 99.05, 53.36 (0.5C), 52.58 (0.5C), 49.71 (0.5C), 47.06 (0.5C), 46.84, 46.17 (0.5C), 45.61 (0.5C),42.42 (0.5C), 41.35, 40.74, 37.14, 30.08 (0.5C), 29.88 (0.5C), 29.29, 28.80, 25.40 (0.5C), 23.87 (0.5C).

[0239] Example 18

[0240] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)adamantane-1-carboxamide (I-18)

[0241] Synthesis of N-(7-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyl-2-yl)benzo[d][1,3]dioxoborhecyl-4-yl)adamantane-1-carboxamide (Ⅳ-18)

[0242] Using 1-adamantanecarboxylic acid (0.61 g, 3.38 mmol) and compound XI-2 (0.74 g, 2.80 mmol) as raw materials, the same procedure as for compound IV-3 was followed to give 1.12 g of a pale yellow solid, with a yield of 94.1%. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.96 (s, 1H, ArH), 7.06-6.86 (m, 2H, ArH), 6.03 (s, 2H, OCH2O), 2.04-1.97 (m, 3H, 3C H (CH2)3), 1.96-1.80 (m, 6H, CH(C H2 )3CH), 1.70 (m, 6H, C(C H2)3 CH), 1.28 (s, 12H, 4CH3).

[0243] Synthesis of (R)-3-(3-(7-(adamantane-1-formamido)benzo[d][1,3]dioxane-4-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (V-18)

[0244] Using compounds IV-18 (0.97 g, 2.28 mmol) and III (0.93 g, 2.09 mmol) as starting materials, the same procedure as for the synthesis of compound V-3 was followed to give 1.10 g of yellow solid, with a yield of 85.5%. 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 8.96 (s, 1H, NHCO), 8.30 (s, 1H, ArH), 7.56 (d, J = 8.4Hz, 1H, ArH), 7.50 (d, J = 8.7 Hz, 1H, ArH), 6.08 (s, 2H, OCH2O), 4.12-3.96(m, 1H, NC H 2CH), 3.89-3.75 (m, 1H, NCH2C H ), 3.73-3.56 (m, 2H, NC H 2CH, NC H 2CH2), 3.50-3.43 (m, 2H, NC) H 2CH2, NCH2CHC H 2), 2.36-2.19 (m, 2H, NCH2CHC H 2, NCH2C H 2), 2.14-2.05 (m, 1H, NCH2C) H 2), 2.01-1.89 (m, 1H, C H(CH2)3CH), 1.80-1.68 (m, 6H,CH(C H2 )3CH ), 1.66-1.49 (m, 4H, C(C H2) 3CH), 1.46-1.37 (m, 2H, 2C) H (CH2)3CH ),1.34 (s, 9H, NBoc), 1.33-1.28 (m, 2H, C(C H2) 3CH).

[0245] Synthesis of (R)-N-(7-(4-amino-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-adamantane-1-carboxamide (VI-18)

[0246] Using compound V-18 (1.03 g, 1.67 mmol) as the starting material, the same procedure as for compound VI-3 was followed to give 0.85 g of white solid, with a yield of 98.8%.

[0247] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)adamantane-1-carboxamide (I-18)

[0248] Using compound VI-18 (0.85 g, 1.65 mmol) as the starting material, the same synthesis procedure as for compound I-3 was followed to give 448 mg of a white solid, yielding 47.7%. HPLC purity: 98.25%. mp 187-190 ℃. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.01 (s, 1H, NHCO), 8.23 ​​(s, 1H, ArH), 7.13 (d, J = 8.6 Hz, ArH), 6.98 (d, J = 8.5 Hz, ArH), 6.90-6.71 (m, 1H, C H =CH2), 6.16-6.02 (m, 3H,OCH2O, CH=C H 2), 5.73-5.59 (m, 1H, CH=C H 2), 4.77-4.62 (m, 1H, NC H 2CH), 4.60-4.52 (m, 0.5H, NCH2C H), 4.31-4.18 (m, 1H, NC H 2CH), 4.12-4.03 (m, 0.5H,NCH2C H ), 3.73-3.62 (m, 0.5H, NC H 2CH2), 3.20 (m, 1H, NC H 2CH2), 3.00-2.91 (m, 0.5H, NC) H 2CH2), 2.33-2.19 (m, 1H, NCH2CHC H 2), 2.15-2.08 (m, 1H, NCH2CHC H 2), 2.06-1.98 (m, 3H, 3C) H (CH2)3CH), 1.97-1.87 (m, 7H, CH(C H2 )3CH, NCH2C H 2), 1.75-1.68 (m, 6H, C(C H2) 3CH ), 1.64-1.52 (m, 1H, NCH2C H 2). 13 C NMR (101 MHz, DMSO-d6) δ (ppm): 176.10, 165.03, 158.50, 156.13, 154.11, 146.05, 140.91, 138.95,128.78, 127.88, 122.35, 122.28, 119.31, 111.55, 102.02, 99.08,53.40 (0.5C),52.62 (0.5C), 49.70 (0.5C), 46.16 (0.5C), 45.61 (0.5C), 42.02 (0.5C), 41.15(3C), 38.89(3C), 36.48, 30.08 (0.5C), 29.88 (0.5C), 28.14 (3C), 25.40 (0.5C), 23.88 (0.5C).

[0249] Example 19

[0250] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-4-(methylamino)benzamide (I-19)

[0251] Synthesis of 4-(((benzyloxy)carbonyl)(methyl)amino)-N-(7-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzo[d][1,3]dioxoboronyl-4-yl)benzamide (Ⅳ-19)

[0252] Using 4-(((benzyloxy)carbonyl)(methyl)amino)benzoic acid (1.31 g, 0.0046 mol) and compound XI-2 (1 g, 0.0038 mol) as starting materials, the same procedure as for compound IV-3 was followed to give 1.09 g of pale yellow solid, with a yield of 54.1%.

[0253] Synthesis of (R)-3-(4-amino-3-(7-(4-(((benzyloxy)carbonyl)(methyl)amino)-benzoylamino)benzo[d][1,3]dioxacyclopentan-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (V-19)

[0254] Using compound IV-19 (1.00 g, 1.90 mmol) and compound III (762 mg, 1.71 mmol) as starting materials, the procedure was the same as for compound III. -3, yielding 918 mg of pale yellow solid, yield 74.5%. 1 H NMR (300 MHz, DMSO-d6)δ (ppm): 10.30 (s, 1H, NHCO), 8.24 (s, 1H, ArH), 8.01 (d, J = 8.7 Hz, 2H,ArH), 7.51 (d, J = 8.5 Hz, 2H, ArH), 7.46-7.27 (m, 5H, ArH), 7.19 (d, J = 8.6Hz, 1H, ArH), 7.03 (d, J = 8.5 Hz, 1H, ArH), 6.15 (s, 2H, OCH2O), 5.15 (d, J= 4.6 Hz, 2H, CH2), 4.73-4.65 (m, 1H, NC H 2CH), 4.19-3.64 (m, 3H, NC H 2CH,NCH2C H NC H 2CH2), 3.33 (s, 3H, NCH3), 3.12-2.86 (m, 1H, NC H 2CH2), 2.31-1.86 (m,3H, NCH2CHC H2 NCH2CH 2), 1.69-1.53 ​​(m, 1H, NCH2C H 2), 1.34 (s, 9H, NBoc).

[0255] Synthesis of (R)-3-(4-amino-3-(7-(4-(methylamino)benzoylamino)benzo[d][1,3]dioxacyclopentan-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (VI-19-1)

[0256] Compound V-19 (0.90 g, 1.25 mmol) was dissolved in 15 mL of anhydrous ethanol, and 5% palladium on carbon (90 mg) was added. The reaction was carried out under hydrogen protection at room temperature for approximately 24 h. The mixture was filtered through diatomaceous earth, and the solvent was removed from the filtrate under reduced pressure. The filtrate was dissolved in 50 mL of ethyl acetate and washed with water (10 mL × 2) and saturated sodium chloride aqueous solution (10 mL × 2), respectively. The solution was dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to give 646 mg of a dark brown solid, which was added directly to the next step without purification. The yield was 88.1%. 1 HNMR (300 MHz, DMSO-d6) δ (ppm): 9.81 (s, 1H, NHCO), 8.23 ​​(s, 1H, ArH), 8.09 (s, 1H, N H CH3), 7.88 (d, J = 8.6 Hz, 2H, ArH), 7.18 (d, J = 8.6 Hz, 1H, ArH), 7.01 (d, J = 8.5 Hz, 1H, ArH), 6.76 (d, J = 8.8 Hz, 2H, ArH), 6.13 (s, 2H,OCH2O), 4.78-4.58 (m, 1H, NC H 2CH), 4.29-4.18 (m, 1H, NCH2C H ), 3.97-3.68 (m, 1H, NC) H 2CH), 3.04-2.95 (m, 4H, NHC H3 NC H 2CH2), 2.29-2.16 (m, 1H, NC H 2CH2),2.13-2.06 (m, 1H, NCH2CHC H 2), 1.94-1.80 (m, 1H, NCH2CHC H 2), 1.60-1.50 (m, 1H, NCH2C)H 2), 1.48-1.43 (m, 1H, NCH2C H 2), 1.29 (s, 9H, NBoc).

[0257] Synthesis of (R)-N-(7-(4-amino-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-4-(methylamino)benzamide (VI-19)

[0258] Using compound V-19-1 (635 mg, 1.08 mol) as the starting material, the same procedure as that for compound VI-3 was followed to obtain 521 mg of pale yellow solid, with a yield of 99.1%.

[0259] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d][1,3]dioxacyclopentan-4-yl)-4-(methylamino)benzamide (I-19)

[0260] Using compound VI-19 (510 mg, 1.05 mmol) as the starting material, the same synthesis as compound I-3 was performed to give 82 mg of white solid, yield 14.4%. HPLC purity: 96.86%. 1 H NMR (300 MHz, DMSO-d6) δ (ppm):9.87 (s, 1H, NHCO), 8.22 (d, J = 5.1 Hz, 1H, ArH), 7.84 (d, J = 7.6 Hz, 2H,ArH), 7.35 (d, J = 5.7 Hz, 1H, ArH), 7.14 (d, J = 8.4 Hz, 1H, ArH), 7.00 (s,1H, N H CH3), 6.92-6.63 (m, 3H, ArH, C H =CH2), 6.21-6.01 (m, 4H, OCH2O, NH2, CH=C H 2), 5.77-5.55 (m, 1H, CH=C H 2), 4.77-4.62 (m, 1H, NC H 2CH), 4.57-4.52 (m, 1H, NCH2C) H ), 4.29-4.12 (m, 1H, NC H2CH), 4.10-3.94 (m, 1H, NC H 2CH2), 3.27-3.09 (m, 1H, NC) H 2CH2), 2.98 (s, 3H, NHC H3 ), 2.33-2.21 (m, 1H, NCH2CHC H 2), 2.15-2.04 (m, 1H, NCH2CHC) H 2), 1.98-1.85 (m, 1H, NCH2C H 2), 1.69-1.48 (m, 1H, NCH2C H 2).

[0261] Example 20

[0262] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-benzo[d][1,3]dioxacyclopentan-4-yl)-4-(pyrrolidine-1-ylmethyl)benzamide (I-20)

[0263] Synthesis of 4-(pyrrolidone-1-ylmethyl)-N-(7-(4,4,5,5-tetramethyl-1,3,2-dioxoborheptacyclopentan-2-yl)benzo[d][1,3]dioxoborheptacyclopentan-4-yl)benzamide (Ⅳ-20)

[0264] Using 4-(pyrrolidone-1-ylmethyl)benzoic acid (754 mg, 3.67 mmol) and compound XI-2 (800 mg, 3.04 mmol) as starting materials, the same procedure as for compound IV-3 was followed to give 830 mg of white solid, with a yield of 60.6%. 1 H NMR(300 MHz, DMSO-d6) δ (ppm): 10.16 (s, 1H, NHCO), 8.00 (d, J = 7.9 Hz, 2H,ArH), 7.95 (d, J = 7.8 Hz, 1H, ArH), 7.61 (d, J = 7.7 Hz, 2H, ArH), 7.38 (d,J = 8.1 Hz, 1H, ArH), 6.05 (s, 2H, OCH2O), 3.98 (s, 2H, CH2), 2.94-2.81 (m,4H, N(C H2 CH2)2), 2.12-1.99 (m, 4H, N(CH2C H2)2), 1.30 (s, 12H, 4CH3).

[0265] Synthesis of (R)-3-(4-amino-3-(7-(4-(pyrrolidin-1-ylmethyl)benzoylamino)-benzo[d][1,3]dioxacyclopentan-4-yl)-1Hpyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (V-20)

[0266] Using compounds IV-20 (800 mg, 1.78 mmol) and III (800 mg, 1.80 mmol) as starting materials, the same procedure as for compound V-3 was followed to give 841 mg of pale yellow solid, with a yield of 73.7%.

[0267] Synthesis of (R)-N-(7-(4-amino-1-(piperidin-3-yl)-1Hpyrazolo[3,4-d]pyrimidin-3-yl]-benzo[d][1,3]dioxacyclopentan-4-yl)-4-(pyrrolidine-1-ylmethyl)benzamide (VI-20)

[0268] Using compound V-20 (841 mg, 1.31 mmol) as the starting material, the same procedure as for compound VI-3 was followed to give 678 mg of pale yellow solid, with a yield of 95.7%. 1 H NMR (300 MHz, DMSO-d6) δ 10.22 (s, 1H, NHCO), 8.24 (s, 1H, ArH), 7.96 (d, J = 8.0 Hz, 2H, ArH), 7.48 (d, J = 8.0 Hz, 2H, ArH), 7.19 (d, J = 8.6 Hz, 1H, ArH), 7.04 (d, J = 8.5 Hz, 1H, ArH), 6.15 (s, 2H,OC H2 O), 4.76-4.61 (s, 1H, NC H 2CH), 4.22-4.01 (m, 1H, NCH2C H ), 3.99-3.85 (m, 1H, NC) H 2CH), 3.72 (s, 2H, CH2), 3.52-3.25 (m, 4H, N(C H2 CH2)2), 3.09-2.91 (m, 1H, NC) H 2CH2), 2.31-2.14 (m, 1H, NC H 2CH2), 2.14-2.03 (m, 1H, NCH2CHCH 2), 2.02-1.83 (m, 1H, NCH2CHC H 2), 1.81-1.69 (m, 4H, N(CH2C H2 )2), 1.66-1.51 (m, 2H,NCH2C H 2), 1.29 (s, 9H, NBoc).

[0269] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-benzo[d][1,3]dioxacyclopentan-4-yl)-4-(pyrrolidine-1-ylmethyl)benzamide (I-20)

[0270] Using compound VI-20 (640 mg, 1.18 mmol) as the starting material, the same procedure as that for compound I-3 was followed to give 189 mg of white solid, with a yield of 27.0%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 10.24 (s, 1H, NHCO), 8.24 (s, 1H, ArH), 7.97 (d, J = 8.0 Hz, 2H, ArH), 7.49 (d, J = 7.9 Hz,2H, ArH), 7.20 (d, J = 8.6 Hz, 1H, ArH), 7.04 (d, J = 8.5 Hz, 1H, ArH), 6.87(dd, J = 15.2, 9.1 Hz, 1H, ArH), 6.84-6.69 (m, 1H, C H =CH2), 6.18-6.02 (m, 4H,OCH2O, CH=C H 2, NH2), 5.75-5.58 (m, 1H, CH=C H 2), 4.82-4.65 (m, 1H, NC H 2CH),4.62-4.49 (m, 0.5H, NCH2C H ), 4.30-4.17 (m, 1H, NC H 2CH), 4.13-3.99 (m, 0.5H,NCH2C H ), 3.72 (s, 2H, CH2), 3.45-3.29 (m, 4H, N(C H2 CH2)2), 3.26-3.14(m, 1H,NCH 2CH2), 3.03-2.91 (m, 1H, NC) H 2CH2), 2.36-2.20 (m, 1H, NCH2CHC H 2), 2.19-2.00(m, 1H, NCH2CHC H 2), 1.97-1.87 (m, 1H, NCH2C H 2), 1.74 (m, 4H, N(CH2C H2 )2), 1.61(m, 1H, NCH2C H 2).

[0271] Example 21

[0272] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidinyl-3-yl)-4-amino-1H-pyrazol[3,4-d]pyrimidin-3-yl)-2,3-benzodihydrofuran-4-yl)-4-(methylamino)benzamide (I-21)

[0273] Synthesis of 4-(((benzyloxy)carbonyl)(methyl)amino)-N-(7-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)2,3-dihydrobenzofuran-4-yl)benzamide (Ⅳ-21)

[0274] Using compound 4-(((benzyloxy)carbonyl)(methyl)amino)benzoic acid (961 mg, 3.37 mmol) and compound XI-1 (792 mg, 3.03 mmol) as starting materials, the same procedure as that for compound IV-1 was followed to give 1.4 g of pale yellow solid in 87.4% yield.

[0275] Synthesis of (R)-3-(4-amino-3-(4-(4-((((benzyloxy)carbonyl)(methyl)amino)benzoylamino)-2,3-benzodihydrofuran-7-yl)-1H-pyrazol[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (V-21)

[0276] Using compounds IV-21 (1.35 g, 2.56 mmol) and III (1.14 g, 2.56 mmol) as starting materials, the same procedure as that for compound V-1 was followed to obtain 630 mg, with a yield of 34.2%. 1H NMR (300 MHz, DMSO-d6) δ10.16 (s, 1H, NHCO), 8.22 (s, 1H, ArH), 7.97 (d, J = 8.3 Hz, 2H, ArH), 7.52(d, J = 8.3 Hz, 2H, ArH), 7.37 (s, 1H, N H CH3), 7.30 (d, J = 9.1 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 5.16 (s, 2H, CH2), 4.76-4.49 (m, 3H, OC H2 CH2, NC H2 CH,), 4.12-3.09 (m, 1H, NCH2C H ), 3.96-3.71 (m, 1H, NC H 2CH), 3.33 (s, 3H, CH3), 3.27(d, J= 9.0 Hz, 2H, OCH2C H2 ), 3.09-2.86 (m, 1H, NC H 2CH2), 2.30-2.14 (m, 1H,NC H 2CH2), 2.13-2.06 (m, 1H, NCH2CHC H 2), 1.94-1.78 (m, 1H, NCH2CHC H 2), 1.64-1.49 (m, 1H, NCH2C) H 2), 1.46-1.30 (m, 1H, NCH2C H 2), 1.33 (s, 9H, NBoc).

[0277] Synthesis of (R)-3-(4-amino-3-(4-(4-(methylamino)benzoylamino)-2,3-benzodihydrofuran-7-yl)-1H-pyrazol[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (VI-21-1)

[0278] Using compound V-21 (570 mg, 0.79 mmol) as the starting material, the same procedure as that for compound VI-19-1 was followed to obtain 431 mg of brown solid, with a yield of 93.31%.

[0279] Synthesis of (R)-N-(7-(4-amino-1-(piperidin-3-yl)-1-1H-pyrazol[3,4-d]pyrimidin-3-yl)-2,3-benzodihydrofuran-4-yl)-4-(methylamino)benzamide (VI-21)

[0280] Using compound VI-21-1 (420 mg, 0.72 mmol) as the starting material, the same procedure as that for the synthesis of compound VI-1 was followed to give 310 mg of a pale yellow solid, with a yield of 88.8%.

[0281] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidinyl-3-yl)-4-amino-1H-pyrazol[3,4-d]pyrimidin-3-yl)-2,3-benzodihydrofuran-4-yl)-4-(methylamino)benzamide (I-21)

[0282] Using compound VI-21 (300 mg, 0.62 mmol) as the starting material, the same synthesis procedure as compound I-1 was followed to obtain the product, yielding the desired result. 1 H NMR (300 MHz, DMSO-d6) δ 9.84 (s, 1H, NHCO), 8.21 (s, 1H, ArH), 7.89 (d,J = 8.0 Hz, 2H, ArH), 7.39-7.14 (m, 2H, ArH), 6.77 (d, J = 8.2 Hz, 3H, ArH,C H =CH2), 6.22-5.99 (m, 1H, CH=C H 2), 5.84-5.65 (m, 1H, CH=C H 2), 4.77-4.52 (m,4H, CH2C H2 O, NC H 2CH, NH), 4.35-3.98 (m, 2H, NCH2C H ), 3.77-3.60 (m, 1H,NC H 2CH2), 3.24 (m, 2H, C H2 CH2O), 2.99 (s, 3H, CH3), 2.35-2.21 (m, 2H, NC H 2CH2,NCH2CHC H 2), 2.16-2.06 (m, 1H, NCH2CHC H 2), 1.97-1.85 (s, 1H, NCH2C H 2), 1.68-1.51 (s, 1H, NCH2C)H 2).

[0283] Example 22

[0284] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidinyl-3-yl)-4-amino-1H-pyrazol[3,4-d]pyrimidin-3-yl)-2,3-benzodihydrofuran-4-yl)-4-(pyrrolo-1-yl)benzamide (I-22)

[0285] Synthesis of 4-(pyrrolo-1-yl)-N-(7-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)2,3-dihydrobenzofuran-4-yl)benzamide (Ⅳ-22)

[0286] Using 4-(pyrrolo-1-yl)benzoic acid (806 mg, 4.22 mmol) and compound XI-1 (1 g, 3.8 mmol) as starting materials, the same procedure as for the synthesis of compound IV-1 was followed to give 1.34 g of pale yellow solid, with a yield of 81.2%.

[0287] Synthesis of (R)-3-(4-amino-3-(4-(4-(pyrrolo-1-yl)benzoylamino)-2,3-benzodihydrofuran-7-yl)-1H-pyrazol[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (V-22)

[0288] Using compounds IV-22 (1.0 g, 2.30 mmol) and III (1.0 g, 2.30 mmol) as starting materials, the same procedure as that for compound V-1 was followed to give 335 mg of a pale yellow solid, with a yield of 23.3%. 1 H NMR (300 MHz, DMSO-d6) δ 9.79 (s, 1H, NHCO), 8.21 (s, 1H, ArH), 7.88 (d, J = 8.4 Hz, 2H,ArH), 7.29-7.13 (m, 2H, ArH), 6.59 (d, J = 8.5 Hz, 2H, ArH), 4.70-4.49 (m,3H, CH2C H2 O, NC H 2CH), 4.13-3.69 (m, 2H, NC H 2C H ), 3.41-3.23 (m, 4H, N(C H2 CH2)2), 3.11-2.72 (m, 1H, NC) H2CH2), 2.37-2.22 (m, 1H, NC H 2CH2), 2.20-2.08 (m, 1H,NCH2CHC H 2), 2.07-2.03 (m, 1H, NCH2CHC H 2), 1.97 (q, J = 7.2, 6.6 Hz, 4H, N(C H2 CH2)2), 1.81-1.72 (m, 1H, NCH2C H 2), 1.64-1.47 (m, 1H, NCH2C H 2).

[0289] Synthesis of (R)-N-(7-(4-amino-1-(piperidin-3-yl)-1H-pyrazol[3,4-d]pyrimidin-3-yl)-2,3-benzodihydrofuran-4-yl)-4-(pyrrolo-1-yl)benzamide (VI-22)

[0290] Using compound VI-22 (300 mg, 0.48 mmol) as the starting material, the same procedure as that for compound VI-1 was followed to obtain 241 mg of a pale yellow solid, with a yield of 95.8%.

[0291] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidinyl-3-yl)-4-amino-1H-pyrazol[3,4-d]pyrimidin-3-yl)-2,3-benzodihydrofuran-4-yl)-4-(pyrrolo-1-yl)benzamide (I-22)

[0292] Using compound VI-22 (221 mg, 0.42 mmol) as the starting material, the same procedure as that for compound I-1 was followed to obtain 32 mg, with a yield of 11.53%. 1 H NMR (300 MHz, DMSO-d6) δ 9.80 (s, 1H, NHCO), 8.22 (s, 1H,ArH), 7.88 (d, J = 8.4 Hz, 2H, ArH), 7.34-7.15 (m, 2H, ArH), 6.6.93-6.66 (m,1H, C H =CH2), 6.59 (d, J = 8.3 Hz, 2H, ArH), 6.25-6.01 (m, 1H, CH=C H 2), 5.86-5.55 (m, 1H, CH=C H 2), 4.77-4.44 (m, 4H, CH2C H2 O, NCH2 CH), 4.41-3.94 (m, 2H,NCH2C H NC H 2CH2), 3.82-3.59 (m, 0.5H, NC H 2CH2), 3.33-3.27 (m, 4H, N(C H2 CH2)2), 3.21-3.09 (m, 2H, C H2 CH2O), 3.03-2.89 (m, 0.5H, NC H 2CH2), 2.34-2.19 (m, 1H,NCH2CHC H 2), 2.16-2.06 (m, 1H, NCH2CHC H 2), 2.02-1.86 (m, 4H, N(CH2C H2 )2), 1.66-1.48 (m, 1H, NCH2C H 2), 1.29-1.09 (m, 1H, NCH2C H 2).

[0293] Example 23

[0294] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidinyl-3-yl)-4-amino-1H-pyrazol[3,4-d]pyrimidin-3-yl)-2,3-benzodihydrofuran-4-yl)-4-(pyrrolo-1-ylmethyl)benzamide (I-22)

[0295] Synthesis of 4-(pyrrolo-1-ylmethyl)-N-(7-(4,4,5,5-tetramethyl-1,3,2,-dioxoboronyl-2-yl)-2,3-benzodihydrofuran-4-yl)benzamide (Ⅳ-23)

[0296] Using 4-(pyrrole-1-methyl)benzoic acid (754 mg, 3.68 mmol) and compound XI-1 (800 mg, 3.06 mmol) as starting materials, the same procedure as for the synthesis of compound IV-1 was followed to give 817 mg of a pale yellow solid, with a yield of 59.5%.

[0297] Synthesis of (R)-3-(4-amino-3-(4-(4-(pyrrolo-1-ylmethyl)benzoylamino)-2,3-benzodihydrofuran-7-yl)-1H-pyrazol[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (V-23)

[0298] Using compounds IV-23 (800 mg, 1.78 mmol) and III (791 mg, 1.78 mmol) as starting materials, the same procedure as that for compound V-1 was followed to give 826 mg of pale yellow solid, with a yield of 72.7%. 1 H NMR (300 MHz, DMSO-d6) δ 10.19 (s, 1H, NHCO), 8.22 (s, 1H, ArH), 7.95 (d, J = 7.8 Hz, 2H, ArH), 7.50 (d, J = 7.9 Hz, 2H, ArH), 7.29 (d, J = 8.2 Hz, 1H, ArH), 7.19 (d,J = 8.4 Hz, 1H, ArH), 4.75-4.55 (m, 3H, OC H2 CH2, NC H 2CH), 4.03-3.82 (m, 1H, NCH2C) H ), 3.73 (s, 2H, CH2), 3.56-3.32 (m, 2H, OCH2C H2 ), 3.29 (t, J = 8.8 Hz,4H, N(C H2 CH2)2), 3.12-2.85 (m, 1H, NC H 2CH), 2.30-2.13 (m, 1H, NC H2 CH2), 2.13-2.01 (m, 1H, NC H2 CH2), 1.99-1.80 (m, 1H, NCH2CHC H 2), 1.74 (t, J = 6.6 Hz, 4H,N(CH2C H2 )2), 1.64-1.53 ​​(m, 1H, NCH2CHC H 2), 1.50-1.42 (s, 2H, NCH2C H2 ), 1.27(s, 9H, NBoc).

[0299] Synthesis of (R)-N-(7-(4-amino-1-(piperidin-3-yl)-1H-pyrazol[3,4-d]pyrimidin-3-yl)-2,3-benzodihydrofuran-4-yl)-4-(pyrrolo-1-ylmethyl)benzamide (VI-23)

[0300] Using compound VI-23 (815 mg, 1.28 mmol) as the starting material, the same procedure as that for compound VI-1 was followed to give 678 mg of pale yellow solid, with a yield of 98.5%.

[0301] Synthesis of (R)-N-(7-(1-(1-acryloylpiperidinyl-3-yl)-4-amino-1H-pyrazol[3,4-d]pyrimidin-3-yl)-2,3-benzodihydrofuran-4-yl)-4-(pyrrolo-1-ylmethyl)benzamide (I-22)

[0302] Using compound VI-23 (650 mg, 1.20 mmol) as the starting material, the same procedure as that for compound I-1 was followed to give 146 mg of white solid, with a yield of 20.4%. 1 H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H, NHCO), 8.23 ​​(s, 1H, ArH), 7.96 (d, J = 8.1 Hz, 2H, ArH), 7.52 (d, J = 7.8 Hz, 2H, ArH), 7.31 (d, J = 8.3 Hz, 1H, ArH), 7.22 (d, J = 8.4 Hz, 1H, ArH), 6.94-6.68 (m,1H, C H =CH2), 6.20-6.05 (m, 1H, CH=C H 2), 5.75-5.58 (m, 1H, CH=C H 2), 4.77-4.51 (m, 3.5H, NC) H 2C H OC H2 CH2), 4.32-4.17 (m, 1H, NC H 2CH), 4.11-4.05 (m, 0.5H,NCH2C H ), 3.82-3.65 (m, 3H, CH2, NC H 2CH2), 3.33-3.27 (m, 4H, N(C H2 CH2)2), 3.23-3.14 (m, 2H, OCH2C H2 ), 3.03-2.88 (m, 1H, NC H 2CH2), 2.29-2.22 (m, 1H,NCH2CHC H 2), 2.17-2.06 (m, 1H, NCH2CHC H2), 1.99-1.92 (m, 1H, NCH2C H 2), 1.79-1.72(m, 4H, N(CH2C H2 )2), 1.55 (d, 1H, NCH2C H 2).

[0303] Example 24

[0304] The pharmacological experiments and results of some of the compounds obtained above are as follows:

[0305] 1. BTK and JAK3 kinase inhibitory activity assay (inhibition rate at 100 nM concentration)

[0306] Experimental method: The 384-well reaction plate was divided into compound wells (100 nM), positive control wells, and negative control wells. Kinase solution was added to the compound wells and positive control wells, and kinase solution was added to the negative control wells.

[0307] Centrifuge with 1×kinase buffer for 30 seconds, then incubate at room temperature for 10 minutes. Add 15 μL of a mixture of ATP and substrate, centrifuge, vortex to mix, and incubate at room temperature (JAK3 for 30 minutes, BTK for 20 minutes). Stop the reaction by adding the stop assay solution, and read the conversion rate using the Caliper EZ reader.

[0308] Data Analysis: Calculation Formulas

[0309] Where: Conversion %_sample is the conversion rate reading of the sample; Conversion %_min is the mean value of the negative control wells, representing the conversion rate reading of the wells without enzyme; Conversion %_max is the mean value of the positive control wells, representing the conversion rate reading of the wells without compound.

[0310] Dose-response curve fitting: With the log value of concentration as the X-axis and the percentage inhibition rate as the Y-axis, the dose-response curve was fitted using the log (inhibitor) vs. response - Variable slope function of GraphPad Prism 5 to obtain the IC50 of each compound on enzyme activity. 50 value.

[0311] Experimental results: The in vitro BTK and JAK3 kinase inhibitory activities of some compounds of the present invention were screened, and the results are shown in Table 1.

[0312] Note: A: Inhibition rate ≥ 75%; B: 75% > Inhibition rate ≥ 50%; C: Inhibition rate < 50%.

[0313] Table 1. Inhibitory activity of some compounds against BTK and JAK3 kinases

[0314] Ⅰ-1 A B Ⅰ-12 A C Ⅰ-2 A A Ⅰ-13 A C Ⅰ-3 A C Ⅰ-14 A C Ⅰ-4 A C Ⅰ-15 A C Ⅰ-5 A B Ⅰ-16 A A Ⅰ-6 A B Ⅰ-17 A C Ⅰ-7 A B Ⅰ-18 A C Ⅰ-8 A A Ⅰ-19 A A Ⅰ-9 A B Ⅰ-21 A A Ⅰ-10 A C Ⅰ-22 A A Ⅰ-11 A C Ibrutinib A B

[0315] Table 1 shows that the compounds of the present invention have good inhibitory activity against BTK and JAK3 kinases, among which compounds I-2, I-8, I-16, and I-19 exhibit good inhibitory activity against BTK and JAK3.

[0316] We selected target compounds with good activity and determined their IC50 values ​​for BTK and JAK3. 50 The results are shown in Table 2.

[0317] Table 2. IC50 of some compounds against BTK and JAK3 kinases 50

[0318] Note: A: IC 50 ≤ 10 nM; B: 10 nM < IC 50 ≤ 30 nM; C: IC50 > 30 nM

[0319] Ⅰ-2 A C Ⅰ-19 A B Ⅰ-8 A B Ibrutinib A C Ⅰ-16 A B

[0320] Example 25

[0321] Liquid chromatography conditions for the target compound: column: BDS Hypersil C18 (4.6 × 250 mm, 5 μm); detection wavelength: 254 nm; column temperature: 30 ℃; flow rate: 1.0 mL / min; injection volume: 10 μL; mobile phase: buffer (3.56 g Na2HPO3 + 1.56 g NaH2PO3 + 1000 mL H2O) - acetonitrile, gradient elution: 0-1 min (acetonitrile 25%), 1-5 min (acetonitrile 25%-75%), 5-18 min (acetonitrile 75%), 18-22 min (acetonitrile 75%-25%), 22-23 min (acetonitrile 25%).

Claims

1. Compounds of general formula (I) or pharmaceutically acceptable salts thereof: （I） in: X 1 Represents -CH2-, X 2 Represents -O-; R 1 represent: , , , , , where R 2 Represents H, F, Cl, Br, I, C1-C6 alkyl, -CF3, -OH, C1-C6 alkoxy, -OCF3, -CN, -NO2, -NH2, C1-C6 alkylamine, -NHCH3, -N(CH3)2, -N(C2H5)2, -CH(CH3CN), -NHCOCH3, , , , , , , , or R 2 It can be monosubstituted, disubstituted, or trisubstituted; Y 1 Y 2 Each represents N or CR 3 R 3 Represents H, F, Cl, Br, I, -CH3, -CF3, -OH, -OCH3, -OCF3, or -CN; Z represents O, S, or NR. 4 R 4 It represents H, -CH3, -C2H5, or cyclopropyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, R 1 represent , , , , , , , where R 5 Represents H, F, Cl, -CH3, t-Bu, -CF3, -CN, -OH, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, -N(C2H5)2, -NHCOCH3 , , , , , or ;R 5 It can be mono-substituted, di-substituted, or tri-substituted.

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein R 5 Representing H, -F, -Cl, -CF3, -OCH3, -CN, -NHCH3, -N(CH3)2, , , ,or R 5 It can be mono-substituted, di-substituted, or tri-substituted.

4. The following compounds according to any one of claims 1 to 3, or pharmaceutically acceptable salts thereof: Ⅰ-1 Ⅰ-2 Ⅰ-21 。 Ⅰ-22 Ⅰ-23 5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, selected from the compounds shown in I-2, I-21 or I-22.

6. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein, Pharmaceutically acceptable salts are acid addition salts formed by the compound of general formula (I) of claim 1 with the following acids: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or ferulic acid.

7. The compound according to any one of claims 4, or a pharmaceutically acceptable salt thereof, wherein, Pharmaceutically acceptable salts are acid addition salts formed by the compound of general formula (I) of claim 1 with the following acids: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or ferulic acid.

8. A pharmaceutical composition, characterized in that, It comprises the compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

9. The method for preparing the compound according to claim 1, wherein the chemical reaction route is as follows: (III) (IV) (V) (VI) （I） in, R 1 X 1 The definition is the same as in claim 1.

10. Use of any compound of claims 1 to 7 or a pharmaceutically acceptable salt thereof in the preparation of BTK and / or JAK3 inhibitor medicaments.

11. The use of claim 10, wherein, The aforementioned BTK and JAK3 dual-target inhibitor drugs are used to treat rheumatoid arthritis or B-cell lymphoma.

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