PI3kδ-mtor dual-target inhibitor, preparation method therefor, and use thereof

Abstract

Disclose in the present invention are a compound of formula (1) having PI3Kδ and mTOR kinase inhibitory activity, or a pharmaceutically acceptable salt thereof; wherein: X, Y, and Z are each independently selected from C or N; M1 is selected from N, O, or S, M2 is selected from N or S, and one and only one of M1 and M2 is N; R1 is selected from C1-6 alkyl; R2 is selected from one or more of hydrogen and halogen; R3 is selected from pyridyl, C1-6 alkyl, phenyl, benzyl, thienyl, pyridylmethyl or pyrazolyl, and is optionally substituted by zero, one or more substituents selected from the following: -SO2(C1-6 alkyl), C1-6 alkyl, C1-6 haloalkyl, and halogen; R4 is selected from H or -NH2; and R5 is selected from H or -NH2. The compound can be used as a dual-target inhibitor for treating diseases responsive to inhibition of PI3K and / or inhibition of mTOR.

Description

PI3Kδ-mTOR dual-target inhibitor and preparation method and application thereof TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical chemistry, in particular to a class of PI3Kδ-mTOR dual-target inhibitors and preparation method and application thereof, the dual-target inhibitor shows inhibitory activity for type I PI3K, and the inhibitory activity for PI3Kα, PI3Kβ and PI3Kγ is weaker than that for PI3Kδ, so it specifically and highly selectively inhibits PI3Kδ. BACKGROUND

[0002] PI3K / AKT / mTOR signaling pathway is a highly conserved signaling network in eukaryotic cells, which plays an important role in the regulation of cell proliferation, apoptosis, metabolism and angiogenesis and various physiological processes, and is one of the most common signaling pathways over-activated in human cancer, which is closely related to the occurrence of drug resistance and disease progression in cancer treatment. The composition of PI3K / AKT / mTOR signaling pathway is relatively complex, including phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3K), protein kinase B (PKB, i.e. Akt) and mammalian target of rapamycin (mTOR), as well as multiple upstream regulators and downstream effectors.

[0003] PI3K and mTOR both belong to the PIKK family, and there is a certain similarity between their catalytic domains, which also promotes the development of PI3K / mTOR dual inhibitors. PI3K / mTOR dual inhibitors target PI3K and mTOR at the same time, compared with mTOR inhibitors alone, they can effectively overcome the problem of negative feedback activation of PI3K signaling pathway observed when using mTORC1 inhibitors alone, and the inhibition of PI3K and mTOR activity not only inhibits cell proliferation, but also induces apoptosis, more surprisingly, dual-target inhibitors show high potency even at low doses, and are less likely to develop drug resistance, which indicates that PI3K / mTOR inhibitors are promising anticancer drugs.

[0004] In previous studies, the inventors developed a class of indazole compounds that can be used to prepare PI3 kinase inhibitors for treating diseases responsive to inhibition of PI3K, which have good inhibitory activity for PI3Kδ and other subtypes, and specific reference can be made to the patent specification with publication number CN114591335A. The patent specifications with publication numbers CN111918653A and CN111918654A disclose mTOR inhibitor compounds.

[0005] Currently, there are several PI3K / mTOR inhibitors in clinical stage. However, most of the inhibitors developed so far are pan-I PI3K / mTOR inhibitors, which target all isoforms of I PI3K, resulting in high toxicity and poor tolerability. Moreover, complete blockade of the PI3K / AKT / mTOR signaling pathway can cause compensatory activation of other signaling pathways, leading to drug resistance. Therefore, the development of isoform-specific dual PI3K and mTOR inhibitors is expected to improve efficacy while reducing the incidence of toxicity and drug resistance to some extent. SUMMARY

[0006] The present application provides compounds of formula (1) having inhibitory activity against PI3Kδ and mTOR kinases, which can be used as dual-target inhibitors.

[0007] Compounds of formula (1)

[0008] or pharmaceutically acceptable salts thereof, racemic mixtures thereof, hydrates, solvates, prodrugs, enantiomers, diastereomers, tautomers thereof;

[0009] wherein:

[0010] X, Y, Z are each independently selected from C or N;

[0011] M 1 selected from N, O or S, M 2 selected from N or S, and M 1 , M 2 only one is N;

[0012] R 1 selected from C 1-6 alkyl (e.g., methyl, ethyl, etc.);

[0013] R 2 selected from one or more of hydrogen, halogen (e.g., F, etc.);

[0014] R 3 selected from pyridyl, C 1-6 alkyl (including alkanyl, cycloalkyl, combinations of alkanyl and cycloalkyl, etc., e.g., methyl, ethyl, isopropyl, cyclopropyl, cyclopropylmethyl , phenyl, benzyl, thienyl, pyridylmethyl (e.g., , etc.), or pyrazolyl, optionally substituted with zero, one or more substituents selected from -SO2(C 1-6 alkyl), C 1-6 alkyl (including alkanyl, cycloalkyl, combinations of alkanyl and cycloalkyl, etc., e.g., methyl, ethyl, isopropyl, cyclopropyl, cyclopropylmethyl haloalkyl (wherein halo can be F, Cl, Br, I, etc., the number of halo is not limited, can be one or more, alkyl includes alkanes, cycloalkanes, combination of alkanes and cycloalkanes, etc., such as methyl, ethyl, isopropyl, cyclopropyl, cyclopropylmethyl, etc.), C 1-6 haloalkyl (wherein halo can be F, Cl, Br, I, etc., the number of halo is not limited, can be one or more, alkyl includes alkanes, cycloalkanes, combination of alkanes and cycloalkanes, etc., such as methyl, ethyl, isopropyl, cyclopropyl, cyclopropylmethyl, etc.), C haloalkyl (wherein halo can be F, Cl, Br, I, etc., the number of halo is not limited, can be one or more, alkyl includes alkanes, cycloalkanes, combination of alkanes and cycloalkanes, etc., such as methyl, ethyl, isopropyl, cyclopropyl, cyclopropylmethyl, etc.), C

[0015] R 4 selected from H or -NH2;

[0016] R 5 selected from H or -NH2.

[0017] Further, the compound of formula (1) can be selected from any one of the following compounds:

[0018] The present application also relates to a pharmaceutical composition comprising the above compound or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof, and the use of the compound or the pharmaceutical composition for inhibiting ΡΙ3Κδ / mTOR kinase activity, and the use of the compound or the pharmaceutical composition for treating, preventing or ameliorating a disease, disorder or condition modulated by, affected by or involving ΡΙ3Κδ / mTOR kinase activity.

[0019] The above compound provided by the present application can exhibit the phenomena of tautomerism, structural isomerism and stereoisomerism. The present application includes any tautomeric or structural or stereoisomeric form thereof and mixtures thereof, which have the ability to modulate kinase activity, and the ability is not limited to any one isomeric or mixed form.

[0020] The present application also provides a pharmaceutical composition comprising the above compound of formula (1) or a pharmaceutically acceptable salt, racemic mixture, hydrate, solvate, prodrug, enantiomer, diastereoisomer, tautomer thereof, and one or more pharmaceutically acceptable carriers, diluents, excipients.

[0021] The compounds described herein can be prepared and / or used as pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include, but are not limited to: (1) salts formed with cations, such as sodium, potassium, ammonium, calcium, or magnesium, (2) salts formed with organic amines, such as N-methyl-glucamine, N-methyl-D-glucamine, L-arginine, L-lysine, or 1-ephenine, and (3) salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or nitrous acid, or salts formed with organic acids, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, hydroxyacetic acid, pyruvic acid, lactic acid, malonic acid, malic acid, citric acid, succinic acid, maleic acid, tartaric acid, xinafoic acid, trifluoroacetic acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 4-methylbicyclo- [2.2.2]oct-2-ene-1-carboxylic acid, 2-naphthalenesulfonic acid, t-butylacetic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, dodecylsulfic acid, gluconic acid, glutamic acid, salicylic acid, hydroxynaphthoic acid, stearic acid, muconic acid, and the like.

[0022] A pharmaceutically acceptable carrier (i.e., a pharmaceutically acceptable carrier) refers to a carrier that is compatible with the active ingredient of the composition (in some embodiments, that stabilizes the active ingredient) and that does not deleteriously affect the subject being treated. Pharmaceutically acceptable carriers and / or excipients can be selected from diluents, fillers, salts, disintegrants, binders, lubricants, glidants, wetting agents, controlled release matrices, coloring agents, flavoring agents, buffering agents, stabilizing agents, solubilizing agents, and combinations thereof.

[0023] Pharmaceutical compositions comprising a compound of Formula (1) described herein and / or a pharmaceutically acceptable salt thereof can be administered in a variety of known manner, e.g., orally, topically, rectally, parenterally, by inhalation, or implantation, etc.

[0024] Depending on the purpose of the treatment, the pharmaceutical composition can be prepared in various types of administration unit dosage forms, such as tablets, pills, powders, liquid preparations, suspensions, emulsions, granules, capsules, elixirs, tinctures, suppositories, and injections (solutions and suspensions), etc.

[0025] For the purpose of molding the pharmaceutical composition in the form of tablets, any excipient known in the art and widely used can be used. For example, carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid, etc.; binders such as water, ethanol, propanol, common sugar syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinyl pyrrolidone, etc.; disintegrants such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, calcium carbonate, fatty acid esters of polyethylene sorbitan, sodium dodecyl sulfate, stearic acid monoglyceride, starch and lactose, etc.; disintegration inhibitors such as white sugar, glycerin tristearate, coconut oil and hydrogenated oil; adsorption promoters such as quaternary amine bases and sodium dodecyl sulfate, etc.; wetting agents such as glycerin, starch, etc.; adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid, etc.; and lubricants such as pure talc, stearate, boric acid powder and polyethylene glycol, etc. can be used. If necessary, a common coating material can be selected to make sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double film-coated tablets and multi-layer tablets.

[0026] For the purpose of molding the pharmaceutical composition in the form of pills, any excipient known in the art and widely used can be used. For example, carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc, etc.; binders such as acacia powder, tragacanth powder, gelatin and ethanol, etc.; disintegrants such as agar and kelp powder, etc. can be used.

[0027] For the purpose of molding the pharmaceutical composition in the form of suppositories, any excipient known in the art and widely used can be used. For example, polyethylene glycol, coconut oil, higher alcohol, ester of higher alcohol, gelatin and semi-synthetic glyceride, etc. can be used.

[0028] For the purpose of preparing the pharmaceutical composition in the form of injections, a solution or suspension is sterilized (preferably, an appropriate amount of sodium chloride, glucose or glycerin, etc. is added) to make injections isotonic with blood. In the preparation of injections, any carrier commonly used in the art can be used. For example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxyethylated isostearyl alcohol and fatty acid ester of polyethylene sorbitan, etc. can be used. In addition, a common dissolving agent, buffer and analgesic, etc. can be added.

[0029] In the present application, the method of administration of the pharmaceutical composition is not particularly limited. Various dosage forms of preparations can be administered according to the age, sex and other conditions and symptoms of the patient. For example, tablets, pills, solutions, suspensions, emulsions, granules or capsules are orally administered; injections can be administered alone or mixed with a delivery solution for injection (e.g., glucose solution and amino acid solution) to be intravenously injected; suppositories are administered to the rectum.

[0030] In another aspect, the present application also provides a method for inhibiting PI3K and / or mTOR activity in vivo or in vitro, comprising contacting PI3K and / or mTOR with an effective amount of a compound of Formula (1) and / or a pharmaceutically acceptable salt thereof.

[0031] In another aspect, the present application also provides a method for inhibiting PI3K and / or mTOR activity in vivo or in vitro, comprising contacting PI3K and / or mTOR with an effective amount of a compound of Formula (1) and / or a pharmaceutically acceptable salt thereof.

[0032] In another aspect, the present application also provides a method for treating a disease responsive to the inhibition of PI3K and / or mTOR in a subject, comprising administering to a subject in need thereof an effective amount of a compound of Formula (1) and / or a pharmaceutically acceptable salt thereof for inhibiting PI3K and / or mTOR in the subject.

[0033] In another aspect, the present application also provides a method for treating a disease responsive to the inhibition of PI3K and / or mTOR in a subject, comprising administering to a subject in need thereof an effective amount of a compound of Formula (1) and / or a pharmaceutically acceptable salt thereof for inhibiting PI3K and / or mTOR in the subject.

[0034] The present application also provides the use of the compound of Formula (1) or a pharmaceutically acceptable salt thereof, a racemic mixture thereof, a hydrate thereof, a solvate thereof, a prodrug thereof, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, or the pharmaceutical composition thereof in the preparation of a PI3K inhibitor and / or an mTOR inhibitor. Further, the PI3K inhibitor can be a PI3K delta inhibitor, an inhibitor of the p110 delta isoform of PI3 kinases (PI3K).

[0035] The present application also provides the use of the compound of Formula (1) or a pharmaceutically acceptable salt thereof, a racemic mixture thereof, a hydrate thereof, a solvate thereof, a prodrug thereof, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, or the pharmaceutical composition thereof in the preparation of a medicament for treating a disease responsive to the inhibition of PI3K and / or the inhibition of mTOR. The PI3K can be PI3K delta, etc. The disease includes inflammatory diseases, autoimmune diseases, cancers, infectious diseases, cardiovascular and cerebrovascular diseases, and nervous system diseases.

[0036] Inflammatory diseases refer to pathological states that result in an inflammatory response, particularly due to neutrophil chemotaxis. Examples of such diseases include inflammatory skin diseases (including psoriasis and atopic dermatitis); systemic scleroderma and sclerosis; reactions associated with inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis); ischemia-reperfusion injury, including surgical tissue reperfusion injury, myocardial ischemia such as myocardial infarction, cardiac arrest, post-cardiac surgery reperfusion, and abnormal constriction of coronary vessels following percutaneous transluminal coronary angioplasty, stroke, and abdominal aortic aneurysm surgical tissue reperfusion injury; cerebral edema secondary to stroke; craniocerebral trauma; hemorrhagic shock; asphyxia; adult respiratory distress syndrome; acute lung injury; Behcet's disease; dermatomyositis; polymyositis; multiple sclerosis; dermatitis; meningitis; encephalitis; uveitis; osteoarthritis; lupus nephritis; autoimmune diseases such as rheumatoid arthritis; Sjogren's syndrome; vasculitis; diseases involving leukocyte diapedesis; sepsis or central nervous system inflammatory diseases secondary to trauma, multiple organ injury syndrome: alcoholic hepatitis; bacterial pneumonia; antigen-antibody complex-mediated diseases, including glomerulonephritis; sepsis; sarcoidosis; immunopathological reactions resulting from tissue / organ transplantation; pulmonary inflammation, including pleuritis, alveolitis, vasculitis, pneumonitis, chronic bronchitis, bronchiectasis, diffuse panbronchiolitis, hypersensitivity pneumonitis, idiopathic pulmonary fibrosis, and cystic fibrosis, and the like.

[0037] Autoimmune diseases refer to diseases or conditions caused by an immune response to self-antigens that results in damage to self-tissues or organs. Examples of autoimmune diseases include, but are not limited to, chronic obstructive pulmonary disease, allergic rhinitis, lupus erythematosus, myasthenia gravis, multiple sclerosis (MS), rheumatoid arthritis, psoriasis, inflammatory bowel disease, asthma, and idiopathic thrombocytopenic purpura, and myeloproliferative disorders, such as myelofibrosis, polycythemia vera / essential thrombocythemia myelofibrosis.

[0038] The inflammatory diseases, autoimmune diseases include rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), systemic vasculitis, allergic rhinitis, asthma, systemic lupus erythematosus, Sjogren's syndrome, pemphigus, multiple sclerosis, psoriasis, Hashimoto's thyroiditis, type I diabetes mellitus, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, Goodpasture's syndrome, pemphigus vulgaris, pemphigoid, primary biliary cirrhosis, multiple sclerosis, Guillain-Barre syndrome, scleroderma, dermatomyositis, mixed connective tissue disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune diseases of the thyroid, idiopathic thrombocytopenic purpura, and the like.

[0039] The cancer includes, but is not limited to, solid tumors or hematological malignancies, including cancers of the skin, tissue, organ, bone, cartilage, blood, and blood vessels, both primary and metastatic cancers. Non-limiting examples of solid tumors include pancreatic cancer; bladder cancer; colorectal cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; kidney cancer, including, for example, metastatic renal cell carcinoma; hepatocellular carcinoma; lung cancer, including, for example, non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and lung adenocarcinoma; ovarian cancer, including, for example, progressive epithelial carcinoma or primary peritoneal cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer, including, for example, squamous cell carcinoma of the head and neck; skin cancer, including, for example, malignant melanoma; neuroendocrine cancer, including metastatic neuroendocrine tumor; brain tumor, including, for example, glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma; bone cancer; soft tissue sarcoma; and thyroid cancer.

[0040] Non-limiting examples of hematological malignancies include acute myeloid leukemia (AML); chronic myeloid leukemia (CML), including accelerated CML and CML blast phase (CML-BP); acute lymphoblastic leukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin lymphoma; non-Hodgkin lymphoma (NHL), including follicular lymphoma and mantle cell lymphoma; B-cell lymphoma; T-cell lymphoma; multiple myeloma (MM); Waldenstrom macroglobulinemia; myelodysplastic syndrome, including refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and refractory anemia with excess blasts in transformation; and myeloproliferative syndrome.

[0041] In some embodiments, the cancer is typically selected from the group consisting of leukemia, multiple myeloma (MM), lymphoma; the leukemia is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML); the lymphoma is Hodgkin lymphoma, non-Hodgkin lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, B-cell lymphoma, T-cell lymphoma, diffuse large B-cell lymphoma (DLBCL).

[0042] The infectious disease includes, but is not limited to, bacterial infection, fungal infection, viral infection, and parasitic infection.

[0043] The cardiovascular and cerebrovascular disease includes, but is not limited to, acute heart failure, hypotension, hypertension, angina pectoris, myocardial infarction, cardiomyopathy, congestive heart failure, atherosclerosis, coronary heart disease, restenosis, and vascular stenosis, as well as traumatic brain injury, stroke, ischemia-reperfusion injury, and arterial.

[0044] The mental diseases include, but are not limited to, neurodevelopmental diseases such as autism; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis; mood disorders such as depression, mania, bipolar disorder and anxiety; thought and will disorders such as schizophrenia; consciousness disorders such as epilepsy; in addition, migraine, attention deficit hyperactivity disorder, prosopagnosia and amnesia, etc.

[0045] In addition, the compound of formula (1) and / or the pharmaceutically acceptable salt thereof described herein can be combined with other active ingredients for the treatment of inflammatory diseases, autoimmune diseases, cancers, infectious diseases or cardiovascular and cerebrovascular diseases. The compound of formula (I) and / or the pharmaceutically acceptable salt thereof can be administered separately from or formulated into a combined preparation with other active ingredients. The other active ingredients refer to those known to be effective for the treatment of PI3K and / or mTOR mediated diseases. DETAILED DESCRIPTION

[0046] The application will be further described in conjunction with specific examples. It should be understood that these examples are only used to illustrate the application and not used to limit the scope of the application. The operation methods in the following examples without specific conditions are generally carried out according to the conventional conditions or the conditions suggested by the manufacturers.

[0047] Example 1: 5-(4-amino-1-(1-(6-fluoro-1-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-1H-pyrazol[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine

[0048] Synthesis of A3: Two-mouth flask was added with A1 (2 g, 9.39 mmol), pinacol diboronic acid (3.58 g, 14.09 mmol), Pd(dppf)Cl2(137 mg, 0.19 mmol), potassium acetate (1.84 g, 18.78 mmol), vacuumed and replaced with argon for three times, 30 mL of anhydrous dioxane was added, vacuumed and replaced with argon again, and after the replacement was completed, the reaction was carried out at 115 °C for 18 h. After the reaction was completed, ethyl acetate and water were added to separate the layers, the organic layer was collected, washed with water for three times, saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography with PE / EA (v / v, 2 / 1) as the developing agent to obtain a light yellow solid (1.7 g, 65.6%).

[0049] Synthesis of B2: Sodium nitrite (28.60 g, 414.40 mmol) was placed in a three-necked flask, vacuumed and replaced with argon for three times, then water (60 mL) and DMF (45 mL) were added, 70 mL 2N hydrochloric acid was added dropwise at 0 °C for 10 min. 6-Fluoroindole (7 g, 51.80 mmol) was dissolved in 50 mL of DMF and added dropwise into the reaction system, then the reaction was carried out at room temperature for 5 h. Ethyl acetate was added to separate the layers, the organic layer was collected, the water layer was extracted with ethyl acetate for three times, the organic layers were combined, washed with saturated sodium bicarbonate and saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated to give the crude product, which was recrystallized from PE / EA to give yellow solid B2 (6.4 g, 75.3%).

[0050] Synthesis of B3: B2 (6 g, 36.55 mmol) was added to a two-necked flask, replaced with argon for three times, then anhydrous THF was added, the reaction solution was cooled to -10 °C, methyl magnesium chloride (36.55 mL, 3.0M in THF) was added dropwise, then the reaction was carried out at room temperature after the addition was completed, saturated ammonium chloride solution was added at low temperature to quench the reaction after the reaction was completed, the organic layer was collected, washed with saturated brine, dried over sodium sulfate, concentrated, and column chromatography was carried out with PE / EA (v / v, 2:1) as the eluent to give light yellow solid B3 (5.5 g, 83.5%).

[0051] Synthesis of B4: B3 (5 g, 27.75 mmol) was added to a single-necked flask, dissolved in 30 mL of dichloromethane, then manganese dioxide (12.06 g, 138.75 mmol) was added in portions, and the reaction was carried out at 50 °C under reflux. After the reaction was completed, the reaction solution was filtered with diatomite while hot, the filter residue was washed with methanol until the filtrate was no longer fluorescent, the filtrate was collected, and the solvent was removed by rotary evaporation to give yellow solid B4 (4.5 g, 91.1%).

[0052] Synthesis of B5: B4 (4.1 g, 23.01 mmol), cuprous iodide (876 mg, 4.6 mmol), L-proline (1.06 g, 9.2 mmol), potassium carbonate (6.36 g, 46.02 mmol) were added to a two-necked flask, which was protected with argon, then 30 mL of DMSO was added, 3-bromopyridine (5.45 g, 34.52 mmol) was added at room temperature, and the reaction was carried out at 120 °C. After the reaction was completed, the reaction solution was cooled to room temperature, 60 mL of ethyl acetate was added and stirred for 20 min, then the insoluble matter was removed by filtration, water was added to the filtrate, the organic layer was collected, washed with saturated brine, dried over sodium sulfate, concentrated, and the crude product was slurried with PE / EA (v / v, 3:1), then filtered to give yellow solid B5 (4.2 g, 71.6%).

[0053] Synthesis of B6: In a single neck flask, B5 (4 g, 15.67 mmol) was taken and methanol was added, sodium borohydride (1.19 g, 31.34 mmol) was added slowly in portions at 0 °C, stirred for half an hour and then allowed to stir at room temperature. After completion of the reaction, saturated ammonium chloride solution was added slowly at 0 °C, stirred for half an hour and then water / ethyl acetate was added to separate the layers, organic layer was collected, washed with saturated brine, dried over anhydrous sodium sulphate and concentrated. Column chromatography was performed using DCM / MeOH (v / v, 50:1) as eluent to get the product as a light yellow solid (3.8 g, 94.3 %).

[0054] Synthesis of B7: In a two neck flask, B6 (3.5 g, 13.6 mmol) was taken, vacuum was applied and purged with argon three times, anhydrous dichloromethane was added, and dichloro sulfoxide (2 mL, 27.2 mmol) was added slowly in portions at 0 °C and allowed to react for 3 h at room temperature. After completion of the reaction, dichloro sulfoxide was distilled off, the reaction mixture was taken in ethyl acetate and the organic layer was extracted with saturated sodium bicarbonate three times, washed with water, saturated sodium chloride and dried over anhydrous sodium sulphate. Concentration was followed by column chromatography using PE / EA (v / v, 1:1) as eluent to get the product as a light yellow solid B8 (3.4 g, 90.7 %).

[0055] Synthesis of B8: In a two neck flask, B7 (3 g, 10.88 mmol) was taken, 3-iodo-1H-4- amino pyrazolo [3, 4-d] pyrimidine (4.26 g, 16.32 mmol), anhydrous potassium carbonate (3 g, 21.76 mmol) were added, vacuum was applied and purged with argon three times, anhydrous DMF was added and allowed to react at 65 °C overnight. After completion of the reaction, water was added to dilute, ethyl acetate was added to extract three times, the organic layers were combined, washed with saturated sodium chloride and dried over anhydrous sodium sulphate. Concentration was followed by column chromatography using DCM / MeOH (v / v, 50:1) as eluent to get the product as a light yellow solid B8 (3.5 g, 64.3 %).

[0056] Synthesis of compound 1: In a two neck flask, B8 (300 mg, 0.6 mmol) was taken, A3 (312 mg, 1.2 mmol), Pd(PPh3)4(69 mg, 0.06 mmol) and anhydrous sodium carbonate (24 mg, 1.8 mmol) were added, vacuum was applied and purged with argon three times, 9 mL of dioxane and 3 mL of water were added, vacuum was again applied and purged with argon, after purging, the reaction was carried out at 115 °C for 6 h. After completion of the reaction, ethyl acetate and water were added to separate the layers, the organic layer was collected, washed with water three times, saturated sodium chloride and dried over anhydrous sodium sulphate. Concentration was followed by column chromatography using DCM / MeOH (v / v, 30:1) as eluent to get the product as a light yellow solid (180 mg, 59.3 %). Light yellow solid; melting range: 274.2-276.3 °C; purity: 100.00 %. 1H NMR(400MHz,DMSO-d6)δ9.04(d,J=2.4Hz,1H),8.63(d,J=4.8Hz,1H),8.34(s,1 H),8.26-8.20(m,1H),7.70(dd,J=10.0,2.0Hz,1H),7.63(dd,J=8.4,4.8Hz,1H) ,7.59-7.52(m,3H),7.45(d,J=8.4Hz,1H),7.37(s,1H),7.20(dd,J=8.4,1.6Hz ,1H),7.11(dd,J=9.2,2.0Hz,1H),6.64(q,J=6.8Hz,1H),2.12(d,J=6.8Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ163.31,162.14(d,J C-F =243.0Hz),158.15,155.87,153.90,148.27,147.56,147.34,144.69,144.27,143.01,139.79(d,J C-F =13.0Hz),135.69,129.42,128.20,124.36,122.53(d,J C-F =11.0Hz),120.35,119.64,114.87,111.55(d,J C-F =25.0Hz),108.79,97.26,96.94(d,J C-F =28.0Hz),49.32,18.41. 19 F NMR(376MHz,DMSO-d6)δ-112.37.HRMS(ESI)m / z Calcd for C 26 H 20 FN 10 O(M+H)+:507.1800; Found:507.1801.

[0057] Example 2: 5-(4-amino-1-(1-(6-fluoro-1-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]thiazol-2-amine 2

[0058] The preparation method is similar to that of Preparation Example 1, except that A3 is replaced with A5 to replace the reactants. The synthetic route of A5 is as follows:

[0059] A4 (1.5 g, 6.55 mmol), diboronic acid pinacol ester (2.5 g, 9.83 mmol), Pd(dppf)Cl2·CH2Cl2 (531 mg, 0.66 mmol), and potassium acetate (1.93 g, 19.65 mmol) were added to a two-necked flask. The mixture was evacuated and purged with argon three times. 30 mL of anhydrous dioxane was added, and the mixture was evacuated again and purged with argon. After complete purging, the mixture was reacted at 105°C for 12 h. After the reaction, ethyl acetate and water were added. The organic layer was collected, washed three times with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. A5 (1.3 g, 72%) was isolated as a pale yellow solid by silica gel column chromatography using PE / EA (v / v, 2 / 1) as a developing solvent.

[0060] White solid; melting range: 273.9-275.8°C; purity: 100.00%. 1 H NMR(400MHz,DMSO-d6)δ9.04(d,J=2.4Hz,1H),8.65-8.61(m,1H),8.36(s,1H) ,8.26-8.20(m,1H),7.79(d,J=8.0Hz,1H),7.71(dd,J=10.0,2.0Hz,1H),7.66- 7.61(m,3H),7.58(dd,J=8.8,5.2Hz,1H),7.52(d,J=2.0Hz,1H),7.26(dd,J=8. 0,1.6Hz,1H),7.16-7.08(m,1H),6.66(q,J=7.2Hz,1H),2.13(d,J=7.2Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ167.84,162.75(d,J C-F =243.0Hz),158.78,156.50,154.58,153.86,148.16,147.91,145.15,143.61,140.40(d,J C-F =12.0Hz),136.29,132.21,130.61,130.02,124.96,123.15(d,J C-F =11.0Hz),122.06,121.30,120.25,117.67,112.15(d,J C-F =26.0Hz),97.87,97.56(d,J C-F =27.0Hz),49.97,19.03. 19 F NMR(376MHz,DMSO-d6)δ-112.21.HRMS(ESI)m / z Calcd for C 26H 20 FN 10 S(M+H) + :523.1572; Found: 523.1574.

[0061] Example 3: 6-(4-amino-1-(1-(6-fluoro-1-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]thiazol-2-amine 3

[0062] The preparation method is similar to that of Preparation Example 2, which can be replaced by the reactant.

[0063] White solid; m.p. 210.1-212.4 °C; purity: 100.00%. 1 H NMR (400 MHz, DMSO-d6) δ 9.04 (d, J = 2.4 Hz, 1H), 8.63 (dd, J = 4.8, 1.2 Hz, 1H), 8.35 (s, 1H), 8.26-8.20 (m, 1H), 7.89 (s, 1H), 7.71 (dd, J = 10.0, 1.6 Hz, 1H), 7.66-7.61 (m, 3H), 7.54 (dd, J = 9.2, 5.2 Hz, 1H), 7.44 (s, 2H), 7.12 (dd, J = 9.2, 2.0 Hz, 1H), 6.65 (q, J = 7.2 Hz, 1H), 2.11 (d, J = 7.2 Hz, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 168.02, 162.72 (d, J = 243.0 Hz), 158.77, 156.44, 154.55, 153.80, 148.13, 147.90, 145.06, 143.57, 140.36 (d, J = 13.5 Hz), 136.28, 132.37, 129.96, 126.35, 125.68, 124.93, 123.03 (d, J = 10.5 Hz), 121.27, 120.24, 118.42, 112.16 (d, J = 25.5 Hz), 97.79, 97.51 (d, J = 27.0 Hz), 49.80, 18.88. C-F = 243.0 Hz), 158.77, 156.44, 154.55, 153.80, 148.13, 147.90, 145.06, 143.57, 140.36 (d, J = 13.5 Hz), 136.28, 132.37, 129.96, 126.35, 125.68, 124.93, 123.03 (d, J = 10.5 Hz), 121.27, 120.24, 118.42, 112.16 (d, J = 25.5 Hz), 97.79, 97.51 (d, J = 27.0 Hz), 49.80, 18.88. C-F = 243.0 Hz), 158.77, 156.44, 154.55, 153.80, 148.13, 147.90, 145.06, 143.57, 140.36 (d, J = 13.5 Hz), 136.28, 132.37, 129.96, 126.35, 125.68, 124.93, 123.03 (d, J = 10.5 Hz), 121.27, 120.24, 118.42, 112.16 (d, J = 25.5 Hz), 97.79, 97.51 (d, J = 27.0 Hz), 49.80, 18.88. C-F = 243.0 Hz), 158.77, 156.44, 154.55, 153.80, 148.13, 147.90, 145.06, 143.57, 140.36 (d, J = 13.5 Hz), 136.28, 132.37, 129.96, 126.35, 125.68, 124.93, 123.03 (d, J = 10.5 Hz), 121.27, 120.24, 118.42, 112.16 (d, J = 25.5 Hz), 97.79, 97.51 (d, J = 27.0 Hz), 49.80, 18.88. C-F = 243.0 Hz), 158.77, 156.44, 154.55, 153.80, 148.13, 147.90, 145.06, 143.57, 140.36 (d, J = 13.5 Hz), 136.28, 132.37, 129.96, 126.35, 125.68, 124.93, 123.03 (d, J = 10.5 Hz), 121.27, 120.24, 118.42, 112.16 (d, J = 25.5 Hz), 97.79, 97.51 (d, J = 27.0 Hz), 49.80, 18.88. C-F = 243.0 Hz), 158.77, 156.44, 154.55, 153.80, 148.13, 147.90, 145.06, 143.57, 140.36 (d, J = 13.5 Hz), 136.28, 132.37, 129.96, 126.35, 125.68, 124.93, 123.03 (d, J = 10.5 Hz), 121.27, 120.24, 118.42, 112.16 (d, J = 25.5 Hz), 97.79, 97.51 (d, J = 27.0 Hz), 49.80, 18.88. 19 F NMR (376 MHz, DMSO-d6) δ -112.31. HRMS (ESI) m / z Calcd for C 26 H 20 FN 10S(M+H) + :523.1572;Found:523.1574.

[0064] Example 4: 3-(Benzo[d]oxazol-5-yl)-1-(1-(6-fluoro-1-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 4

[0065] The preparation method is similar to that of Example 1, except that the reactants are replaced.

[0066] White solid; melting range: 231.3-232.2°C; purity: 98.10%. 1 H NMR (400MHz, DMSO-d6) δ9.04(d,J=2.8Hz,1H),8.85(s,1H),8.63(d,J=4.4Hz,1H),8.37(s,1H),8.27-8.20(m,1H),7.98(s ,1H),7.91(d,J=8.4Hz,1H),7.73-7.57(m,4H),7.13(dd,J=9.2,2.0Hz,1H),6.68(q,J=7.2Hz,1H),2.14(d,J=7.2Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ162.75(d,J C-F =243.0Hz),158.82,156.57,155.52,154.65,150.15,148.13,147.85,144.55,143.56,140.75,140.37(d,J C-F =13.0Hz),136.27,129.96,126.71,124.94,123.13(d,J C-F =11.0Hz),120.56,120.25,112.28,112.18(d,J C-F =25.0Hz),97.98,97.54(d,J C-F =28.0Hz),49.99,18.99. 19 F NMR(376MHz,DMSO-d6)δ-112.33.HRMS(ESI)m / z Calcd for C 26 H 19 FN9O(M+H) + :492.1691;Found:492.1693.

[0067] Example 5: 5-(4-amino-1-(1-(6-fluoro-1-methyl-1H-indazol-3-yl)ethyl)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine5

[0068] The preparation method is similar to that of Preparation Example 1, and 3-bromopyridine is replaced with iodomethane, and the reactants are changed.

[0069] A two-necked flask was charged with B4 (1.2 g, 6.74 mmol) and sodium hydroxide (809 mg, 20.22 mmol), vacuumed and replaced with argon for three times, tetrahydrofuran was added, iodomethane (1.9 g, 13.48 mmol) was added, and the reaction was carried out at room temperature. After the completion of the reaction was monitored by TLC, water and ethyl acetate were added for layer separation, the organic layer was washed with water for three times, saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by silica gel column chromatography with PE / EA (v / v, 5 / 1) as the developing agent to obtain a light yellow solid (1.18 g, 91%).

[0070] White solid; melting range 314.5-315.8 °C; purity: 96.45%. 1 H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 7.56 (s, 2H), 7.50-7.44 (m, 3H), 7.37 (d, J = 1.6 Hz, 1H), 7.20 (dd, J = 8.4, 1.6 Hz, 1H), 6.93 (td, J = 9.2, 2.0 Hz, 1H), 6.53 (q, J = 6.8 Hz, 1H), 4.00 (s, 3H), 2.05 (d, J = 6.8 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 163.93, 161.78 (d, J = 240.0 Hz), 158.69, 156.32, 154.31, 148.85, 144.98, 144.87, 144.06, 141.72 (d, J = 12.0 Hz), 128.93, 122.48 (d, J = 11.0 Hz), 120.93, 118.47, 115.45, 110.44 (d, J = 26.0 Hz), 109.38, 97.79, 96.08 (d, J = 27.0 Hz), 49.92, 35.94, 19.25. C-F C-F C-F C-F C-F 19 F NMR (376 MHz, DMSO-d6) δ -114.89. HRMS (ESI) m / z Calcd for C​​​​​22 H 19 FN9O(M+H) + :444.1691;Found:444.1694.

[0071] Example 6: 5-(4-amino-1-(1-(1-ethyl-6-fluoro-1H-indazol-3-yl)ethyl)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine 6

[0072] The preparation method is similar to that of Example 5, and iodomethane is replaced by iodoethane.

[0073] White solid; m.p. 293.5-294.6 °C; purity: 99.17%. 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.59-7.42 (m, 6H), 7.20 (dd, J = 8.0, 1.6 Hz, 1H), 6.92 (td, J = 9.2, 2.4 Hz, 1H), 6.54 (q, J = 6.8 Hz, 1H), 4.39 (q, J = 7.2 Hz, 2H), 2.05 (d, J = 6.8 Hz, 3H), 1.39 (t, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 163.93, 161.75 (d, J = 240.0 Hz), 158.71, 156.34, 154.32, 148.85, 144.99, 144.89, 144.15, 140.85 (d, J = 13.0 Hz), 128.94, 122.62 (d, J = 11.0 Hz), 120.93, 118.55, 115.46, 110.45 (d, J = 26.0 Hz), 109.39, 97.79, 96.01 (d, J = 27.0 Hz), 50.04, 43.68, 19.34, 15.25. C-F = 240.0 Hz), 158.71, 156.34, 154.32, 148.85, 144.99, 144.89, 144.15, 140.85 (d, J = 13.0 Hz), 128.94, 122.62 (d, J = 11.0 Hz), 120.93, 118.55, 115.46, 110.45 (d, J = 26.0 Hz), 109.39, 97.79, 96.01 (d, J = 27.0 Hz), 50.04, 43.68, 19.34, 15.25. C-F = 240.0 Hz), 158.71, 156.34, 154.32, 148.85, 144.99, 144.89, 144.15, 140.85 (d, J = 13.0 Hz), 128.94, 122.62 (d, J = 11.0 Hz), 120.93, 118.55, 115.46, 110.45 (d, J = 26.0 Hz), 109.39, 97.79, 96.01 (d, J = 27.0 Hz), 50.04, 43.68, 19.34, 15.25. C-F = 240.0 Hz), 158.71, 156.34, 154.32, 148.85, 144.99, 144.89, 144.15, 140.85 (d, J = 13.0 Hz), 128.94, 122.62 (d, J = 11.0 Hz), 120.93, 118.55, 115.46, 110.45 (d, J = 26.0 Hz), 109.39, 97.79, 96.01 (d, J = 27.0 Hz), 50.04, 43.68, 19.34, 15.25. C-F = 240.0 Hz), 158.71, 156.34, 154.32, 148.85, 144.99, 144.89, 144.15, 140.85 (d, J = 13.0 Hz), 128.94, 122.62 (d, J = 11.0 Hz), 120.93, 118.55, 115.46, 110.45 (d, J = 26.0 Hz), 109.39, 97.79, 96.01 (d, J = 27.0 Hz), 50.04, 43.68, 19.34, 15.25. C-F = 240.0 Hz), 158.71, 156.34, 154.32, 148.85, 144.99, 144.89, 144.15, 140.85 (d, J = 13.0 Hz), 128.94, 122.62 (d, J = 11.0 Hz), 120.93, 118.55, 115.46, 110.45 (d, J = 26.0 Hz), 109.39, 97.79, 96.01 (d, J = 27.0 Hz), 50.04, 43.68, 19.34, 15.25. 19 F NMR (376 MHz, DMSO-d6) δ -114.95.HRMS (ESI) m / z Calcd for C 23 H 21 FN9O(M+H) + :458.1848;Found:458.1851.

[0074] Example 7: 5-(4-amino-1-(1-(6-fluoro-1-isopropyl-1H-indazol-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine 7

[0075] The preparation method is similar to that of Preparation Example 5, except that iodomethane is replaced by 2-iodopropane, sodium hydroxide is replaced by cesium carbonate, and the solvent is anhydrous DMF.

[0076] To a two-necked flask were added 4-6a (700 mg, 3.93 mmol), cesium carbonate (2.56 g, 7.86 mmol), and 2-iodopropane (1 g, 5.89 mmol). The mixture was evacuated and replaced with argon three times. Anhydrous DMF was added and the reaction was allowed to proceed at 65°C. After completion of the reaction, as monitored by TLC, water and ethyl acetate were added and the layers were separated. The aqueous layer was extracted three times with ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by silica gel column chromatography using PE / EA (v / v, 5 / 1) as a developing solvent to obtain a light yellow solid (770 mg, 89%).

[0077] White solid; melting range: 256.4-258.2°C; purity: 100.00%. 1 H NMR (400MHz, DMSO-d6) δ8.34(s,1H),7.58-7.52(m,3H),7.50-7.44(m,2H),7.37(d,J=1.6Hz,1H),7.20(dd,J=8.0,1.6Hz,1H),6.92(t d,J=9.2,2.4Hz,1H),6.53(q,J=6.8Hz,1H),4.91(p,J=6.8Hz,1H),2.05(d,J=6.8Hz,3H),1.49(d,J=6.8Hz,3H),1.46(d,J=6.8Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ163.94,161.64(d,J C-F =240.0Hz),158.71,156.34,154.34,148.86,144.98,144.89,143.98,140.43(d,J C-F =13.0Hz),128.95,122.69(d,J C-F =11.0Hz),120.93,118.53,115.46,110.42(d,J C-F =26.0Hz),109.40,97.79,96.07(d,J C-F=26.0Hz),50.26,50.15,22.39,22.31,19.51. 19 F NMR(376MHz,DMSO-d6)δ-115.13.HRMS(ESI)m / z Calcd for C 24 H 23 FN9O(M+H) + :472.2004;Found:472.2005.

[0078] Example 8: 5-(4-amino-1-(1-(1-(cyclopropylmethyl)-6-fluoro-1H-indazol-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine 8

[0079] The preparation method is similar to that of Preparation Example 7, except that 2-iodopropane is replaced by bromomethylcyclopropane, and cesium carbonate is replaced by potassium carbonate.

[0080] White solid; melting range: 253.2-254.9°C; purity: 100.00%. 1 H NMR (400MHz, DMSO-d6) δ8.34(s,1H),7.60-7.52(m,3H),7.51-7.42(m,2H),7.37(d,J=1.6Hz,1H),7.20(dd,J=8.0,1.6Hz,1H),6.95-6. 89(m,1H),6.54(q,J=6.8Hz,1H),4.26(d,J=7.2Hz,2H),2.06(d,J=6.8Hz,3H),1.33-1.24(m,1H),0.53-0.45(m,2H),0.44-0.38(m,2H). 13 C NMR(101MHz,DMSO-d6)δ163.93,161.80(d,J C-F =240.0Hz),158.71,156.33,154.34,148.85,144.98,144.88,144.14,141.27(d,J C-F =13.0Hz),128.94,122.54(d,J C-F =11.0Hz),120.92,118.55,115.45,110.41(d,J C-F =26.0Hz),109.38,97.79,96.20(d,J C-F =26.0Hz),52.93,50.01,19.33,11.78,4.12,4.10.19 F NMR (376 MHz, DMSO-d6) δ -115.01. HRMS (ESI) m / z Calcd for C 25 H 23 FN9O (M+H) + : 484.2004; Found: 484.2008.

[0081] Example 9: 5-(4-amino-1-(1-(6-fluoro-1-phenyl-1H-indazol-3-yl)ethyl)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine 9

[0082] The preparation method is similar to that of Preparation Example 1, which can be replaced by the reactants.

[0083] White solid; m.p. 203.2-204.5 °C; purity: 97.40%. 1 H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.81-7.75 (m, 2H), 7.63-7.55 (m, 6H), 7.48-7.39 (m, 3H), 7.22 (dd, J = 8.4, 1.6 Hz, 1H), 7.13-7.05 (m, 1H), 6.65 (q, J = 6.8 Hz, 1H), 2.13 (d, J = 6.8 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 163.94, 162.55 (d, J = 242.0 Hz), 158.75, 156.44, 154.48, 148.89, 146.95, 145.25, 144.90, 140.12 (d, J = 12.0 Hz), 139.57, 130.21, 128.85, 127.33, 123.07 (d, J = 11.0 Hz), 122.68, 120.97, 120.09, 115.49, 111.77 (d, J = 26.0 Hz), 109.40, 97.88, 97.30 (d, J = 27.0 Hz), 49.98, 19.08. C-F C-F C-F C-F C-F 19 F NMR (376 MHz, DMSO-d6) δ -112.91. HRMS (ESI) m / z Calcd for C 27 H 21 FN9O (M+H) + ​​​​​:506.1848;Found:506.1849.

[0084] Example 10: 5-(4-amino-1-(1-(6-fluoro-1-(3-(methylsulfonyl)phenyl)-1H-indazol-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine 10

[0085] The preparation method is similar to that of Example 1, except that the reactants are replaced.

[0086] White solid; melting range: 221.3-222.9°C; purity: 95.34%. 1 H NMR (400MHz, DMSO-d6) δ8.35 (s, 1H), 8.25 (t, J = 2.0Hz, 1H), 8.21-8.16 (m, 1H), 7.99-7.94(m,1H),7.88(t,J=8.0Hz,1H),7.73(dd,J=10.0,2.0Hz,1H),7.60(d d,J=8.8,5.6Hz,1H),7.55(s,2H),7.45(d,J=8.4Hz,1H),7.37(d,J=1.6Hz,1H) ,7.22-17.12(m,2H),6.66(q,J=7.2Hz,1H),3.35(s,3H),2.13(d,J=7.2Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ163.93,162.80(d,J C-F =243.0Hz),158.76,156.50,154.50,148.89,148.04,145.33,144.89,142.79,140.19,140.13(d,J C-F =11.0Hz),131.69,128.80,126.99,125.47,123.32(d,J C-F =11.0Hz),120.98,120.71,120.41,115.48,112.29(d,J C-F =26.0Hz),109.41,97.88,97.63(d,J C-F =27.0Hz),49.94,43.92,19.07. 19 F NMR(376MHz,DMSO-d6)δ-112.19.HRMS(ESI)m / zCalcd for C 28 H 23 FN9O3S(M+H)+ :584.1623;Found:584.1625.

[0087] Example 11: 5-(4-amino-1-(1-(6-fluoro-1-(4-(methylsulfonyl)phenyl)-1H-indazol-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine 11

[0088] The preparation method is similar to that of Example 1, except that the reactants are replaced.

[0089] White solid; melting range: 202.8-203.9°C; purity: 96.03%. 1 H NMR(400MHz, DMSO-d6)δ8.35(s,1H),8.15-8.08(m,4H),7.83(dd,J=10.0,2.4Hz,1H),7.60-7.53(m,3H),7.45(d, J=8.4Hz,1H),7.37(d,J=1.6Hz,1H),7.22-7.13(m,2H),6.66(q,J=7.2Hz,1H),3.30(s,3H),2.12(d,J=7.2Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ163.92,162.87(d,J C-F =243.0Hz),158.76,156.51,154.51,148.88,148.43,145.36,144.88,143.47,140.08(d,J C-F =12.0Hz),138.46,129.42,128.77,123.25(d,J C-F =11.0Hz),122.25,120.96,120.73,115.47,112.46(d,J C-F =25.0Hz),109.40,98.16(d,J C-F =28.0Hz),97.87,49.87,44.18,18.93. 19 F NMR(376MHz,DMSO-d6)δ-111.90.HRMS(ESI)m / z Calcd for C 28 H 23 FN9O3S(M+H) + :584.1623; Found:584.1627.

[0090] Example 12: 5-(4-amino-1-(1-(1-benzyl-6-fluoro-1H-indazol-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine 12

[0091] The preparation method is similar to that of Example 7, except that the reactants are replaced.

[0092] White solid; melting range: 244.1-245.3°C; purity: 100.00%. 1 H NMR (400MHz, DMSO-d6) δ8.33 (s, 1H), 7.59-7.54 (m, 3H), 7.52-7.45 (m, 2H), 7.37 (d, J = 2.0Hz, 1H), 7.34-7.29 (m, 2H), 7.29-7. 23(m,3H),7.20(dd,J=8.0,1.6Hz,1H),6.94(td,J=9.2,2.4Hz,1H),6.56(q,J=7.2Hz,1H),5.63(s,2H),2.07(d,J=7.2Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ163.94,161.90(d,J C-F =241.0Hz),158.69,156.30,154.34,148.86,145.01,144.90,144.79,141.47(d,J C-F =13.0Hz),137.73,129.03,128.93,128.05,127.84,122.65(d,J C-F =11.0Hz),120.92,118.80,115.44,110.71(d,J C-F =26.0Hz),109.39,97.84,96.27(d,J C-F =26.0Hz),52.21,49.98,19.22. 19 F NMR(376MHz,DMSO-d6)δ-114.51.HRMS(ESI)m / zCalcd for C 28 H 23 FN9O(M+H) + :520.2004;Found:520.2004.

[0093] Example 13: 5-(4-amino-1-(1-(6-fluoro-1-(pyridin-2-ylmethyl)-1H-indazol-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine 13

[0094] The preparation method is similar to that of Example 7, except that the reactants are replaced.

[0095] Pale yellow solid; melting range: 231.6-232.4°C; purity: 100.00%. 1 H NMR(400MHz,DMSO-d6)δ8.53-8.50(m,1H),8.32(s,1H),7.73(td,J=7.6,2.0 Hz,1H),7.55(s,2H),7.53-7.44(m,3H),7.35(d,J=1.6Hz,1H),7.29(dd,J=7 .2,4.8Hz,1H),7.18(dd,J=8.4,1.6Hz,1H),7.03(d,J=8.0Hz,1H),6.95(td, J=9.2,2.4Hz,1H),6.53(q,J=7.2Hz,1H),5.72(s,2H),2.03(d,J=7.2Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ163.94,161.92(d,J C-F =241.0Hz),158.72,157.04,156.35,154.35,149.78,148.86,145.02,144.89,142.07(d,J C-F =13.0Hz),137.59,128.92,123.28,122.61(d,J C-F =11.0Hz),121.92,120.93,118.76,115.45,110.76(d,J C-F =26.0Hz),109.39,97.83,96.48(d,J C-F =26.0Hz),54.15,50.01,19.26. 19 FNMR(376MHz,DMSO-d6)δ-114.58.HRMS(ESI)m / z Calcd for C 27 H 22 FN 10 O(M+H) + :521.1957;Found:521.1956.

[0096] Example 14: 5-(4-amino-1-(1-(6-fluoro-1-(pyridin-4-yl)-1H-indazol-3-yl)ethyl)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine 14

[0097] The preparation method is similar to that of Preparation Example 1, which can be changed by replacing the reactants.

[0098] White solid; m.p. 207.8-208.6 °C; purity: 100.00%. 1 H NMR (400 MHz, DMSO-d6) δ 8.74-8.70 (m, 2H), 8.35 (s, 1H), 7.95 (dd, J = 10.0, 1.6 Hz, 1H), 7.92-7.89 (m, 2H), 7.58-7.52 (m, 3H), 7.44 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 1.6 Hz, 1H), 7.21-7.13 (m, 2H), 6.65 (q, J = 6.8 Hz, 1H), 2.12 (d, J = 6.8 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 163.92, 162.95 (d, J = 243.0 Hz), 158.77, 156.53, 154.53, 151.72, 148.88, 148.83, 146.11, 145.40, 144.87, 140.00 (d, J = 13.0 Hz), 128.75, 123.24 (d, J = 12.0 Hz), 121.05, 120.97, 115.48, 115.20, 112.62 (d, J = 26.0 Hz), 109.40, 98.76 (d, J = 28.0 Hz), 97.88, 49.89, 18.84. C-F = 243.0 Hz), 158.77, 156.53, 154.53, 151.72, 148.88, 148.83, 146.11, 145.40, 144.87, 140.00 (d, J = 13.0 Hz), 128.75, 123.24 (d, J = 12.0 Hz), 121.05, 120.97, 115.48, 115.20, 112.62 (d, J = 26.0 Hz), 109.40, 98.76 (d, J = 28.0 Hz), 97.88, 49.89, 18.84. C-F = 243.0 Hz), 158.77, 156.53, 154.53, 151.72, 148.88, 148.83, 146.11, 145.40, 144.87, 140.00 (d, J = 13.0 Hz), 128.75, 123.24 (d, J = 12.0 Hz), 121.05, 120.97, 115.48, 115.20, 112.62 (d, J = 26.0 Hz), 109.40, 98.76 (d, J = 28.0 Hz), 97.88, 49.89, 18.84. C-F = 243.0 Hz), 158.77, 156.53, 154.53, 151.72, 148.88, 148.83, 146.11, 145.40, 144.87, 140.00 (d, J = 13.0 Hz), 128.75, 123.24 (d, J = 12.0 Hz), 121.05, 120.97, 115.48, 115.20, 112.62 (d, J = 26.0 Hz), 109.40, 98.76 (d, J = 28.0 Hz), 97.88, 49.89, 18.84. C-F = 243.0 Hz), 158.77, 156.53, 154.53, 151.72, 148.88, 148.83, 146.11, 145.40, 144.87, 140.00 (d, J = 13.0 Hz), 128.75, 123.24 (d, J = 12.0 Hz), 121.05, 120.97, 115.48, 115.20, 112.62 (d, J = 26.0 Hz), 109.40, 98.76 (d, J = 28.0 Hz), 97.88, 49.89, 18.84. C-F = 243.0 Hz), 158.77, 156.53, 154.53, 151.72, 148.88, 148.83, 146.11, 145.40, 144.87, 140.00 (d, J = 13.0 Hz), 128.75, 123.24 (d, J = 12.0 Hz), 121.05, 120.97, 115.48, 115.20, 112.62 (d, J = 26.0 Hz), 109.40, 98.76 (d, J = 28.0 Hz), 97.88, 49.89, 18.84. 19 F NMR (376 MHz, DMSO-d6) δ -111.54.HRMS (ESI) m / z Calcd for C 26 H 20 FN 10 O (M+H) + : 507.1800; Found: 507.1804.

[0099] Example 15: 5-(4-amino-1-(1-(6-fluoro-1-(pyridin-4-yl)-1H-indazol-3-yl)ethyl)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine 14

[0100] The preparation method is similar to that of Example 1, and the reactants are changed.

[0101] White solid; m.p. 203.7-205.1 °C; purity: 96.42%. 1 H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.90 (dd, J = 3.2, 1.6 Hz, 1H), 7.78 (dd, J = 5.2, 3.2 Hz, 1H), 7.67 (dd, J = 10.0, 2.0 Hz, 1H), 7.61 (dd, J = 5.2, 1.6 Hz, 1H), 7.58 - 7.52 (m, 3H), 7.46 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.21 (dd, J = 8.0, 1.6 Hz, 1H), 7.12 - 7.05 (m, 1H), 6.63 (q, J = 6.8 Hz, 1H), 2.11 (d, J = 6.8 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 163.93, 162.69 (d, J = 243.0 Hz), 158.75, 156.44, 154.47, 148.89, 146.44, 145.25, 144.89, 140.06 (d, J = 13.0 Hz), 138.16, 128.84, 127.70, 122.99 (d, J = 11.0 Hz), 122.93, 120.97, 119.64, 115.48, 113.84, 111.76 (d, J = 26.0 Hz), 109.40, 97.88, 97.49 (d, J = 27.0 Hz), 49.98, 19.07. C-F = 243.0 Hz), 158.75, 156.44, 154.47, 148.89, 146.44, 145.25, 144.89, 140.06 (d, J = 13.0 Hz), 138.16, 128.84, 127.70, 122.99 (d, J = 11.0 Hz), 122.93, 120.97, 119.64, 115.48, 113.84, 111.76 (d, J = 26.0 Hz), 109.40, 97.88, 97.49 (d, J = 27.0 Hz), 49.98, 19.07. C-F = 243.0 Hz), 158.75, 156.44, 154.47, 148.89, 146.44, 145.25, 144.89, 140.06 (d, J = 13.0 Hz), 138.16, 128.84, 127.70, 122.99 (d, J = 11.0 Hz), 122.93, 120.97, 119.64, 115.48, 113.84, 111.76 (d, J = 26.0 Hz), 109.40, 97.88, 97.49 (d, J = 27.0 Hz), 49.98, 19.07. C-F = 243.0 Hz), 158.75, 156.44, 154.47, 148.89, 146.44, 145.25, 144.89, 140.06 (d, J = 13.0 Hz), 138.16, 128.84, 127.70, 122.99 (d, J = 11.0 Hz), 122.93, 120.97, 119.64, 115.48, 113.84, 111.76 (d, J = 26.0 Hz), 109.40, 97.88, 97.49 (d, J = 27.0 Hz), 49.98, 19.07. C-F = 243.0 Hz), 158.75, 156.44, 154.47, 148.89, 146.44, 145.25, 144.89, 140.06 (d, J = 13.0 Hz), 138.16, 128.84, 127.70, 122.99 (d, J = 11.0 Hz), 122.93, 120.97, 119.64, 115.48, 113.84, 111.76 (d, J = 26.0 Hz), 109.40, 97.88, 97.49 (d, J = 27.0 Hz), 49.98, 19.07. C-F = 243.0 Hz), 158.75, 156.44, 154.47, 148.89, 146.44, 145.25, 144.89, 140.06 (d, J = 13.0 Hz), 138.16, 128.84, 127.70, 122.99 (d, J = 11.0 Hz), 122.93, 120.97, 119.64, 115.48, 113.84, 111.76 (d, J = 26.0 Hz), 109.40, 97.88, 97.49 (d, J = 27.0 Hz), 49.98, 19.07. 19 F NMR (376 MHz, DMSO-d6) δ -112.68. HRMS (ESI) m / z Calcd for C 25 H 19 FN9OS (M+H): 512.1412; Found: 512.1415. +

[0102] Example 16: 5-(4-amino-1-(1-(6-fluoro-1-(1-methyl-1H-pyrazol-3-yl)-1H-indazol-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine 16 ​

[0103] The preparation method is similar to that of Example 1, except that the reactants are replaced.

[0104] Yellow solid; melting range: 269.4-270.3°C; purity: 100.00%. 1 H NMR (400MHz, DMSO-d6) δ8.34(s,1H),7.94(dd,J=10.0,2.4Hz,1H),7.86(d,J=2.0Hz,1H),7.56-7.50(m,3H),7.45(d,J=8.0Hz,1H),7.37(d,J =1.6Hz,1H),7.20(dd,J=8.0,1.6Hz,1H),7.13-7.03(m,1H),6.61(q,J=7.2Hz,1H),6.55(d,J=2.4Hz,1H),3.94(s,3H),2.10(d,J=7.2Hz,3H). 13 C NMR(101MHz,DMSO)δ163.92,162.46(d,J C-F =242.0Hz),158.76,156.46,154.46,149.31,148.87,146.89,145.26,144.88,139.47(d,J C-F =14.0Hz),133.08,128.81,122.85(d,J C-F =11.0Hz),120.96,119.60,115.47,111.93(d,J C-F =25.0Hz),109.40,98.96(d,J C-F =28.0Hz),97.86,96.27,50.02,39.47,19.09. 19 F NMR(376MHz,DMSO-d6)δ-112.82.HRMS(ESI)m / z Calcd for C 25 H 21 FN 11 O(M+H) + :510.1909;Found:510.1911.

[0105] Example 17: 5-(4-amino-1-(1-(6-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine 17

[0106] The preparation method is similar to that in Preparation Example 1, which is only replaced by the reactants.

[0107] White solid; m.p. 265.9-267.2 °C; purity: 98.62%. 1 H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.34 (s, 1H), 7.92 (s, 1H), 7.57-7.43 (m, 5H), 7.36 (d, J = 1.6 Hz, 1H), 7.19 (dd, J = 8.0, 1.6 Hz, 1H), 7.04 (td, J = 9.2, 2.0 Hz, 1H), 6.59 (d, J = 6.8 Hz, 1H), 3.93 (s, 3H), 2.08 (d, J = 6.8 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 163.92, 162.53 (d, J = 242.0 Hz), 158.75, 156.44, 154.42, 148.87, 146.11, 145.20, 144.88, 140.55 (d, J = 13.0 Hz), 132.23, 128.84, 124.58, 123.22, 122.94 (d, J = 11.0 Hz), 120.96, 119.14, 115.47, 111.45 (d, J = 26.0 Hz), 109.40, 97.82, 96.84 (d, J = 27.0 Hz), 49.92, 39.64, 19.15. C-F = 242.0 Hz), 158.75, 156.44, 154.42, 148.87, 146.11, 145.20, 144.88, 140.55 (d, J = 13.0 Hz), 132.23, 128.84, 124.58, 123.22, 122.94 (d, J = 11.0 Hz), 120.96, 119.14, 115.47, 111.45 (d, J = 26.0 Hz), 109.40, 97.82, 96.84 (d, J = 27.0 Hz), 49.92, 39.64, 19.15. C-F = 242.0 Hz), 158.75, 156.44, 154.42, 148.87, 146.11, 145.20, 144.88, 140.55 (d, J = 13.0 Hz), 132.23, 128.84, 124.58, 123.22, 122.94 (d, J = 11.0 Hz), 120.96, 119.14, 115.47, 111.45 (d, J = 26.0 Hz), 109.40, 97.82, 96.84 (d, J = 27.0 Hz), 49.92, 39.64, 19.15. C-F = 242.0 Hz), 158.75, 156.44, 154.42, 148.87, 146.11, 145.20, 144.88, 140.55 (d, J = 13.0 Hz), 132.23, 128.84, 124.58, 123.22, 122.94 (d, J = 11.0 Hz), 120.96, 119.14, 115.47, 111.45 (d, J = 26.0 Hz), 109.40, 97.82, 96.84 (d, J = 27.0 Hz), 49.92, 39.64, 19.15. C-F = 242.0 Hz), 158.75, 156.44, 154.42, 148.87, 146.11, 145.20, 144.88, 140.55 (d, J = 13.0 Hz), 132.23, 128.84, 124.58, 123.22, 122.94 (d, J = 11.0 Hz), 120.96, 119.14, 115.47, 111.45 (d, J = 26.0 Hz), 109.40, 97.82, 96.84 (d, J = 27.0 Hz), 49.92, 39.64, 19.15. C-F = 242.0 Hz), 158.75, 156.44, 154.42, 148.87, 146.11, 145.20, 144.88, 140.55 (d, J = 13.0 Hz), 132.23, 128.84, 124.58, 123.22, 122.94 (d, J = 11.0 Hz), 120.96, 119.14, 115.47, 111.45 (d, J = 26.0 Hz), 109.40, 97.82, 96.84 (d, J = 27.0 Hz), 49.92, 39.64, 19.15. 19 F NMR (376 MHz, DMSO-d6) δ -113.19.HRMS (ESI) m / z Calcd for C 25 H 21 FN 11 O (M+H) : 510.1909; Found: 510.1911. +

[0108] Example 18: 5-(4-amino-1-(1-(1-(1-ethyl-1H-pyrazol-4-yl)-6-fluoro-1H-indazol-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine 18

[0109] The preparation method is similar to that in Preparation Example 1, which is only replaced by the reactants.

[0110] ​4-Iodopyrazole (2 g, 10.31 mmol) and potassium carbonate (2.85 g, 20.62 mmol) were added to a two-necked flask, and the atmosphere was evacuated and replaced with argon three times. Anhydrous DMF was added, and iodoethane (2.41 g, 15.47 mmol) was slowly added. The reaction was allowed to proceed at 65°C. After completion of the reaction, as monitored by TLC, water and ethyl acetate were added, and the layers were separated. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by silica gel column chromatography using PE / EA (v / v, 10 / 1) as a developing solvent to obtain a yellow solid (2.1 g, 92%).

[0111] Pale yellow solid; melting range: 269.8-271.1°C; purity: 98.90%. 1 H NMR (400MHz, DMSO-d6) δ8.38(s,1H),8.33(s,1H),7.93(s,1H),7.57-7.46(m,4H),7.45(d,J=8.0Hz,1H),7.36(d,J=1.6Hz,1H),7.19(dd, J=8.0,1.2Hz,2H),7.04(td,J=9.2,2.0Hz,1H),6.59(q,J=6.8Hz,1H),4.22(q,J=7.2Hz,2H),2.08(d,J=6.8Hz,3H),1.45(t,J=7.2Hz,2H). 13 CNMR(101MHz,DMSO-d6)δ163.92,162.53(d,J C-F =242.0Hz),158.74,156.44,154.41,148.87,146.08,145.19,144.88,140.55(d,J C-F =13.0Hz),132.08,128.85,123.19,123.08,122.93(d,J C-F =11.0Hz),120.96,119.13,115.46,111.44(d,J C-F =25.0Hz),109.40,97.83,96.87(d,J C-F =26.0Hz),49.93,47.44,19.16,15.87. 19 F NMR(376MHz,DMSO-d6)δ-113.23.HRMS(ESI)m / z Calcd for C 26 H 23 FN 11 O(M+H) + :524.2066; Found:524.2068.

[0112] Example 19: 5-(4-amino-1-(1-(6-fluoro-1-(1-isopropyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine 19

[0113] The preparation method is similar to that of Preparation Example 18, except that iodoethane is replaced with 2-iodopropane and anhydrous potassium carbonate is replaced with anhydrous cesium carbonate.

[0114] White solid; melting range: 216.3-217.6°C; purity: 100.00%. 1 H NMR (400MHz, DMSO-d6) δ8.38(s,1H),8.34(s,1H),7.93(s,1H),7.57-7.49(m,4H),7.45(d,J=8.4Hz,1H),7.37(d,J=1.6Hz,1H),7.20(dd,J= 8.0,1.6Hz,1H),7.04(td,J=9.2,2.0Hz,1H),6.60(q,J=7.2Hz,1H),4.58(hept,J=6.8Hz,1H),2.08(d,J=7.2Hz,3H),1.49(d,J=6.8Hz,6H). 13 C NMR(101MHz,DMSO-d6)δ163.93,162.52(d,J C-F =242.0Hz),158.75,156.43,154.41,148.87,146.05,145.19,144.89,140.57(d,J C-F =13.0Hz),131.81,128.85,122.92,122.90(d,J C-F =12.0Hz),121.64,120.95,119.11,115.46,111.42(d,J C-F =26.0Hz),109.40,97.83,96.92(d,J C-F =27.0Hz),54.31,49.93,23.06,19.17. 19 F NMR(376MHz,DMSO-d6)δ-113.22.HRMS(ESI)m / z Calcd for C 27 H 25 FN 11 O(M+H) + :538.2222;Found:538.2223.

[0115] Example 20: 5-(4-amino-1-(1-(1-cyclopropyl-1H-pyrazol-4-yl)-6-fluoro-1H-indazol-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine 20

[0116] The preparation method is similar to that of Example 18, except that iodoethane is replaced with bromocyclopropane, and anhydrous potassium carbonate is replaced with anhydrous cesium carbonate.

[0117] White solid; melting range: 210.5-211.3°C; purity: 100.00%. 1 H NMR (400MHz, DMSO-d6) δ8.40(s,1H),8.33(s,1H),7.91(s,1H),7.56-7.49(m,4H),7.45(d,J=8.4Hz,1H),7.36(d,J=1.6Hz,1H),7.19(dd,J=8.0 ,1.6Hz,1H),7.04(td,J=9.2,2.0Hz,1H),6.59(q,J=7.2Hz,1H),3.87-3 .78(m,1H),2.08(d,J=7.2Hz,3H),1.19-1.13(m,2H),1.05-0.98(m,2H). 13 C NMR(101MHz,DMSO-d6)δ163.93,162.54(d,J C-F =242.0Hz),158.75,156.44,154.42,148.87,146.14,145.20,144.89,140.58(d,J C-F =13.0Hz),132.46,128.85,123.63,123.00,122.88(d,J C-F =12.0Hz),120.95,119.13,115.47,111.45(d,J C-F =26.0Hz),109.39,97.83,96.99(d,J C-F =27.0Hz),49.93,33.86,19.15,6.84. 19 F NMR(376MHz,DMSO-d6)δ-113.19.HRMS(ESI)m / z Calcd for C 27 H 23 FN 11 O(M+H) + :536.2066;Found:536.2068.

[0118] Example 21: 5-(4-amino-1-(1-(1-(difluoromethyl)-1H-pyrazol-4-yl)-6-fluoro-1H-indazol-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine 21

[0119] The preparation method is similar to that of Preparation Example 1, except that 3-iodopyridine is replaced with 21-B.

[0120] 4-Iodopyrazole (2.5 g, 12.89 mmol), diethyl bromofluoromethylphosphonate (5.16 g, 19.33 mmol), and potassium fluoride (1.5 g, 25.78 mmol) were added to a single-necked flask, followed by acetonitrile and the reaction was carried out at 40°C. After completion of the reaction, monitored by TLC, the solvent was removed by rotary evaporation, water and ethyl acetate were added, and the mixture was separated. The organic layer was collected, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by silica gel column chromatography using PE / EA (v / v, 10 / 1) as a developing solvent to obtain a yellow oily liquid (1.9 g, 60%).

[0121] Pale yellow solid; melting range: 297.0-298.1°C; purity: 100.00%. 1 H NMR (400MHz, DMSO-d6) δ8.94(s,1H),8.38(s,1H),8.34(s,1H),7.88(t,J=58.8Hz,1H),7.68(dd,J=9.6,2.0Hz,1H),7.57-7.50(m,3H),7.45( d,J=8.0Hz,1H),7.36(d,J=1.6Hz,1H),7.19(dd,J=8.0,2.0Hz,1H),7.09(td,J=9.2,2.0Hz,1H),6.61(q,J=7.2Hz,1H),2.09(d,J=7.2Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ163.92,162.77(d,J C-F =243.0Hz),158.76,156.47,154.46,148.88,147.07,145.28,144.88,140.47(d,J C-F =13.0Hz),136.15,128.81,125.68,123.06(d,J C-F =11.0Hz),121.42,120.96,119.47,115.47,111.88(d,J C-F= 248.0 Hz), 109.40, 97.84, 97.28 (d, J = 27.0 Hz), 49.90, 19.06. C-F = 248.0 Hz), 109.40, 97.84, 97.28 (d, J = 27.0 Hz), 49.90, 19.06. C-F = 248.0 Hz), 109.40, 97.84, 97.28 (d, J = 27.0 Hz), 49.90, 19.06. 19 = 248.0 Hz), 109.40, 97.84, 97.28 (d, J = 27.0 Hz), 49.90, 19.06. 25 H 19 F3N 11 O(M+H) + : 546.1721; Found: 546.1721.

[0122] Example 22: 5-(4-amino-1-(1-(6-fluoro-1-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-indazol-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine 22

[0123] The preparation method is similar to that of Preparation Example 1, and 3-iodopyridine is replaced by 22-B.

[0124] A 4-iodopyrazole (2.0 g, 10.31 mmol) was weighed into a single-necked flask, cesium carbonate (6.7 g, 20.62 mmol) was added, 20 mL of DMF was added, and the reaction was carried out at room temperature for 5 min, then 2,2,2-trifluoroethyl trifluoromethanesulfonate (3 g, 12.89 mmol) was added, and the reaction was continued at room temperature. After the completion of the reaction was monitored by TLC, water and ethyl acetate were added to separate the layers, the aqueous layer was extracted with ethyl acetate three times, the combined organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by silica gel column chromatography using PE / EA (v / v, 3 / 1) as the developing agent to obtain a yellow oily liquid (2.68 g, 94%).

[0125] White solid; melting range: 299.1-300.7°C; purity: 100.00%. 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.34 (s, 1H), 8.18 (s, 1H), 7.59-7.49 (m, 4H), 7.45 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 1.6 Hz, 1H), 7.20 (dd, J = 8.0, 1.6 Hz, 1H), 7.11-7.04 (m, 1H), 6.61 (q, J = 6.8 Hz, 1H), 5.23 (q, J = 9.2 Hz, 2H), 2.09 (d, J = 6.8 Hz, 3H).13 C NMR(101MHz,DMSO)δ163.93,162.64(d,J C-F =242.0Hz),158.74,156.45,154.43,148.88,146.61,145.24,144.87,140.45(d,J C-F =13.0Hz),133.97,128.82,125.46,124.42,124.03(q,J C-F =278.0Hz),123.07(d,J C-F =11.0Hz),120.97,119.30,115.47,111.65(d,J C-F =26.0Hz),109.40,97.84,96.87(d,J C-F =28.0Hz),52.41(q,J C-F =34.0Hz),40.60,19.10. 19 F NMR(376MHz,DMSO-d6)δ-70.14,-112.85.HRMS(ESI)m / z Calcd for C 26 H 20 F4N 11 O(M+H) + :578.1783;Found:578.1783.

[0126] Example 23: 5-(4-amino-1-(1-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-6-fluoro-1H-indazol-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine 23

[0127] The preparation method is similar to that of Example 18, except that iodoethane is replaced with bromomethylcyclopropane, and anhydrous potassium carbonate is replaced with anhydrous cesium carbonate.

[0128] White solid; melting range: 300.2-302.1°C; purity: 99.46%. 1H NMR(400MHz,DMSO-d6)δ8.40(s,1H),8.34(s,1H),7.95(s,1H),7.58-7.47(m, 4H),7.45(d,J=8.0Hz,1H),7.37(d,J=1.6Hz,1H),7.19(dd,J=8.4,1.6Hz,1H) ,7.05(dd,J=9.2,2.0Hz,1H),6.60(q,J=6.8Hz,1H),4.04(d,J=7.2Hz,2H),2. 08(d,J=6.8Hz,3H),1.38-1.27(m,1H),0.61-0.51(m,2H),0.46-0.40(m,2H). 13 C NMR(101MHz,DMSO-d6)δ163.93,162.53(d,J C-F =242.0Hz),158.75,156.44,154.42,148.87,146.12,145.20,144.89,140.55(d,J C-F =13.0Hz),132.07,128.85,123.42,123.17,122.96(d,J C-F =11.0Hz),120.96,119.14,115.47,111.44(d,J C-F =26.0Hz),109.40,97.83,96.85(d,J C-F =27.0Hz),56.87,49.95,19.18,12.03,4.11. 19 F NMR(376MHz,DMSO-d6)δ-113.17.HRMS(ESI)m / z Calcd for C 28 H 25 FN 11 O(M+H) + :550.2222;Found:550.2226.

[0129] Example 24: 5-(4-amino-1-(1-(6-fluoro-1-(pyridin-3-yl)-1H-indazol-3-yl)propyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine 24

[0130] The preparation method is similar to that of Preparation Example 1, except that methylmagnesium chloride is replaced with ethylmagnesium chloride.

[0131] White solid; melting range: 206.3-207.9°C; purity: 99.75%.1 H NMR(400MHz,DMSO-d6)δ9.03(d,J=2.4Hz,1H),8.63(dd,J=4.8,1.2Hz,1H),8.35(s,1 H),8.25-8.20(m,1H),7.75-7.69(m,2H),7.63(dd,J=8.4,4.8Hz,1H),7.56(s,2H),7. 45(d,J=8.0Hz,1H),7.37(d,J=1.6Hz,1H),7.21(dd,J=8.0,1.6Hz,1H),7.14(dd,J=9 .2,2.4Hz,1H),6.38(dd,J=9.6,6.0Hz,1H),2.77-2.58(m,2H),0.89(t,J=7.2Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ163.94,162.76(d,J C-F =243.0Hz),158.79,156.55,155.35,148.90,148.17,147.26,145.48,144.90,143.63,140.36(d,J C-F =13.0Hz),136.28,130.04,128.84,124.96,123.40(d,J C-F =11.0Hz),120.97,120.41,115.49,112.14(d,J C-F =26.0Hz),109.41,97.66,97.53(d,J C-F =27.0Hz),55.78,25.90,11.27. 19 F NMR(376MHz,DMSO-d6)δ-112.37.HRMS(ESI)m / z Calcd for C 27 H 22 FN 10 O(M+H) + :521.1957;Found:521.1956.

[0132] Example 25: 5-(4-amino-1-(1-(1-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine 25

[0133] The preparation method is similar to that of Example 1, except that 6-chloroindole is replaced with indole.

[0134] White solid; Melting range: 303.7-305.2 °C; Purity: 100.00%. 1 H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 2.4 Hz, 1H), 8.62 (dd, J = 4.8, 1.6 Hz, 1H), 8.35 (s, 1H), 8.26 - 8.21 (m, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.64 (dd, J = 8.4, 4.8 Hz, 1H), 7.54 (d, J = 9.2 Hz, 3H), 7.50 - 7.42 (m, 2H), 7.36 (d, J = 1.6 Hz, 1H), 7.22 - 7.16 (m, 2H), 6.67 (q, J = 6.8 Hz, 1H), 2.14 (d, J = 6.8 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 163.93, 158.76, 156.45, 154.53, 148.87, 147.94, 147.76, 145.20, 144.89, 143.58, 140.03, 136.62, 129.98, 128.87, 128.51, 124.97, 123.26, 122.56, 121.29, 120.94, 115.47, 111.17, 109.39, 97.86, 50.05, 19.04. HRMS (ESI) m / z Calcd for C 26 H 21 N 10 O (M+H) + : 489.1894; Found: 489.1897.

[0135] Example 26: 5-(4-amino-1-(1-(6-methyl-1-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine 26

[0136] The preparation method is similar to that of Preparation Example 1, except that 6-chloroindole is replaced by 6-methylindole.

[0137] Pale yellow solid; Melting range: 227.2-228.7 °C; Purity: 100.00%. 1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.61 (d, J = 4.4 Hz, 1H), 8.35 (s, 1H), 8.22 (d, J = 8.4 Hz, 1H), 7.67 - 7.61 (m, 2H), 7.57 (s, 2H), 7.45 (d, J = 8.0 Hz, 1H), 7.42 - 7.35 (m, 2H), 7.20 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.62 (q, J = 6.8 Hz, 1H), 2.42 (s, 3H), 2.12 (d, J = 6.8 Hz, 3H). 13 CNMR (101 MHz, DMSO-d6) δ 163.93, 158.74, 156.42, 154.50, 148.86, 147.76, 147.65, 145.15, 144.89, 143.53, 140.59, 138.69, 136.70, 129.91, 128.87, 124.94, 124.59, 121.42, 120.92, 120.86, 115.44, 110.48, 109.39, 97.84, 50.12, 21.96, 19.05. HRMS (ESI) m / z Calcd for C 27 H 23 N 10 O (M+H) + : 503.2051; Found: 503.2055.

[0138] Example 27: 5-(4-amino-7-(1-(6-fluoro-1-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)benzo[d]oxazol-2-amine 27

[0139] The preparation method is similar to that of Preparation Example 1, except that B8 is replaced by B8-27.

[0140] Into a two-necked flask, 27-A (3 g, 19.54 mmol) and NIS (5.27 g, 23.44 mmol) were added, vacuumed and argon-purged for three times, anhydrous DMF was added, and the reaction was carried out at room temperature. After the reaction was completed as monitored by TLC, water was added with stirring, and a large amount of solid was precipitated. The solid was filtered, washed with water and a small amount of acetone, and dried to obtain a yellow solid (5.3 g, 97%).

[0141] To a two-necked flask were added B7 (500 mg, 1.8 mmol), 27-B (750 mg, 2.7 mmol), and anhydrous potassium carbonate (500 mg, 3.6 mmol). The atmosphere was replaced with argon three times, and anhydrous DMF was added. The reaction was allowed to react at 65°C overnight. After completion of the reaction, monitored by TLC, water and ethyl acetate were added, and the layers were separated. The aqueous layer was extracted three times with ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by silica gel column chromatography using DCM / MeOH (v / v, 50 / 1) as the developing solvent to obtain a white solid (460 mg, 49%).

[0142] The product from the previous step (400 mg, 0.77 mmol) was weighed and placed in a pressure tube. 8 mL of 7.0 M NH3 (MeOH) was added and the mixture was reacted at 120°C for 5 h. After completion of the reaction, the solvent was removed by rotary evaporation, and the resulting solid was purified by slurrying with PE / EA (v / v, 3 / 1). The solid was filtered and collected to yield product B8-27 (354 mg, 92%).

[0143] White solid; melting range: 205.4-206.9°C; purity: 98.16%. 1 H NMR(400MHz,DMSO-d6)δ9.07(d,J=2.8Hz,1H),8.63(dd,J=4.8,1.6Hz,1H),8.29-8.21(m ,2H),7.71(dd,J=10.0,2.0Hz,1H),7.63(dd,J=8.4,4.8Hz,1H),7.51(dd,J=8.8,5.2Hz,1 H),7.47(s,2H),7.43(s,1H),7.37(d,J=8.4Hz,1H),7.22(d,J=2.0Hz,1H),7.12(td,J=9 .2,2.0Hz,1H),7.00(dd,J=8.0,2.0Hz,1H),6.63(q,J=6.8Hz,1H),2.06(d,J=6.8Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ163.78,162.84(d,J C-F =243.0Hz),157.88,152.31,150.36,148.42,148.13,147.67,144.81,143.75,140.28(d,J C-F =12.0Hz),136.37,130.48,130.00,124.91,122.78(d,J C-F =11.0Hz),120.98,120.94,120.27,117.29,115.73,112.19(d,JC-F = 26.0 Hz), 109.06, 100.41, 97.52 (d, J = 28.0 Hz), 46.40, 19.70. C-F = 26.0 Hz), 109.06, 100.41, 97.52 (d, J = 28.0 Hz), 46.40, 19.70. 19 F NMR (376 MHz, DMSO-de) δ -112.31. HRMS (ESI) m / z Calcd for C 27 H 21 FN9O(M+H) + : 506.1848; Found: 506.1851.

[0144] Example 28: 3-(2-Aminobenzo[d]oxazol-5-yl)-l-(l-(6-fluoro-l-(pyridin-3-yl)-lH- indazol-3-yl)ethyl)-lH-pyrazolo[3,4-d]pyrimidine-4,6-diamine 28

[0145] The preparation method is similar to that of Preparation Example 1, except that B8 is replaced by B8-28.

[0146] A single-necked flask was charged with 28-A (3 g, 15.63 mmol), 30 mL of water, 30 mL of THF and triethylamine (8.7 mL, 62.52 mmol), and an 85% hydrazine hydrate solution (1.14 mL, 18.75 mmol) was slowly added dropwise. After the addition was completed, the reaction was allowed to proceed at room temperature overnight. After the reaction was completed as monitored by TLC, ice water was added to the reaction solution, and the resulting solid was filtered, washed with water and a small amount of acetone, and dried to obtain a yellow solid (1.88 g, 71%).

[0147] A two-necked flask was charged with the product of the previous step (1.5 g, 8.85 mmol), NIS (3.98 g, 17.7 mmol), and anhydrous DMF, and the mixture was replaced with argon three times. The reaction was carried out at 80°C. After the reaction was completed as monitored by TLC, the reaction was cooled to room temperature, water was added, and a large amount of solid was precipitated. The solid was filtered, washed with water and a small amount of acetone, and dried to obtain an off-white solid (2.38 g, 91%).

[0148] The synthesis step was the same as B8-27.

[0149] Light yellow solid; melting range: 224.8-225.7°C; purity: 100.00%. 1H NMR (400MHz, DMSO-d6) δ9.04(d,J=2.8Hz,1H),8.62(d,J=4.8Hz,1H),8.25-8.21(m,1H),7.70(dd,J=9.6,2.4Hz,1H),7.66-7.56 (m,2H),7.52(s,2H),7.41(d,J=8.0Hz,1H),7.31(d,J=1.6Hz,1H),7.17-7.09(m,2H),6.42-6.32(m,3H),2.04(d,J=7.2Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ163.87,162.91,162.75(d,J C-F =243.0Hz),158.94,157.64,148.65,148.50,148.08,145.32,144.77,143.57,140.38(d,J C-F =13.0Hz),136.35,129.94,129.68,124.96,123.50(d,J C-F =11.0Hz),120.68,120.40,115.21,112.01(d,J C-F =25.0Hz),109.23,97.45(d,J C-F =27.0Hz),93.06,49.04,19.01. 19 F NMR(376MHz,DMSO-d6)δ-112.44.HRMS(ESI)m / z Calcd for C 26 H 21 FN 11 O(M+H) + :522.1909;Found:522.1912.

[0150] Example 29: 5-(4-amino-1-(1-(6-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]thiazol-2-amine 29

[0151] The preparation method is similar to that of Example 1, except that the reactants are replaced.

[0152] White solid; melting range: 257.6-258.2°C; purity: 100.00%. 1H NMR (400MHz, DMSO-d6) δ8.35(s,2H),7.93(s,1H),7.80(d,J=8.0Hz,1H),7.63(s,2H),7.57-7.51(m,2H),7.49(dd,J=9.6,2. 4Hz, 1H), 7.26 (dd, J=8.0, 1.6Hz, 1H), 7.04 (td, J=9.2, 2.0Hz, 1H), 6.61 (q, J=7.2Hz, 1H), 3.94 (s, 3H), 2.09 (d, J=7.2Hz, 3H). 13 C NMR(101MHz,DMSO-d6)δ167.84,162.54(d,J C-F =243.0Hz),158.76,156.45,154.49,153.87,146.08,145.04,140.58(d,J C-F =13.0Hz),132.24,132.19,130.65,124.60,123.22,122.97(d,J C-F =11.0Hz),122.05,121.30,119.14,117.66,111.44(d,J C-F =25.0Hz),97.84,96.84(d,J C-F =27.0Hz),49.98,39.63,19.16. 19 F NMR(376MHz,DMSO-d6)δ-113.19.HRMS(ESI)m / zCalcd for C 25 H 21 FN 11 S(M+H) + :526.1681; Found:526.1679.

[0153] Example 30: 5-(4-amino-7-(1-(6-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzo[d]thiazol-2-amine 30

[0154] The preparation method is similar to that of Preparation Example 27, except that the reactants are replaced.

[0155] White solid; melting range: 265.2-266.9°C; purity: 100.00%. 1H NMR (400MHz, DMSO-d6) δ8.34(s,1H),8.24(s,1H),7.93(s,1H),7.71(d,J=8.0Hz,1H),7.56(s,2H),7.52-7.4 0(m,3H),7.37(d,J=1.6Hz,1H),7.10-7.00(m,2H),6.59(q,J=7.2Hz,1H),3.93(s,3H),2.04(d,J=7.2Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ167.69,162.63(d,J C-F =243.0Hz),157.89,153.93,152.34,150.47,146.61,140.46(d,J C-F =13.0Hz),132.35,132.33,130.05,124.63,123.27,122.56(d,J C-F =11.0Hz),121.75,121.02,119.13,117.93,117.07,111.52(d,J C-F =26.0Hz),100.33,96.82(d,J C-F =27.0Hz),46.52,39.64,19.86. 19 F NMR(376MHz,DMSO-d6)δ-113.03.HRMS(ESI)m / z Calcd for C 26 H 22 FN 10 S(M+H) + :525.1728;Found:525.1729.

[0156] Example 31: 5-(4-amino-7-(1-(6-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzo[d]oxazol-2-amine 31

[0157] The preparation method is similar to that of Preparation Example 27, except that the reactants are replaced.

[0158] Pale yellow solid; melting range: 210.9-212.5°C; purity: 97.35%. 1H NMR(400MHz,DMSO-d6)δ8.35(s,1H),8.24(s,1H),7.93(s,1H),7.53-7.34(m,6H),7.22(d, J=1.6Hz,1H),7.08-6.98(m,2H),6.59(q,J=7.2Hz,1H),3.94(s,3H),2.04(d,J=7.2Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ163.79,162.62(d,J C-F =242.0Hz),157.87,152.29,150.34,147.68,146.62,144.82,140.44(d,J C-F =12.0Hz),132.31,130.49,124.61,123.28,122.56(d,J C-F =11.0Hz),120.94,120.87,119.14,117.22,115.72,111.51(d,J C-F =26.0Hz),109.06,100.41,96.82(d,J C-F =27.0Hz),46.50,39.64,19.86. 19 F NMR(376MHz,DMSO-d6)δ-113.09.HRMS(ESI)m / z Calcd for C 26 H 22 FN 10 O(M+H) + :509.1957;Found:509.1955.

[0159] Example 32: 5-(4-amino-1-(1-(6-fluoro-1-(pyridin-4-yl)-1H-indazol-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]thiazol-2-amine 32

[0160] The preparation method is similar to that of Example 1, except that the reactants are replaced.

[0161] White solid; melting range: 230.9-232.2°C; purity: 99.58%. 1H NMR (400MHz, DMSO-d6) δ8.77-8.68(m,2H),8.36(s,1H),7.97-7.88(m,3H),7.79(d,J=8.0Hz,1H),7.64(s,2H),7.57(dd,J=8.8,5.2H z,1H),7.53(d,J=2.0Hz,1H),7.26(dd,J=8.0,1.6Hz,1H),7.16(td,J=9.2,2.0Hz,1H),6.66(q,J=7.2Hz,1H),2.13(d,J=7.2Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ167.84,162.95(d,J C-F =243.0Hz),158.78,156.52,154.61,153.84,151.66,148.80,146.12,145.25,140.01(d,J C-F =12.0Hz),132.22,130.56,123.27(d,J C-F =11.0Hz),122.06,121.30,121.05,117.67,115.22,112.61(d,J C-F =25.0Hz),98.75(d,J C-F =28.0Hz),97.89,49.95,18.85. 19 F NMR(376MHz,DMSO-d6)δ-111.55.HRMS(ESI)m / z Calcd for C 26 H 20 FN 10 S(M+H) + :523.1572;Found:523.1569.

[0162] Example 33: 5-(4-amino-7-(1-(6-fluoro-1-(pyridin-4-yl)-1H-indazol-3-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzo[d]thiazol-2-amine 33

[0163] The preparation method is similar to that of Preparation Example 27, except that the reactants are replaced.

[0164] White solid; melting range: 211.2-212.7°C; purity: 98.80%. 1H NMR (400MHz, DMSO-d6) δ8.75-8.68(m,2H),8.25(s,1H),7.98-7.90(m,3H),7.71(d,J=8.0Hz,1H),7.58-7.50(m,3H),7.48( s,1H),7.38(d,J=1.6Hz,1H),7.20-7.13(m,1H),7.08(dd,J=8.0,1.6Hz,1H),6.64(q,J=6.8Hz,1H),2.08(d,J=6.8Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ167.68,163.04(d,J C-F =243.0Hz),157.81,153.91,152.24,151.66,150.46,149.31,146.18,139.91(d,J C-F =12.0Hz),132.27,130.08,122.97(d,J C-F =11.0Hz),121.75,121.18,121.04,117.94,117.26,115.30,112.51(d,J C-F =25.0Hz),100.35,98.71(d,J C-F =28.0Hz),46.52,19.58. 19 F NMR(376MHz,DMSO-d6)δ-111.52.HRMS(ESI)m / z Calcd for C 27 H 21 FN9S(M+H) + :522.1619;Found:522.1615.

[0165] Example 34: 5-(4-amino-7-(1-(6-fluoro-1-(pyridin-4-yl)-1H-indazol-3-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzo[d]oxazol-2-amine 34

[0166] The preparation method is similar to that of Preparation Example 27, except that the reactants are replaced.

[0167] White solid; melting range: 306.1-307.2°C; purity: 96.25%. 1H NMR (400MHz, DMSO-d6) δ8.77-8.68(m,2H),8.25(s,1H),7.98-7.91(m,3H),7.51(dd,J=8.8,5.2Hz,1H),7.47(s,2H),7.43(s,1H),7.3 8(d,J=8.0Hz,1H),7.23(d,J=1.6Hz,1H),7.20-7.13(m,1H),7.01(dd,J=8.0,2.0Hz,1H),6.63(q,J=7.2Hz,1H),2.07(d,J=7.2Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ163.79,163.03(d,J C-F =243.0Hz),157.90,152.34,151.66,150.38,149.34,147.68,146.17,144.81,139.90(d,J C-F =13.0Hz),130.44,122.96(d,J C-F =11.0Hz),121.05,120.95,117.37,115.74,115.28,112.63(d,J C-F =25.0Hz),109.06,100.45,98.70(d,J C-F =28.0Hz),46.46,19.58. 19 F NMR(376MHz,DMSO-d6)δ-111.51.HRMS(ESI)m / z Calcd for C 27 H 21 FN9O(M+H) + :506.1848;Found:506.1846.

[0168] Example 35: 5-(4-amino-1-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine 35

[0169] The preparation method is similar to that of Example 1, except that the reactants are replaced.

[0170] White solid; melting range: 290.3-291.5°C; purity: 98.85%. 1H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J = 6.8 Hz, 2H), 7.91 (s, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.57 - 7.33 (m, 6H), 7.19 (dd, J = 8.0, 1.6 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 6.61 (q, J = 7.2 Hz, 1H), 3.94 (s, 3H), 2.10 (d, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 163.92, 158.73, 156.39, 154.43, 148.85, 145.76, 145.07, 144.88, 140.33, 132.32, 128.91, 127.85, 124.62, 123.59, 122.07, 121.76, 121.01, 120.93, 115.45, 110.84, 109.38, 97.81, 39.64, 50.05, 19.18. HRMS (ESI) m / z Calcd for C 25 H 22 N 11 O (M+H) + : 492.2003; Found: 492.2000.

[0171] Example 36: 5-(4-amino-1-(1-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)ethyl)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]thiazol-2-amine 36

[0172] The preparation method is similar to that of Preparation Example 1, and the reactants are changed.

[0173] White solid; m.p.: 198.6-200.3 °C; purity: 100.00%. 1 H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J = 6.8 Hz, 2H), 7.91 (s, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.57 - 7.33 (m, 6H), 7.19 (dd, J = 8.0, 1.6 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 6.61 (q, J = 7.2 Hz, 1H), 3.94 (s, 3H), 2.10 (d, J = 7.2 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 167.83, 158.74, 156.40, 154.50, 153.86, 145.74, 144.91, 140.35, 132.34, 132.15, 130.70, 127.87, 124.64, 123.57, 122.06, 122.05, 121.76, 121.29, 121.04, 117.64, 110.84, 97.82, 50.10, 39.63, 19.20. HRMS (ESI) m / z Calcd for C 25 H 22 N 11 S(M+H) + :508.1775; Found: 508.1776.

[0174] Example 37: 5-(4-amino-7-(l-(l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-3-yl)ethyl)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)benzo[d]oxazol-2-amine 37

[0175] The preparation method is similar to that of Preparation Example 27, which can be changed by replacing the reactants.

[0176] Yellow solid; m.p.: 281.9-283.2 °C; purity: 95.89%. 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.24 (s, 1H), 7.91 (s, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.47 - 7.34 (m, 6H), 7.20 (d, J = 1.6 Hz, 1H), 7.12 (t, J = 7.2 Hz, 1H), 6.99 (dd, J = 8.0, 1.6 Hz, 1H), 6.60 (q, J = 6.8 Hz, 1H), 3.94 (s, 3H), 2.04 (d, J = 6.8 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 163.80, 157.87, 152.28, 150.36, 147.68, 146.24, 144.82, 140.23, 132.43, 130.54, 127.95, 124.67, 123.64, 122.06, 121.87, 120.94, 120.91, 120.62, 117.15, 115.72, 110.82, 109.07, 100.41, 46.59, 39.63, 19.99. HRMS (ESI) m / z Calcd for C 26 H23 N 10 O(M+H) + :491.2051 ; Found: 491.2055.

[0177] Example 38: 5-(4-amino-7-(l-(l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-3-yl)ethyl)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)benzo[d]thiazol-2-amine 38

[0178] The preparation method is similar to that of Preparation Example 27, which can be replaced by the reactant.

[0179] White solid; m.p.: 259.0-260.3 °C; purity: 97.98%. 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.25 (s, 1H), 7.91 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.55 (s, 2H), 7.47 - 7.34 (m, 4H), 7.12 (t, J = 7.6 Hz, 1H), 7.06 (dd, J = 8.0, 1.6 Hz, 1H), 6.61 (q, J = 6.8 Hz, 1H), 3.94 (s, 3H), 2.05 (d, J = 6.8 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 167.67, 157.87, 153.92, 152.31, 150.48, 146.21, 140.23, 132.44, 132.40, 130.02, 127.97, 124.70, 123.60, 122.04, 121.88, 121.74, 121.05, 120.61, 117.91, 116.97, 110.83, 100.30, 46.60, 39.63, 19.99. HRMS (ESI) m / z Calcd for C 26 H 23 N 10 S(M+H) + :507.1822; Found: 507.1820.

[0180] Example 39: 5-(4-amino-l-(l-(l-(pyridin-4-yl)-lH-indazol-3-yl)ethyl)-lH-pyrazolo[3,4- d]pyrimidin-3-yl)benzo[d]oxazol-2-amine 39

[0181] The preparation method is similar to that in Preparation Example 1, except that the reactants are changed.

[0182] White solid; m.p.: 294.4-295.6 °C; purity: 98.19%. 1 H NMR (400 MHz, DMSO-d6) δ 8.74-8.71 (m, 2H), 8.36 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.94-7.89 (m, 2H), 7.58-7.48 (m, 4H), 7.44 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 1.6 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.19 (dd, J = 8.4, 1.6 Hz, 1H), 6.67 (q, J = 6.8 Hz, 1H), 2.14 (d, J = 6.8 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 163.92, 158.76, 156.48, 154.55, 151.68, 148.87, 148.72, 146.44, 145.30, 144.87, 139.67, 128.99, 128.80, 124.12, 123.18, 121.45, 120.94, 115.46, 115.19, 112.14, 109.39, 97.87, 50.01, 18.87. RMS (ESI) m / z Calcd for C 26 H 21 N 10 O (M+H) + : 489.1894; Found: 489.1896.

[0183] Example 40: 5-(4-amino-1-(1-(1-(pyridin-4-yl)-1H-indazol-3-yl)ethyl)-1H- pyrazol[3,4-d]pyrimidin-3-yl)benzo[d]thiazol-2-amine 40

[0184] The preparation method is similar to that in Preparation Example 1, except that the reactants are changed.

[0185] White solid; m.p.: 211.6-213.2 °C; purity: 100.00%. 1H NMR (400 MHz, DMSO-d6) δ 8.75 - 8.69 (m, 2H), 8.36 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.95 - 7.88 (m, 2H), 7.78 (d, J = 8.0 Hz, 1H), 7.62 (s, 2H), 7.58 - 7.48 (m, 3H), 7.27 - 7.21 (m, 2H), 6.67 (q, J = 6.8 Hz, 1H), 2.14 (d, J = 6.8 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 167.83, 158.78, 156.49, 154.63, 153.86, 151.68, 148.70, 146.44, 145.13, 139.69, 132.20, 130.61, 129.00, 124.11, 123.18, 122.04, 121.48, 121.28, 117.66, 115.21, 112.15, 97.88, 50.07, 18.88. HRMS (ESI) m / z Calcd for C 26 H 21 N 10 S (M+H) + : 505.1666; Found: 505.1667.

[0186] Example 41: 5-(4-amino-7-(1-(1-(pyridin-4-yl)-1H-indazol-3-yl)ethyl)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)benzo[d]oxazol-2-amine 41

[0187] The preparation method is similar to that of Example 27, by changing the reactants.

[0188] White solid; m.p. 308.8-309.6 °C; purity: 100.00%. 1 H NMR (400 MHz, DMSO-d6) δ 8.77 - 8.68 (m, 2H), 8.25 (s, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.96 - 7.91 (m, 2H), 7.58 - 7.48 (m, 2H), 7.47 (s, 2H), 7.42 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.28 - 7.21 (m, 2H), 7.00 (dd, J = 8.0, 1.6 Hz, 1H), 6.65 (q, J = 7.2 Hz, 1H), 2.09 (d, J = 7.2 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 163.78, 157.88, 152.31, 151.64, 150.41, 149.22, 147.67, 146.51, 144.81, 139.58, 130.48, 129.08, 124.10, 123.24, 121.18, 121.01, 120.94, 117.29, 115.72, 115.29, 112.10, 109.06, 100.44, 46.54, 19.68. HRMS (ESI) m / z Calcd for C 27 H 22 N9O(M+H) + : 488.1942; Found: 488.1941.

[0189] Example 42: 5-(4-amino-7-(1-(1-(pyridin-4-yl)-1H-indazol-3-yl)ethyl)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)benzo[d]thiazol-2-amine 42

[0190] The preparation method is similar to that of Example 27, by changing the reactants.

[0191] White solid; m.p. 302.9-303.5 °C; purity: 100.00%. 1 H NMR (400 MHz, DMSO-d6) δ 8.77 - 8.69 (m, 2H), 8.25 (s, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.96 - 7.90 (m, 2H), 7.70 (d, J = 7.6 Hz, 1H), 7.57 - 7.50 (m, 4H), 7.46 (s, 1H), 7.37 (s, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.07 (dd, J = 8.0, 1.6 Hz, 1H), 6.66 (q, J = 7.2 Hz, 1H), 2.09 (d, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 167.67, 157.89, 153.92, 152.36, 151.65, 150.54, 149.21, 146.50, 139.58, 132.34, 130.05, 129.10, 124.10, 123.25, 121.74, 121.18, 121.16, 117.94, 117.13, 115.30, 112.11, 100.35, 46.58, 19.68. HRMS (ESI) m / z Calcd for C 27 H22 N9 S (M+H) + : 504.1713; Found: 504.1715.

[0192] Example 43: (S)-5-(4-amino-7-(1-(1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)ethyl)- 7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzo[d]oxazole-2-amine (S-37)

[0193] Synthesis of 43-B:

[0194] Into a two-necked flask, 43-A (3.5 g, 14.57 mmol), S-(-)-t-butylsulfinamide (3.53 g, 29.14 mmol) were added under argon protection, 20 mL of anhydrous THF was added, tetraethyl titanate (6.65 g, 29.14 mmol) was added, heated to reflux, and the reaction was allowed to proceed overnight. After the reaction was completed, water was added and stirred for 20 min, a large amount of solid was produced, suction filtration was performed, the filter residue was repeatedly washed with ethyl acetate, the organic layer was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then purified by slurry with PE / EA (v / v, 2 / 1) to obtain yellow solid 43-B (3.5 g, 70%).

[0195] Synthesis of 43-C:

[0196] Into a two-necked flask, 43-B (3 g, 8.73 mmol) was added under argon protection, dissolved in anhydrous toluene, cooled to -78°C, and DIBAL-H (17.5 mL, 1M in hexane) was slowly added. The reaction was allowed to proceed at -78°C for 3 h. After the reaction was completed, methanol and water (v:v, 1:5) were slowly added dropwise at low temperature to quench the reaction, stirred for 30 min, and then filtered through diatomite, the filter residue was repeatedly washed with ethyl acetate, the organic layer was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then separated by silica gel column chromatography with PE / EA (v / v, 2 / 1) as the developing agent to obtain light yellow solid 43-C (2.5 g, 83.3%).

[0197] Synthesis of 43-D:

[0198] Into a single-necked flask, 43-C (2 g, 5.79 mmol) was weighed, 15 mL of methanol was added, 5 mL of 6M hydrochloric acid was added at room temperature, and the reaction was allowed to proceed at room temperature for 2 h. After the reaction was completed, the methanol was removed by rotary evaporation, water / ethyl acetate was added to the concentrated solution to separate the layers, the aqueous layer was adjusted to basicity with sodium hydroxide solution, the aqueous phase was extracted with ethyl acetate three times, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain yellow oily liquid 43-D (1.1 g, 78%).

[0199] 43-E was synthesized as follows:

[0200] Into a single-neck flask, 43-D (1 g, 4.14 mmol) and 4,6-dichloropyrimidine-5- carboxaldehyde (1.03 g, 5.38 mmol) were added, 10 mL of anhydrous ethanol, triethylamine (828 mg, 8.18 mmol) were added, and the reaction was carried out at 90 °C for 18 h. After the reaction was completed, most of the solvent was removed by rotary evaporation, ethyl acetate and water were added to the concentrated solution to separate the layers, and the organic layer was collected. The organic layer was washed with water three times, saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography using PE / EA (v / v, 3 / 1) as the developing agent to obtain 43-E (950 mg, 60.5%) as a light yellow solid.

[0201] 43-F was synthesized as follows:

[0202] Into a two-neck flask, 43-E (900 mg, 2.38 mmol) and NIS (643 mg, 2.86 mmol) were added, vacuumed and replaced with argon three times, anhydrous DMF was added, and the reaction was carried out at 85 °C for 3 h. After the reaction was completed, saturated aqueous sodium thiosulfate solution and ethyl acetate were added to separate the layers, the organic layer was collected, saturated brine was added, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography using PE / EA (v / v, 2 / 1) as the developing agent to obtain 43-F (910 mg, 75%) as a light yellow solid.

[0203] 43-G was synthesized as follows:

[0204] Into a pressure tube, the product from the previous step (840 mg, 1.67 mmol) was weighed, 5 mL of NH3(7.0 M solution in MeOH) was added, and the reaction was carried out at 120 °C for 5 h. After the reaction was completed, the solvent was removed by rotary evaporation, and the resulting solid was purified by slurry with PE / EA (v / v, 3 / 1), filtered, and the solid collected to obtain the product 43-G (780 mg, 96.5%).

[0205] (S)-37 was synthesized as follows:

[0206] The experimental procedure was the same as that for the synthesis of compound 1, except that B8 was replaced by 43-G, to obtain a white solid in a yield of 54%.

[0207] White solid; melting range: 269.8-271.2 °C; chiral HPLC: AD-H column, mobile phase: n-hexane / isopropanol = 30 / 70, showed an enantiomeric excess percentage (ee%) of more than 99.99%. 1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.25 (s, 1H), 7.92 (s, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.48 - 7.40 (m, 4H), 7.39 - 7.35 (m, 2H), 7.22 (d, J = 1.6 Hz, 1H), 7.13 (t, J = 7.2 Hz, 1H), 7.00 (dd, J = 8.0, 2.0 Hz, 1H), 6.62 (q, J = 7.2 Hz, 1H), 3.95 (s, 3H), 2.05 (d, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 163.79, 157.86, 152.26, 150.37, 147.68, 146.23, 144.82, 140.24, 132.42, 130.54, 127.94, 124.67, 123.64, 122.06, 121.86, 120.93, 120.91, 120.62, 117.14, 115.72, 110.82, 109.06, 100.43, 46.59, 39.64, 19.99. HRMS (ESI) m / z Calcd for C 26 H 23 N 10 O (M+H) + : 491.2051; Found: 491.2050.

[0208] Example 44: (R)-5-(4-amino-7-(l-(l-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-3- yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzo[d]oxazol-2-amine (R-37)

[0209] The preparation method is the same as that in Preparation Example 43, except that S-(-)-tert-butylsulfonamide is replaced by R-(+)-tert-butylsulfonamide.

[0210] White solid; m.p. 261.5-263.3 °C; chiral HPLC: AD-H column, mobile phase n-hexane / isopropanol = 30 / 70, showed enantiomeric excess percentage (ee%) more than 99.99. 1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.25 (s, 1H), 7.92 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.47 - 7.40 (m, 4H), 7.39 - 7.34 (m, 2H), 7.21 (d, J = 1.6 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 7.00 (dd, J = 8.0, 1.6 Hz, 1H), 6.61 (q, J = 7.2 Hz, 1H), 3.94 (s, 3H), 2.05 (d, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, DMSO) δ 163.79, 157.86, 152.26, 150.37, 147.68, 146.23, 144.82, 140.24, 132.42, 130.54, 127.94, 124.67, 123.64, 122.06, 121.86, 120.93, 120.90, 120.62, 117.13, 115.71, 110.82, 109.06, 100.42, 46.59, 39.64, 19.99. HRMS (ESI) m / z Calcd for C 26 H 23 N 10 O (M+H) + : 491.2051; Found: 491.2050.

[0211] Example 45: 5-(4-amino-7-(1-(1-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzo[d]oxazol-2-amine (43)

[0212] The preparation method is the same as that of Example 43, except that S-(-)-tert-butylsulfonamide is replaced by tert-butylsulfonamide, and the reducing agent is sodium borohydride.

[0213] White solid; m.p. 243.2-241.1 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.45 (dd, J = 4.8, 1.2 Hz, 1H), 8.28 (s, 1H), 8.22 (s, 1H), 7.98 (s, 1H), 7.94 - 7.87 (m, 2H), 7.52 (s, 1H), 7.47 (s, 2H), 7.38 (d, J = 8.0 Hz, 1H), 7.25 (dd, J = 8.0, 4.8 Hz, 1H), 7.21 (d, J = 1.6 Hz, 1H), 6.99 (dd, J = 8.4, 1.6 Hz, 1H), 6.54 (q, J = 6.8 Hz, 1H), 6.08 (brs, 2H), 3.93 (s, 3H), 2.00 (d, J = 6.8 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 163.77, 157.72, 151.93, 149.95, 147.58, 144.79, 144.53, 143.73, 133.17, 130.89, 130.74, 129.46, 125.26, 121.93, 121.49, 120.91, 118.54, 118.13, 117.47, 116.20, 115.67, 109.03, 100.56, 45.16, 39.66, 21.89. HRMS (ESI) m / z Calcd for C26H22N10O (M+H)+: 491.2051; Found: 491.2049.

[0214] The advantageous effects of the present application are demonstrated below by test examples.

[0215] Kinase Inhibition Activity Test

[0216] 1. Experimental Method 1: IC50of PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ enzyme activity inhibition 50 Evaluation Test

[0217] ADP-Glo TMKinase assay. The test compound was diluted to a series of concentrations required for the test, 50 nL of each was transferred to a 384 well plate, 50 nL of DMSO was added to the negative control well and the positive control well, PI3K a, b, g and d were diluted to 1.25 nM, 1.25 nM, 10 nM, 1.25 nM respectively with kinase buffer solution, then 2 μL per well was added to the 384 well plate, 2.5 μL was added to the negative and positive control wells, centrifuged for 30 seconds, shaken to mix, then incubated at room temperature for 10 minutes, 2.5 μL of a mixture of ATP and PIP2 was added, centrifuged for 30 seconds, shaken to mix, then incubated at room temperature for 2 hours, 5 μL of ADP-Glo Reagent was added, shaken to mix, then incubated at room temperature for 3 hours, 10 μL of Kinase Detection Reagent was added, shaken to mix, then incubated at room temperature for 1 hour, the sample was treated by centrifugation, etc., and the RLUs were read using an Enspire microplate reader, and the inhibition rate was calculated according to the formula.

[0218] The log value of the concentration was taken as the X axis, and the percentage inhibition rate was taken as the Y axis, and the log(inhibitor)vs.response-Variable slope fitting dose-effect curve was used by the analysis software GraphPad Prism 5, so as to obtain the IC 50 value of the enzyme activity of each compound.

[0219] 2. Experimental method 2: mTOR enzyme activity inhibition IC 50 Evaluation test

[0220] The Lance Ultra kinase assay was used to detect the inhibitory activity of the test compound on mTOR kinase. mTOR kinase was purchased from Eurofins, ULight-4E-BP1(Thr37 / 46)Peptide and Eu-anti-P-4E-BP1(Thr37 / 46) were purchased from PerkinElmer, Triton X-100, MgCl2, DTT and EGTA were purchased from Sigma, EDTA and HEPES(pH7.5) were purchased from Gibco, and the 384 well Echo plate was purchased from Labcyte.

[0221] Test compounds were diluted to a final concentration of 100-fold in 100% DMSO, followed by a 3-fold serial dilution in DMSO, and 200 nL of test article solution was added to 384-well plates by Echo. 10 μL of kinase solution (mTOR kinase was added in 1x kinase buffer at a final concentration of 4 nM) was added to each well, and 10 μL of 1x kinase buffer (formula: 50 mM HEPES, pH 7.5, 10 mM MgCl2, 0.01% Triton X-100, 0.01% 10% BSA, 2 mM DTT) was added to the no enzyme control wells instead, and incubated at room temperature for 10 min. Substrate 4E-BP1 and ATP were added in 1x kinase buffer to make a 2x substrate solution (ATP final concentration of 8 μM, 4E-BP1 final concentration of 50 nM). The reaction was started by adding 10 μL of 2x substrate solution to each well of the assay plate, and incubated at room temperature for 1 h. A 2x final concentration of detection solution was then prepared (including 8 mM final concentration of EDTA and 2 nM final concentration of 4E-BP1 phosphorylation antibody), and the reaction was stopped by adding 20 μL of detection solution to each well of the assay plate, and the Lance signal ratio (665 nm / 615 nm) was read by Envision. The inhibition was calculated according to the formula, IC 50 The IC50values were calculated from the inhibition values at different concentrations.

[0222] Where the minimum value is the reading of the control well without kinase; and the maximum value is the reading of the control well with DMSO.

[0223] Table 1 shows the IC50values of the compounds of the present application against PI3Kα, PI3Kδ and mTOR, and Table 2 shows the IC50values of some of the compounds against type I PI3K and mTOR. 50 Table 1 shows the IC50values of the compounds of the present application against PI3Kα, PI3Kδ and mTOR, and Table 2 shows the IC50values of some of the compounds against type I PI3K and mTOR. 50 Table 1 shows the IC50values of the compounds of the present application against PI3Kα, PI3Kδ and mTOR, and Table 2 shows the IC50values of some of the compounds against type I PI3K and mTOR.

[0224] 3. Experimental Results

[0225] Table 1: Inhibitory activities of dual-target inhibitors (compounds 1-43 prepared above) against PI3Kα, PI3Kδ and mTOR (where "E" means IC 50 >10 μΜ; "D" means 10 μΜ > IC 50 >1 μΜ; "C" means 1 μΜ > IC 50 >100 nM; "B" means 100 nM > IC 50 >10 nM; "A" means IC 50 <10 nM).

[0226] Table 1

[0227] Table 2: Inhibitory activities of the partial dual-target inhibitors against PI3K and mTOR (where "E" means IC 50 > 10 μΜ; "D" means IC 50 > 1 μΜ; "C" means IC 50 > 100 nM; "B" means IC 50 > 10 nM; "A" means IC 50 < 10 nM).

[0228] Table 2

[0229] From the results of Table 1, it can be seen that the dual-target inhibitors of the present application all exhibit good inhibitory activities against PI3Kδ and mTOR, and show weak inhibitory activities against PI3Kα. Based on the activity results of the above compounds, we selected 7 compounds to determine their inhibitory activities against PI3K, and the results are shown in Table 2. We found that these compounds specifically act on PI3Kδ and mTOR, and exhibit weak inhibitory activities against the other three subtypes of PI3K, which also means that we have indeed successfully obtained highly selective PI3Kδ / mTOR dual inhibitors.

[0230] Evaluation of the proliferation inhibitory activity of cells

[0231] The anti-proliferation activity test was performed by using CCK8 method for Mino, MOLM13, NCI-H1975, PANC-1 cells, and by using MTS method for MV-4-11, B16-F10 cell lines.

[0232] (1) Preparation of culture medium: FBS (10 / 20 mL), 1000x PS (50 μL), IMDM / DMEM / 1640 (10 / 20 mL) were sequentially added into a 50 mL centrifuge tube, and mixed for standby use. Except for MOLM13 cells which were cultured with 20% Gibco FBS, other cell lines were cultured with 10% Cellcook FBS.

[0233] (2) Cell culture and plating: the cells were taken out from the carbon dioxide incubator and observed under an inverted microscope to observe the cell state. When the cell density was 80-90%, the cells were passaged and tested. The cells were collected in a 15 mL centrifuge tube, centrifuged at 800 rpm for 3 min, and the supernatant was discarded. 2 mL of culture medium was added to resuspend the cells, 10 μL of trypan blue + 10 μL of cell suspension were mixed in a 1.5 mL centrifuge tube, and 10 μL was taken to a counting plate for counting. The plating amount was calculated as follows: Mino (5 x 10 3 cells / well), MV-4-11 (1 x 10 4 cells / well), MOLM13 (5 x 10 3A549 (2 x 10 cells / well), MCF-7 (2 x 10 cells / well), PANC-1 (2 x 10 cells / well), B16-F10 (5 x 10 cells / well), NCI-H1975 (5 x 10 cells / well) were plated in 96-well plates. The required cell suspension was determined according to cell density and plating density. Cells were plated and then incubated in a CO2 incubator. 3 A549 (2 x 10 cells / well), MCF-7 (2 x 10 cells / well), PANC-1 (2 x 10 cells / well), B16-F10 (5 x 10 cells / well), NCI-H1975 (5 x 10 cells / well) were plated in 96-well plates. The required cell suspension was determined according to cell density and plating density. Cells were plated and then incubated in a CO2 incubator. 2 A549 (2 x 10 cells / well), MCF-7 (2 x 10 cells / well), PANC-1 (2 x 10 cells / well), B16-F10 (5 x 10 cells / well), NCI-H1975 (5 x 10 cells / well) were plated in 96-well plates. The required cell suspension was determined according to cell density and plating density. Cells were plated and then incubated in a CO2 incubator. 3 A549 (2 x 10 cells / well), MCF-7 (2 x 10 cells / well), PANC-1 (2 x 10 cells / well), B16-F10 (5 x 10 cells / well), NCI-H1975 (5 x 10 cells / well) were plated in 96-well plates. The required cell suspension was determined according to cell density and plating density. Cells were plated and then incubated in a CO2 incubator.

[0234] (3) Dosing: Compound stock solution was diluted in DMSO in 96-well V-bottom plates in 8 concentration steps from 10 mM in 5-fold dilution steps. 198 μL cell culture medium was added to the 96-well plates and 2 μL of compound was pipetted from the 500x compound stock plate into the cell culture medium in the 96-well plate. In the vehicle control, 2 μL DMSO was added. After addition of the compound or DMSO, the compound plate was placed on a plate shaker for gentle mixing. 20 μL of the 5x compound working solution was added to the cell culture plate; in the vehicle control, 20 μL DMSO-cell culture medium mixture was added, the final DMSO concentration being 2‰; in the blank control, 20 μL cell culture medium was added. After mixing by tapping the plate, the plate was incubated in the incubator for 3 days, after which 10 μL CCK8 (20 μL MTS) was added to the corresponding wells, the plate was mixed by tapping and incubated in the incubator for 1-3 h before reading on the microplate reader.

[0235] (4) Data analysis: Using CCK8 as an example, the inhibition rate was calculated according to the following formula: (OD Sample - OD Blank ) / (ODDMSO- OD Blank ) x 100%, wherein OD Sample represents the absorbance value (OD 450 - OD 650 ) of the dosing well, ODDMSO represents the absorbance value (OD 450 - OD 650 ) of the DMSO control well, and OD Blank represents the absorbance value (OD 450 - OD 650 ) of the medium control. IC 50 values were calculated using GraphPad Prism software. For MTS, the wavelengths were 490 nM and 690 nM, respectively.

[0236] Table 3: Anti-proliferative activity of preferred compounds on lymphoma and leukemia cells.

[0237] Table 3

[0238] To verify whether the PI3K5 / mTOR dual-target inhibitor is more effective than the PI3K5 and mTOR inhibitors alone, we tested the preferred compound at the cellular level. We selected mantle cell lymphoma (MCL) and acute leukemia cell lines because it has been reported that idelalisib shows intrinsic resistance in the treatment of mantle cell lymphoma and has poor anti-proliferative effects on most MCL cells. The results are shown in Table 3, which shows that the preferred compound shows better inhibitory activity than idelalisib in the MCL cell line mino, the acute leukemia cell lines MV-4-11 and MOLM-13, especially in mino cells, which are almost not affected by idelalisib. The IC 50 At about 10 μΜ, while the dual-target inhibitor can effectively inhibit the proliferation of mino cells, and the inhibitory effect is better than that of idelalisib. It is worth noting that we found that the pan-PI3K / mTOR inhibitor gedatolisib and the mTOR inhibitor sapacitabine have better anti-proliferative inhibitory effects at the cellular level than our compound, because gedatolisib targets all I-type PI3Ks and can more effectively block the PI3K / AKT / mTOR signaling pathway, thus having a better inhibitory effect. Sapacitabine not only acts on mTOR and I-type PI3Ks, but also targets other kinases, and the kinase profile data shows that it has poor selectivity, which also makes it more effective in inhibiting cell proliferation.

[0239] Table 4: Anti-proliferative activity of the preferred compound on solid tumor cells.

[0240] Table 4

[0241] In addition to lymphoma and leukemia cells, we also tested the anti-proliferative activity of the PI3K5 / mTOR dual-target inhibitor on solid tumor cells, and the results are shown in Table 4. We selected the pancreatic cancer cell line PANC-1, the melanoma cell line B16-F10 and the non-small cell lung cancer cell line NCI-H1975 for testing, and the results showed that the PI3K5 / mTOR dual-target inhibitor of the present application can more effectively inhibit the proliferation of cells than idelalisib.

[0242] The data from the above cell tests suggest that, compared to a PI3K5 inhibitor alone, simultaneously targeting PI3K5 and mTOR shows stronger anti-proliferative inhibitory activity on both hematological tumor cells and solid tumor cells, and can overcome the resistance of PI3K5 to some extent, such as in MCL cells, idelalisib has almost no inhibitory activity, while the dual-target inhibitor shows good inhibitory activity.

[0243] It is to be understood that even though numerous characteristics and embodiments of the application have been set forth in the foregoing disclosure, the details can be varied without departing from the application, which is defined by the following claims.

Claims

1. Compound of formula (1) or a pharmaceutically acceptable salt, racemic mixture, hydrate, solvate, prodrug, enantiomer, diastereomer, or tautomer thereof; in: X, Y, and Z are each independently selected from C or N; M 1 Selected from N, O or S, M 2 Selected from N or S, and M 1 、M 2 There is only one N; R 1 Selected from C 1-6 alkyl; R 2 One or more selected from hydrogen and halogen; R 3 Selected from pyridyl, C 1-6 alkyl, phenyl, benzyl, thienyl, pyridylmethyl or pyrazolyl, which is optionally substituted by zero, one or more substituents selected from the group consisting of: -SO2(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, halogen; R 4 Selected from H or -NH2; R 5 Selected from H or -NH2.

2. The compound of formula (1) according to claim 1 or a pharmaceutically acceptable salt thereof, a racemic mixture, a hydrate, a solvate, a prodrug, an enantiomer, a diastereomer, or a tautomer thereof, characterized in that: The compound of formula (1) is selected from any one of the following compounds:

3. A pharmaceutical composition, characterized in that The invention comprises a compound of formula (1) as described in claim 1 or 2 or a pharmaceutically acceptable salt thereof, a racemic mixture, a hydrate, a solvate, a prodrug, an enantiomer, a diastereomer, a tautomer, and one or more pharmaceutically acceptable carriers, diluents, and excipients.

4. Use of the compound of formula (1) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, a racemic mixture, a hydrate, a solvate, a prodrug, an enantiomer, a diastereomer, a tautomer thereof, or the pharmaceutical composition according to claim 3 in the preparation of a PI3K inhibitor and / or an mTOR inhibitor.

5. The use according to claim 4, characterized in that The PI3K inhibitor is a PI3Kδ inhibitor.

6. Use of a compound of formula (1) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, a racemic mixture, a hydrate, a solvate, a prodrug, an enantiomer, a diastereomer, a tautomer thereof, or a pharmaceutical composition according to claim 3 in the preparation of a medicament for treating a disease responsive to inhibition of PI3K and / or inhibition of mTOR.

7. The use according to claim 6, characterized in that The PI3K is PI3Kδ.

8. The use according to claim 6, characterized in that The diseases are inflammatory diseases, autoimmune diseases, cancer, infectious diseases, cardiovascular and cerebrovascular diseases, and nervous system diseases.

9. The use according to claim 8, characterized in that The inflammatory diseases and autoimmune diseases are rheumatoid arthritis, chronic obstructive pulmonary disease, allergic rhinitis, asthma, lupus erythematosus, psoriasis and multiple sclerosis; The cancer is a solid tumor or a hematological malignancy selected from leukemia, multiple myeloma, and lymphoma; the leukemia is acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia; the lymphoma is Hodgkin's lymphoma, non-Hodgkin's lymphoma, mantle cell lymphoma, follicular lymphoma, B-cell lymphoma, T-cell lymphoma, and diffuse large B-cell lymphoma; The infectious diseases are bacterial infections, fungal infections, viral infections, and parasitic infections; The cardiovascular and cerebrovascular diseases are acute heart failure, hypotension, hypertension, angina pectoris, myocardial infarction, cardiomyopathy, congestive heart failure, atherosclerosis, coronary heart disease, restenosis and vascular stenosis, as well as traumatic brain injury, stroke, ischemia-reperfusion injury and arteriosclerosis; The nervous system diseases include neurodevelopmental diseases, neurodegenerative diseases, mood disorders, thinking and will disorders, consciousness disorders, migraines, attention deficit hyperactivity disorder, prosopagnosia and amnesia.

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