A compound for inhibiting phosphatidylinositol-3-kinase gamma subtype activity and its preparation method and application

Abstract

The present application relates to a kind of compound for inhibiting phosphatidylinositol-3-kinase gamma subtype activity and its preparation method and application, the compound for inhibiting phosphatidylinositol-3-kinase gamma subtype activity has as shown in structure formula I, has the effect of strongly inhibiting RI3K gamma activity.Moreover, compared with RI3K alpha / beta / delta, the inhibitory effect of the compound on RI3K gamma activity is significant, the purpose of high selectivity inhibition to RI3K gamma activity is achieved.Therefore, the compound has important application value in the preparation of phosphatidylinositol-3-kinase gamma subtype inhibitor and the drug for preventing and / or treating cancer, respiratory disease or immunological disease.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology and relates to a compound that inhibits the activity of phosphatidylinositol-3-kinase γ isoform, its preparation method and application. Background Technology

[0002] Phosphatidylinositol-3-kinase (PI3K) is a family of lipases that phosphorylate phosphatidylinositol at the 3'-OH group of the plasma membrane. It is involved in multiple intracellular signaling pathways and plays an important role in normal physiology and disease development. PI3K can be divided into three classes (I, II, and III), each with different functions and structures. Class I PI3K is the most extensively studied, and it is further divided into four subtypes: PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ.

[0003] Phosphatidylinositol-3-kinase γ (PI3Kγ) acts as a second messenger in vivo and participates in various cellular physiological activities, such as cell survival, proliferation, and metabolism. PI3Kγ is highly expressed in the hematopoietic system, making it an ideal drug target for the treatment of hematological malignancies and immune-related diseases. In in vivo experiments, normal mice were able to survive and be fertile regardless of whether PI3Kγ expression was knocked out or PI3Kγ kinase activity was lost, indicating that inhibition of PI3Kγ may have low toxicity [Science, 2000, 287(5455), 1040-1046].

[0004] Previous studies have confirmed that chronic inflammation can participate in various pathological processes of cancer occurrence, growth, and metastasis, and tumor-associated inflammation has been considered the seventh characteristic of tumors. Studies have shown that PI3Kγ is one of the key subunits regulating tumor-associated inflammation, and is mainly highly expressed on inflammatory cells; PI3Kγ activation can lead to the aggregation of macrophages and neutrophils in the tumor stroma, and plays a central regulatory role in the chemokine-induced leukocyte migration process [Immunology, 2002, 105(2), 125-136.]. Studies on PI3Kγ mice have found that PI3Kγ has important regulatory effects on the chemotaxis of neutrophils and macrophages and the activation of T cells. Knocking out the PI3Kγ gene can inhibit the aggregation and activation of neutrophils, and at the same time, it can damage the function of T lymphocytes and macrophages. Therefore, PI3Kγ is considered an effective target for the treatment of inflammatory diseases [Nephron, 2002, 91(2), 262-269.].

[0005] Studies have found that PI3Kγ is highly expressed in various tumors, such as multiple myeloma (MM), liver cancer, and pancreatic ductal carcinoma (PDAC) [Blood, 2010, 116(9), 1460-1468]. PI3Kγ expression can promote the growth of malignant tumors and prevent T cell-mediated tumor death by promoting macrophage migration and regulating the polarization of macrophages, neutrophils, and lymphocytes in vitro and in vivo [Cancer Cell, 2011, 19(6), 715-727]. In vitro and in vivo experiments showed that inhibition of PI3Kγ activity reduced MM proliferation, inhibited MM cell adhesion and migration, and promoted apoptosis of primary MM cells [Blood Cancer Journal, 2017, 7(3), e539]. Furthermore, in clinical models of malignant tumors treated with doxorubicin (DOX), PI3Kγ inhibitors can limit tumor growth while preventing DOX-induced cardiotoxicity, thereby improving survival [Circulation, 2018, 138(7), 696-711]. In addition, inhibition of pulmonary PI3Kγ can treat complex multicellular diseases characterized by adaptive T-cell activation in lung tissue and subsequent granulocyte influx and activation, such as asthma and COPD [Biochim Biophys Acta, 2015, 1851(6), 882-897]. In addition, since the PI3Kγ subtype is specific in immune tissues, it can be used to treat immune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) by inhibiting the biological activity of PI3Kγ [Journal of Medicinal Chemistry, 2012, 55(20), 8559-8581].

[0006] In summary, these findings reveal the crucial role of PI3Kγ signaling inhibition in immune responses, thus providing a highly selective phosphatidylinositol-3-kinase γ subtype inhibitor with significant application value in the treatment of various diseases, including cancer, respiratory diseases, and immune disorders.

[0007] To achieve this objective, the present invention adopts the following technical solution:

[0008] In a first aspect, the present invention provides a compound that inhibits the activity of phosphatidylinositol-3-kinase γ isoform, the compound having the structure shown in Formula I;

[0009]

[0010] Where X is selected from any one of -CH2-, -CH2-CH2-, -CH(CH3)- or -C(CH3)2-;

[0011] R 1 Selected from any one of substituted or unsubstituted C1-C8 chain alkyl or H, wherein the substituted substituent is selected from C3-C5 cycloalkyl or halogen;

[0012] R 2 Selected from Any one of H, C1-C3 alkyl chain or C1-C3 alkoxy;

[0013] R 4 Selected from

[0014] R 7 and R 8 Each is independently selected from any one of unsubstituted or substituted C1-C3 alkyl chains, unsubstituted or halogenated C3-C5 cycloalkyl chains, C2-C4 oxecycloalkyl chains, unsubstituted or cyano-substituted phenyl chains, or H. In the substituted C1-C3 alkyl chains, the substituent is selected from any one of C1-C3 alkoxy groups, unsubstituted or substituted C3-C5 cycloalkyl chains, or halogens. In the substituted C3-C5 cycloalkyl chains, the substituent is an unsubstituted or halogenated C1-C3 alkyl chain.

[0015] R 10 Selected from unsubstituted or substituted C1-C5 alkyl chains, C3-C5 cycloalkyl chains, or Any one of them, wherein the substituent is selected from C3-C5 cycloalkyl or C1-C3 alkoxy;

[0016] R 3 R 5 R 6 R 9 R 11 R 12 R 13 and R 14 Each is independently selected from H or C1-C3 chain alkyl groups.

[0017] Preferably, R 1 It is selected from any one of substituted or unsubstituted C1-C6 chain alkyl or H, wherein the substituted substituent is selected from cyclopropyl or fluorine.

[0018] In this invention, the dashed line The indicated location is the substitution site.

[0019] Preferably, R 1Selected from Any one of H, CH3, or CH2CH3.

[0020] Preferably, R 3 Selected from H or CH3.

[0021] Preferably, R 5 Selected from H or CH3.

[0022] Preferably, R 6 It is CH3.

[0023] Preferably, R 7 and R 8 Each is independently selected from H, CH3, CH2CH3, CH2CF3, Any one of them.

[0024] Preferably, R 9 It is CH3.

[0025] Preferably, R 10 Selected from CH3, CH2CH3, Any one of them.

[0026] Preferably, R 11 It is CH2CH3.

[0027] Preferably, R 12 It is CH3.

[0028] Preferably, R 13 It is CH3.

[0029] Preferably, R 14 It is CH3.

[0030] Preferably, R 2 Choose from any of the following structures:

[0031] H, CH3, CH2CH3, OCH2CH3.

[0032] Preferably, the compound that inhibits the activity of the γ isoform of phosphatidylinositol-3-kinase has any one of the following structures:

[0033]

[0034]

[0035]

[0036] The C1-C8 mentioned in this invention refers to having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms.

[0037] The C1-C6 mentioned in this invention refers to having 1, 2, 3, 4, 5 or 6 carbon atoms.

[0038] The C1-C5 mentioned in this invention refers to having 1, 2, 3, 4 or 5 carbon atoms.

[0039] The C1-C3 mentioned in this invention refers to having 1, 2 or 3 carbon atoms.

[0040] The C3-C5 mentioned in this invention refers to having 3, 4, or 5 carbon atoms.

[0041] In this invention, unless otherwise stated, the term "alkyl" includes straight-chain alkyl, branched-chain alkyl, and cycloalkyl groups, such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, or cyclobutyl.

[0042] In this invention, unless otherwise stated, the term "chain alkyl" includes straight-chain alkyl and branched-chain alkyl, such as, but not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, etc.

[0043] In this invention, unless otherwise stated, the term "alkoxy" refers to a group consisting of an alkyl group and an oxygen atom, wherein the alkyl group includes straight-chain alkyl groups and branched-chain alkyl groups, and may be, for example, but not limited to, methyl, ethyl, n-propyl, isopropyl, etc.

[0044] In this invention, the halogen includes fluorine, chlorine, bromine or iodine, and halogenation refers to the substitution of hydrogen by fluorine, chlorine, bromine or iodine.

[0045] Those skilled in the art will understand that the compounds described in this invention can exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they can also form inner salts. Acid addition salts include, but are not limited to: hydrochlorides, hydrofluorides, hydrobromates, hydroiodates, sulfates, pyrosulfonates, phosphates, nitrates, methanesulfonates, ethanesulfonates, 2-hydroxyethanesulfonates, benzenesulfonates, toluenesulfonates, aminosulfonates, 2-naphthalenesulfonates, formates, acetoacetic acid, pyruvic acid, ceramides, cinnamates, benzoates, acetates, dihydroxyacetates, trifluoroacetates, trimethylacetates, propionates, butyrates, hexanoates, heptanoates, undecanoates, stearates, ascorbic acid salts, camphorates, camphor sulfonates, citrates, fumarates, malates, maleates, hydroxymaleates, etc. Salts, oxalates, salicylates, succinates, gluconates, quinates, dihydroxynaphthylates, glycolates, tartrates, lactates, 2-(4-hydroxybenzoyl)benzoates, cyclopentanepropionates, digluconates, 3-hydroxy-2-naphthylcarboxylate, nicotinates, pyrates, pectin esters, 3-phenylpropionates, picrates, pentanoates, itaconic acid salts, trifluoromethanesulfonates, dodecyl sulfates, p-toluenesulfonates, naphthalene disulfonates, malonates, adipates, alginates, mandelates, gluconate, glycerol phosphates, sulfosalicylates, hemisulfonic acid or thiocyanates, aspartate salts, etc. Alkali addition salts include alkali metal salts, alkaline earth metal salts, and ammonium salts, specifically including but not limited to: sodium salts, lithium salts, potassium salts, ammonium salts, aluminum salts, magnesium salts, calcium salts, barium salts, iron salts, ferrous salts, manganese salts, manganese salts, zinc salts, ammonium salts (including salts formed with NH3 and organic amines (NH4 salts), methylammonium salts, trimethylammonium salts, diethylammonium salts, triethylammonium salts, propanemonium salts, tripropylammonium salts, isopropylammonium salts, tert-butylammonium salts, N,N'-dibenzyl ethylenediammonium salts, dicyclohexammonium salts, and 1,6-hexammonium salts. , benzyl ammonium salt, ethanol ammonium salt, N,N-dimethyl ethanol ammonium salt, N,N-diethyl ethanol ammonium salt, triethanolammonium salt, tromethamine salt, lysine salt, arginine salt, histidine salt, glucosamine salt, N-methylglucosamine ammonium salt, dimethylglucosamine ammonium salt, ethylglucosamine ammonium salt, glucosamine ammonium salt, betaine salt, caffeine salt, chloroprocaine salt, procaine salt, lidocaine salt, pyridine salt, methylpyridine salt, piperidine salt, morpholine salt, piperazine salt, purine salt, theobromine salt, choline salt, etc.

[0046] The compounds of the present invention may exist in the form of solvates (such as hydrates), wherein the solvates contain a polar solvent, particularly water, methanol, or ethanol, as a structural element of the compound's crystal lattice. The amount of the polar solvent, particularly water, may be stoichiometric or non-stoichiometric.

[0047] Depending on their molecular structure, the compounds of the present invention can be chiral, and therefore may exist in various enantiomeric forms. Thus, these compounds can exist in racemic or optically active forms. The compounds of the present invention or their intermediates can be isolated as enantiomeric compounds by chemical or physical methods known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are obtained from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as tartaric acid in R and S forms, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline), or various optically active camphorsulfonic acids. Optically active resolving agents (e.g., dinitrobenzoylphenylglycine immobilized on silica gel, cellulose triacetate, or other carbohydrate derivatives, or chiral derivatized isobutylene ester polymers) can be used. Chromatographic enantiomer separation can also be advantageously performed, with suitable eluents being aqueous or alcoholic solvent mixtures, such as hexane / isopropanol / acetonitrile. The respective stable isomers can also be separated by known methods, such as extraction, filtration, or column chromatography.

[0048] The present invention also provides stereoisomers, racemates, tautomers, isotope-labeled compounds, nitrogen oxides, solvates, or pharmaceutically acceptable salts thereof of the compounds that inhibit the activity of the γ isoform of phosphatidylinositol-3-kinase.

[0049] In a second aspect, the present invention provides a method for preparing a compound that inhibits the activity of the γ isoform of phosphatidylinositol-3-kinase as described in the first aspect, the method comprising mixing compound B and compound C and reacting them to obtain compound I, the reaction formula being:

[0050]

[0051] Among them, Y 1 Selected from

[0052] dotted line The indicated location is the substitution site.

[0053] Y 2 It is selected from any one of F, Cl, Br or I.

[0054] Preferably, the preparation method of compound B includes mixing an acyl halide or acid anhydride with compound A and reacting to obtain compound B, wherein the reaction formula is:

[0055]

[0056] Preferably, in the reaction of compound B and compound C, the reaction temperature is 15-150°C and the reaction time is 1-20 h.

[0057] Preferably, in the reaction of acyl halide or acid anhydride with compound A, the reaction temperature is 15-150°C and the reaction time is 1-20 h.

[0058] Specific values ​​within the 15-60℃ range include, for example, 15℃, 20℃, 25℃, 30℃, 35℃, 40℃, 45℃, 50℃, 55℃, 60℃, 65℃, 70℃, 75℃, 80℃, 85℃, 90℃, 95℃, 100℃, 110℃, 120℃, 130℃, 140℃, and 150℃.

[0059] The specific values ​​in the above 1-20h range are, for example, 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, etc.

[0060] Preferably, the reaction of compound B with compound C further includes mixing with a base and / or a catalyst to carry out the reaction. The catalyst includes any one or a combination of at least two of 1,1'-bis(diphenylphosphine)ferrocene, palladium dichloride, palladium acetate, tetra(triphenylphosphine)palladium, or tris(dibenzylacetone)dipalladium. The combination of at least two is, for example, a combination of palladium dichloride and palladium acetate, a combination of tetra(triphenylphosphine)palladium and tris(dibenzylacetone)dipalladium, a combination of 1,1'-bis(diphenylphosphine)ferrocene and palladium dichloride, etc., and any other combination is acceptable.

[0061] Preferably, the alkali includes organic alkali and / or inorganic alkali, wherein the inorganic alkali includes any one or a combination of at least two of alkali metal or alkaline earth metal hydrides, hydroxides, alkoxides, acetates, fluorides, phosphates, carbonates or bicarbonates, and the combination of at least two is, for example, a combination of alkali metal phosphate and alkaline earth metal carbonate, a combination of alkali metal acetate and alkali metal hydroxide, or a combination of alkaline earth metal bicarbonate and alkaline earth metal hydroxide.

[0062] The organic base includes any one or a combination of at least two of the following: amine compounds, pyridine compounds, pyrrole compounds, quinoline compounds, imidazole compounds, amino-substituted naphthalene compounds, or nitrogen-containing heterocyclic alkanes. The combination of at least two compounds includes, for example, a combination of an amine compound and a pyridine compound, a combination of a pyrrole compound and a quinoline compound, a combination of a quinoline compound and an imidazole compound, etc. Any other combination is also acceptable.

[0063] Preferably, the inorganic base includes any one or a combination of at least two of sodium amide, sodium hydride, lithium diisopropylamide, sodium methoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium acetate, sodium phosphate, potassium phosphate, potassium fluoride, cesium fluoride, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate, or cesium carbonate. The combination of at least two is, for example, a combination of sodium amide and sodium hydride, a combination of lithium diisopropylamide and sodium methoxide, a combination of potassium phosphate and potassium fluoride, etc., and any other combination is acceptable.

[0064] Preferably, the organic base includes triethylamine, trimethylamine, N,N-diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, tri-n-hexylamine, tricyclohexylamine, N-methylcyclohexylamine, N-methylpyrrolidine, N-methylpiperidine, N-ethylpiperidine, N,N-dimethylaniline, N-methylmorpholine, pyridine, 2,3-methylpyridine, 4-methylpyridine, 2-methyl-5-ethylpyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine, 4-dimethylaminopyridine, quinoline, methylquinoline, N, N,N,N-Tetramethylethylenediamine, N,N-dimethyl-1,4-diazacyclohexane, N,N-diethyl-1,4-diazacyclohexane, 1,8-bis(dimethylamino)naphthalene, diazabicyclooctane, diazabicyclononane, diazabicycloundecane, or butylimidazole or methylimidazole, wherein the combination of at least two is, for example, a combination of triethylamine and trimethylamine, a combination of tri-n-butylamine and tri-n-hexylamine, a combination of quinoline and methylquinoline, etc., and any other combination is acceptable.

[0065] Preferably, the reaction of the acyl halide or anhydride with compound A and the reaction of compound B with compound C optionally include mixing with a solvent to carry out the reaction. The solvent includes any one or a combination of at least two of ether compounds, unsubstituted or halogenated hydrocarbon compounds, or ester compounds. The combination of at least two compounds may include, for example, a combination of an unsubstituted hydrocarbon compound and a halogenated hydrocarbon compound, a combination of an ether compound and an ester compound, a combination of an ether compound and an unsubstituted hydrocarbon compound, etc., and any other combination is acceptable.

[0066] Preferably, the solvent comprises any one or a combination of at least two of the following: ethyl propyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexylmethyl ether, dimethyl ether, diethyl ether, dimethyl ethylene glycol, biphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, dioxane, dichlorodiethyl ether, polyethers of ethylene oxide and / or propylene oxide, pentane, hexane, heptane, octane, nonane, methylene chloride, dichloromethane, trichloromethane, carbon tetrachloride, fluorobenzene, chlorobenzene, dichlorobenzene, cyclohexane, methylcyclohexane, petroleum ether, octane, benzene, toluene, chlorobenzene, bromobenzene, xylene, methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate, dimethyl carbonate, dibutyl carbonate, or ethylene carbonate. The combination of at least two is, for example, a combination of n-butyl ether and anisole, a combination of dimethyl ether and diethyl ether, a combination of dioxane and dichlorodiethyl ether, etc., and any other combination is acceptable.

[0067] Thirdly, the present invention provides the use of compounds that inhibit the activity of phosphatidylinositol-3-kinase γ isoform as described in the first aspect in the preparation of phosphatidylinositol-3-kinase γ isoform inhibitors.

[0068] Fourthly, the present invention provides the use of compounds that inhibit the activity of phosphatidylinositol-3-kinase γ isoform as described in the first aspect in the preparation of medicaments for the prevention and / or treatment of cancer, respiratory diseases or immune diseases.

[0069] Preferably, the cancer treatment drug includes an immunotherapy drug for cancer.

[0070] Preferably, the cancer includes pancreatic tumors, ductal carcinoma, lung cancer, head and neck cancer, rectal cancer, uterine cancer, prostate cancer, kidney cancer, or breast cancer.

[0071] Preferably, the respiratory diseases include asthma, rhinitis, bronchitis, emphysema, pulmonary fibrosis, or chronic obstructive pulmonary disease.

[0072] Preferably, the immune disease includes allergies, rheumatoid arthritis, or systemic lupus erythematosus.

[0073] Fifthly, the present invention provides an immunotherapeutic drug for cancer, said immunotherapeutic drug for cancer comprising any one or a combination of at least two of the following: a compound that inhibits the activity of the γ isoform of phosphatidylinositol-3-kinase as described in the first aspect, or a stereoisomer, racemate, tautomer, isotope label, nitride, solvate, or pharmaceutically acceptable salt thereof.

[0074] Preferably, the immunotherapy drug for cancer further includes combination drugs, which include any one or a combination of at least two of the following: PD-1 antibody, PD-L1 antibody, CTLA4 antibody, glucocorticoid receptor agonist, β2-adrenergic receptor agonist, antimuscarinic agent, p38 inhibitor, xanthine derivative, paclitaxel, docetaxel, albumin-bound paclitaxel, cisplatin, carboplatin, nedaplatin, oxalate platinum, lobaplatin, etoposide, teniposide, 5-fluorouracil, capecitabine, tegafur, irinotecan, topotecan hydrochloride, gemcitabine, PDE4 antagonist, AKT inhibitor, or ER antagonist. The combination of at least two drugs includes, for example, a combination of an antimuscarinic agent and a p38 inhibitor, a combination of a glucocorticoid receptor agonist and a β2-adrenergic receptor agonist, a combination of an AKT inhibitor and an ER antagonist, etc., and any other combination is acceptable.

[0075] Preferably, the combination therapy includes PD-1 antibody and / or PD-L1 antibody.

[0076] Preferably, the cancer includes pancreatic tumors, ductal carcinoma, lung cancer, head and neck cancer, rectal cancer, uterine cancer, prostate cancer, kidney cancer, or breast cancer.

[0077] Preferably, the immunotherapy drug for cancer further includes pharmaceutically acceptable excipients.

[0078] Preferably, the excipients include any one or a combination of at least two of the following: disintegrants, glidants, lubricants, colorants, carriers, diluents, flavoring agents, binders, or fillers. The combination of at least two is, for example, a combination of lubricant and colorant, a combination of binder and filler, a combination of carrier and diluent, etc., and any other combination is acceptable.

[0079] The compounds, stereoisomers, racemates, tautomers, isotope labels, nitrogen oxides, solvates, or pharmaceutically acceptable salts thereof that inhibit the activity of phosphatidylinositol-3-kinase γ isoforms, as described in this invention, phosphatidylinositol-3-kinase γ isoform inhibitors, and drugs that inhibit the activity of phosphatidylinositol-3-kinase γ isoforms can be used to treat airway obstructive diseases, including asthma, including bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, exercise-induced asthma, and drug-induced asthma. Asthma (including aspirin and NSAID-induced asthma) and dust-induced asthma, including intermittent and persistent asthma of all severity, and other causes of airway hyperresponsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; alpha-1 antitrypsin deficiency; EGPA (eosinophilic polyangiitis, also known as Churg-Strauss syndrome or... Allergic granulomatosis; ABPA (allergic bronchopulmonary aspergillosis); CEP (chronic eosinophilic pneumonia); Farmer's lung and related diseases; hypersensitivity pneumonia; pulmonary fibrosis, including cryptogenic fibrotic alveolitis, idiopathic interstitial pneumonia, fibrosis complicated by antitumor therapy, and chronic infections, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitis and thrombotic diseases of the pulmonary vessels and pulmonary hypertension; antitussive activity, including treatment of persistent cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis, including drug-induced rhinitis and vasomotor rhinitis; perennial and seasonal allergic rhinitis, including neurogenic rhinitis (hay fever); nasal polyposis; acute viral infections, including the common cold, and infections caused by respiratory syncytial virus, influenza, coronaviruses (including SARS), and adenovirus; acute lung injury; adult respiratory distress syndrome (ARDS), and exacerbations of each of the above respiratory disease states, especially exacerbations of all types of asthma or COPD. It can also be used to treat CNS-related inflammatory diseases, such as MS. It can also be used to treat cancers, such as pancreatic intraepithelial neoplasia, ductal carcinoma, and breast cancer.

[0080] The numerical range described in this invention includes not only the point values ​​listed above, but also any point values ​​within the numerical ranges not listed above. Due to space limitations and for the sake of brevity, this invention will not exhaustively list all the specific point values ​​included in the range.

[0081] Compared with the prior art, the present invention has the following beneficial effects:

[0082] This invention creatively provides a compound having the structure shown in Formula I, which exhibits a strong inhibitory effect on PI3Kγ activity. Moreover, compared to PI3Kα / β / δ, the compound shows a significantly greater inhibitory effect on PI3Kγ activity, achieving the goal of highly selective inhibition of PI3Kγ activity. This compound has important application value in the preparation of phosphatidylinositol-3-kinase γ subtype inhibitors and in the prevention and / or treatment of cancer, respiratory diseases, or immune diseases.

[0083] Furthermore, when the compound is used in combination with PD-1 / PD-L1 antibodies, it exhibits a better tumor-suppressing effect. Attached Figure Description

[0084] Figure 1 This is a graph showing the antitumor effects of different drug administration treatments in Test Example 3. Detailed Implementation

[0085] To further illustrate the technical means and effects of the present invention, the following describes the technical solution of the present invention in conjunction with preferred embodiments of the present invention. However, the present invention is not limited to the scope of the embodiments.

[0086] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by methods known to those skilled in the art.

[0087] The intermediates and their preparation methods involved in the following examples are as follows:

[0088] Intermediate 1: 1-Methyl-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoron-2-yl)-1H-pyrazole

[0089]

[0090] 1-Methyl-3-nitro-pyrazole (5 g, 39.34 mmol) was dissolved in dry tetrahydrofuran (115 mL), cooled to -78 °C, and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborane (9.95 g, 10.9 mL, 53.5 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at -78 °C for 40 min. Subsequently, LDA (29.5 mL, 2 M in THF, 29.5 mmol) was slowly added dropwise at -78 °C. After the addition was complete, the mixture was stirred at -78 °C for 1 h. After the reaction was complete, the reaction mixture was brought to room temperature, and the reaction solution was added to a mixture of water (60 mL) and acetic acid (20 mL), and stirred for 10 min. The mixture was extracted with ethyl acetate and water, the organic layer was separated, dried over anhydrous sodium sulfate, and the organic solvent was removed by vacuum distillation to give 9.8 g of white solid. 1H NMR (400MHz, DMSO-d6) δ7.19 (d, J = 3.0Hz, 1H), 4.07 (s, 3H), 1.31 (s, 12H).

[0091] Intermediate 2: 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxorane-2-yl)-1H-pyrazole-3-amine

[0092]

[0093] Under nitrogen protection, dry Pd / C (850 mg, 10% purity, 720.95 μmol) was added to a methanol solution (25 mL) of intermediate 1 (2.5 g, 9.88 mmol). Hydrogen was purged several times to replace the nitrogen in the reactor with hydrogen (15 psi). The mixture was stirred at room temperature for 3 h. After the reaction was complete, the suspension was filtered through a diatomaceous earth filter. Ethyl acetate and water were added to extract the filtrate, the organic layer was separated, dried over anhydrous sodium sulfate, and the organic solvent was removed by vacuum distillation to give 2.1 g of a white solid product. 1 H NMR (400MHz, DMSO-d6) δ5.78-5.63(m,1H),3.73-3.70(m,3H),1.27(s,12H).

[0094] Intermediate 3: N-(1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxorane-2-yl)-1H-pyrazol-3-yl)acetamide

[0095]

[0096] Acetic anhydride (4.81 g, 4.41 mL, 47.07 mmol) was added to a 25 mL solution of intermediate 2 (2.1 g, 9.41 mmol) in dichloromethane. The mixture was stirred at room temperature for 16 h. Three-quarters of the organic solvent was removed by vacuum distillation. The filtrate was extracted with dichloromethane and water, and the organic layer was separated. The residue was dried over anhydrous sodium sulfate and the organic solvent was removed by vacuum distillation to give 1.6 g of a white solid crude product. The crude product can be used in the next reaction without further purification. 1 H NMR (400MHz, DMSO-d6) δ10.41(s,1H),6.78(s,1H),3.86(s,3H),1.99-1.96(m,3H),1.29(s,12H).

[0097] Intermediate 4: Methyl 4-bromo-2-fluoro-6-methylbenzoate

[0098]

[0099] Under nitrogen protection, MeI (60.91 g, 26.71 mL, 429 mmol) was slowly added to a DMF solution (500 mL) of 4-bromo-2-fluoro-6-methylbenzoic acid (50 g, 215 mmol) and K₂CO₃ (88.96 g, 643.7 mmol). After the addition was complete, the mixture was stirred at 80 °C for 1 h. After the reaction was complete, the reaction solution was cooled to room temperature, and 20 mL of H₂O was added. The reaction was quenched by stirring for 1 h. The suspension was separated by filtration. The filter cake was washed with ethyl acetate (200 mL x 3). The filtrate was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was separated by column chromatography to obtain 45 g of the title compound as a brown solid. LC-MS (ESI): R T =0.97min,masscalcd.For C9H8BrFO2 245.97 m / z found 246.7[M+H] + . 1 H NMR (400MHz, CDCl3) δ7.20(s,1H),7.12-7.06(m,1H),3.85(s,3H),2.30(s,3H).

[0100] Intermediate 5: Methyl 4-bromo-2-(bromomethyl)-6-fluorobenzoate

[0101]

[0102] Under nitrogen protection, NBS (21.15 g, 119 mmol) and BPO (2.45 g, 10.12 mmol) were added to a 400 mL solution of intermediate 4 (25 g, 101.19 mmol) in CCl4. The mixture was stirred at 80 °C for 4 h. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was separated by column chromatography to give 34 g of the yellow oily title compound. 1 H NMR (400MHz, CDCl3) δ7.41(s,1H),7.31-7.28(m,1H),4.62(s,2H),3.99(s,3H).

[0103] Intermediate 6: (S)-5-bromo-2-(1-cyclopropylethyl)-7-fluoroisoindol-1-one

[0104]

[0105] Under nitrogen protection, (1S)-1-cyclopropylethylamine hydrochloride (17.00 g, 139.8 mmol), boric acid (1.29 g, 20.86 mmol), K₂CO₃ (43.25 g, 312.92 mmol), intermediate 5 (34 g, 104 mmol), and CH₃CN (350 mL) were added sequentially to a round-bottom flask. The mixture was stirred at 50 °C for 16 h. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was separated by column chromatography to obtain 17 g of the target compound as a yellow solid. LC-MS (ESI): R T =0.81min,mass calcd.For C13H13BrFNO 297.02 m / z found 297.8[M+H] + .

[0106] Intermediate 7: (S)-5-bromo-2-(1-cyclopropylethyl)-7-((4-methoxybenzyl)amino)isoindoline-1-one

[0107]

[0108] Intermediate 6 (5 g, 16.77 mmol) was added to (4-methoxyphenyl)methylamine (29.91 g, 218.01 mmol, 28.21 mL). The mixture was stirred at 100 °C for 16 h. Ethyl acetate and water were added to extract the reaction mixture. The organic layer was separated, dried over magnesium sulfate, and the organic solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by column chromatography to give 7 g of the target compound as a yellow oil. LC-MS (ESI): R T =0.98min,mass calcd.For C 21 H 23 BrN2O2 414.09 m / z found 437.0[M+Na] + .

[0109] Intermediate 8: 7-amino-5-bromo-2-[(1S)-1-cyclopropylethyl]isoindoline-1-one

[0110]

[0111] Intermediate 7 (6.9 g, 16.61 mmol) was added to TFA (100 mL). The mixture was stirred at 40 °C for 3 h. After the reaction was complete, the organic solvent was removed by vacuum distillation. The crude product was dissolved in ethyl acetate (500 mL), and then neutralized with a saturated NaHCO3 solution. The organic layer was separated, dried over magnesium sulfate, filtered, and then distilled under reduced pressure to obtain the crude product. The crude product was separated by column chromatography to obtain the target compound. LC-MS (ESI): R T= 3.63 min, mass calcd. For C 13 H 15 BrN2O 294.04 m / z,found 294.6[M+H] + .

[0112] Intermediate 9: (S)-N-(6-bromo-2-(1-cyclopropylethyl)-3-oxoisoindol-4-yl)ethanesulfonamide

[0113]

[0114] Under nitrogen protection, intermediate 8 (200 mg, 677.57 μmol), DMAP (16.6 mg, 135.51 μmol), DIPEA (613 mg, 826 μL, 4.74 mmol), and DCM (10 mL) were added sequentially to a round-bottom flask. The mixture was cooled to 0 °C, and ethanesulfonyl chloride (435.6 mg, 320 μL, 3.39 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 2 h. Subsequently, Et3N (206 mg, 283 μL, 2.03 mmol), pyridine (161 mg, 164 μL, 2.03 mmol), and ethanesulfonyl chloride (200 mg) were added sequentially at room temperature. The reaction mixture was stirred at room temperature for another 2 h. After the reaction was complete, the reaction mixture was added to 20 mL of water, and the organic matter was extracted with dichloromethane. The organic solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by column chromatography to obtain 200 mg of the target compound in a yellow oil. LC-MS(ESI):R T =0.87min,mass calcd.for C 15 H 19 BrN2O3S 386.03 m / z,found 386.9[M+H] + .

[0115] Intermediate 10: 5-Bromo-7-fluoro-2-isopropylisoindol-1-one

[0116]

[0117] The above compound was prepared according to the method of intermediate 9. LC-MS (ESI): R T =0.75min,masscalcd.for C 11 H 11 BrFNO 271.00 m / z,found 271.8[M+H] + .

[0118] Intermediate 11: 5-bromo-2-isopropyl-7-(methylthio)isoindol-1-one

[0119]

[0120] Under nitrogen protection, NaSMe (320 mg, 290.91 μL, 4.57 mmol) was slowly added dropwise to a 7 mL NMP solution of intermediate 10 (700 mg, 2.57 mmol). After the addition was complete, the mixture was stirred at room temperature for 30 min. After the reaction was complete, the reaction mixture was extracted with ethyl acetate and water, and the organic phase was collected and dried over anhydrous sodium sulfate. The organic solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by column chromatography to obtain 800 mg of the title compound as a white solid. LC-MS (ESI): R T =0.81min,masscalcd.for C 12 H 14 BrNOS 299.00 m / z,found 299.9[M+H] + .

[0121] Intermediate 12: 5-bromo-2-isopropyl-7-(methanesulfonyl)isoindol-1-one

[0122]

[0123] Under nitrogen protection, m-CPBA (1.72 g, 80% purity, 7.99 mmol) was slowly added dropwise to a 25 mL solution of intermediate 11 (800 mg, 2.66 mmol) in DCM. After the addition was complete, the mixture was stirred at room temperature for 4 h. Once the reaction was complete, it was quenched with a saturated Na₂SO₃ solution (40 mL). The reaction mixture was diluted with dichloromethane and washed with a saturated NaHCO₃ solution. The organic phase was separated and dried over anhydrous sodium sulfate. The organic solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by column chromatography to obtain 600 mg of the title compound as a white solid. LC-MS (ESI)R T =0.71min,mass calcd.for C 12 H 14 BrNO3S 330.99m / z,found 331.9[M+H] + .

[0124] Intermediate 13: (S)-N-(6-bromo-2-(1-cyclopropylethyl)-3-oxoisoindol-4-yl)-N-(methylsulfonyl)methanesulfonamide

[0125]

[0126] Under nitrogen protection and at 0°C, DIPEA (788 mg, 1.06 mL, 6.10 mmol) and DMAP (24.8 mg, 203 μmol) were added sequentially to a 6 mL solution of intermediate 8 (600 mg, 2.03 mmol) containing DCM. Then, MsCl (720 mg, 486 μL, 6.29 mmol) was slowly added dropwise to the mixture at 0°C. After the addition was complete, the mixture was stirred at room temperature for 1 h. Once the reaction was complete, 1 M HCl (10 mL) was added at 0°C, and the mixture was stirred at room temperature for 30 min. The organic phase was separated by dichloromethane extraction. The organic solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by column chromatography to obtain 820 mg of the title compound as a yellow solid. LC-MS (ESI): R T =0.79min,mass calcd.For C 15 H 19 BrN2O5S2 449.99 m / z found 473.0[M+Na] + .

[0127] Intermediate 14: (S)-N-(6-bromo-2-(1-cyclopropylethyl)-3-oxoisoindole-4-yl)methanesulfonamide

[0128]

[0129] Under nitrogen protection, TBAF (3.27 mL, 1 M in THF, 3.27 mmol) was added dropwise to a 10 mL solution of intermediate 13 (820 mg, 1.82 mmol). The mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction solution was quenched with water (15 mL), and the organic phase was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The organic solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by column chromatography to obtain 550 mg of the title compound as a yellow solid. LC-MS (ESI): R T =0.83min,masscalcd.For C 14 H 17 BrN2O3S 372.01 m / z found 372.9[M+H] + .

[0130] Intermediate 15: N-(6-bromo-2-((S)-1-cyclopropylethyl)-3-oxoisoindol-4-yl)-2-methylpropane-2-sulfinamide

[0131]

[0132] Under nitrogen protection, intermediate 8 (250 mg, 846.96 μmol), 2-methylpropane-2-sulfinyl chloride (297.77 mg, 2.12 mmol, 261.20 μL), and pyridine (3 mL) were added sequentially to a round-bottom flask, followed by the dropwise addition of N,N-dimethylpyridine-4-amine (21 mg, 169 μmol). The reaction was carried out at 50 °C for 16 h. After the reaction was complete, the reaction solution was cooled to room temperature, and the organic solvent was removed by vacuum distillation. The reaction solution was added to 15 mL of water, and the organic matter was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The organic solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by column chromatography to obtain 211 mg of the target compound as a white solid. LC-MS (ESI): R T =0.87min,mass calcd.For C 17 H 23 BrN2O2S 398.07 m / z found 398.9[M+H] + .

[0133] Intermediate 16: (S)-N-(6-bromo-2-(1-cyclopropylethyl)-3-oxoisoindol-4-yl)-2-methylpropane-2-sulfonamide

[0134]

[0135] To a solution of intermediate 15 (190 mg, 476 μmol) in dichloromethane (5 mL), m-CPBA (168 mg, 952 μmol) was added. The mixture was stirred at room temperature for 16 h. After the reaction was complete, the reaction solution was cooled to room temperature and added to 10 mL of water. The organic matter was extracted with dichloromethane and dried over anhydrous sodium sulfate. The organic solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by column chromatography to obtain 195 mg of the target compound as a white solid. LC-MS (ESI): R T =0.90min,mass calcd.forC 17 H 23 BrN2O3S 414.06 m / z,found 414.9[M+H] + .

[0136] Intermediate 17: (S)-N-(6-bromo-2-(1-cyclopropylethyl)-3-oxoisoindol-4-yl)-2-methoxyethanesulfonamide

[0137]

[0138] The above compound was prepared according to the method of intermediate 15. LC-MS (ESI): RT = 0.84 min, mass calcd. for C16 H 21 BrN2O4S 416.04 m / z,found 416.9[M+H]+.

[0139] Intermediate 18: (S)-N-(6-bromo-2-(1-cyclopropylethyl)-3-oxoisoindol-4-yl)-1,3-dimethyl-1H-pyrazole-4-sulfonamide

[0140]

[0141] The above compound was prepared according to the method of intermediate 15. LC-MS (ESI): R T =0.85min,masscalcd.for C 18 H 21 BrN4O3S 452.05 m / z,found 453.0[M+H] + .

[0142] Intermediate 19: (S)-5-bromo-2-(1-cyclopropylethyl)-7-(methylthio)isoindol-1-one

[0143]

[0144] The above compound was prepared according to the method of intermediate 11. LC-MS (ESI): R T =0.87min,masscalcd.For C 14 H 16 BrNOS 325.01 m / z found 325.9[M+H] + .

[0145] Intermediate 20: (S)-5-bromo-2-(1-cyclopropylethyl)-7-(methanesulfonyl)isoindol-1-one

[0146]

[0147] The above compound was prepared according to the method of intermediate 12. LC-MS (ESI): R T =0.77min,masscalcd.For C 14 H 16 BrNO3S 357.00 m / z found 358.0[M+H] + .

[0148] Intermediate 21: (S)-7-(benzylthio)-5-bromo-2-(1-cyclopropylethyl)isoindol-1-one

[0149]

[0150] Intermediate 6 (4 g, 13.42 mmol), benzyl mercaptan (1.85 g, 14.89 mmol, 1.75 mL), DMF (30 mL), and K₂CO₃ (5.56 g, 40.25 mmol) were added sequentially to a round-bottom flask. The mixture was stirred at 50 °C for 16 h. After the reaction was complete, the reaction solution was cooled to room temperature. The reaction solution was extracted with ethyl acetate and water, and the organic layer was separated, dried over anhydrous sodium sulfate, and the organic solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by column chromatography to give 4.7 g of the target compound as a yellow solid. LC-MS (ESI): R T =0.95min mass calcd.For C 20 H 20 BrNOS 401.04 m / z found 401.9[M+H] + .

[0151] Intermediate 22: (S)-6-bromo-2-(1-cyclopropylethyl)-3-oxoisodihydroindole-4-sulfonyl chloride

[0152]

[0153] NCS (4.68 g, 35.04 mmol) was slowly added to a mixed solution of intermediate 21 (4.7 g, 11.68 mmol) in AcOH (40 mL) and H₂O (3.6 mL). The mixture was stirred at room temperature for 3 h. The reaction mixture was extracted with ethyl acetate and water, and the organic layer was separated, dried over anhydrous sodium sulfate, and the organic solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by column chromatography to give 2.4 g of the title compound as a white solid. LC-MS (ESI): R T =0.85min mass calcd.For C 13 H 13 BrClNO3S 376.95m / z found 377.8[M+H] + .

[0154] Intermediate 23: (S)-6-bromo-2-(1-cyclopropylethyl)-N-((1-(hydroxymethyl)cyclopropyl)methyl)-3-oxoisodihydroindole-4-sulfonamide

[0155]

[0156] To a solution of intermediate 22 (350 mg, 924.29 μmol) in dichloromethane (5 mL), [1-(aminomethyl)cyclopropyl]methanol (186.98 mg, 1.85 mmol) and DIPEA (644 μL, 3.70 mmol) were added. The mixture was stirred at room temperature for 16 h. After the reaction was complete, the organic solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by column chromatography to give 350 mg of the title compound as a white solid. LC-MS (ESI): R T =0.79min,mass calcd.For C 18 H 23 BrN2O4S 442.06 m / z found443.0[M+H] + .

[0157] Intermediate 24: (S)-6-bromo-2-(1-cyclopropylethyl)-N-((1-(fluoromethyl)cyclopropyl)methyl)-3-oxoisodihydroindole-4-sulfonamide

[0158]

[0159] Under N2 protection and at 0°C, DAST (179 μL, 1.35 mmol) was slowly added dropwise to a 4 mL solution of intermediate 23 (300 mg, 677 μmol) in dichloromethane. After the addition was complete, the mixture was stirred at room temperature for 2 h. After the reaction was complete, 20 mL of water was added to quench the reaction, and the reaction mixture was extracted with dichloromethane. The organic layer was separated, dried over anhydrous sodium sulfate, and the organic solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by column chromatography to obtain 250 mg of the title compound as a white solid. LC-MS (ESI): R T =0.95 minmass calcd. For C 18 H 22 BrFN2O3S 444.05 m / z found 444.9[M+H] + .

[0160] Intermediate 25: 3-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

[0161]

[0162] Under nitrogen protection and at 0°C, NaH (7.07 g, 60% purity, 177 mmol) was added to a THF (150 mL) solution of 3-nitro-1H-pyrazole (10 g, 88.44 mmol, 1 eq). After the addition was complete, the reaction solution was slowly heated to room temperature and stirred at room temperature for 1 h. Subsequently, SEMCl (15.48 g, 16.43 mL, 92.86 mmol) was slowly added dropwise at 0°C. After the addition was complete, the reaction solution was slowly heated to room temperature and stirred at room temperature for 2 h. After the reaction was complete, NH4Cl (50 mL) was added at 0°C to quench the reaction. The reaction solution was extracted with ethyl acetate, and the organic phase was separated and dried over anhydrous sodium sulfate. The organic solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by column chromatography to obtain 15 g of the title compound as a yellow solid. 1 H NMR (400MHz, CDCl3) δ7.68 (d, J = 2.5Hz, 1H), 6.99 (d, J = 2.5Hz, 1H), 5.52 (s, 2H), 3.73-3.55 (m, 2H), 0.99-0.82 (m, 2H), 0.05-0.03 (m, 9H).

[0163] Intermediate 26: 3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoron-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

[0164]

[0165] The above compound was prepared by the method of intermediate 1. 1 H NMR (400MHz, DMSO-d6) δ7.30(s,1H),5.66(s,2H),3.58(t,J=7.9Hz,2H),1.32(s,12H),0.84(t,J=7.9Hz,2H),0.06(s,9H).

[0166] Intermediate 27: 5-(4,4,5,5-tetramethyl-1,3,2-dioxoron-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-amine

[0167]

[0168] The above compound was prepared by the method of intermediate 2. 1 H NMR (400MHz, CDCl3) δ6.10 (s, 1H), 5.49 (s, 2H), 3.53 (d, J = 8.3Hz, 2H), 1.34 (s, 12H), 0.92-0.89 (m, 2H), 0.02 (s, 9H).

[0169] Intermediate 28: N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxorane-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)acetamide

[0170]

[0171] The above compound was prepared according to the method of intermediate 3. LC-MS (ESI): R T =0.90min,masscalcd.For C 17 H 32 BN3O4Si 381.23 m / z found 382.1[M+H] + .

[0172] Intermediate 29: (S)-N-(5-(2-(1-cyclopropylethyl)-7-(methylsulfonylamino)-1-oxoisoindoline-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-yl)acetamide

[0173]

[0174] Under argon protection, intermediate 14 (300 mg, 804 μmol), intermediate 28 (613 mg, 1.61 mmol), Cs₂CO₃ (785.6 mg, 2.41 mmol), Pd(dppf)Cl₂ (58.8 mg, 80.4 μmol), 1,4-dioxane (8 mL), and H₂O (2 mL) were added sequentially to a 40 mL microwave-safe tube. The reaction was carried out under argon protection for 2 h. The crude product was obtained by vacuum distillation. The crude product was separated by column chromatography to yield 320 mg of a yellow solid. LC-MS (ESI): R T =0.89min,mass calcd.For C 25 H 37 N5O5SSi547.23 m / z found 548.2[M+H] + .

[0175] Intermediate 30: (S)-N-(5-(2-(1-cyclopropylethyl)-7-(methylsulfonyl)-1-oxoisoindol-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-yl)acetamide

[0176]

[0177] The above compound was prepared according to the method of intermediate 29. LC-MS (ESI): R T =0.83min,masscalcd.For C 25 H 36 N4O5SSi 532.22 m / z found 533.1[M+H] + .

[0178] Intermediate 31: (S)-6-bromo-2-(1-cyclopropylethyl)-3-oxoisodihydroindole-4-sulfonamide

[0179]

[0180] A 5 mL solution of 1,4-dioxane containing 150 mg (396.12 μmol, 1 eq) of intermediate 22 was added to a 4.88 mL (31.69 mmol) aqueous solution of 25% NH3. The mixture was stirred at room temperature for 16 h. The organic solvent was removed by vacuum distillation. The filtrate was extracted with ethyl acetate and water, and the organic layer was separated. The residue was dried over anhydrous sodium sulfate and the organic solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by column chromatography to give 135 mg of a white solid. LC-MS (ESI): R T =0.76min,mass calcd.For C 13 H 15 BrN2O3S358.00 m / z found 358.9[M+H] + .

[0181] Intermediate 32: (S)-N-(6-bromo-2-(1-cyclopropylethyl)-3-oxoisoindol-4-yl)acetamide

[0182]

[0183] The above compound was prepared according to the method of intermediate 3. LC-MS (ESI): R T =0.85min,masscalcd.for C 15 H 17 BrN2O2 336.05 m / z,found 336.9[M+H] + .

[0184] Intermediate 33: (S)-6-bromo-2-(1-cyclopropylethyl)-N-methyl-3-oxoisodihydroindole-4-sulfonamide

[0185]

[0186] To a 10 mL solution of intermediate 22 (500 mg, 1.32 mmol, 1 eq) in dichloromethane, add methaneamine hydrochloride (356.61 mg, 5.28 mmol, 4 eq) and DIPEA (1.02 g, 7.92 mmol, 1.38 mL, 6 eq). Stir at room temperature for 2 h. After the reaction is complete, remove the organic solvent by vacuum distillation to obtain a crude product (1.6 g, 64%). The crude product can be used for the next reaction without further purification. The crude product was separated by column chromatography to give the title compound as a white solid (420 mg). LC-MS (ESI): R T =0.90min,mass calcd.For C 14 H 17 BrN2O3S 372.01 m / z found 373.0[M+H] + .

[0187] Intermediate 34: (S)-N-(5-(2-(1-cyclopropylethyl)-7-(N-methylaminosulfonyl)-1-oxoisoindol-5-yl)-1-((2-(trimethylsilyl))ethoxy)methyl)-1H-pyrazole-3-yl)acetamide

[0188]

[0189] The above compound was prepared according to the method of intermediate 29. LC-MS (ESI): R T =0.88min,masscalcd.For C 25 H 37 N5O5SSi 547.23 m / z found 548.2[M+H] + .

[0190] Intermediate 35: N-(6-bromo-2-((S)-1-cyclopropylethyl)-3-oxoisoindol-4-yl)-2-methylpropane-2-sulfinamide

[0191]

[0192] The above compound was prepared according to the method of intermediate 33. LC-MS (ESI): R T =0.80min,masscalcd.For C 15 H 19 BrN2O3S 386.03 m / z found 386.9[M+H] + .

[0193] Intermediate 36: (S)-6-bromo-N-cyclobutyl-2-(1-cyclopropylethyl)-3-oxoisodihydroindole-4-sulfonamide

[0194]

[0195] The above compound was prepared according to the method of intermediate 33. LC-MS (ESI): R T =1.07min,masscalcd.For C 17 H 21 BrN2O3S 412.05 m / z found 413.0[M+H] + .

[0196] Intermediate 37: 6-Bromo-2-isopropyl-N-methyl-3-oxoisodihydroindole-4-sulfonamide

[0197]

[0198] The above compound was prepared according to the method of intermediate 33. LCMS(ESI):R T =0.76min,masscalcd.For C 13 H 10 BrFN2O 346.00 m / z found 346.9[M+H] + .

[0199] Intermediate 38: (S)-N-(5-(2-(1-cyclopropylethyl)-1-oxo-7-aminosulfonyl isoindole-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)acetamide

[0200]

[0201] The above compound was prepared according to the method of intermediate 29. LC-MS (ESI): R T =0.84min masscalcd.For C 24 H 35 N5O5SSi 533.21 m / z found 534.2[M+H] + .

[0202] Intermediate 39: (S)-6-bromo-2-(1-cyclopropylethyl)-N-(cyclopropylmethyl)-3-oxoisodihydroindole-4-sulfonamide

[0203]

[0204] The above compound was prepared according to the method of intermediate 33. LC-MS (ESI): R T =0.97min,masscalcd.For C 17 H 21 BrN2O3S 412.05 m / z found 413.1[M+H] + .

[0205] Intermediate 40: (S)-6-bromo-N-cyclopropyl-2-(1-cyclopropylethyl)-3-oxoisodihydroindole-4-sulfonamide

[0206]

[0207] The above compound was prepared according to the method of intermediate 33. LC-MS (ESI): R T =0.95min masscalcd.For C 16 H 19 BrN2O3S 398.03 m / z found 399.0[M+H] + .

[0208] Intermediate 41: (S)-6-bromo-2-(1-cyclopropylethyl)-N-ethyl-3-oxoisodihydroindole-4-sulfonamide

[0209]

[0210] The above compound was prepared according to the method of intermediate 33. LC-MS (ESI): R T =0.85min,masscalcd.for C 15 H 19 BrN2O3S 386.03 m / z,found 386.9[M+H] + .

[0211] Intermediate 42: (S)-6-bromo-2-(1-cyclopropylethyl)-N-(oxetane-3-yl)-3-oxoisodihydroindole-4-sulfonamide

[0212]

[0213] The above compound was prepared according to the method of intermediate 33. LC-MS (ESI): R T =0.79min masscalcd.For C 16 H 19 BrN2O4S 414.02 m / z found 436.9[M+Na] +.

[0214] Intermediate 43: (S)-6-bromo-2-(1-cyclopropylethyl)-N-(3,3-difluorocyclobutyl)-3-oxoisodihydroindole-4-sulfonamide

[0215]

[0216] The above compound was prepared according to the method of intermediate 33. LC-MS (ESI): R T =0.89min,masscalcd.For C 17 H 19 BrF2N2O3S 448.03 m / z found 448.9[M+H] + .

[0217] Intermediate 44: (S)-6-bromo-2-(1-cyclopropylethyl)-N-(2-methoxyethyl)-3-oxoisodihydroindole-4-sulfonamide

[0218]

[0219] The above compound was prepared according to the method of intermediate 33. LC-MS (ESI): R T =0.82min,masscalcd.For C 16 H 21 BrN2O4S 416.04 m / z found 416.9[M+H] + .

[0220] Intermediate 45: (S)-6-bromo-2-(1-cyclopropylethyl)-3-oxo-N-(2,2,2-trifluoroethyl)isodihydroindole-4-sulfonamide

[0221]

[0222] The above compound was prepared according to the method of intermediate 33. LC-MS (ESI): R T =0.88min,masscalcd.For C 15 H 16 BrF3N2O3S 440.00 m / z found 440.9[M+H] + .

[0223] Intermediate 46: 7-(benzylthio)-5-bromo-2-isopropylisoindol-1-one

[0224]

[0225] The above compound was prepared according to the method of intermediate 21. LC-MS (ESI): R T =0.91min,masscalcd.For C 18 H 18 BrNOS 375.03 m / z found 398.0[M+Na] + .

[0226] Intermediate 47: 6-bromo-2-isopropyl-3-oxoisodihydroindole-4-sulfonyl chloride

[0227]

[0228] The above compound was prepared according to the method of intermediate 22. LC-MS (ESI): R T =0.80min,masscalcd.For C 11 H 11 BrClNO3S 350.93 m / z found 351.8[M+H] + .

[0229] Intermediate 48: 6-bromo-2-isopropyl-3-oxoisoindoline-4-sulfonamide

[0230]

[0231] The above compound was prepared according to the method of intermediate 31. LC-MS (ESI): R T =0.70min,masscalcd.For C 11 H 13 BrN2O3S 331.98 m / z found 354.8[M+Na] + .

[0232] Intermediate 49: (S)-N-(6-bromo-2-(1-cyclopropylethyl)-3-oxoisoindol-4-yl)cyclopropanesulfonamide

[0233]

[0234] Under nitrogen protection, intermediate 8 (200 mg, 678 μmol) and pyridine (4 mL) were added sequentially to a round-bottom flask. After cooling the mixture to 0 °C, DMAP (8.3 mg, 68 μmol) and cyclopropanesulfonyl chloride (762 mg, 5.42 mmol, 8 eq) were added sequentially. The mixture was stirred at 50 °C for 12 h. After the reaction was complete, the organic solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by column chromatography to obtain 250 mg of the target compound as a white solid. LC-MS (ESI): RT =0.88min,mass calcd.ForC 16 H 19 BrN2O3S 398.03 m / z,found 399.0[M+H] + .

[0235] Intermediate 50: (S)-N-(6-bromo-2-(1-cyclopropylethyl)-3-oxoisoindol-4-yl)propane-1-sulfonamide

[0236]

[0237] Under nitrogen protection, intermediate 8 (250 mg, 847 μmol), DMAP (21 mg, 169 μmol), DIPEA (766 mg, 5.93 mmol), and DCM (10 mL) were added sequentially to a round-bottom flask. The mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction solution was quenched in 20 mL of water, and the reaction solution was extracted with DCM. The organic solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by column chromatography to obtain 300 mg of the target compound as a yellow oil. LC-MS (ESI): R T =4.12min,mass calcd.forC 16 H 21 BrN2O3S 400.05 m / z,found 401.0[M+H] + .

[0238] Intermediate 51: 5-bromo-2-(2-cyclopropylpropane-2-yl)-7-fluoroisoindol-1-one

[0239]

[0240] The above compound was prepared according to the method of intermediate 6. LC-MS (ESI): R T =0.85min masscalcd.For C 14 H 15 BrFNO 311.03 m / z found 311.9[M+H] + .

[0241] Intermediate 52: 7-(benzylthio)-5-bromo-2-(2-cyclopropylpropane-2-yl)isoindol-1-one

[0242]

[0243] The above compound was prepared according to the method of intermediate 21. LC-MS (ESI): R T=0.97min masscalcd.For C 21 H 22 BrNOS 415.06 m / z found 415.9[M+H] + .

[0244] Intermediate 53: 6-bromo-2-(2-cyclopropylpropyl-2-3-oxo-isodihydroindole-4-sulfonyl chloride

[0245]

[0246] The above compound was prepared according to the method of intermediate 22. LC-MS (ESI): R T =0.89min masscalcd.For C 14 H 15 BrClNO3S 390.96 m / z found 391.9[M+H] + .

[0247] Intermediate 54: 6-bromo-2-(2-cyclopropylpropane-2-yl)-N-methyl-3-oxoisodihydroindole-4-sulfonamide

[0248]

[0249] The above compound was prepared according to the method of intermediate 33. LC-MS (ESI): R T =0.86min masscalcd.For C 15 H 19 BrN2O3S 386.03 m / z found 386.9[M+H] + .

[0250] Intermediate 55: (S)-5-bromo-2-(3,3-dimethylbut-2-yl)-7-fluoroisoindol-1-one

[0251]

[0252] The above compound was prepared according to the method of intermediate 6. LC-MS (ESI): R T =0.86min,masscalcd.For C 14 H 17 BrFNO 313.05 m / z found 313.9[M+H] + .

[0253] Intermediate 56: (S)-7-(benzylthio)-5-bromo-2-(3,3-dimethylbut-2-yl)isoindol-1-one

[0254]

[0255] The above compound was prepared according to the method of intermediate 21. LC-MS (ESI): R T =0.96min,masscalcd.For C 21 H 24 BrNOS 417.08 m / z found 418.0[M+H] + .

[0256] Intermediate 57: (S)-6-bromo-2-(3,3-dimethylbutane-2-yl)-3-oxoisodihydroindole-4-sulfonyl chloride

[0257] The above compound was prepared according to the method of intermediate 22. LC-MS (ESI): R T =0.90min,masscalcd.For C 14 H 17 BrClNO3S 392.98 m / z found 393.9[M+H] + .

[0258] Intermediate 58: (S)-6-bromo-2-(3,3-dimethylbut-2-yl)-N-methyl-3-oxoisodihydroindole-4-sulfonamide

[0259]

[0260] The above compound was prepared according to the method of intermediate 33. LC-MS (ESI): R T =0.86min,masscalcd.for C 15 H 21 BrN2O3S 388.05 m / z,found 388.9[M+H] + .

[0261] Intermediate 59: 5-bromo-2-(tert-butyl)-7-fluoroisoindol-1-one

[0262]

[0263] The above compound was prepared according to the method of intermediate 6. LC-MS (ESI): R T =0.81min,masscalcd.For C 12 H 13 BrFNO 285.02 m / z found 285.9[M+H] + .

[0264] Intermediate 60: 7-(benzylthio)-5-bromo-2-(tert-butyl)isoindol-1-one

[0265]

[0266] The above compound was prepared according to the method of intermediate 21. LC-MS (ESI): R T =0.96min,masscalcd.For C 19 H 20 BrNOS 389.04 m / z found 389.9[M+H] + .

[0267] Intermediate 61: 6-bromo-2-(tert-butyl)-3-oxoisodihydroindole-4-sulfonyl chloride

[0268]

[0269] The above compound was prepared according to the method of intermediate 22. LC-MS (ESI): R T =0.92min,masscalcd.For C 12 H 13 BrClNO3S 364.95 m / z found 365.7[M+H] + .

[0270] Intermediate 62: 6-bromo-2-(tert-butyl)-N-methyl-3-oxoisodihydroindole-4-sulfonamide

[0271]

[0272] The above compound was prepared according to the method of intermediate 33. LC-MS (ESI): R T =0.82min,masscalcd.for C 13 H 17 BrN2O3S 360.01 m / z,found 360.9[M+H] + .

[0273] Intermediate 63: (S)-bromo-7-fluoro-2-(1,1,1-trifluoropropane-2-yl)isoindol-1-one

[0274]

[0275] The above compound was prepared according to the method of intermediate 6. LC-MS (ESI): R T=0.82min,masscalcd.For C 11 H8BrF4NO 324.97 m / z found 325.8[M+H] + .

[0276] Intermediate 64: (S)-(benzylthio)-5-bromo-2-(1,1,1-trifluoropropane-2-yl)isoindol-1-one

[0277]

[0278] The above compound was prepared according to the method of intermediate 21. LC-MS (ESI): R T =0.95min,masscalcd.For C 18 H 15 BrF3NOS 429.00 m / z found 429.9[M+H] + .

[0279] Intermediate 65: (S)-6-bromo-3-oxo-2-(1,1,1-trifluoropropane-2-yl)isodihydroindole-4-sulfonyl chloride

[0280]

[0281] The above compound was prepared according to the method of intermediate 21. LC-MS (ESI): R T =0.85min,masscalcd.For C 11 H8BrClF3NO3S 404.90 m / z found 405.8[M+H] + .

[0282] Intermediate 66: (S)-6-bromo-N-methyl-3-oxo-2-(1,1,1-trifluoropropane-2-yl)isodihydroindole-4-sulfonamide

[0283]

[0284] The above compound was prepared according to the method of intermediate 33. LC-MS (ESI): R T =0.82min,masscalcd.for C 12 H 12 BrF3N2O3S 399.97 m / z,found 400.9[M+H] + .

[0285] Intermediate 67: (S)-6-bromo-N-(3-cyanophenyl)-2-(1-cyclopropylethyl)-3-oxoisodihydroindole-4-sulfonamide

[0286]

[0287] DMAP (290 mg, 2.38 mmol, 3 eq) was added to a solution of intermediate 22 (300 mg, 792.25 μmol, 1 eq) in dichloromethane (187 mg, 1.58 mmol, 2 eq) and pyridine (6 mL). The mixture was stirred at 50 °C for 16 h. After the reaction was complete, the reaction solution was cooled to room temperature. The reaction solution was extracted with ethyl acetate and water, and the organic phase was collected after separation. The organic phase was dried over anhydrous sodium sulfate and the organic solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by column chromatography to obtain 330 mg of the title compound as a white solid. LC-MS (ESI): R T =0.90min,mass calcd.For C 20 H 18 BrN3O3S 459.03 m / z found460.0[M+H] + .

[0288] Intermediate 68: 6-Bromo-N-(3-cyanophenyl)-2-isopropyl-3-oxoisodihydroindole-4-sulfonamide

[0289]

[0290] The above compound was prepared according to the method of intermediate 67. LC-MS (ESI): R T =0.85min,masscalcd.For C 18 H 16 BrN3O3S 433.01 m / z found 434.0[M+H] + .

[0291] Intermediate 69: 3-(2,5-dimethyl-1H-pyrrolo-1-yl)-1-methyl-1H-pyrazole

[0292]

[0293] A solution of methylpyrazole-3-amine (60 g, 617.8 mmol, 1 eq) and hexane-2,5-dione (70.5 g, 618 mmol, 72.47 mL, 1 eq) in toluene (600 mL) was added to 4-methylbenzenesulfonic acid (5.32 g, 30.89 mmol, 0.05 eq). The mixture was stirred at 135 °C for 36 h. After the reaction was complete, the organic solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by column chromatography to give 820 mg of the title compound as a yellow oil. LC-MS (ESI): R T =0.75min,mass calcd.for C10H13N3175.11 m / z,found 175.8[M+H] + . 1 H NMR (400MHz, CDCl3) δ7.41 (d, J = 2.0Hz, 1H), 6.17 (d, J = 2.3Hz, 1H), 5.87 (s, 2H), 3.94 (s, 3H), 2.12 (s, 6H).

[0294] Intermediate 70: (3-(2,5-dimethyl-1H-pyrrolo-1-yl)-1-methyl-1H-pyrazol-5-yl)boronic acid

[0295]

[0296] Under nitrogen protection at -75°C, n-butyllithium (27.39 mL, 2.5 M in hexane, 68.5 mmol, 1.2 eq) was slowly added dropwise to a 300 mL solution of intermediate 69 (10 g, 57.07 mmol, 1 eq) in tetrahydrofuran. After the addition was complete, the mixture was stirred at room temperature for 3 h. After the reaction was complete, the reaction was quenched with 1 M HCl (10 mL) at 0°C, and the pH was adjusted to 6. The organic solvent was removed by vacuum distillation. The mixture was extracted with ethyl acetate and water, and the organic layer was separated, dried over anhydrous sodium sulfate, and the organic solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by column chromatography to obtain 11 g of the title compound as a brown solid. LC-MS (ESI): RT = 0.69 min, mass calcd. For C 10 H 14 BN3O2 219.12 m / z,found 219.9[M+H]+. 1 H NMR (400MHz, CDCl3) δ6.75-6.39(m,1H),5.95-5.79(m,2H),4.25-3.88(m,3H),2.14-2.04(m,6H).

[0297] Intermediate 71: Methyl 4-bromo-2-(bromomethyl)-6-chlorobenzoate

[0298]

[0299] The above compound was prepared according to the method of intermediate 5. LC-MS (ESI): R T =0.97min,masscalcd.For C9H7Br2ClO2 339.85 m / z found 341.2[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.91-7.84(m,1H),7.73-7.49(m,1H),3.97-3.86(m,3H),1.98(m,2H).

[0300] Intermediate 72: (S)-5-bromo-7-chloro-2-(1-cyclopropylethyl)isoindol-1-one

[0301]

[0302] The above compound was prepared according to the method of intermediate 6. LC-MS (ESI): R T =0.86min,masscalcd.For C 13 H 13 BrClNO 312.99 m / z found 313.8[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.84(s,1H),7.76(s,1H),4.52(s,2H),4.03(q,J=7.3Hz,1H),3.62-3.48(m,1 H),1.26(d,J=6.8Hz,3H),1.16-1.04(m,1H),0.63-0.52(m,1H),0.45-0.34(m,2H),0.28-0.18(m,1H).

[0303] Intermediate 73: (S)-7-chloro-2-(1-cyclopropylethyl)-5-(3-(2,5-dimethyl-1H-pyrrolo-1-yl)-1-methyl-1H-pyrazol-5-yl)isoindoline-1-one

[0304]

[0305] Under nitrogen protection, intermediate 72 (860 mg, 2.73 mmol, 1 eq), 1,4-dioxane (8 mL), water (2 mL), Na₂CO₃ (869 mg, 8.20 mmol, 3 eq), intermediate 70 (898 mg, 3.28 mmol, 80% purity, 1.2 eq), and Pd(dppf)Cl₂ (200 mg, 273 μmol, 0.1 eq) were added sequentially to a microwave tube. The reaction was carried out at 90 °C for 1 h. After the reaction was complete, the reaction solution was cooled to room temperature. The organic solvent was removed by vacuum distillation. The mixture was extracted with ethyl acetate and water, and the organic layer was separated, dried over anhydrous sodium sulfate, and the organic solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by column chromatography to obtain 780 mg of the target compound as a white solid. LC-MS (ESI): R T =0.96min,mass calcd.For C 23 H 25 ClN4O 408.17 m / z found 409.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.85(s,1H),7.75(s,1H),6.67(s,1H),5.78(s,2H),4.61(s,2H),3.95(s,3H),3.64-3.54(m, 1H), 2.10 (s, 6H), 1.30 (d, J = 6.8Hz, 3H), 1.20-1.11 (m, 1H), 0.64-0.54 (m, 1H), 0.47-0.35 (m, 2H), 0.29-0.21 (m, 1H).

[0306] Intermediate 74: (S)-2-(1-cyclopropylethyl)-5-(3-(2,5-dimethyl-1H-pyrrolo-1-yl)-1-methyl-1H-pyrazol-5-yl)-7-vinylisoindoline-1-one

[0307]

[0308] Under nitrogen protection, intermediate 73 (580 mg, 1.42 mmol, 1 eq), 1,4-dioxane (8 mL), water (1 mL), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborane (436.9 mg, 2.84 mmol, 2 eq), Cs₂CO₃ (1.39 g, 4.26 mmol, 3 eq), and XPhos Pd G₃ (120 mg, 142 μmol, 0.1 eq) were added sequentially to a microwave tube. The reaction was carried out at 120 °C for 1 h. After the reaction was complete, the reaction solution was cooled to room temperature. The organic solvent was removed by vacuum distillation. The mixture was extracted with ethyl acetate and water, and the organic layer was separated, dried over anhydrous sodium sulfate, and the organic solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by column chromatography to obtain 560 mg of the target compound as a white solid. LC-MS (ESI): R T =0.95min,mass calcd.For C 25 H 28 N4O400.23 m / z found 401.5[M+H] + .

[0309] Intermediate 75: (S)-2-(1-cyclopropylethyl)-5-(3-(2,5-dimethyl-1H-pyrrolo-1-yl)-1-methyl-1H-pyrazol-5-yl)-7-ethylisoindoline-1-one

[0310]

[0311] Under nitrogen protection, dry PtO2 (90 mg, 397 μmol, 0.3 eq) was added to a 3 mL solution of intermediate 74 (530 mg, 1.32 mmol, 1 eq) in tetrahydrofuran. Hydrogen was purged several times to replace the nitrogen in the reactor with hydrogen (15 psi). The mixture was stirred at room temperature for 3 h. After the reaction was complete, the suspension was filtered through a diatomaceous earth filter, and the diatomaceous earth was washed with ethyl acetate. The filtrate was distilled to dryness under reduced pressure to give 480 mg of a white solid product. LC-MS (ESI): R T =0.95min,mass calcd.For C 25 H 30 N4O402.24 m / z found 403.1[M+H] + .

[0312] Intermediate 76: (S)-5-(3-amino-1-methyl-1H-pyrazol-5-yl)-2-(1-cyclopropylethyl)-7-ethylisoindole-1-one

[0313]

[0314] To a 4 mL ethanol solution of intermediate 75 (450 mg, 1.12 mmol, 1 eq), NH₂OH·HCl (1.17 g, 16.8 mmol, 15 eq) and Et₃N (260 mg, 2.57 mmol, 358 μl, 2.3 eq) were added. The mixture was stirred at 95 °C for 16 h. After the reaction was complete, the reaction solution was cooled to room temperature. The organic solvent was removed by vacuum distillation. The mixture was extracted with ethyl acetate and water, and the organic layer was collected, dried over anhydrous sodium sulfate, and the organic solvent was removed by vacuum distillation to give 450 mg of the title compound as a white solid. LC-MS (ESI): R T =0.68min,mass calcd.For C 19 H 24 N4O 324.20 m / z found 325.4[M+H] + .

[0315] Intermediate 77: (S)-5-bromo-2-(1-cyclopropylethyl)-7-ethoxyisoindol-1-one

[0316]

[0317] Intermediate 6 (400 mg, 1.34 mmol, 1 eq), ethanol (8 mL), and K₂CO₃ (556 mg, 4.02 mmol, 3 eq) were added sequentially to a round-bottom flask. The mixture was stirred at 80 °C for 16 h. After the reaction was complete, the reaction solution was cooled to room temperature. The organic solvent was removed by vacuum distillation. The mixture was extracted with ethyl acetate and water, and the organic layer was collected, dried over anhydrous sodium sulfate, and the organic solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by column chromatography to obtain 175 mg of the target compound as a white solid. LC-MS (ESI): RT = 0.83 min, mass calcd. For C 15 H 18 BrNO2 323.05 m / z found 323.9[M+H] + .

[0318] Intermediate 78: (S)-5-bromo-2-(1-cyclopropylethyl)-7-(ethyl(4-methoxybenzyl)amino)isoindoline-1-one

[0319]

[0320] The above compound was prepared according to the method of intermediate 7. LC-MS (ESI): R T =0.88min,masscalcd.For C 23 H 27 BrN2O2 442.13 m / z found 443.0[M+H]+ .

[0321] Intermediate 79: (S)-N-(5-(2-(1-cyclopropylethyl)-7-(ethyl(4-methoxybenzyl)amino)-1-oxoisoindol-5-yl)-1-methyl-1H-pyrazole-3-yl)acetamide

[0322]

[0323] The above compound was prepared according to the method of intermediate 29. LC-MS (ESI): R T =0.69min,masscalcd.For C 29 H 35 N5O3 501.27 m / z found 502.3[M+H] + .

[0324] Intermediate 80: (S)-N-((4-bromofuran-2-yl)methyl)-1-cyclopropylethylamine

[0325]

[0326] To a methanol (10 mL) solution of 4-bromofuran-2-carboxaldehyde (863 mg, 4.93 mmol, 1.2 eq) and (S)-1-cyclopropylethylamine hydrochloride (500 mg, 4.11 mmol, 1 eq), triethylamine (416 mg, 4.11 mmol, 1 eq) and NaBH3CN (775 mg, 12.3 mmol, 3 eq) were added. The mixture was stirred at room temperature for 16 h. After the reaction was complete, the organic solvent was removed by vacuum distillation. The mixture was extracted with ethyl acetate and water, and the organic layer was separated, dried over magnesium sulfate, filtered, and then distilled under vacuum to obtain the crude product. The crude product was separated by column chromatography to obtain 670 mg of the target compound as a white solid. LC-MS (ESI): R T =0.58min,mass calcd.For C 10 H 14 BrNO 243.03 m / z found 243.9[M+H] + . 1H NMR(400MHz,DMSO-d6)δ7.84-7.76(m,1H),6.48-6.38(m,1H),3.79-3.67(m,2H),2.26-1.90(m,1H),1.90-1.76(m,1H), 1.03(d,J=6.3Hz,3H),0.72-0.55(m,1H),0.48-0.38(m,1H),0.35-0.29(m,1H),0.20-0.11(m,1H),0.02--0.07(m,1H).

[0327] Intermediate 81: (3aS,6R)-5-bromo-2-((S)-1-cyclopropylethyl)-1-oxo-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-7-carboxylic acid

[0328]

[0329] To a 10 mL solution of intermediate 80 (670 mg, 2.74 mmol, 1 eq) in toluene, furan-2,5-dione (296 mg, 3.02 mmol, 1.1 eq) was added. The mixture was stirred at room temperature for 16 h. After the reaction was complete, the organic solvent was removed by vacuum distillation. The mixture was extracted with ethyl acetate and water, and the organic layer was collected, dried over magnesium sulfate, filtered, and then distilled under vacuum to obtain the crude product. The crude product was separated by column chromatography to obtain 590 mg of the target compound as a white solid. LC-MS (ESI): R T =0.72min,mass calcd.For C 14 H 16 BrNO4341.03 m / z found 341.9[M+H] + .

[0330] Intermediate 82: (S)-6-bromo-2-(1-cyclopropylethyl)-3-oxoisodihydroindole-4-carboxylic acid

[0331]

[0332] A solution of intermediate 81 (590 mg, 1.72 mmol, 1 eq) in 1,4-dioxane (8 mL) was added to a solution of BF3·Et2O (1.10 g, 7.76 mmol, 958 μl, 4.5 eq). The mixture was stirred at 110 °C for 2 h. After the reaction was complete, the organic solvent was removed by vacuum distillation. The mixture was extracted with ethyl acetate and water, and the organic layer was separated, dried over magnesium sulfate, filtered, and then distilled under reduced pressure to obtain the crude product. The crude product was separated by column chromatography to obtain 550 mg of the target compound as a white solid. LC-MS (ESI): R T =0.82min,mass calcd.ForC14 H 14 BrNO3 323.02 m / z found 323.9[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.21-8.20(m,2H),3.76-3.57(m,2H),3.01(m,1H),1.37-1.33(m,3H),0.64-0.58(m,1H),0.44(m,2H),0.34-0.26(m,2H).

[0333] Intermediate 83: (S)-6-bromo-2-(1-cyclopropylethyl)-N-methyl-3-oxoisodihydroindole-4-carboxamide

[0334]

[0335] To a DMF (10 mL) solution of intermediate 82 (570 mg, 1.76 mmol, 1 eq) and methylamine hydrochloride (125 mg, 1.85 mmol, 1.05 eq), DIPEA (909 mg, 7.03 mmol, 1.23 mL, 4 eq) and HATU (735 mg, 1.93 mmol, 1.1 eq) were added. The mixture was stirred at room temperature for 16 h. After the reaction was complete, the organic solvent was removed by vacuum distillation. The mixture was extracted with ethyl acetate and water, and the organic layer was separated, dried over magnesium sulfate, filtered, and then distilled under reduced pressure to obtain the crude product. The crude product was separated by column chromatography to obtain 420 mg of the target compound as a white solid. LC-MS (ESI): R T =0.86min,mass calcd.For C 15 H 17 BrN2O2 336.05 m / z found337.4[M+H] + .

[0336] Intermediate 84: 5-(3-amino-1-methyl-1H-pyrazol-5-yl)-2-methylisoindololin-1-one

[0337]

[0338] The above compound was prepared according to the method of intermediate 76, with mass calcd for C. 13 H 14 N4O 242.1 m / z,found 243.0[M+H] + .

[0339] Intermediate 85: 4-Bromo-N-(6-bromopyridin-2-yl)butyramide

[0340]

[0341] To a solution of 6-bromopyridin-2-amine (5 g, 28.9 mmol, 1 eq) and 4-bromobutyryl chloride (6.43 g, 34.68 mmol, 4.02 mL, 1.2 eq) in acetonitrile (50 mL), pyridine (3.43 g, 43.35 mmol, 3.50 mL, 1.5 eq) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 16 h. After the reaction was complete, 3 / 4 of the organic solvent was removed by vacuum distillation. The filtrate was extracted with ethyl acetate and water, the organic layer was separated, dried over anhydrous sodium sulfate, and the organic solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by column chromatography to give 7.1 g of the title compound as a white solid. LC-MS (ESI): R T =0.79min,mass calcd.ForC9H 10 Br2N2O 319.92 m / z found 320.7[M+H] + . 1 H NMR(400MHz, DMSO-d6)δ10.85(s,1H),8.08(d,J=8.0Hz,1H),7.71(t,J=8.0Hz,1H), 7.30(d,J=7.8Hz,1H),3.68-3.53(m,2H),2.54(t,J=7.2Hz,2H),2.13-1.99(m,2H).

[0342] Intermediate 86: 1-(6-bromopyridin-2-yl)pyrrolidine-2-one

[0343]

[0344] To a DMF (20 mL) solution of intermediate 85 (3.6 g, 11.18 mmol, 1 eq), K₂CO₃ (4.02 g, 29.07 mmol, 2.6 eq) was added. The reaction was carried out at 60 °C for 4 h. After the reaction was complete, the reaction solution was cooled to room temperature. Three-quarters of the organic solvent was removed by vacuum distillation. The filtrate was extracted with ethyl acetate and water, the organic layer was separated, dried over anhydrous sodium sulfate, and the organic solvent was removed by vacuum distillation to give 2.6 g of the title compound as a white solid. LC-MS (ESI): R T =0.80min,mass calcd.ForC9H9BrN2O 239.99 m / z found 240.5[M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.28(d,J=8.2Hz,1H),7.74(t,J=7.9Hz,1H),7.36(d, J=7.7Hz,1H),3.92(t,J=7.2Hz,2H),2.57(t,J=8.0Hz,2H),2.09-1.97(m,2H).

[0345] Intermediate 87: (S)-N-(5-(7-amino-2-(1-cyclopropylethyl)-1-oxoisoindol-5-yl)-1-methyl-1H-pyrazol-3-yl)acetamide

[0346]

[0347] The above compound was prepared according to the method of intermediate 29. LC-MS (ESI): R T =0.69min,masscalcd.for C 19 H 23 N5O2 353.19 m / z,found 354.4[M+H] + .

[0348] Intermediate 88: (S)-5-(3-amino-1-methyl-1H-pyrazol-5-yl)-2-(1-cyclopropylethyl)-7-methylisoindoline-1-one

[0349]

[0350] The above compound was prepared according to the method of intermediate 76, with mass calcd for C. 18 H 22 N4O 310.2 m / z,found 311.0[M+H] + .

[0351] Intermediate 89: 5-(3-amino-1-methyl-1H-pyrazol-5-yl)-4-methylisoindol-1-one

[0352]

[0353] The above compound was prepared according to the method of intermediate 76, with mass calcd for C. 13 H 14 N4O 242.1 m / z,found 242.9[M+H] + .

[0354] Intermediate 90: 5-(3-amino-1-methyl-1H-pyrazol-5-yl)-2-ethylisoindololin-1-one

[0355]

[0356] The above compound was prepared according to the method of intermediate 76, with mass calcd for C. 14 H 16 N4O 256.1 m / z,found 257.0[M+H] + .

[0357] Intermediate 91: 5-(3-amino-1-methyl-1H-pyrazol-5-yl)-7-methylisoindololin-1-one

[0358]

[0359] The above compound was prepared according to the method of intermediate 76, with mass calcd for C. 14 H 16 N4O 242.1 m / z,found 242.9[M+H] + .

[0360] Intermediate 92: 5-(3-amino-1-methyl-1H-pyrazol-5-yl)-2-(cyclopropylmethyl)isoindoline-1-one

[0361]

[0362] The above compound was prepared according to the method of intermediate 76, with mass calcd for C. 18 H 22 N4O 282.1 m / z,found 283.0[M+H] + .

[0363] Intermediate 93: N-(5-bromo-1-methyl-1H-pyrazol-3-yl)acetamide

[0364]

[0365] 5-Bromo-1-methyl-1H-pyrazole-3-amine (2.5 g, 15 mmol), triethylamine (6 mL), and toluene (15 mL) were added to a round-bottom flask, followed by the addition of acetic anhydride (2.1 mL, 3.75 mmol) to the mixture. The reaction was carried out at 40 °C for 2 h. After the reaction was complete, the reaction solution was cooled to room temperature, and the organic solvent was removed by vacuum distillation. The reaction solution was added to 100 mL of water, and the organic matter was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The organic solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by column chromatography to obtain 1.9 g of the target compound as a yellowish-white solid. (mass calcd. for C6H8BrN3O 216.99 m / z, found 217.7 [M+H]) + .

[0366] Intermediate 94: 6-bromo-8-((4-methoxybenzyl)amino)-3,4-dihydroisoquinoline-1(2H)-one

[0367]

[0368] 480.0 mg (2 mmol) of 6-bromo-8-fluoro-3,4-dihydroisoquinoline-1(2H)-one was added to (4-methoxyphenyl)methylamine (5 mL). The mixture was stirred at 100 °C for 16 h. Ethyl acetate and water were added to extract the reaction mixture. The organic layer was separated, dried over magnesium sulfate, and the organic solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by column chromatography to yield 586 mg of the target compound in a yellow oil. (mass calcd. for C) 17 H 17 BrN2O2 360.05 m / z,found 360.8[M+H] + .

[0369] Intermediate 95: 8-amino-6-bromo-3,4-dihydroisoquinoline-1(2H)-one

[0370]

[0371] The above compound was prepared from intermediate 94 using the same method as intermediate 8, with a mass calcd for C9H9BrN2O2 of 39.99 m / z and a found calcd of 240.9 [M+H]. + .

[0372] Intermediate 96: N-(6-bromo-1-oxo-1,2,3,4-tetrahydroisoquinoline-8-yl)ethanesulfonamide

[0373]

[0374] The above compound was prepared from intermediate 95 using the method described for intermediate 9, mass calcd.forC 11 H 13 BrN2O3 331.98 m / z,found 332.7[M+H]+.

[0375] Intermediate 97: N-(1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-yl) ethanesulfonamide

[0376]

[0377] Under nitrogen protection, intermediate 96 (332.0 mg, 1 mmol), pinacol diboronate (333.1 mg, 1.3 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (73.2 mg, 0.1 mol), and potassium acetate (215.9 mg, 2.2 mmol) were added sequentially to a sealed tube. Dry dioxane (15 mL) was added, and the mixture was heated to 100 °C and reacted for 3 h. After the reaction was complete, the mixture was concentrated and purified by silica gel column chromatography to obtain 306 mg of the target compound. (mass calcd. for C) 17 H 25 BN2O5S 380.16m / z,found 381.0[M+H]+.

[0378] Example 1

[0379] This embodiment provides a compound named: (S)-N-(5-(2-(1-cyclopropylethyl)-7-(methanesulfonyl)-1-oxoisoindol-5-yl)-1-methyl-1H-pyrazole-3-yl)acetamide, with the following structure:

[0380]

[0381] Its preparation method is as follows:

[0382] Under Ar protection, intermediate 20 (150 mg, 419 μmol), intermediate 3 (111 mg, 419 μmol), Cs₂CO₃ (477.48 mg, 1.47 mmol), Pd(dppf)Cl₂ (30.64 mg, 41.87 μmol), 1,4-dioxane (4 mL), and H₂O (1 mL) were added sequentially to a 40 mL microwave-safe tube. The reaction was carried out under Ar protection at 110 °C for 2 h. The crude product was obtained by vacuum distillation. The crude product was separated by column chromatography to yield 31 mg of a white solid. LC-MS (ESI): R T= 2.47min, mass calcd.forC 20 H 24 N4O4S 416.15 m / z,found 416.8[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.54(s,1H),8.16(s,1H),8.07-7.95(m,1H),6.79(s,1H),4.73(s,2H),3.83(s,3H),3.64(s,3H),3.6 3-3.58(m,1H),2.02(s,3H),1.32(d,J=6.8Hz,3H),1.23-1.09(m,1H),0.67-0.54(m,1H),0.50-0.36(m,2H),0.31-0.19(m,1H).

[0383] Example 2

[0384] This embodiment provides the compound: (S)-N-(5-(2-(1-cyclopropylethyl)-7-(methanesulfonyl)-1-oxoisoindol-5-yl)-1H-pyrazol-3-yl)acetamide, the structure of which is as follows:

[0385]

[0386] Its preparation method is as follows:

[0387] TFA (6.68 g, 4.34 mL, 58.57 mmol) was added dropwise to a solution of intermediate 29 (390 mg, 732 μmol) in dichloromethane (6 mL). After the addition was complete, the mixture was stirred at room temperature for 1 h. Subsequently, the organic solvent was removed by vacuum distillation. The crude product was separated by column chromatography to obtain 143.6 mg of the compound as a white solid. LC-MS (ESI): R T =1.96min,mass calcd.ForC 19 H 22 N4O4S 402.14 m / z found 402.8[M+H]+. 1H NMR (400MHz, DMSO-d6) δ13.54-12.99(m,1H),11.00-10.22(m,1H),8.42-8.29(m,1H),8.27(s,1H),7.45-6.52(m,1H),4.69(s,2H),3.62(s,3 H),3.62-3.55(m,1H),2.08-2.02(m,3H),1.31(d,J=6.8Hz,3H),1.23- 1.11(m,1H),0.66-0.55(m,1H),0.50-0.35(m,2H),0.30-0.22(m,1H).

[0388] Example 3

[0389] This embodiment provides the compound: N-(5-(2-isopropyl-7-(methanesulfonyl)-1-oxoisoindol-5-yl)-1-methyl-1H-pyrazole-3-yl)acetamide, the structure of which is as follows:

[0390]

[0391] The LC-MS(ESI)R was prepared using intermediates 3 and 12, following the method described in Example 1. T = 2.57 min, masscalcd.for C 18 H 22 N4O4S 390.14 m / z,found 390.8[M+H] + .1H NMR(400MHz, CDCl3)8.27(s,1H),7.95(s,1H),7.80(s,1H),6.89(s,1H),4.77-4.63 (m,1H),4.47(s,2H),3.79(s,3H),3.65(s,3H),2.18(s,3H),1.34(d,J=6.8Hz,6H).

[0392] Example 4

[0393] This embodiment provides the compound: (S)-N-(5-(2-(1-cyclopropylethyl)-1-oxo-7-aminosulfonylisoindol-5-yl)-1-methyl-1H-pyrazole-3-yl)acetamide, the structure of which is as follows:

[0394]

[0395] The sample was prepared using intermediates 3 and 31, following the method described in Example 1. LC-MS(ESI):R T =0.68min,mass calcd.for C 19H 23 N5O4S 417.15 m / z,found 418.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.53(s,1H),8.08(s,1H),7.90(s,1H),7.73(s,2H),6.76(s,1H),4.77(s,2H),3.82(s,3H),3.70-3.5 9(m,1H),2.09-1.90(m,3H),1.33(d,J=6.8Hz,3H),1.24-1.11(m,1H),0.69-0.55(m,1H),0.48-0.37(m,2H),0.30-0.21(m,1H).

[0396] Example 5

[0397] This embodiment provides the compound: (S)-N-(6-(3-acetamido-1-methyl-1H-pyrazol-5-yl)-2-(1-cyclopropylethyl)-3-oxoisoindole-4-yl)acetamide, the structure of which is as follows:

[0398]

[0399] The sample was prepared using intermediates 3 and 32, following the method described in Example 1. LC-MS(ESI):R T =3.01min,mass calcd.for C 21 H 25 N5O3 395.20 m / z,found 395.8[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.48(s,1H),10.34(s,1H),8.41(s,1H),7.41(s,1H),6.66(s,1H),4.61(s,2H),3.77(s,3H),3.61-3.46(m ,1H),2.17(s,3H),2.01(s,3H),1.30(d,J=6.8Hz,3H),1.21-1.08(m,1H),0.67-0.52(m,1H),0.47-0.34(m,2H),0.30-0.21(m,1H).

[0400] Example 6

[0401] This embodiment provides the compound: (S)-N-(5-(2-(1-cyclopropylethyl)-7-(N-methylaminosulfonyl)-1-oxoisoindol-5-yl)-1-methyl-1H-pyrazole-3-yl)acetamide, the structure of which is as follows:

[0402]

[0403] The sample was prepared using intermediate 3 and intermediate 33, following the method described in Example 1. LC-MS(ESI):R T = 2.80 min, mass calcd. For C 20 H 25 N5O4S 431.16 m / z found 431.9[M+H] + . 1 H NMR(400MHz, CDCl3)δ8.16(s,1H),8.00(s,1H),7.78(s,1H),7.53-7.43(m,1H),6.91(s,1H),4.75-4.53(m,2H),3.87-3.77 (m,4H),2.69(d,J=5.2Hz,3H),2.21(s,3H),1.41(d,J=6.8Hz,3H),1.13-0.99(m,1H),0.77-0.65(m,1H),0.58-0.36(m,3H).

[0404] Example 7

[0405] This embodiment provides the compound: (S)-N-(5-(2-(1-cyclopropylethyl)-7-(N,N-dimethylaminosulfonyl)-1-oxoisoindol-5-yl)-1-methyl-1H-pyrazole-3-yl)acetamide, with the following structure:

[0406]

[0407] The sample was prepared using intermediates 3 and 35, following the method described in Example 1. LC-MS (ESI):R T =0.70min,mass calcd.for C 21 H 27 N5O4S 445.18 m / z,found 446.1[M+H] + . 1H NMR(400MHz,DMSO-d6)δ10.52(s,1H),8.08(s,1H),7.91(s,1H),6.78(s,1H),4.65(s,2H),3.82(s,3H),3.67-3.56(m,1H),2 .83(s,6H),2.02(s,3H),1.29(d,J=6.8Hz,3H),1.17-1.08(m,1H),0.65-0.52(m,1H),0.47-0.35(m,2H),0.28-0.14(m,1H).

[0408] Example 8

[0409] This embodiment provides the compound: (S)-N-(5-(2-(1-cyclopropylethyl)-7-(N-methylaminosulfonyl)-1-oxoisoindol-5-yl)-1H-pyrazole-3-yl)acetamide, with the following structure:

[0410]

[0411] The preparation method is as follows: TFA (2 mL) was added dropwise to a solution of intermediate 34 (350 mg, 639 μmol) in dichloromethane (2 mL). After the addition was complete, the mixture was stirred at room temperature for 2 h. Subsequently, the organic solvent was removed by vacuum distillation. 4 M ammonia-methanol solution (3 mL) was added to dissolve the compound, and stirring was continued at room temperature for 1 h. After the reaction was complete, the organic solvent was removed by vacuum distillation. The crude product was separated by column chromatography to obtain 33 mg of the target compound as a white solid. LC-MS (ESI): R T = 2.31 min, mass calcd. For C 19 H 23 N5O4S 41715 m / z found 417.9[M+H] + . 1 H NMR(400MHz,MeOD)δ8.43-8.29(m,1H),8.28-8.12(m,1H),7.68-6.39(m,2H),4.81-4.70(m,2H),4.62(s,2H),3.78-3 .65(m,1H),2.61(s,3H),2.18(s,3H),1.43(d,J=6.8Hz,3H),1.26-1.13(m,1H),0.77-0.66(m,1H),0.57-0.33(m,3H).

[0412] Example 9

[0413] This embodiment provides the compound: (S)-N-(5-(2-(1-cyclopropylethyl)-7-(methanesulfonamide)-1-oxoisoindol-5-yl)-1-methyl-1H-pyrazole-3-yl)acetamide, with the following structure:

[0414]

[0415] The sample was prepared using intermediates 3 and 14, following the method described in Example 1. LC-MS (ESI):R T = 3.07 min, mass calcd. For C 20 H 25 N5O4S 431.16 m / z found 431.8[M+H] + . 1 H NMR(400MHz, CDCl3)9.65(s,1H),7.86(s,1H),7.64(s,1H),7.24(s,1H),6.82(s,1H),4.61-4.44(m,2H),3.80(s,3H),3.7 3-3.65(m,1H),3.11(s,3H),2.18(s,3H),1.37(d,J=6.8Hz,3H),1.08-0.98(m,1H),0.72-0.64(m,1H),0.53-0.32(m,3H).

[0416] Example 10

[0417] This embodiment provides the compound: (S)-N-(5-(7-(N-cyclobutylaminosulfonyl)-2-(1-cyclopropylethyl)-1-oxoisoindol-5-yl)-1-methyl-1H-pyrazole-3-yl)acetamide, with the following structure:

[0418]

[0419] The sample was prepared using intermediates 3 and 36, following the method described in Example 1. LC-MS(ESI):R T = 3.48 min, mass calcd. for C 23 H 29 N5O4S 471.19 m / z,found 471.8[M+H] + . 1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),8.10(s,1H),8.05-7.98(m,1H),7.89(s ,1H),6.79(s,1H),4.77(s,2H),3.82(s,3H),3.75-3.62(m,2H),2.02(s,3H), 1.96-1.83(m,2H),1.80-1.64(m,2H),1.55-1.42(m,2H),1.35(d,J=6.8Hz,3H ),1.26-1.13(m,1H),0.69-0.56(m,1H),0.51-0.36(m,2H),0.34-0.22(m,1H).

[0420] Example 11

[0421] This embodiment provides the compound: N-(5-(2-isopropyl-7-(N-methylaminosulfonyl)-1-oxoisoindol-5-yl)-1-methyl-1H-pyrazole-3-yl)acetamide, with the following structure:

[0422]

[0423] The sample was prepared using intermediates 3 and 37, following the method described in Example 1. LC-MS (ESI):R T = 2.52 min, mass calcd. For C 18 H 23 N5O4S 405.15 m / z found 406.1[M+H] + . 1 H NMR (400MHz, CDCl3) δ8.16(s,1H),7.95(s,1H),7.77(s,1H),7.51-7.44(m,1H),6.91(s,1H),4.76 -4.66(m,1H),4.50(s,2H),3.83(s,3H),2.70(d,J=5.2Hz,3H),2.21(s,3H),1.37(d,J=6.8Hz,6H).

[0424] Example 12

[0425] This embodiment provides the compound: (S)-N-(5-(2-(1-cyclopropylethyl)-1-oxo-7-aminosulfonyl isoydindol-5-yl)-1H-pyrazole-3-yl)acetamide, with the following structure:

[0426]

[0427] The intermediate 38 was prepared according to the method of Example 8. LC-MS(ESI):R T =1.94min masscalcd.For C 18 H 21 N5O4S 403.13 m / z found 403.8[M+H] + . 1 H NMR(400MHz,DMSO-d6)13.05(br.s.,1H),10.31(br.s.,1H),8.47-8.06(m,2H),7.78-7.46(m,2H),7.19-6.27(m,1H),4.73(s,2H), 3.79-3.61(m,1H),2.07(s,3H),1.35(d,J=6.8Hz,3H),1.25-1.16(m,1H),0.68-0.58(m,1H),0.52-0.39(m,2H),0.36-0.26(m,1H).

[0428] Example 13

[0429] This embodiment provides the compound: (S)-N-(5-(2-(1-cyclopropylethyl)-7-(N-(cyclopropylmethyl)aminosulfonyl)-1-oxoisoindol-5-yl)-1-methyl-1H-pyrazole-3-yl)acetamide, with the following structure:

[0430]

[0431] The sample was prepared using intermediates 3 and 39, following the method described in Example 1. LC-MS(ESI):R T = 3.36 min, mass calcd. For C 23 H 29 N5O4S 471.19 m / z found 471.9[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.54(s,1H),8.12-8.08(m,1H),7.95-7.88(m,2H),6.79(s,1H),4.77(s,2H),3.83(s,3H),3.66-3.63(m,1H),2.82-2 .74(m,2H),2.03(s,3H),1.35(d,J=6.8Hz,3H),1.26-1.14(m,1H),0.76 -0.58(m,2H),0.51-0.39(m,2H),0.33-0.19(m,3H),0.05-0.07(m,2H).

[0432] Example 14

[0433] This embodiment provides the compound: (S)-N-(5-(2-(1-cyclopropylethyl)-7-(N-cyclopropylaminosulfonyl)-1-oxoisoindol-5-yl)-1-methyl-1H-pyrazole-3-yl)acetamide, with the following structure:

[0434]

[0435] The sample was prepared using intermediates 3 and 40, following the method described in Example 1. LC-MS(ESI):R T = 3.23 min, mass calcd. For C 22 H 27 N5O4S 457.18 m / z found 457.9[M+H] + . 1 H NMR(400MHz,DMSO-d6)10.53(s,1H),8.15-8.10(m,1H),7.99(s,1H),7.96-7.92(m,1H),6.79(s,1H),4.78(s,2H),3.83(s,3H),3.70-3.62 (m,1H),2.29-2.18(m,1H),2.02(s,3H),1.33(d,J=6.8Hz,3H),1.24-1.13(m,1H),0.66-0.57(m,1H),0.53-0.41(m,6H),0.34-0.22(m,1H).

[0436] Example 15

[0437] This embodiment provides the compound: (S)-N-(5-(2-(1-cyclopropylethyl)-7-(N-ethylaminosulfonyl)-1-oxoisoindol-5-yl)-1-methyl-1H-pyrazole-3-yl)acetamide, with the following structure:

[0438]

[0439] The sample was prepared using intermediates 3 and 41, following the method described in Example 1. LC-MS(ESI):R T =3.12min,mass calcd.for C 21 H 27 N5O4S 445.18 m / z,found 445.8[M+H] + . 1H NMR(400MHz, CDCl3)8.14(s,1H),7.87(s,1H),7.74(s,1H),7.56-7.51(m,1H),6.88(s,1H),4.71-4.51(m,2H),3.85-3.76(m,4H),3. 08-2.98(m,2H),2.19(s,3H),1.39(d,J=7.2Hz,3H),1.10(t,J=6.8Hz,3H),1.07-1.00(m,1H),0.74-0.64(m,1H),0.53-0.35(m,3H).

[0440] Example 16

[0441] This embodiment provides the compound: (S)-N-(5-(2-(1-cyclopropylethyl)-7-(N-(oxetane-3-yl)aminosulfonyl)-1-oxoisoindol-5-yl)-1-methyl-1H-pyrazole-3-yl)acetamide, with the following structure:

[0442]

[0443] The sample was prepared using intermediates 3 and 42, following the method described in Example 1. LC-MS(ESI):R T = 2.73 min, mass calcd. For C 22 H 27 N5O5S 473.17 m / z found 473.8[M+H] + .1H NMR(400MHz, CDCl3)8.45-8.40(m,1H),8.08(s,1H),7.86(s,1H),7.76(s,1H),6.89(s,1H),4.72-4.51(m,7H), 3.86-3.77(m,4H),2.18(s,3H),1.40(d,J=6.8Hz,3H),1.12-0.98(m,1H),0.75-0.67(m,1H),0.54-0.36(m,3H).

[0444] Example 17

[0445] This embodiment provides the compound: (S)-N-(5-(2-(1-cyclopropylethyl)-7-(N-(3,3-difluorocyclobutyl)aminosulfonyl)-1-oxoisoindol-5-yl)-1-methyl-1H-pyrazole-3-yl)acetamide, with the following structure:

[0446]

[0447] The sample was prepared using intermediates 3 and 43, following the method described in Example 1. LC-MS (ESI):R T = 4.67 min, mass calcd. For C 23 H 27 F2N5O4S 507.18 m / z found 507.8[M+H] + . 1 H NMR (400MHz, CDCl3) δ8.25-8.19(m,1H),8.14(s,1H),7.93(s,1H),7.80(s,1H),6.93(s,1H),4.76-4.55(m,2H),3.84(s,3H),3.83-3.73( m,2H),2.85-2.69(m,2H),2.65-2.43(m,2H),2.21(s,3H),1.42(d,J=6.8Hz,3H),1.14-1.01(m,1H),0.78-0.68(m,1H),0.55-0.37(m,3H).

[0448] Example 18

[0449] This embodiment provides the compound: (S)-N-(5-(2-(1-cyclopropylethyl)-7-(N-(2-methoxyethyl)aminosulfonyl)-1-oxoisoindoline-5-yl)-1-methyl-1H-pyrazole-3-yl)acetamide, with the following structure:

[0450]

[0451] Preparation method: Intermediate 3 and intermediate 44 were used to prepare the sample according to the method described in Example 1. LC-MS (ESI): RT = 2.96 min, mass calcd. for C 22 H 29 N5O5S 475.19 m / z,found 475.9[M+H] + . 1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),8.12-8.07(m,1H),7.90-7.88(m,1H),7. 87-7.82(m,1H),6.79(s,1H),4.76(s,2H),3.82(s,3H),3.71-3.57(m,1H),3.25 -3.16(m,2H),3.08-3.04(m,2H),2.93(s,3H),2.02(s,3H),1.34(d,J=7.0Hz,3 H),1.24-1.11(m,1H),0.66-0.55(m,1H),0.49-0.39(m,2H),0.34-0.24(m,1H).

[0452] Example 19

[0453] This embodiment provides a compound: (S)-N-(5-(2-(1-cyclopropylethyl)-7-(N-((1-(fluoromethyl)cyclopropyl)methyl)aminosulfonyl)-1-oxoisoindol-5-yl)-1-methyl-1H-pyrazole-3-yl)acetamide, with the following structure:

[0454]

[0455] The above compound was prepared using intermediates 3 and 24 according to the method described in Example 1. LC-MS (ESI): R T = 3.59 min, mass calcd. For C 24 H 30 FN5O4S 503.20 m / z found 503.9[M+H] + . 1 HNMR(400MHz,CDCl3)d 8.12(s,1H),8.02-7.95(m,2H),7.76(s,1H),6.91(s,1H),4.72-4.51(m,2H),3.86-3.77(m,4H),3.33-3.22(m,2H),2.28-2.15 (m,7H),1.88-1.77(m,1H),1.57-1.46(m,1H),1.40(d,J=6.8Hz,3H),1.11-1.01(m,1H),0.75-0.64(m,1H),0.54-0.36(m,3H).

[0456] Example 20

[0457] This embodiment provides the compound: (S)-N-(5-(2-(1-cyclopropylethyl)-1-oxo-7-(N-(2,2,2-trifluoroethyl)aminosulfonyl)isoindoline-5-yl)-1-methyl-1H-pyrazole-3-yl)acetamide, with the following structure:

[0458]

[0459] The sample was prepared using intermediates 3 and 45, following the method described in Example 1. LC-MS (ESI): R T = 3.51 min, mass calcd. for C 21 H 24 F3N5O4S 499.15 m / z,found 499.8[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.53(s,1H),8.58(s,1H),8.14-8.09(m,1H),7.92-7.88(m,1H),6.80(s,1H),4.77(s,2H),3.97-3.86(m,2H),3.82 (s,3H),3.72-3.61(m,1H),2.02(s,3H),1.33(d,J=7.0Hz,3H),1.23-1.13(m,1H),0.68-0.55(m,1H),0.48-0.40(m,2H),0.33-0.24(m,1H).

[0460] Example 21

[0461] This embodiment provides the compound: N-(5-(2-isopropyl-1-oxo-7-aminosulfonylisoindol-5-yl)-1-methyl-1H-pyrazole-3-yl)acetamide, with the following structure:

[0462]

[0463] The sample was prepared using intermediates 3 and 48, following the method described in Example 1. LC-MS (ESI):R T = 3.50 min, mass calcd. For C 17 H 21 N5O4S 391.13 m / z found 391.8[M+H] + . 1H NMR (400MHz, CDCl3) δ8.14(s,1H),7.86(s,1H),7.76(s,1H),6.88(s,1H),6.63(s,2 H),4.77-4.67(m,1H),4.51(s,2H),3.82(s,3H),2.21(s,3H),1.37(d,J=6.8Hz,6H).

[0464] Example 22

[0465] This embodiment provides the compound: (S)-N-(5-(2-(1-cyclopropylethyl)-7-(methylsulfonamide)-1-oxoisoindol-5-yl)-1H-pyrazole-3-yl)acetamide, with the following structure:

[0466]

[0467] The intermediate 29 was prepared using the method described in Example 8. LC-MS(ESI):R T = 2.43 min, masscalcd. For C 19 H 23 N5O4S 471.15 m / z found 471.8[M+H] + . 1 H NMR(400MHz,DMSO-d6)13.05-12.43(m,1H),10.53-10.10(m,1H),9.56(s,1H),8.00-7.59(m,2H),7.08-6.31(m,1H),4.61(s,2H),3.72-3.5 1(m,1H),3.33-3.21(m,3H),2.06(s,3H),1.33(d,J=7.2Hz,3H),1.23- 1.13(m,1H),0.66-0.56(m,1H),0.53-0.36(m,2H),0.34-0.25(m,1H).

[0468] Example 23

[0469] This embodiment provides a compound: (S)-N-(5-(7-(cyclopropanesulfonamide)-2-(1-cyclopropylethyl)-1-oxoisoindol-5-yl)-1-methyl-1H-pyrazole-3-yl)acetamide, with the following structure:

[0470]

[0471] The sample was prepared using intermediates 3 and 49, following the method described in Example 1. LC-MS(ESI):R T= 3.35min, mass calcd.for C 22 H 27 N5O4S 457.18 m / z,found 457.8[M+H] + . 1 H NMR(400MHz, CDCl3)9.62(s,1H),7.82(s,1H),7.69(s,1H),7.23(s,1H),6.81(s,1H),4.61-4.42(m,2H),3.81(s,3H),3.74-3.62(m,1 H),2.65-2.55(m,1H),2.18(s,3H),1.37(d,J=6.8Hz,3H),1.33-1.27(m,2H),1.08-0.97(m,3H),0.72-0.62(m,1H),0.53-0.33(m,3H).

[0472] Example 24

[0473] This embodiment provides a compound: (S)-N-(5-(2-(1-cyclopropylethyl)-1-oxo-7-(propylsulfonylamino)isoindol-5-yl)-1-methyl-1H-pyrazole-3-yl)acetamide, with the following structure:

[0474]

[0475] The method described in Example 1 is used to prepare the sample using intermediates 3 and 50. LC-MS(ESI):R T = 2.98 min, mass calcd.for C 22 H 29 N5O4S 459.19 m / z found 459.9[M+H] + . 1 H NMR(400MHz, CDCl3)9.63(br.s.,1H),7.89(s,1H),7.67(s,1H),7.25(s,1H),6.83(s,1H),4.65-4.46(m,2H),3.83(s,3H),3.77-3.65(m,1 H),3.21-3.12(m,2H),2.20(s,3H),1.99-1.84(m,2H),1.39(d,J=6.8Hz,3H),1.05(t,J=7.8Hz,4H),0.75-0.66(m,1H),0.54-0.35(m,3H).

[0476] Example 25

[0477] This embodiment provides the compound: (S)-N-(5-(2-(1-cyclopropylethyl)-7-(ethylsulfonamide)-1-oxoisoindol-5-yl)-1-methyl-1H-pyrazole-3-yl)acetamide, with the following structure:

[0478]

[0479] The sample was prepared using intermediates 3 and 9, as described in Example 1. LC-MS(ESI):R T = 3.51 min, mass calcd. for C 21 H 27 N5O4S 445.18 m / z,found 445.8[M+H] + . 1 H NMR(400MHz, CDCl3)d9.63(s,1H),7.75(s,1H),7.66(s,1H),7.22(s,1H),6.81(s,1H),4.60-4.42(m,2H),3.80(s,3H),3.76- 3.64(m,1H),3.20(q,J=7.2Hz,2H),2.18(s,3H),1.43-1.36(m,6H),1.08-0.97(m,1H),0.72-0.64(m,1H),0.51-0.34(m,3H).

[0480] Example 26

[0481] This embodiment provides the compound: (S)-N-(5-(2-(1-cyclopropylethyl)-7-(1,1-dimethylethylsulfonamide)-1-oxoisoindol-5-yl)-1-methyl-1H-pyrazole-3-yl)acetamide, with the following structure:

[0482]

[0483] The sample was prepared using intermediates 3 and 16, as described in Example 1. LC-MS(ESI):R T = 3.70 min, mass calcd. for C 23 H 31 N5O4S 473.21 m / z,found 473.9[M+H] + . 1H NMR(400MHz,DMSO-d6)δ10.50(s,1H),9.64(s,1H),7.57(s,1H),7.43(s,1H),6.64(s,1H),4.64(s,2H),3.76(s,3H),3.64-3.50(m ,1H),2.01(s,3H),1.36(s,9H),1.31(d,J=6.8Hz,3H),1.21-1.08(m,1H),0.64-0.53(m,1H),0.48-0.35(m,2H),0.31-0.21(m,1H).

[0484] Example 27

[0485] This embodiment provides the compound: (S)-N-(5-(2-(1-cyclopropylethyl)-7-(2-methoxyethylsulfonamide)-1-oxoisoindol-5-yl)-1-methyl-1H-pyrazole-3-yl)acetamide, with the following structure:

[0486]

[0487] The method described in Example 1 was used to prepare the sample using intermediates 3 and 17. LC-MS(ESI):R T = 3.28min, mass calcd.for C 22 H 29 N5O5S 475.19 m / z,found 475.8[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.48(s,1H),9.63(s,1H),7.51(s,1H),7.44(s,1 H),6.68(s,1H),4.63(s,2H),3.78(s,3H),3.70-3.65(m,2H),3.65-3.59(m ,2H),3.58-3.49(m,1H),3.12(s,3H),2.01(s,3H),1.31(d,J=6.8Hz,3H),1 .22-1.09(m,1H),0.65-0.54(m,1H),0.48-0.36(m,2H),0.30-0.19(m,1H).

[0488] Example 28

[0489] This embodiment provides the compound: (S)-N-(5-(2-(1-cyclopropylethyl)-7-(cyclopropylmethylsulfonylamino)-1-oxoisoindoline-5-yl)-1-methyl-1H-pyrazole-3-yl)acetamide, with the following structure:

[0490]

[0491] Preparation method: Under nitrogen protection, DIPEA (790 mg, 1.06 mL, 6.11 mmol, 6 eq), DMAP (49.8 mg, 407 μmol, 0.4 eq), triethylamine (412 mg, 567 μL, 4.07 mmol, 4 eq), and pyridine (564 mg, 576 μL, 7.13 mmol, 7 eq) were added dropwise to a solution of intermediate 87 (360 mg, 1.02 mmol, 1 eq) and cyclopropylmethanesulfonyl chloride (709 mg, 4.58 mmol, 4.5 eq) in dichloromethane (6 mL). After the addition was complete, the mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction solution was extracted with dichloromethane and water, and the organic phase was separated and dried over anhydrous sodium sulfate. The organic solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by column chromatography to obtain 7 mg of the target compound as a white solid. LC-MS (ESI): R T = 2.96 min, masscalcd.for C 23 H 29 N5O4S 471.19 m / z,found 472.0[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.47(s,1H),9.68(s,1H),7.50(s,1H),7.44(s,1H) ,6.68(s,1H),4.64(s,2H),3.77(s,3H),3.59-3.51(m,1H),3.40-3.34(m,2H ),2.01(s,3H),1.31(d,J=6.8Hz,3H),1.19-1.12(m,1H),1.08-0.97(m,1H), 0.62-0.55(m,1H),0.54-0.49(m,2H),0.45-0.37(m,2H),0.28-0.21(m,3H).

[0492] Example 29

[0493] This embodiment provides the compound: (S)-N-(5-(2-(1-cyclopropylethyl)-7-(1,3-dimethyl-1H-pyrazole-4-sulfonamide)-1-oxoisoindol-5-yl)-1-methyl-1H-pyrazole-3-yl)acetamide, with the following structure:

[0494]

[0495] The method described in Example 1 was used to prepare the sample using intermediates 3 and 18. LC-MS(ESI):RT = 3.40 min, mass calcd. for C 24 H 29 N7O4S 511.20 m / z,found 511.9[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.49(s,1H),9.98(s,1H),8.43(s,1H),7.41(s,1H),7.34(s,1H),6.63(s,1H),4.60(s,2H),3.72(d,J=7.8Hz,6H),3. 60-3.48(m,1H),2.22(s,3H),2.02(s,3H),1.29(d,J=6.8Hz,3H),1.19 -1.05(m,1H),0.63-0.51(m,1H),0.46-0.33(m,2H),0.28-0.19(m,1H).

[0496] Example 30

[0497] This embodiment provides the compound: N-(5-(2-(2-cyclopropylpropyl-2-yl)-7-(N-methylaminosulfonyl)-1-oxoisoindol-5-yl)-1-methyl-1H-pyrazole-3-yl)acetamide, with the following structure:

[0498]

[0499] The method described in Example 1 was used to prepare the sample using intermediates 3 and 54. LC-MS(ESI):R T = 3.43 min, mass calcd. For C 21 H 27 N5O4S 445.18 m / z found 446.1[M+H] + . 1 H NMR(400MHz, CDCl3)8.15(s,1H),8.02(s,1H),7.72(s,1H),7.58-7.50(m,1H),6.89(s,1H),4.73(s,2H),3.81(s ,3H),2.69(d,J=5.2Hz,3H),2.21(s,3H),1.50(s,6H),1.47-1.41(m,1H),0.66-0.58(m,2H),0.56-0.49(m,2H).

[0500] Example 31

[0501] This embodiment provides the compound: (S)-N-(5-(2-(3,3-dimethylbutane-2-yl)-7-(N-methylaminosulfonyl)-1-oxoisoindoline-5-yl)-1-methyl-1H-pyrazol-3-yl)acetamide, with the following structure:

[0502]

[0503] The sample was prepared using intermediates 3 and 58, as described in Example 1. LC-MS(ESI):R T = 2.82 min, mass calcd. for C 21 H 29 N5O4S 447.19 m / z,found 447.8[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.54(s,1H),8.11-8.04(m,1H),7.97-7.88(m,1H),7.64-7.52(m,1H),6.79(s,1H),4. 73(s,2H),4.28-4.18(m,1H),3.83(s,3H),2.49-2.49(m,3H),2.02(s,3H),1.27(d,J=7.3Hz,3H),0.97(s,9H). 1 H NMR (400MHz, CDCl3) δ8.18-8.13(m,1H),7.85(s,1H),7.76-7.71(m,1H),7.52-7.45(m,1H),6.90(s,1H),4.59( s,2H),4.45-4.37(m,1H),3.83(s,3H),2.67(d,J=5.3Hz,3H),2.20(s,3H),1.33(d,J=7.0Hz,3H),1.04(s,9H).

[0504] Example 32

[0505] This embodiment provides the compound: N-(5-(2-(tert-butyl)-7-(N-methylaminosulfonyl)-1-oxoisoindol-5-yl)-1-methyl-1H-pyrazole-3-yl)acetamide, with the following structure:

[0506]

[0507] The sample was prepared using intermediates 3 and 62, as described in Example 1. LC-MS(ESI):R T = 2.31 min, mass calcd.for C 19 H25 N5O4S 419.16 m / z,found 419.9[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.54(s,1H),8.11-8.05(m,1H),7.92-7.85(m,1H),7.61-7.51 (m,1H),6.78(s,1H),4.80(s,2H),3.81(s,3H),2.52(s,3H),2.02(s,3H),1.53(s,9H).

[0508] Example 33

[0509] This embodiment provides the compound: (S)-N-(1-methyl-5-(7-(N-methylaminosulfonyl)-1-oxo-2-(1,1,1-trifluoropropane-2-yl)isoindoline-5-yl)-1H-pyrazol-3-yl)acetamide, with the following structure:

[0510]

[0511] The sample was prepared using intermediates 3 and 66, as described in Example 1. LC-MS(ESI):R T = 2.31 min, mass calcd.for C 18 H 20 F3N5O4S 459.12 m / z,found 459.8[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.55(s,1H),8.16-8.12(m,1H),7.99-7.91(m,1H),7.22-7.11(m,1H),6.82(s,1H),5.18-5.06(m ,1H),4.85(d,J=18.1Hz,1H),4.64(d,J=18.1Hz,1H),3.84(s,3H),2.55-2.53(m,3H),2.02(s,3H),1.54(d,J=7.0Hz,3H).

[0512] Example 34

[0513] This embodiment provides the compound: (S)-N-(5-(7-(N-(3-cyanophenyl)aminosulfonyl)-2-(1-cyclopropylethyl)-1-oxoisoindol-5-yl)-1-methyl-1H-pyrazole-3-yl)acetamide, with the following structure:

[0514]

[0515] The preparation was carried out using intermediates 3 and 67, as described in Example 1. LC-MS(ESI):R T =3.23min,mass calcd.for C 26 H 26 N6O4S 518.17 m / z,found 518.8[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.52(s,1H),9.24(s,1H),8.09-7.93(m,2H),7.42(s,4H),6.75(s,1H),4.73(s,2H),3.75(s,3H),3. 71-3.64(m,1H),2.01(s,3H),1.40-1.32(m,3H),1.25-1.14(m,1H),0.66-0.57(m,1H),0.51-0.39(m,2H),0.39-0.31(m,1H).

[0516] Example 35

[0517] This embodiment provides the compound: N-(5-(7-(N-(3-cyanophenyl)aminosulfonyl)-2-isopropyl-1-oxoisoindol-5-yl)-1-methyl-1H-pyrazole-3-yl)acetamide, with the following structure:

[0518]

[0519] The method described in Example 1 was used to prepare the sample using intermediates 3 and 68. LC-MS(ESI):R T = 2.84 min, mass calcd. For C 24 H 24 N6O4S 492.16 m / z found 492.8[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.55-10.42(m,2H),8.08(s,1H),7.97(s,1H),7.53-7.47(m,2H),7.46-7.40 (m,2H),6.76(s,1H),4.64(s,2H),4.55-4.44(m,1H),3.76(s,3H),2.01(s,3H),1.30(d,J=6.5Hz,6H).

[0520] Example 36

[0521] This embodiment provides the compound: (S)-N-(5-(2-(1-cyclopropylethyl)-7-ethyl-1-oxoisoindol-5-yl)-1-methyl-1H-pyrazole-3-yl)acetamide, with the following structure:

[0522]

[0523] Preparation method: Acetic anhydride (708 mg, 6.94 mmol, 650 μl, 5 eq) was added to a 5 mL solution of intermediate 76 in dichloromethane. The mixture was stirred at room temperature for 16 h. Three-quarters of the organic solvent was removed by vacuum distillation. The filtrate was extracted with dichloromethane and water, and the organic layer was separated. The residue was dried over anhydrous sodium sulfate and the organic solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by column chromatography to obtain a white solid compound (60.6 mg, 11.92%). LC-MS (ESI): R T = 3.24 min, masscalcd. For C 21 H 26 N4O2 366.21 m / z found 366.8[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.45(s,1H),7.56(s,1H),7.40(s,1H),6.67(s,1H),4.59-4.40(m,2H),3.78(s,3H),3.66-3.51(m,1H),3.20-3.07( m,2H),2.01(s,3H),1.28(d,J=6.8Hz,3H),1.21(t,J=7.5Hz,3H),1.16 -1.07(m,1H),0.62-0.53(m,1H),0.46-0.34(m,2H),0.28-0.19(m,1H).

[0524] Example 37

[0525] This embodiment provides the compound: (S)-N-(5-(2-(1-cyclopropylethyl)-7-ethoxy-1-oxoisoindol-5-yl)-1-methyl-1H-pyrazole-3-yl)acetamide, with the following structure:

[0526]

[0527] The preparation was carried out using intermediates 3 and 77, as described in Example 1. LC-MS(ESI):R T = 3.01 min, mass calcd. For C 21 H 26N4O3 382.20 m / z found 382.8[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.46(s,1H),7.25(s,1H),7.06(s,1H),6.68(s,1H),4.50(s,2H),4.25-4.16(m,2H),3.78(s,3H),3.56-3.46(m ,1H),2.01(s,3H),1.39-1.32(m,3H),1.25(d,J=6.8Hz,3H),1.14-1.03(m,1H),0.61-0.50(m,1H),0.45-0.29(m,2H),0.26-0.17(m,1H).

[0528] Example 38

[0529] This embodiment provides the compound: (S)-N-(5-(2-(1-cyclopropylethyl)-7-(ethylamino)-1-oxoisoindol-5-yl)-1-methyl-1H-pyrazole-3-yl)acetamide, with the following structure:

[0530]

[0531] Preparation method: TFA (4.32 g, 37.9 mmol, 2.80 mL, 100 eq) was added to a solution of intermediate 79 (190 mg, 379 μmol, 1 eq) in dichloromethane (2 mL). The mixture was stirred at 50 °C for 3 h. After the reaction was complete, the organic solvent was removed by vacuum distillation. The mixture was extracted with ethyl acetate and water, and the organic layer was separated, dried over magnesium sulfate, filtered, and then distilled under reduced pressure to obtain the crude product (70.5 mg, 49%). The crude product was separated by column chromatography to obtain the target compound as a white solid. LC-MS (ESI): R T = 3.42 min, masscalcd. For C 21 H 27 N5O2 381.22 m / z found 381.8[M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.42(s,1H),6.80(s,1H),6.69-6.63(m,1H),6.59(d,J=6.3Hz,2H),4.47(s,2H),3.76(s,3H),3.58-3.45(m,1H),3.29- 3.15(m,2H),2.00(s,3H),1.26(d,J=6.8Hz,3H),1.22-1.17(m,3H),1.1 4-1.05(m,1H),0.62-0.50(m,1H),0.45-0.31(m,2H),0.27-0.16(m,1H).

[0532] Example 39

[0533] This embodiment provides the compound: (S)-6-(3-acetamido-1-methyl-1H-pyrazole-5-yl)-2-(1-cyclopropylethyl)-N-methyl-3-oxoisodihydroindole-4-carboxamide, with the following structure:

[0534]

[0535] The sample was prepared using intermediates 3 and 83, as described in Example 1. LC-MS(ESI):R T = 2.97 min, mass calcd. For C 21 H 25 N5O3 395.20 m / z found 395.8[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.32-11.15(m,1H),10.50(s,1H),8.27(s,1H),7.97(s,1H),6.75(s,1H),4.72(s,2H),3.81(s,3H),3.73-3.55(m, 1H),2.89(d,J=4.3Hz,3H),2.02(s,3H),1.33(d,J=6.8Hz,3H),1.22-1.11(m,1H),0.79-0.55(m,1H),0.52-0.38(m,2H),0.34-0.18(m,1H).

[0536] Example 40

[0537] This embodiment provides the compound: (S)-2-(1-cyclopropylethyl)-5-(1-methyl-3-((6-(2-oxopyrrolidin-1-yl)pyridin-2-yl)amino)-1H-pyrazole-5-yl)-7-(methanesulfonyl)isoindoline-1-one, with the following structure:

[0538]

[0539] Preparation method: The compound from Example 1, (S)-N-(5-(2-(1-cyclopropylethyl)-7-(methanesulfonyl)-1-oxoisoindol-5-yl)-1-methyl-1H-pyrazol-3-yl)acetamide (320 mg, 768.32 μmol, 1 eq), was dissolved in 10 mL of 4 M HCl in 1,4-dioxane, and H₂O (1 mL) was slowly added dropwise. The reaction was carried out at 70 °C for 2 h. After the reaction was complete, the reaction solution was cooled to room temperature, and the organic solvent was removed by vacuum distillation, yielding a yellow solid compound. Subsequently, under Ar protection, 1-(6-bromo-2-pyridyl)pyrrolidone-2-one (141 mg, 584 μmol, 0.8 eq), Cs₂CO₃ (833 mg, 2.56 mmol, 3.5 eq), 1,4-dioxane (8 mL), Pd₂(dba)₃ (67 mg, 73 μmol, 0.1 eq), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (84.5 mg, 146 μmol, 0.2 eq) were added to a sealed tube. The reaction was carried out at 100 °C for 16 h. After the reaction was complete, the reaction solution was cooled to room temperature. The organic solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by column chromatography to obtain the target compound (29.3 mg, 7.4%) as a white solid. LC-MS (ESI): R T = 3.69 min, mass calcd. For C 27 H 30 N6O4S 534.20m / z found 535.2[M+H] + . 1 H NMR(400MHz, CDCl3)δ8.30(s,1H),7.85-7.81(m,1H),7.79(s,1H),7.60-7.53(m, 1H),6.83-6.75(m,2H),6.58(s,1H),4.75-4.51(m,2H),4.10(t,J=7.2Hz,2H),3.8 5(s,3H),3.83-3.77(m,1H),3.66(s,3H),2.65(t,J=8.0Hz,2H),2.16-2.08(m,2H ),1.39(d,J=6.8Hz,3H),1.09-0.99(m,1H),0.72-0.64(m,1H),0.53-0.37(m,3H).

[0540] Example 41

[0541] This embodiment provides the compound: (S)-N-(5-(2-(1-cyclopropylethyl)-7-methyl-1-oxoisoindoline-5-yl)-1-methyl-1H-pyrazole-3-yl)acetamide, with the following structure:

[0542]

[0543] The method described in Example 36 is prepared using intermediates 3 and 88. (mass calcd.forC) 20 H 24 N4O2 352.2 m / z,found 353.1[M+H] + .

[0544] Example 42

[0545] This embodiment provides the compound: N-(1-methyl-5-(4-methyl-1-oxoisoindol-5-yl)-1H-pyrazol-3-yl)acetamide, with the following structure:

[0546]

[0547] The method described in Example 36 is prepared using intermediates 3 and 89. (mass calcd.forC) 15 H 16 N4O2 284.1 m / z,found 285.0[M+H] + .

[0548] Example 43

[0549] This embodiment provides the compound: N-(5-(2-ethyl-1-oxoisoindoline-5-yl)-1-methyl-1H-pyrazole-3-yl)acetamide, with the following structure:

[0550]

[0551] The method described in Example 36 is prepared using intermediates 3 and 90. (mass calcd.forC) 16 H 18 N4O2 298.1 m / z,found 299.1[M+H] + .

[0552] Example 44

[0553] This embodiment provides the compound: N-(1-methyl-5-(7-methyl-1-oxoisoindoline-5-yl)-1H-pyrazol-3-yl)acetamide, with the following structure:

[0554]

[0555] The method described in Example 36 is prepared using intermediates 3 and 91. (mass calcd.forC) 15 H 16 N4O2 284.1 m / z,found 284.8[M+H] + .

[0556] Example 45

[0557] This embodiment provides the compound: N-(5-(2-(cyclopropylmethyl)-1-oxoisoindoline-5-yl)-1-methyl-1H-pyrazol-3-yl)acetamide, with the following structure:

[0558]

[0559] The method described in Example 36 is prepared using intermediates 3 and 92. (mass calcd.forC) 18 H 20 N4O2 324.1 m / z,found 325.0[M+H] + .

[0560] Example 46

[0561] This embodiment provides the compound: N-(1-methyl-5-(2-methyl-1-oxoisoindol-5-yl)-1H-pyrazol-3-yl)acetamide, with the following structure:

[0562]

[0563] The method described in Example 36 is prepared using intermediates 3 and 84. (mass calcd.forC) 15 H 16 N4O2 284.1 m / z,found 285.0[M+H] + .

[0564] Example 47

[0565] This embodiment provides the compound: N-(5-(8-(ethylsulfonamide)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)-1-methyl-1H-pyrazol-3-yl)acetamide, with the following structure:

[0566]

[0567] Under nitrogen protection, intermediates 93 (109 mg, 0.5 mmol), 97 (285 mg, 0.75 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (36.6 mg, 0.05 mol), and potassium phosphate (318.5 mg, 1.5 mmol) were mixed, and dioxane (3 mL) and water (0.5 mL) were added. The mixture was heated to 90 °C and reacted for 11 h. After the reaction was complete, the mixture was concentrated and purified by silica gel column chromatography to obtain 66 mg of the target compound. 17 H 21 N5O4S 391.13 m / z,found 391.9[M+H]+.

[0568] Biological testing evaluation

[0569] Test Example 1 - Testing the inhibitory effect of the compounds in each example on the activity of PI3Kα / β / γ / δ kinases.

[0570] Experimental instruments: Centrifuges were purchased from Eppendorf, pipettes were purchased from Eppendorf and Gilson, and microplate readers were purchased from Thermo Fisher Scientific, USA, specifically the Varioskan LUX multi-functional microplate reader.

[0571] Experimental materials:

[0572] name Item number ΡΙ3Kα(p110α / p85α) Invitrogen#PV4788 ΡΙ3Kβ(p110β / p85α) Eurofins#14-603M ΡΙ3Kγ Invitrogen#PR8641C ΡΙ3Kδ(p110β) Millipore #14-604-M ADP-Glo ​​Kinase Assay Promege#v9102 / 3 PIP2 Life Technologies #PR8982B HEPES Gibco#11344-041 EDTA Gibco#15575-038 <![CDATA[MgCl2]]> Sigma#M2670-500g 96well plate Corning#3365

[0573] Experimental Methods: This experiment employed the ADP-Glo ​​lipid kinase assay method from Promega. The lipid kinase PI3Kα / β / γ / δ undergoes a catalytic reaction in the presence of a 1:3 mixture of substrate phosphoinositol-4,5-bisphosphate (PIP2) and apoliposide phosphatidylserine (PS) (PIP2:3PS) and ATP. ATP is converted to ADP. The activity of the lipid kinase is characterized by measuring the ADP content in the reaction, and the half-maximal inhibitory concentration (IC50) of the compound inhibiting the activity of PI3Kα / β / γ / δ kinases is determined. 50 .

[0574] The specific experimental procedure is as follows:

[0575] The kinase reaction was performed in a white 96-well plate. 2 μL of the compound of the present invention at different concentrations diluted with ddH2O containing 1% DMSO was added to each well. For the positive control wells, 2 μL of ddH2O containing 1% DMSO was added. Then, 2 μL of 0.1–2 nM PI3K kinase solution diluted with 5× kinase buffer (HEPES 250 mM, MgCl2 15 mM, NaCl 250 mM, BSA 0.05%) was added to each well. For the negative control wells, 2 μL of 5× kinase buffer was added. 4 μL of 50 μM substrate PIP2:3PS prepared with 10× dilution buffer and ddH2O was added to all wells. Finally, 2 μL of 50–100 μM ATP solution diluted with water was added to start the reaction. After reacting at room temperature for 90–120 min, 10 μL of ADP-Glo ​​Reagent (containing 10 mM MgCl2, MgCl2, NaCl, BSA 0.05%) was added to each well. The chemiluminescence value was measured using a Varioskan LUX microplate reader after reacting with MgCl2 at room temperature for 60 min to remove excess ATP. Then, 20 μL of kinase detection reagent was added to each well, and the reaction was carried out at room temperature in the dark for 20 min.

[0576] Experimental data processing method: % inhibition rate = 100 - [(test compound value - negative control value)] / (positive control value - negative control value) × 100. The IC50 was calculated using a four-parameter nonlinear logic formula to fit different concentrations and corresponding percentage inhibition rate data. 50 Values. Results are shown in Table 1 (Note: "-" indicates no detection).

[0577] Table 1

[0578]

[0579]

[0580] Test Example 2 - Determination of the inhibitory effect of the compounds from each example on the phosphorylation of AKT protein in the mouse macrophage-like cell line Raw264.7

[0581] Experimental instruments: Cell counter (Countstar-IC-1000) from Counterstar, CO2 incubator (Thermo Fisher Scientific MCO-15AC) from Thermo Fisher Scientific, pipettes (RAININ Multichannel), microplate reader (Envision multiple plate reader) from Perkin Elmer, centrifuge (Centrifuge ST 40R) from Thermo Fisher Scientific, water supply system (Milli-Q Reference system) from Millipore, ultra-low temperature freezer from Haier, and cryogenic storage boxes from Mr. Frosty. TM Gradient cooling box Cat#5100-0001.

[0582] Experimental methods: The inhibitory effects of various compounds on PI3Kγ-induced AKT protein phosphorylation in Raw264.7 cells were detected using the Phospho-AKT (ser473) kit, as detailed below:

[0583] Raw264.7 cell line (Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, #TIB-71) was cultured in RPMI 1640 medium (Invitrogen #11875093) containing 10% fetal bovine serum (FBS) (Gibco #10091148) and 1% penicillin and streptomycin (P / S (Invitrogen #15140122)) at 37°C and 5% CO2. Cells were collected before the experiment, counted, and seeded into 96-well cell culture plates at a density of 60,000 cells / 45 μL / well using RPMI-1640 medium without FBS. Cells were incubated overnight at 37°C and 5% CO2. After 18 hours of serum starvation, 45 μL of pre-prepared compound solutions of different concentrations were added to the cells to obtain a final DMSO concentration of 0.2%, and the cells were incubated at 37°C and 5% CO2 for 60 minutes. Cells were then stimulated for 5 minutes with 25 nM C5a solution (R&D System, #2150-C5 / CF) in the presence of the compound. The culture medium was aspirated, and 50 μL / well of lysis buffer was added. The cells were shaken at room temperature for 45 minutes, and then 16 μL / well of the lysate was transferred to a 384-well plate. A solvent control well was prepared, with no compound added. Premixed Phospho-AKT antibody reagent (Cisbio, #64AKSPEG) was added to each well at a density of 4 μL / well. The plate was centrifuged at 1000 rpm for 1 minute at room temperature, then incubated at 22°C for 4 hours, and read using an Envision microplate reader.

[0584] Experimental data processing method: % Inhibition rate = 100 - (Test compound value / Solvent control value) × 100. GraphPad Prism was used to fit different concentrations and corresponding inhibition rate data to a four-parameter nonlinear logic formula to calculate the IC50. 50 The values ​​are shown in Table 2.

[0585] Table 2

[0586] compound <![CDATA[IC 50 (μM)]]> Example 1 44.9 Example 6 24.1 Example 7 14.7 Example 9 5 Example 25 3.1 Example 37 5.8 Example 38 2.8 Example 39 76.8 Example 41 31

[0587] Test Example 3 - Efficacy testing of the compound in a syngeneic mouse tumor model

[0588] Experimental subjects: Female Balb / c mice aged 6-8 weeks.

[0589] Experimental methods:

[0590] 1) CT-26 tumor cells were placed in 1640 medium supplemented with 10% heat-inactivated fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin, and cultured at 37°C in air containing 5% CO2. The tumor cells were passaged twice a week as usual, and cells growing in the exponential growth phase were harvested and counted for tumor inoculation.

[0591] 3) CT-26 tumor cells obtained from culture were subcutaneously inoculated on the right side of mice, with approximately 5 × 10⁶ cells per mouse. 5 A 26-gauge needle was used for injection when the tumor volume reached approximately 100 mm. 3 Thirty-two mice were randomly divided into four groups of eight mice each, based on tumor volume (body weight could also be considered): a control group, a PD-1 antibody group (PD-1 antibody purchased from Bioxcell, CAT No. BE0146), a compound group (Example 25), and a combination therapy group of the compound (Example 25) and PD-1 antibody. The administration methods for each group were as follows:

[0592] Control group: Orally administered normal saline once a day, sodium chloride concentration 0.9%, administration volume 10 mL / kg.

[0593] PD-1 antibody group: PD-1 antibody was injected intraperitoneally twice a week, with each injection dose of 10 mg / kg.

[0594] Compound group: The compound of Example 25 was administered orally once daily at a dose of 10 mg / kg.

[0595] The combination therapy group of the compound and the PD-1 antibody: The compound of Example 25 was administered orally once a day at a dose of 10 mg / kg, and the PD-1 antibody was injected intraperitoneally twice a week at a dose of 10 mg / kg each time.

[0596] During the experiment, animal care and use were conducted in accordance with the guidelines of the American Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC, accreditation number 001516). Morbidity and mortality were assessed daily after grouping. General health status of mice was assessed daily throughout the experimental phase. During routine monitoring, any effects of treatment on normal behavior, such as activity level, food and water consumption, weight gain / loss (measured daily), eye / hair pads, and any other abnormal effects, were examined. Any observed clinical symptoms or unexpected deaths were recorded based on the number of animals in each subset. Tumor volume was measured twice weekly in two dimensions using calipers, and the volume was expressed in mm using the following formula. 3 This means: V = 0.5a × b 2 , where a and b are the long and short diameters of the tumor, respectively. When the tumor volume in mice exceeds 2000 mm... 3 Euthanasia was performed at the time, and the tumor-suppressing effects in each group were observed. Figure 1 Note: In the experiment, once the tumor volume of the animals reached the maximum allowable value, they were euthanized as required. There were no surviving animals in the compound group, control group, and PD-1 antibody group on days 12, 14, and 16, respectively.

[0597] The above test results show that:

[0598] (1) Compared with PI3Kα / β / δ, the compounds in each embodiment showed a significant inhibitory effect on PI3Kγ activity, proving that the compounds provided by the present invention have a highly selective inhibitory effect on PI3Kγ activity.

[0599] (2) Each compound significantly inhibited the phosphorylation of AKT protein induced by PI3Kγ in Raw264.7 cell line, further proving that the compounds provided by this invention have a strong inhibitory effect on the activity of PI3Kγ.

[0600] (3) Data from the CT26 tumor model in syngeneic mice ( Figure 1 This indicates that the compounds provided by this invention, when used in combination with PD-1 antibodies, have a better tumor-suppressing effect than PD-1 antibodies alone.

[0601] The applicant declares that this invention illustrates, through the above embodiments, a compound that inhibits the activity of phosphatidylinositol-3-kinase γ isoform, its preparation method, and its application. However, this invention is not limited to the above embodiments, meaning that this invention does not necessarily rely on the above embodiments for implementation. Those skilled in the art should understand that any improvements to this invention, equivalent substitutions of raw materials, additions of auxiliary components, and selection of specific methods, etc., all fall within the protection and disclosure scope of this invention.

[0602] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

[0603] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not describe the various possible combinations separately.

Claims

1. A compound that inhibits the activity of the γ isoform of phosphatidylinositol-3-kinase, characterized in that, The compound that inhibits the activity of phosphatidylinositol-3-kinase γ isoform has the structure shown in Formula I; Where X is selected from any one of -CH2-, -CH2-CH2-, -CH(CH3)- or -C(CH3)2-; R 1 Selected from any one of substituted or unsubstituted C1-C8 chain alkyl or H, wherein the substituted substituent is selected from C3-C5 cycloalkyl or halogen; R 2 Selected from Any one of H, C1-C3 alkyl chain or C1-C3 alkoxy; R 4 Selected from R 7 and R 8 Each is independently selected from any one of unsubstituted or substituted C1-C3 alkyl chains, unsubstituted or halogenated C3-C5 cycloalkyl chains, C2-C4 oxecycloalkyl chains, unsubstituted or cyano-substituted phenyl chains, or H. In the substituted C1-C3 alkyl chains, the substituent is selected from any one of C1-C3 alkoxy groups, unsubstituted or substituted C3-C5 cycloalkyl chains, or halogens. In the substituted C3-C5 cycloalkyl chains, the substituent is an unsubstituted or halogenated C1-C3 alkyl chain. R 10 Selected from unsubstituted or substituted C1-C5 alkyl chains, C3-C5 cycloalkyl chains, or Any one of them, wherein the substituent is selected from C3-C5 cycloalkyl or C1-C3 alkoxy; R 3 R 5 R 6 R 9 R 11 R 12 R 13 and R 14 Each is independently selected from H or C1-C3 chain alkyl groups.

2. The compound for inhibiting the activity of phosphatidylinositol-3-kinase γ isoform as described in claim 1, characterized in that, R 1 It is selected from any one of substituted or unsubstituted C1-C6 chain alkyl or H, wherein the substituted substituent is selected from cyclopropyl or fluorine.

3. The compound for inhibiting the activity of phosphatidylinositol-3-kinase γ isoform as described in claim 2, characterized in that, R 1 Selected from Any one of H, CH3, or CH2CH3.

4. The compound for inhibiting the activity of phosphatidylinositol-3-kinase γ isoform as described in claim 1, characterized in that, R 3 Selected from H or CH3.

5. The compound for inhibiting the activity of phosphatidylinositol-3-kinase γ isoform as described in claim 1, characterized in that, R 5 Selected from H or CH3.

6. The compound for inhibiting the activity of phosphatidylinositol-3-kinase γ isoform as described in claim 1, characterized in that, R 6 It is CH3.

7. The compound for inhibiting the activity of phosphatidylinositol-3-kinase γ isoform as described in claim 1, characterized in that, R 7 and R 8 Each is independently selected from H, CH3, CH2CH3, CH2CF3, Any one of them.

8. The compound for inhibiting the activity of phosphatidylinositol-3-kinase γ isoform as described in claim 1, characterized in that, R 9 It is CH3.

9. The compound for inhibiting the activity of phosphatidylinositol-3-kinase γ isoform as described in claim 1, characterized in that, R 10 Selected from CH3, CH2CH3, Any one of them.

10. The compound for inhibiting the activity of phosphatidylinositol-3-kinase γ isoform as described in claim 1, characterized in that, R 11 It is CH2CH3.

11. The compound for inhibiting the activity of phosphatidylinositol-3-kinase γ isoform as described in claim 1, characterized in that, R 12 It is CH3.

12. The compound for inhibiting the activity of phosphatidylinositol-3-kinase γ isoform as described in claim 1, characterized in that, R 13 It is CH3.

13. The compound for inhibiting the activity of phosphatidylinositol-3-kinase γ isoform as described in claim 1, characterized in that, R 14 It is CH3.

14. The compound for inhibiting the activity of phosphatidylinositol-3-kinase γ isoform as described in claim 1, characterized in that, R 2 Choose from any of the following structures: H、CH3、CH2CH3、OCH2CH3。 15. The compound for inhibiting the activity of the γ isoform of phosphatidylinositol-3-kinase as described in claim 1, characterized in that, The compound that inhibits the activity of phosphatidylinositol-3-kinase γ isoform has any one of the following structures:

16. A method for preparing a compound that inhibits the activity of the γ isoform of phosphatidylinositol-3-kinase as described in any one of claims 1-15, characterized in that, The preparation method includes mixing compound B and compound C and reacting them to obtain compound I, with the reaction formula as follows: Among them, Y 1 Selected from Y 2 It is selected from any one of F, Cl, Br or I.

17. The preparation method according to claim 16, characterized in that, The preparation method of compound B includes mixing acyl halide or acid anhydride with compound A and reacting to obtain compound B, as shown in the reaction formula:

18. The preparation method according to claim 16, characterized in that, In the reaction of compound B with compound C, the reaction temperature is 15-150℃ and the reaction time is 1-20h.

19. The preparation method according to claim 17, characterized in that, In the reaction of acyl halide or acid anhydride with compound A, the reaction temperature is 15-150°C and the reaction time is 1-20 h.

20. The preparation method according to claim 16, characterized in that, The reaction of compound B with compound C further includes mixing with a base and / or a catalyst, wherein the catalyst comprises any one or a combination of at least two of 1,1'-bis(diphenylphosphine)ferrocene, palladium dichloride, palladium acetate, tetra(triphenylphosphine)palladium, or tri(dibenzylideneacetone)dipalladium.

21. The preparation method according to claim 20, characterized in that, The base includes organic bases and / or inorganic bases. The inorganic base includes any one or a combination of at least two of the following: hydrides, hydroxides, alkoxides, acetates, fluorides, phosphates, carbonates, or bicarbonates of alkali metals or alkaline earth metals. The organic base includes any one or a combination of at least two of the following: amine compounds, pyridine compounds, pyrrole compounds, quinoline compounds, imidazole compounds, amino-substituted naphthalene compounds, or nitrogen-containing heterocyclic alkanes.

22. The preparation method according to claim 21, characterized in that, The inorganic base includes any one or a combination of at least two of the following: sodium amino acid, sodium hydride, lithium diisopropylamino acid, sodium methoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium acetate, sodium phosphate, potassium phosphate, potassium fluoride, cesium fluoride, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate, or cesium carbonate.

23. The preparation method according to claim 21, characterized in that, The organic bases include triethylamine, trimethylamine, N,N-diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, tri-n-hexylamine, tricyclohexylamine, N-methylcyclohexylamine, N-methylpyrrolidine, N-methylpiperidine, N-ethylpiperidine, N,N-dimethylaniline, N-methylmorpholine, pyridine, 2,3-methylpyridine, 4-methylpyridine, 2-methyl-5-ethylpyridine, 2,6-dimethylpyridine, 2,4-methylpyridine, etc. Any one or a combination of at least two of the following: 6-trimethylpyridine, 4-dimethylaminopyridine, quinoline, methylquinoline, N,N,N,N-tetramethylethylenediamine, N,N-dimethyl-1,4-diazacyclohexane, N,N-diethyl-1,4-diazacyclohexane, 1,8-bis(dimethylamino)naphthalene, diazabicyclooctane, diazabicyclononane, diazabicycloundecane, or butylimidazole or methylimidazole.

24. The preparation method according to claim 16 or 17, characterized in that, The reaction of the acyl halide or anhydride with compound A and the reaction of compound B with compound C may optionally include mixing with a solvent to carry out the reaction, said solvent comprising any one or a combination of at least two of ether compounds, unsubstituted or halogenated hydrocarbon compounds, or ester compounds.

25. The preparation method according to claim 24, characterized in that, The solvent comprises any one or a combination of at least two of the following: ethyl propyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexylmethyl ether, dimethyl ether, diethyl ether, dimethyl ethylene glycol, biphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, dioxane, dichlorodiethyl ether, polyethers of ethylene oxide and / or propylene oxide, pentane, hexane, heptane, octane, nonane, methylene chloride, dichloromethane, trichloromethane, carbon tetrachloride, fluorobenzene, chlorobenzene, dichlorobenzene, cyclohexane, methylcyclohexane, petroleum ether, octane, benzene, toluene, chlorobenzene, bromobenzene, xylene, methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate, dimethyl carbonate, dibutyl carbonate, or ethylene carbonate.

26. Use of the compound that inhibits the activity of phosphatidylinositol-3-kinase γ isoform as described in any one of claims 1-15 in the preparation of an inhibitor of phosphatidylinositol-3-kinase γ isoform.

27. The use of the compound that inhibits the activity of the phosphatidylinositol-3-kinase γ isoform as described in any one of claims 1-15 in the preparation of a medicament for the prevention and / or treatment of cancer, respiratory diseases or immune diseases.

28. The application as described in claim 27, characterized in that, The drugs mentioned for treating cancer include immunotherapy drugs used for cancer.

29. The application as described in claim 27, characterized in that, The cancers mentioned include pancreatic tumors, ductal carcinoma, lung cancer, head and neck cancer, rectal cancer, uterine cancer, prostate cancer, kidney cancer, or breast cancer.

30. The application as described in claim 27, characterized in that, The respiratory diseases mentioned include asthma, rhinitis, bronchitis, emphysema, pulmonary fibrosis, or chronic obstructive pulmonary disease.

31. The application as described in claim 27, characterized in that, The immune diseases mentioned include allergies, rheumatoid arthritis, or systemic lupus erythematosus.

32. An immunotherapy drug for cancer, characterized in that, The immunotherapeutic agents for cancer include any one or a combination of at least two of the compounds that inhibit the activity of the γ isoform of phosphatidylinositol-3-kinase as described in any one of claims 1-15, or their racemates or pharmaceutically acceptable salts.

33. The immunotherapy drug for cancer as described in claim 32, characterized in that, The immunotherapy drugs for cancer also include combination drugs, which include any one or a combination of at least two of the following: PD-1 antibody, PD-L1 antibody, CTLA4 antibody, glucocorticoid receptor agonist, β2-adrenergic receptor agonist, antimuscarinic agent, p38 inhibitor, xanthine derivative, paclitaxel, docetaxel, albumin-bound paclitaxel, cisplatin, carboplatin, nedaplatin, oxalate platinum, lobaplatin, etoposide, teniposide, 5-fluorouracil, capecitabine, tegafur, irinotecan, topotecan hydrochloride, gemcitabine, xanthine derivative, PDE4 antagonist, AKT inhibitor, or ER antagonist.

34. The immunotherapy drug for cancer as described in claim 33, characterized in that, The combination therapy includes PD-1 antibody and / or PD-L1 antibody.

35. The immunotherapy drug for cancer as described in claim 32, characterized in that, The cancers mentioned include pancreatic tumors, ductal carcinoma, lung cancer, head and neck cancer, rectal cancer, uterine cancer, prostate cancer, kidney cancer, or breast cancer.

36. The immunotherapy drug for cancer as described in claim 32, characterized in that, The immunotherapy drugs used for cancer also include pharmaceutically acceptable excipients.

37. The immunotherapy drug for cancer as described in claim 36, characterized in that, The excipients include any one or a combination of at least two of the following: disintegrants, glidants, lubricants, colorants, carriers, diluents, flavoring agents, binders, or fillers.

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