CN117186072A - Compound for inhibiting phosphatidylinositol-3-kinase gamma subtype activity and preparation method and application thereof - Google Patents
Compound for inhibiting phosphatidylinositol-3-kinase gamma subtype activity and preparation method and application thereof Download PDFInfo
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- CN117186072A CN117186072A CN202210619083.7A CN202210619083A CN117186072A CN 117186072 A CN117186072 A CN 117186072A CN 202210619083 A CN202210619083 A CN 202210619083A CN 117186072 A CN117186072 A CN 117186072A
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Abstract
The invention relates to a compound for inhibiting phosphatidylinositol-3-kinase gamma subtype activity, a preparation method and application thereof, wherein the compound for inhibiting phosphatidylinositol-3-kinase gamma subtype activity has a structure shown in a formula I and has a strong effect of inhibiting Pi I3K gamma activity. Moreover, compared with the Pi I3K alpha/beta/delta, the compound has remarkable inhibition effect on the Pi I3K gamma activity, and the aim of highly selectively inhibiting the Pi I3K gamma activity is fulfilled. Therefore, the compound has important application value in preparing phosphatidylinositol-3-kinase gamma subtype inhibitors and medicines for preventing and/or treating cancers, respiratory diseases or immune diseases.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and relates to a compound for inhibiting phosphatidylinositol-3-kinase gamma subtype activity, and a preparation method and application thereof.
Background
Phosphatidylinositol-3-kinase (PI 3K) is a family of lipases capable of phosphorylating 3' -OH-group phosphatidylinositol on plasma membranes, which are involved in multiple signaling pathways within cells and play an important role in normal physiology and disease development and progression. PI3 ks can be divided into three classes (I, II and III), which differ in function and structure. The most widely studied is type I PI3K, and the type PI3K is divided into four subtypes of PI3K alpha, piI 3K beta, piI 3K delta and PiI 3K gamma.
Phosphatidylinositol-3-kinase gamma (PI 3K gamma) plays a second messenger role in vivo and is involved in various physiological activities of cells such as survival, proliferation, metabolism, etc. The PI3K gamma is highly expressed in a hematopoietic system, so that the PI3K gamma becomes an ideal drug target for treating blood tumor and immune related diseases. In vivo experiments, whether knockdown of pi3kγ expression or loss of pi3kγ kinase activity, normal mice are viable and fertile, suggesting that inhibition of pi3kγ may be less toxic [ Science, 2000, 287 (5455), 1040-1046].
Previous studies have demonstrated that chronic inflammation can be involved in various pathological processes of cancer development, growth and metastasis, and tumor-related inflammation has been considered as the seventh feature of tumors. Research shows that PI3K gamma is one of key subunits for regulating tumor-related inflammation, and is mainly highly expressed on inflammatory cells; PI3kγ activation can lead to macrophage and neutrophil aggregation in tumor stroma, playing a central regulatory role in chemokine-induced leukocyte migration [ Immunology, 2002, 105 (2), 125-136 ]. Through research on PI3K gamma mice, the PI3K gamma has important regulation effects on chemotaxis of granulocytes and macrophages and activation of T cells. Knockout of the PI3K gamma gene can inhibit the aggregation and activation of neutrophils and simultaneously can damage the functions of T lymphocytes and macrophages, so PI3K gamma is considered to be an effective target in the treatment of inflammatory diseases [ Nephron (Nephron), 2002, 91 (2), 262-269].
PI3kγ was found to be highly expressed in various tumors such as Multiple Myeloma (MM), liver cancer, pancreatic ductal carcinoma (PDAC) and the like [ Blood, 2010, 116 (9), 1460-1468]. Expression of PI3kγ favors malignant tumor growth by promoting macrophage migration and modulating polarization of macrophages, neutrophils and lymphocytes in vitro and in vivo, and prevents T cell-mediated tumor death [ Cancer cells, 2011,19 (6), 715-727]. In vitro and in vivo experiments, inhibition of PI3K gamma activity reduced MM proliferation, inhibited MM cell adhesion and migration, and promoted apoptosis of MM primary cells [ journal of blood cancers (Blood cancer journal), 2017, 7 (3), e539]. Furthermore, in clinical models using Doxorubicin (DOX) for the treatment of malignant tumors, inhibitors of PI3K gamma can prevent DOX-induced cardiac toxic side effects while limiting tumor growth and thereby improve survival [ Circulation, 2018, 138 (7), 696-711]. In addition, complex multicellular diseases can be treated by inhibition of lung PI3K gamma, which are characterized by lung tissue adaptive immune T cell activation and subsequent granulocyte influx and activation, e.g. asthma, COPD, etc. (biologicalactomy and biophysical journal (Biochim Biophys Acta), 2015, 1851 (6), 882-897). Furthermore, since the PI3K gamma subtype has specificity in immune tissues, immune diseases such as rheumatoid arthritis (Rheumatoid Arthritis, RA) and systemic lupus erythematosus (Systemic Lupus Erythematosus, SLE) are treated by inhibiting the biological activity of PI3K gamma [ journal of pharmaceutical chemistry (Journal of Medicinal Chemistry), 2012, 55 (20), 8559-8581].
In summary, these disclosures disclose the important role of inhibition of PI3K gamma signaling in immune response, and thus provide a phosphatidylinositol-3-kinase gamma subtype inhibitor with high selectivity, which has important application value in the treatment of various diseases such as cancer, respiratory diseases, immune diseases, and the like.
In order to achieve the aim of the invention, the invention adopts the following technical scheme:
in a first aspect, the present invention provides a compound that inhibits phosphatidylinositol-3-kinase gamma subtype activity, the compound that inhibits phosphatidylinositol-3-kinase gamma subtype activity having a structure as shown in formula I;
wherein X is selected from-CH 2 -、-CH 2 -CH 2 -、-CH(CH 3 ) -or-C (CH) 3 ) 2 -any one of the following;
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 the group consisting ofH. Any one of C1-C3 alkanyl or C1-C3 alkoxy;
R 4 selected from the group consisting of
R 7 And R is 8 Each independently selected from any one of unsubstituted or substituted C1-C3 alkanyl, unsubstituted or halogenated C3-C5 cycloalkyl, C2-C4 oxacycloalkanyl, unsubstituted or cyano-substituted phenyl or H, wherein in the substituted C1-C3 alkanyl the substituted substituent is selected from any one of C1-C3 alkoxy, unsubstituted or substituted C3-C5 cycloalkyl or halogen, and wherein in the substituted C3-C5 cycloalkyl the substituted substituent is unsubstituted or halogenated C1-C3 alkanyl;
R 10 Selected from unsubstituted or substituted C1-C5-alkanyl, C3-C5-cycloalkyl orAny one of the substituents being 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 is 14 Each independently selected from H or C1-C3 alkanyl.
Preferably, R 1 Selected from any one of substituted or unsubstituted C1-C6 chain alkyl or H, wherein the substituted substituent is selected from cyclopropyl or fluorine.
In the present invention, the dotted lineThe indicated position is the substitution site.
Preferably, R 1 Selected from the group consisting ofH、CH 3 Or CH (CH) 2 CH 3 Any one of the following.
Preferably, R 3 Selected from H or CH 3 。
Preferably, R 5 Selected from H or CH 3 。
Preferably, R 6 Is CH 3 。
Preferably, R 7 And R is 8 Each independently selected from H, CH 3 、CH 2 CH 3 、CH 2 CF 3 、 Any one of the following.
Preferably, R 9 Is CH 3 。
Preferably, R 10 Selected from CH 3 、CH 2 CH 3 、Any one of the following.
Preferably, R 11 Is CH 2 CH 3 。
Preferably, R 12 Is CH 3 。
Preferably, R 13 Is CH 3 。
Preferably, R 14 Is CH 3 。
Preferably, R 2 Selected from any one of the following structures:
H、CH 3 、CH 2 CH 3 、OCH 2 CH 3 。
preferably, the compound that inhibits phosphatidylinositol-3-kinase gamma subtype activity has any one of the following structures:
the term C1-C8 in the context of the present invention means having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms.
The term C1-C6 as used herein means having 1, 2, 3, 4, 5 or 6 carbon atoms.
The term C1-C5 in the context of the present invention means having 1, 2, 3, 4 or 5 carbon atoms.
The term C1-C3 in the context of the present invention means having 1, 2 or 3 carbon atoms.
The term C3-C5 as used herein means having 3, 4 or 5 carbon atoms.
In the present invention, unless otherwise specified, the term "alkyl" includes straight chain alkyl, branched alkyl, and cycloalkyl groups, such as may be, but not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl or cyclobutyl, and the like.
In the present invention, unless otherwise specified, the term "alkanyl" includes straight chain alkyl and branched alkyl groups, such as may be, but not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.
In the present invention, unless otherwise indicated, the term "alkoxy" refers to a group consisting of one alkyl group and one oxygen atom, including straight chain alkyl groups and branched chain alkyl groups, such as may be, but not limited to: methyl, ethyl, n-propyl, isopropyl, and the like.
In the present invention, the halogen includes fluorine, chlorine, bromine or iodine, and the halo means that hydrogen is substituted with fluorine, chlorine, bromine or iodine.
Those skilled in the art will appreciate that the compounds of the present invention may exist in various pharmaceutically acceptable salt forms. If these compounds have a basic center, they may form acid addition salts; if these compounds have an acidic center, they may form base addition salts; these compounds may also form internal salts if they contain both acidic (e.g., carboxyl) and basic (e.g., amino) centers. Acid addition salts include, but are not limited to: hydrochloride, hydrofluoride, hydrobromide, hydroiodide, sulphate, pyrosulphate, phosphate, nitrate, mesylate, ethanesulphonate, 2-hydroxyethanesulphonate, benzenesulfonate, tosylate, sulfamate, 2-naphthalenesulfonate, formate, acetoacetate, pyruvic acid, lunar silicate, cinnamate, benzoate, acetate, dihydroxyacetate, trifluoroacetate, trimethylacetate, propionate, butyrate, caproate, heptanoate, undecanoate, stearate, ascorbate, campholate, camphorsulfonate, citrate, fumarate, malate, maleate, hydroxymaleate, oxalate, salicylate, succinate, gluconate, quiniate, pamoate, glycolate, tartrate, lactate, 2- (4-hydroxybenzoyl) benzoate, cyclopentanate, digluconate, 3-hydroxy-2-naphtalate, nicotinate, pamoate, pectinate, 3-phenylpropionate, bitter salt, pivalate, itaconic acid, triflate, dodecyl sulfate, p-toluenesulfonate, naphthalenesulfonate, malonic acid, adipic acid, mandelate Glucoheptonate, glycerophosphate, sulfosalicylate, semi-sulfuric or thiocyanate, aspartate, and the like. Base addition salts such as alkali metal salts, alkaline earth metal salts, and ammonium salts, and the like, specifically include, but are not limited to: sodium salt, lithium salt, potassium salt, ammonium salt, aluminum salt, magnesium salt, calcium salt, barium salt, iron salt, ferrous salt, manganese salt, manganous salt, zinc salt, ammonium salt (including NH) 3 Salts with organic amines (NH) 4 Salts), methylammonium salt, trimethylammonium salt, diethylammonium salt, triethylammonium salt, propylammonium salt, tripropylammonium salt, isopropylammonium salt, t-butylammonium salt, N' -dibenzylethylenediammonium salt, dicyclohexylammonium salt, 1, 6-hexanediammonium salt, benzylammonium salt, ethylammonium salt, N-dimethylethylammonium salt, N-diethylethylammonium salt, triethanolamine salt, tromethamine salt, lysine salt, arginine salt, histidine salt, glucammonium salt, N-methylglucammonium salt, dimethylglucammonium salt, ethylglucammonium salt, meglumine salt, betaine salt, caffeine salt, chloroprocaine salt, procaine salt, lidocaine salt, pyridinium salt, picolinium salt, piperidine salt, morpholine salt, piperazine salt, purine salt, theobromine salt, choline salt) and the like.
The compounds of the present invention may exist in the form of solvates (e.g., hydrates) comprising a polar solvent as a structural element of the compound lattice, such as, inter alia, water, methanol or ethanol. The polar solvent, in particular water, may be present in stoichiometric or non-stoichiometric amounts.
Depending on its molecular structure, the compound of the invention may be chiral and thus various enantiomeric forms may exist. These compounds may thus be present in racemic or optically active form. The compounds of the invention or intermediates thereof may be isolated as enantiomer compounds by chemical or physical methods well known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are prepared from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as tartaric acid, 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 in R and S form. By means of optically active resolving agents (for example dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatised methacrylate polymers immobilised on silica). Chromatographic enantiomer resolution may also advantageously be carried out, suitable eluents for this purpose being aqueous or alcoholic solvent mixtures, for example hexane/isopropanol/acetonitrile. The corresponding stable isomers may also be separated according to known methods, for example by extraction, filtration or column chromatography.
The invention also provides stereoisomers, racemates, tautomers, isotopic labels, nitroxides, solvates or pharmaceutically acceptable salts thereof of said compounds inhibiting phosphatidylinositol-3-kinase gamma subtype activity.
In a second aspect, the present invention provides a method for preparing a compound which inhibits phosphatidylinositol-3-kinase gamma subtype activity as described in the first aspect, the method comprising mixing compound B with compound C, and reacting to obtain compound I, where the reaction formula is:
wherein Y is 1 Selected from the group consisting of
Dotted lineThe indicated position is the substitution site.
Y 2 Selected from any one of F, cl, br or I.
Preferably, the preparation method of the compound B comprises the steps of mixing acyl halide or anhydride with the compound A for reaction to obtain the compound B, wherein the reaction formula is as follows:
preferably, in the reaction of compound B with compound C, the temperature of the reaction is 15-150 ℃ and the time of the reaction is 1-20h.
Preferably, in the reaction of the acid halide or anhydride with compound a, the temperature of the reaction is 15-150 ℃ and the time of the reaction is 1-20h.
The specific values of the above 15-60deg.C are 15 deg.C, 20 deg.C, 25 deg.C, 30 deg.C, 35 deg.C, 40 deg.C, 45 deg.C, 50 deg.C, 55 deg.C, 60 deg.C 65 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃, 95 ℃, 100 ℃, 110 ℃, 120 ℃, 130 ℃, 140 ℃, 150 ℃, etc.
Specific values in the above 1 to 20h are, for example, 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, etc.
Preferably, the reaction of the compound B and the compound C further comprises mixing with a base and/or a catalyst to perform the reaction, wherein the catalyst comprises any one or at least two of 1,1 '-bis-diphenylphosphine ferrocene, palladium dichloride, palladium acetate, tetra (triphenylphosphine) palladium or tris (dibenzylideneacetone) dipalladium, for example, a combination of palladium dichloride and palladium acetate, a combination of tetra (triphenylphosphine) palladium and tris (dibenzylideneacetone) dipalladium, a combination of 1,1' -bis-diphenylphosphine ferrocene and palladium dichloride, and the like, and other arbitrary combinations can be adopted.
Preferably, the base comprises an organic base and/or an inorganic base comprising any one or a combination of at least two of a hydride, hydroxide, alkoxide, acetate, fluoride, phosphate, carbonate or bicarbonate of an alkali metal or alkaline earth metal, for example a combination of an alkali metal phosphate and an alkaline earth metal carbonate, a combination of an alkali metal acetate and an alkali metal hydroxide, an alkaline earth metal bicarbonate and an alkaline earth metal hydroxide.
The organic base includes any one or a combination of at least two of an amine compound, a pyridine compound, a pyrrole compound, a quinoline compound, an imidazole compound, an amino-substituted naphthalene compound and an azacycloalkane compound, 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, and the like, and any other combination modes can be adopted.
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 fluoride, cesium fluoride, sodium carbonate, potassium bicarbonate, sodium bicarbonate or cesium carbonate, 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, and the like, and any other combination means is possible.
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, any one or a combination of at least two of N-tetramethyl ethylenediamine, N-dimethyl-1, 4-diazacyclohexane, N-diethyl-1, 4-diazacyclohexane, 1, 8-bis (dimethylamino) naphthalene, diazabicyclooctane, diazabicyclononane, diazabicycloundecane or butylimidazole or methylimidazole, for example, a combination of triethylamine and trimethylamine, a combination of tri-N-butylamine and tri-N-hexylamine, a combination of quinoline and methylquinoline, and the like, and any other combination may be used.
Preferably, the reaction of the acyl halide or anhydride with the compound a and the reaction of the compound B with the compound C also optionally include mixing with a solvent to perform the reaction, wherein the solvent includes any one or a combination of at least two of an ether compound, an unsubstituted or halogenated hydrocarbon compound or an ester compound, 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, or any other combination manner may be used.
Preferably, the solvent comprises any one or a combination of at least two of ethyl propyl ether, n-butyl ether, anisole, phenetole, cyclohexylmethyl ether, dimethyl ether, diethyl ether, dimethylethylene glycol, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisoamyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, dioxane, dichloro diethyl ether, polyethers of ethylene oxide and/or propylene oxide, pentane, hexane, heptane, octane, nonane, methylene chloride, chloroform, 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 of these compounds may be any other combination, for example, a combination of n-butyl ether and anisole, a combination of dimethyl ether and diethyl ether, a combination of dioxane and diethyl ether dichloride, and the like.
In a third aspect, the present invention provides the use of a compound inhibiting phosphatidylinositol-3-kinase gamma subtype activity as described in the first aspect for the preparation of a phosphatidylinositol-3-kinase gamma subtype inhibitor.
In a fourth aspect, the present invention provides the use of a compound inhibiting phosphatidylinositol-3-kinase gamma subtype activity as described in the first aspect for the manufacture of a medicament for the prevention and/or treatment of cancer, respiratory disease or immune disease.
Preferably, the drug for treating cancer includes an immunotherapeutic drug for cancer.
Preferably, the cancer comprises pancreatic tumor, ductal cancer, lung cancer, head and neck cancer, rectal cancer, uterine cancer, prostate cancer, renal cancer or breast cancer.
Preferably, the respiratory disease comprises asthma, rhinitis, bronchitis, emphysema, pulmonary fibrosis or chronic obstructive pulmonary disease.
Preferably, the immune disorder comprises allergy, rheumatoid arthritis or systemic lupus erythematosus.
In a fifth aspect, the present invention provides an immunotherapeutic agent for cancer comprising a compound inhibiting phosphatidylinositol-3-kinase gamma subtype activity as described in the first aspect, or any one or a combination of at least two of stereoisomers, racemates, tautomers, isotopic labels, nitrogen oxides, solvates, or pharmaceutically acceptable salts thereof.
Preferably, the immunotherapeutic agent for cancer further comprises a combination comprising any one or a combination of at least two of a PD-1 antibody, a PD-L1 antibody, a CTLA4 antibody, a glucocorticoid receptor agonist, a β2 adrenergic receptor agonist, an antimuscarinic agent, a p38 inhibitor, a xanthine derivative, paclitaxel, docetaxel, albumin paclitaxel, cisplatin, carboplatin, nedaplatin, platinum oxalate, lobaplatin, etoposide, 5-fluorouracil, capecitabine, tegafur, irinotecan, topotecan hydrochloride, gemcitabine, a PDE4 antagonist, an AKT inhibitor, or an ER antagonist. The combination of at least two of them, for example, the combination of antimuscarinic agent and p38 inhibitor, the combination of glucocorticoid receptor agonist and β2 adrenergic receptor agonist, the combination of AKT inhibitor and ER antagonist, etc., may be any other combination.
Preferably, the combination comprises a PD-1 antibody and/or a PD-L1 antibody.
Preferably, the cancer comprises pancreatic tumor, ductal cancer, lung cancer, head and neck cancer, rectal cancer, uterine cancer, prostate cancer, renal cancer or breast cancer.
Preferably, the immunotherapeutic agent for cancer further comprises pharmaceutically acceptable excipients.
Preferably, the auxiliary material comprises any one or a combination of at least two of a disintegrating agent, a glidant, a lubricant, a coloring agent, a carrier, a diluent, a flavoring agent, a binding agent or a filling agent, for example, a combination of the lubricating agent and the coloring agent, a combination of the binding agent and the filling agent, a combination of the carrier and the diluent, and the like, and any other combination mode can be adopted.
The compounds inhibiting phosphatidylinositol-3-kinase gamma subtype activity or stereoisomers, racemates, tautomers, isotopic labels, nitrogen oxides, solvates or pharmaceutically acceptable salts thereof, phosphatidylinositol-3-kinase gamma subtype inhibitors and medicaments inhibiting phosphatidylinositol-3-kinase gamma subtype activity can be used for treating airway obstructive diseases, and the diseases comprise: asthma, including bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, exercise-induced asthma, drug-induced asthma (including aspirin and NSAID-induced asthma) and dust-induced asthma, including intermittent and persistent and all severity asthma, 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 granuloma); ABPA (allergic bronchopulmonary aspergillosis); CEP (chronic eosinophilic pneumonia); farmer lung and related diseases; hypersensitivity pneumonitis; pulmonary fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonia, fibrosis and chronic infections concurrent with anti-tumor therapies, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitis of pulmonary vessels and thrombotic diseases and pulmonary arterial hypertension; cough-relieving activity, including treatment of chronic cough, and iatrogenic cough associated with inflammatory and secretory conditions of the airways; acute and chronic rhinitis including drug rhinitis and vasomotor rhinitis; perennial and seasonal allergic rhinitis, including neurogenic rhinitis (hay fever); nasal polyposis; acute viral infections, including the common cold, as well as infections caused by respiratory syncytial virus, influenza, coronaviruses (including SARS) and adenoviruses, acute lung injury, adult Respiratory Distress Syndrome (ARDS), and exacerbations of each of the above-mentioned respiratory disease states, in particular exacerbations of all types of asthma or COPD. But also in the treatment of CNS-related inflammatory diseases, such as MS. It can also be used for treating cancer such as pancreatic intraepithelial neoplasia, ductal carcinoma and breast cancer.
The numerical ranges recited herein include not only the recited point values, but also any point values between the recited numerical ranges that are not recited, and are limited to, and for the sake of brevity, the invention is not intended to be exhaustive of the specific point values that the recited range includes.
Compared with the prior art, the invention has the following beneficial effects:
the invention creatively provides a compound with a structure shown in a formula I, which has a strong effect of inhibiting the activity of Pi I3K gamma. Moreover, compared with the Pi I3K alpha/beta/delta, the compound has remarkable inhibition effect on the Pi I3K gamma activity, and the aim of highly selectively inhibiting the Pi I3K gamma activity is fulfilled. The compound has important application value in preparing phosphatidylinositol-3-kinase gamma subtype inhibitors and medicines for preventing and/or treating cancers, respiratory diseases or immune diseases.
In addition, the compound has better tumor inhibition effect when being combined with PD-1/PD-L1 antibody.
Drawings
FIG. 1 is a graph showing the antitumor effect of the different administration treatments in test example 3.
Detailed Description
In order to further describe the technical means adopted by the present invention and the effects thereof, the following describes the technical scheme of the present invention in combination with the preferred embodiments of the present invention, but the present invention is not limited to the scope of the embodiments.
Unless otherwise indicated, the starting materials and reagents used in the following examples are commercially available or may be prepared by methods known to those skilled in the art.
The intermediates and methods for their preparation are as follows:
intermediate 1: 1-methyl-3-nitro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole
1-methyl-3-nitro-pyrazole (5 g,39.34 mmol) was dissolved in dry tetrahydrofuran (115 mL), cooled to-78deg.C, and 2-isopropoxy-4, 5-tetramethyl-1, 3, 2-dioxaborane (9.95 g,10.9mL,53.5 mmol) was slowly added dropwise. After the completion of the dropwise addition, stirring was carried out at-78℃for 40min. LDA (29.5mL,2M in THF,29.5mmol) was then slowly added dropwise at-78deg.C. After the completion of the dropwise addition, the mixture was stirred at-78℃for 1 hour. After the reaction was completed, the reaction was allowed to warm to room temperature, and the reaction solution was added to a mixture of water (60 mL) and acetic acid (20 mL), followed by stirring for 10min. Ethyl acetate and water were added for extraction, and the organic layer was separated, dried over anhydrous sodium sulfate, and the organic solvent was distilled off under reduced pressure to obtain 9.8g of a white solid. 1 H NMR(400MHz,DMSO-d 6 )δ7.19(d,J=3.0Hz,1H),4.07(s,3H),1.31(s,12H).
Intermediate 2: 1-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazol-3-amine
To a methanol solution (25 mL) of intermediate 1 (2.5 g,9.88 mmol) under nitrogen was added dry Pd/C (850 mg,10% purity, 720.95. Mu. Mol). The hydrogen was purged several times and the nitrogen in the reactor was replaced with hydrogen (15 psi). Stirring for 3h at room temperature. After the reaction was complete, the suspension was filtered through a pad of celite. Ethyl acetate and water were added to extract the filtrate, an organic layer was separated, dried over anhydrous sodium sulfate, and the organic solvent was distilled off under reduced pressure to obtain 2.1g of a white solid product. 1 H NMR(400MHz,DMSO-d 6 )δ5.78-5.63(m,1H),3.73-3.70(m,3H),1.27(s,12H).
Intermediate 3: n- (1-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaboran-2-yl) -1H-pyrazol-3-yl) acetamide
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To a solution of intermediate 2 (2.1 g,9.41 mmol) in dichloromethane (25 mL) was added acetic anhydride (4.81 g,4.41mL,47.07 mmol). Stirring was carried out at room temperature for 16h. 3/4 of the organic solvent was distilled off under reduced pressure. Dichloromethane and water were added to extract the filtrate, the organic layer was separated, dried over anhydrous sodium sulfate, and the organic solvent was distilled off under reduced pressure to obtain 1.6g of a crude white solid, and the obtained crude product was used for the next reaction without further purification. 1 H NMR(400MHz,DMSO-d 6 )δ10.41(s,1H),6.78(s,1H),3.86(s,3H),1.99-1.96(m,3H),1.29(s,12H).
Intermediate 4: 4-bromo-2-fluoro-6-methyl-benzoic acid methyl ester
Under nitrogen, 4-bromo-2-fluoro-6-methyl-benzoic acid (50 g,215 mmol), K 2 CO 3 (88.96 g,643.7 mmol) in DMF (500 mL) and MeI (60.91 g,26.71mL,429 mmol) were added slowly. After the completion of the dropwise addition, stirring was carried out at 80℃for 1 hour. After the reaction was completed, the reaction mixture was cooled to room temperature, and 20mL of H was added 2 O, stir for 1h to quench the reaction. The suspension was isolated by filtration. The filter cake was washed with ethyl acetate (200 ml x 3). The filtrate was concentrated to dryness under reduced pressure to give a crude product. The crude product was isolated by column chromatography to give 45g of the title compound as a brown solid. LC-MS (ESI): R T =0.97min,mass calcd.For C 9 H 8 BrFO 2 245.97 m/z found 246.7[M+H] + . 1 H NMR(400MHz,CDCl 3 )δ7.20(s,1H),7.12-7.06(m,1H),3.85(s,3H),2.30(s,3H).
Intermediate 5: 4-bromo-2- (bromomethyl) -6-fluoro-benzoic acid methyl ester
CCl to intermediate 4 (25 g,101.19 mmol) under nitrogen 4 Solution (400 mL), NBS (21.15 g,119 mmol) and BPO (2.45 g,10.12 mmol) were added. Stirring for 4h at 80 ℃. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was isolated by column chromatography to give 34g of the title compound as a yellow oil. 1 H NMR(400MHz,CDCl 3 )δ7.41(s,1H),7.31-7.28(m,1H),4.62(s,2H),3.99(s,3H).
Intermediate 6: (S) -5-bromo-2- (1-cyclopropylethyl) -7-fluoroisoindol-1-one
(1S) -1-cyclopropylethylamine hydrochloride (17.00 g,139.8 mmol), boric acid (1.29 g,20.86 mmol) and K were successively added under nitrogen 2 CO 3 (43.25 g,312.92 mmol), intermediate 5 (34 g,104 mmol) and CH 3 CN (350 mL) was added to the round bottom flask. Stirring for 16h at 50 ℃. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was separated by column chromatography to give 17g of the title 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] + .
Intermediate 7: (S) -5-bromo-2- (1-cyclopropylethyl) -7- ((4-methoxybenzyl) amino) isoindolin-1-one
Intermediate 6 (5 g,16.77 mmol) was added to (4-methoxyphenyl) methylamine (29.91 g,218.01mmol,28.21 mL). Stirring at 100deg.C for 16 hr, adding ethyl acetate and water to extract reaction solution, separating organic layer, drying with magnesium sulfate, and distilling under reduced pressure to remove organic solvent to obtain crude product. The crude product was isolated by column chromatography to give 7g of the title compound as a yellow oil. LC-MS (ESI): R T =0.98min,mass calcd.For C 21 H 23 BrN 2 O 2 414.09 m/z found 437.0[M+Na] + .
Intermediate 8: 7-amino-5-bromo-2- [ (1S) -1-cyclopropylethyl ] isoindolin-1-one
Intermediate 7 (6.9 g,16.61 mmol) was added to TFA (100 mL). Stirring for 3h at 40 ℃. After the completion of the reaction, the organic solvent was distilled off under reduced pressure. After dissolving the crude product by adding ethyl acetate (500 mL), naHCO was added 3 And (5) neutralizing a saturated solution. Separating the liquid, taking an organic layer, drying by magnesium sulfate, filtering, and distilling under reduced pressure to obtain a crude product. The crude product is separated by column chromatography to obtain the target compound. LC-MS (ESI): R T =3.63min,mass calcd.For C 13 H 15 BrN 2 O 294.04 m/z,found 294.6[M+H] + .
Intermediate 9: (S) -N- (6-bromo-2- (1-cyclopropylethyl) -3-oxoisoindol-4-yl) ethanesulfonamide
Intermediate 8 (200 mg, 677.57. Mu. Mol), DMAP (16.6 mg, 135.51. Mu. Mol), DIPEA (313 mg, 826. Mu.L, 4.74 mmol) and DCM (10 mL) were added sequentially to a round bottom flask under nitrogen, and after cooling the mixture to 0deg.C, ethanesulfonyl chloride (435.6 mg, 320. Mu.L, 3.39 mmol) was slowly added dropwise. Stirring for 2h at normal temperature. Then Et is added in sequence at normal temperature 3 N (206 mg, 283. Mu.L, 2.03 mmol), pyridine (161 mg, 164. Mu.L, 2.03 mmol), ethanesulfonyl chloride (200 mg). The reaction solution was stirred at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was added to 20mL of water, and the organic matter was extracted with methylene chloride. The organic solvent is distilled off under reduced pressure to obtain a crude product. The crude product was isolated by column chromatography to give 200mg of the title compound as a yellow oil. LC-MS (ESI): R T =0.87min,mass calcd.for C 15 H 19 BrN 2 O 3 S 386.03 m/z,found 386.9[M+H] + .
Intermediate 10: 5-bromo-7-fluoro-2-isopropyl isoindol-1-one
The above compound was prepared by the method described with reference to intermediate 9, LC-MS (ESI): R T =0.75min,mass calcd.for C 11 H 11 BrFNO 271.00 m/z,found 271.8[M+H] + .
Intermediate 11: 5-bromo-2-isopropyl-7- (methylthio) isoindol-1-one
To a solution of intermediate 10 (700 mg,2.57 mmol) in NMP (7 mL) under nitrogen, naSMe (320 mg, 290.91. Mu.L, 4.57 mmol) was slowly added dropwise. After the completion of the dropwise addition, stirring at room temperature for 30min. After the reaction is completed, ethyl acetate and water are used for extracting the reaction liquid, and the organic phase is separated and dried by anhydrous sodium sulfate. The organic solvent was distilled off under reduced pressure to give a crude product. The crude product was isolated by column chromatography to give 800mg of the title compound as a white solid. LC-MS (ESI): R T =0.81min,mass calcd.for C 12 H 14 BrNOS 299.00 m/z,found 299.9[M+H] + .
Intermediate 12: 5-bromo-2-isopropyl-7- (methylsulfonyl) isoindol-1-one
To a solution of intermediate 11 (800 mg,2.66 mmol) in DCM (25 mL) under nitrogen was slowly added dropwise m-CPBA (1.72 g,80% purity,7.99 mmol). After the completion of the dropwise addition, stirring at normal temperature for 4 hours. After the reaction is completed, na 2 SO 3 The reaction was quenched with saturated solution (40 mL). Dilute with dichloromethane, use NaHCO 3 The reaction solution was washed with a saturated solution. The organic phase was separated and dried over anhydrous sodium sulfate. The organic solvent was distilled off under reduced pressure to give a crude product. The crude product was isolated by column chromatography to give 600mg of the title compound as a white solid. LC-MS (ESI) R T =0.71min,mass calcd.for C 12 H 14 BrNO 3 S 330.99m/z,found 331.9[M+H] + .
Intermediate 13: (S) -N- (6-bromo-2- (1-cyclopropylethyl) -3-oxoisoindol-4-yl) -N- (methylsulfonyl) methanesulfonamide
To a solution of intermediate 8 (600 mg,2.03 mmol) in DCM (6 mL) was added DIPEA (788 mg,1.06mL,6.10 mmol) and DMAP (24.8 mg, 203. Mu. Mol) successively under nitrogen at 0deg.C. Subsequently, msCl (720 mg, 486. Mu.L, 6.29 mmol) was slowly added dropwise to the mixed solution at 0 ℃. After the completion of the dropwise addition, stirring for 1h at normal temperature. After the reaction was completed, 1MHCl (10 mL) was added at 0℃and stirred at room temperature for 30min. The organic phase was separated by extraction with dichloromethane. The organic solvent was distilled off under reduced pressure to give a crude product. The crude product was isolated by column chromatography to give 820mg of the title compound as a yellow solid. LC-MS (ESI): R T =0.79min,mass calcd.For C 15 H 19 BrN 2 O 5 S 2 449.99 m/z found 473.0[M+Na] + .
Intermediate 14: (S) -N- (6-bromo-2- (1-cyclopropylethyl) -3-oxoisoindol-4-yl) methanesulfonamide
To a solution of intermediate 13 (820 mg,1.82 mmol) in tetrahydrofuran (10 mL) under nitrogen was added dropwise TBAF (3.27mL,1M in THF,3.27mmol). Stirring for 2h at normal temperature. After the reaction was completed, the reaction mixture was quenched by adding water (15 mL), and the organic phase was separated by extraction with ethyl acetate and dried over anhydrous sodium sulfate. The organic solvent was distilled off under reduced pressure to give a crude product. The crude product was isolated by column chromatography to give 550mg of the title compound as a yellow solid. LC-MS (ESI): R T =0.83min,mass calcd.For C 14 H 17 BrN 2 O 3 S 372.01 m/z found 372.9[M+H] + .
Intermediate 15: n- (6-bromo-2- ((S) -1-cyclopropylethyl) -3-oxoisoindol-4-yl) -2-methylpropan-2-sulfinamide
Intermediate 8 (250 mg, 846.96. Mu. Mol), 2-methylpropane-2-sulfinyl chloride (297.77 mg,2.12mmol, 261.20. Mu.L), pyridine (3 mL) was added sequentially to the round bottom flask under nitrogen, followed by dropwise addition of N, N-dimethylpyridine-4-amine (21 mg, 169. Mu. Mol) to the mixture. The reaction was carried out at 50℃for 16h. After the reaction was completed, the reaction mixture was cooled to room temperature, and the organic solvent was distilled off under reduced pressure. The reaction solution was added to 15mL of water, and the organic matter was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The organic solvent is distilled off under reduced pressure to obtain a crude product. The crude product was isolated by column chromatography to give 211mg of the title compound as a white solid. LC-MS (ESI): R T =0.87min,mass calcd.For C 17 H 23 BrN 2 O 2 S 398.07 m/z found 398.9[M+H] + .
Intermediate 16: (S) -N- (6-bromo-2- (1-cyclopropylethyl) -3-oxoisoindol-4-yl) -2-methylpropane-2-sulfonamide
To a solution of intermediate 15 (190 mg, 476. Mu. Mol) in dichloromethane (5 mL) was added m-CPBA (168 mg, 952. Mu. Mol). Stirring was carried out at room temperature for 16h. After the reaction was completed, the reaction solution was cooled to room temperature, and then added to 10mL of water, and the organic matter was extracted with methylene chloride and dried over anhydrous sodium sulfate. The organic solvent is distilled off under reduced pressure to obtain a crude product. The crude product was isolated by column chromatography to yield 195mg of the title compound as a white solid. LC-MS (ESI): R T =0.90min,mass calcd.for C 17 H 23 BrN 2 O 3 S 414.06 m/z,found 414.9[M+H] + .
Intermediate 17: (S) -N- (6-bromo-2- (1-cyclopropylethyl) -3-oxoisoindol-4-yl) -2-methoxyethane sulfonamide
The above compound was prepared by the method described with reference to intermediate 15, LC-MS (ESI): rt= 0.84min,mass calcd.for C 16 H 21 BrN 2 O 4 S 416.04 m/z,found 416.9[M+H]+.
Intermediate 18: (S) -N- (6-bromo-2- (1-cyclopropylethyl) -3-oxoisoindol-4-yl) -1, 3-dimethyl-1H-pyrazole-4-sulfonamide
The above compound was prepared by the method described with reference to intermediate 15, LC-MS (ESI): R T =0.85min,mass calcd.for C 18 H 21 BrN4O 3 S 452.05 m/z,found 453.0[M+H] + .
Intermediate 19: (S) -5-bromo-2- (1-cyclopropylethyl) -7- (methylthio) isoindol-1-one
The above compound was prepared by the method described with reference to intermediate 11, LC-MS (ESI): R T =0.87min,mass calcd.For C 14 H 16 BrNOS 325.01 m/z found 325.9[M+H] + .
Intermediate 20: (S) -5-bromo-2- (1-cyclopropylethyl) -7- (methylsulfonyl) isoindol-1-one
The above compound is prepared by the method of reference intermediate 12, LC-MS (ESI): R T =0.77min,mass calcd.For C 14 H 16 BrNO 3 S 357.00 m/z found 358.0[M+H] + .
Intermediate 21: (S) -7- (benzylthio) -5-bromo-2- (1-cyclopropylethyl) isoindol-1-one
Intermediate 6 (4 g,13.42 mmol), benzyl mercaptan (1.85 g,14.89mmol,1.75 mL), DMF (30 mL) and K were taken in sequence 2 CO 3 (5.56 g,40.25 mmol) was added to a round bottom flask. Stirring for 16h at 50 ℃. After the reaction was completed, the reaction solution was cooled to room temperature. Extracting the reaction liquid with ethyl acetate and water, separating the liquid, taking an organic layer, drying with anhydrous sodium sulfate, and distilling under reduced pressure to remove the organic solvent to obtain a crude product. The crude product was isolated by column chromatography to give 4.7g of the title 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] + .
Intermediate 22: (S) -6-bromo-2- (1-cyclopropylethyl) -3-oxoisoindoline-4-sulfonyl chloride
AcOH (40 mL) to intermediate 21 (4.7 g,11.68 mmol) with H 2 A mixed solution of O (3.6 mL) was slowly added NCS (4.68 g,35.04 mmol). Stirring for 3h at normal 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 distilled off under reduced pressure to obtain a crude product. The crude product was isolated by column chromatography to give 2.4g of the title compound as a white solid. LC-MS (ESI): R T =0.85min mass calcd.For C 13 H 13 BrClNO 3 S 376.95 m/z found 377.8[M+H] + .
Intermediate 23: (S) -6-bromo-2- (1-cyclopropylethyl) -N- ((1- (hydroxymethyl) cyclopropyl) methyl) -3-oxoisoindoline-4-sulfonamide
Dichloromethane towards intermediate 22 (350 mg, 924.29. Mu. Mol)Alkane (5 mL) solution was added [1- (aminomethyl) cyclopropyl ]]Methanol (186.98 mg,1.85 mmol) and DIPEA (644 μl,3.70 mmol). Stirring for 16h at normal temperature. After the reaction is completed, the organic solvent is removed by reduced pressure distillation, and the crude product is obtained. The crude product was isolated by column chromatography to give 350mg of the title compound as a white solid. LC-MS (ESI): R T =0.79min,mass calcd.For C 18 H 23 BrN 2 O 4 S 442.06 m/z found 443.0[M+H] + .
Intermediate 24: (S) -6-bromo-2- (1-cyclopropylethyl) -N- ((1- (fluoromethyl) cyclopropyl) methyl) -3-oxoisoindoline-4-sulfonamide
At N 2 DAST (179. Mu.L, 1.35 mmol) was slowly added dropwise to a solution of intermediate 23 (300 mg, 677. Mu. Mol) in dichloromethane (4 mL) at 0deg.C for protection. After the completion of the dropwise addition, stirring at normal temperature for 2 hours. After the completion of the reaction, 20mL of water was added for quenching, the reaction solution was extracted with methylene chloride, the organic layer was separated, dried over anhydrous sodium sulfate, and the organic solvent was distilled off under reduced pressure to obtain a crude product. The crude product was isolated by column chromatography to give 250mg of the title compound as a white solid. LC-MS (ESI): R T =0.95min mass calcd.For C 18 H 22 BrFN 2 O 3 S 444.05 m/z found 444.9[M+H] + .
Intermediate 25: 3-Nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole
To a solution of 3-nitro-1H-pyrazole (10 g,88.44mmol,1 eq) in THF (150 mL) at 0deg.C under nitrogen was added NaH (7.07 g,60% purity,177 mmol). After the addition, the reaction solution was slowly warmed to room temperature and stirred at room temperature for 1h. SEMCl (15.48 g,16.43mL,92.86 mmol) was then slowly added dropwise at 0deg.C. After the completion of the dropwise addition, the reaction solution was slowly warmed to room temperature and stirred at room temperature for 2 hours. After the reaction is completedNH is added at 0 DEG C 4 The reaction was quenched with Cl (50 mL). The reaction solution was extracted with ethyl acetate, and the organic phase was separated and dried over anhydrous sodium sulfate. The organic solvent was distilled off under reduced pressure to give a crude product. The crude product was isolated by column chromatography to give 15g of the title compound as a yellow solid. 1 H NMR(400MHz,CDCl 3 )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).
Intermediate 26: 3-nitro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole
The above compound was prepared by the method of intermediate 1, 1 H NMR(400MHz,DMSO-d 6 )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).
intermediate 27:5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-3-amine
The above compound is prepared by the method of intermediate 2, 1 H NMR(400MHz,CDCl 3 )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).
Intermediate 28: n- (5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-3-yl) acetamide
The above compound was prepared by the method described with reference to intermediate 3, LC-MS (ESI): R T =0.90min,mass calcd.For C 17 H 32 BN 3 O 4 Si 381.23 m/z found 382.1[M+H] + .
Intermediate 29: (S) -N- (5- (2- (1-cyclopropylethyl) -7- (methylsulfonylamino) -1-oxoisoindolin-5-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-3-yl) acetamide
Intermediate 14 (300 mg, 804. Mu. Mol), intermediate 28 (613 mg,1.61 mmol), cs are successively reacted under argon 2 CO 3 (785.6mg,2.41mmol),Pd(dppf)Cl 2 (58.8 mg, 80.4. Mu. Mol), 1, 4-dioxane (8 mL) and H 2 O (2 mL) was added to a 40mL microwave tube. And carrying out microwave reaction for 2h under the protection of argon. And (5) distilling under reduced pressure to obtain a crude product. The crude product was isolated by column chromatography to give 320mg of the product as a yellow solid. LC-MS (ESI): R T =0.89min,mass calcd.For C 25 H 37 N 5 O 5 SSi 547.23 m/z found 548.2[M+H] + .
Intermediate 30: (S) -N- (5- (2- (1-cyclopropylethyl) -7- (methylsulfonyl) -1-oxoisoindol-5-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-3-yl) acetamide
The above compound was prepared by the method described with reference to intermediate 29, LC-MS (ESI): R T =0.83min,mass calcd.For C 25 H 36 N 4 O 5 SSi 532.22 m/z found 533.1[M+H] + .
Intermediate 31: (S) -6-bromo-2- (1-cyclopropylethyl) -3-oxoisoindoline-4-sulfonamide
Toward intermediate 22 (150 mg, 396.12. Mu.)mol,1 eq) of 1, 4-dioxane solution (5 mL) was added 25% NH 3 Aqueous (4.88 mL,31.69 mmol). Stirring was carried out at room temperature for 16h. The organic solvent was distilled off under reduced pressure. Ethyl acetate and water were added to extract the filtrate, and the organic layer was separated, dried over anhydrous sodium sulfate, and the organic solvent was distilled off under reduced pressure to obtain a crude product. The crude product was isolated by column chromatography to give 135mg of a white solid. LC-MS (ESI): R T =0.76min,mass calcd.For C 13 H 15 BrN 2 O 3 S 358.00 m/z found 358.9[M+H] + .
Intermediate 32: (S) -N- (6-bromo-2- (1-cyclopropylethyl) -3-oxoisoindol-4-yl) acetamide
The above compound was prepared by the method described with reference to intermediate 3, LC-MS (ESI): R T =0.85min,mass calcd.for C 15 H 17 BrN 2 O 2 336.05 m/z,found 336.9[M+H] + .
Intermediate 33: (S) -6-bromo-2- (1-cyclopropylethyl) -N-methyl-3-oxoisoindoline-4-sulfonamide
To a solution of intermediate 22 (500 mg,1.32mmol,1 eq) in dichloromethane (10 mL) was added, in order, methanolamine hydrochloride (356.61 mg,5.28mmol,4 eq) and DIPEA (1.02 g,7.92mmol,1.38mL,6 eq). Stirring was carried out at room temperature for 2h. After completion of the reaction, the organic solvent was distilled off under reduced pressure to give a crude product (1.6 g, 64%), which was used in the next reaction without further purification. The crude product was isolated by column chromatography to give 420mg of the title compound as a white solid. LC-MS (ESI): R T =0.90min,mass calcd.For C 14 H 17 BrN 2 O 3 S 372.01 m/z found 373.0[M+H] + .
Intermediate 34: (S) -N- (5- (2- (1-cyclopropylethyl) -7- (N-methylsulfamoyl) -1-oxoisoindol-5-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-3-yl) acetamide
The above compound was prepared by the method described with reference to intermediate 29, LC-MS (ESI): R T =0.88min,mass calcd.For C 25 H 37 N 5 O 5 SSi 547.23 m/z found 548.2[M+H] + .
Intermediate 35: n- (6-bromo-2- ((S) -1-cyclopropylethyl) -3-oxoisoindol-4-yl) -2-methylpropan-2-sulfinamide
The above compound is prepared by the method described with reference to intermediate 33, LC-MS (ESI): R T =0.80min,mass calcd.For C 15 H 19 BrN 2 O 3 S 386.03 m/z found 386.9[M+H] + 。
Intermediate 36: (S) -6-bromo-N-cyclobutyl-2- (1-cyclopropylethyl) -3-oxoisoindoline-4-sulfonamide
The above compound is prepared by the method described with reference to intermediate 33, LC-MS (ESI): R T =1.07min,mass calcd.For C 17 H 21 BrN 2 O 3 S 412.05 m/z found 413.0[M+H] + .
Intermediate 37: 6-bromo-2-isopropyl-N-methyl-3-oxoisoindoline-4-sulfonamide
Preparation of the above compound by reference to intermediate 33, LCMS (ESI):R T =0.76min,mass calcd.For C 13 H 10 BrFN 2 O 346.00 m/z found 346.9[M+H] + .
Intermediate 38: (S) -N- (5- (2- (1-cyclopropylethyl) -1-oxo-7-sulfamoyl isoindol-5-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-3-yl) acetamide
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The above compound was prepared by the method described with reference to intermediate 29, LC-MS (ESI): R T =0.84min mass calcd.For C 24 H 35 N 5 O 5 SSi 533.21 m/z found 534.2[M+H] + .
Intermediate 39: (S) -6-bromo-2- (1-cyclopropylethyl) -N- (cyclopropylmethyl) -3-oxoisoindoline-4-sulfonamide
The above compound is prepared by the method described with reference to intermediate 33, LC-MS (ESI): R T =0.97min,mass calcd.For C 17 H 21 BrN 2 O 3 S 412.05 m/z found 413.1[M+H] + .
Intermediate 40: (S) -6-bromo-N-cyclopropyl-2- (1-cyclopropylethyl) -3-oxoisoindoline-4-sulfonamide
The above compound is prepared by the method described with reference to intermediate 33, LC-MS (ESI): R T =0.95min mass calcd.For C 16 H 19 BrN 2 O 3 S 398.03 m/z found 399.0[M+H] + .
Intermediate 41: (S) -6-bromo-2- (1-cyclopropylethyl) -N-ethyl-3-oxoisoindoline-4-sulfonamide
The above compound is prepared by the method described with reference to intermediate 33, LC-MS (ESI): R T =0.85min,mass calcd.for C 15 H 19 BrN 2 O 3 S 386.03 m/z,found 386.9[M+H] + .
Intermediate 42: (S) -6-bromo-2- (1-cyclopropylethyl) -N- (oxetan-3-yl) -3-oxoisoindoline-4-sulfonamide
The above compound is prepared by the method described with reference to intermediate 33, LC-MS (ESI): R T =0.79min mass calcd.For C 16 H 19 BrN 2 O 4 S 414.02 m/z found 436.9[M+Na] + .
Intermediate 43: (S) -6-bromo-2- (1-cyclopropylethyl) -N- (3, 3-difluorocyclobutyl) -3-oxoisoindoline-4-sulfonamide
The above compound is prepared by the method described with reference to intermediate 33, LC-MS (ESI): R T =0.89min,mass calcd.For C 17 H 19 BrF 2 N 2 O 3 S 448.03 m/z found 448.9[M+H] + .
Intermediate 44: (S) -6-bromo-2- (1-cyclopropylethyl) -N- (2-methoxyethyl) -3-oxoisoindoline-4-sulfonamide
The above compound is prepared by the method described with reference to intermediate 33, LC-MS (ESI): R T =0.82min,mass calcd.For C 16 H 21 BrN 2 O 4 S 416.04 m/z found 416.9[M+H] + .
Intermediate 45: (S) -6-bromo-2- (1-cyclopropylethyl) -3-oxo-N- (2, 2-trifluoroethyl) isoindoline-4-sulfonamide
The above compound is prepared by the method described with reference to intermediate 33, LC-MS (ESI): R T =0.88min,mass calcd.For C 15 H 16 BrF 3 N 2 O 3 S 440.00 m/z found 440.9[M+H] + .
Intermediate 46:7- (benzylthio) -5-bromo-2-isopropyl isoindol-1-one
The above compound was prepared by the method described with reference to intermediate 21, LC-MS (ESI): R T =0.91min,mass calcd.For C 18 H 18 BrNOS 375.03 m/z found 398.0[M+Na] + .
Intermediate 47: 6-bromo-2-isopropyl-3-oxoisoindoline-4-sulfonyl chloride
The above compound was prepared by the method described with reference to intermediate 22, LC-MS (ESI): R T =0.80min,mass calcd.For C 11 H 11 BrClNO 3 S 350.93 m/z found 351.8[M+H] + .
Intermediate 48: 6-bromo-2-isopropyl-3-oxoisoindoline-4-sulfonamide
The above compound is prepared by the method described with reference to intermediate 31LC-MS (ESI) of R T =0.70min,mass calcd.For C 11 H 13 BrN 2 O 3 S 331.98 m/z found 354.8[M+Na] + .
Intermediate 49: (S) -N- (6-bromo-2- (1-cyclopropylethyl) -3-oxoisoindol-4-yl) cyclopropanesulfonamide
Intermediate 8 (200 mg, 678. Mu. Mol), pyridine (4 mL) was added sequentially to a round bottom flask under nitrogen, and after cooling the mixture to 0deg.C, DMAP (8.3 mg, 68. Mu. Mol) was added sequentially, cyclopropanesulfonyl chloride (762 mg,5.42mmol,8 eq). Stirring is carried out at 50℃for 12h. After the reaction is completed, the organic solvent is removed by reduced pressure distillation to obtain a crude product. The crude product was isolated by column chromatography to give 250mg of the title compound as a white solid. LC-MS (ESI): R T =0.88min,mass calcd.For C 16 H 19 BrN 2 O 3 S 398.03 m/z,found 399.0[M+H] + .
Intermediate 50: (S) -N- (6-bromo-2- (1-cyclopropylethyl) -3-oxoisoindol-4-yl) propane-1-sulfonamide
Intermediate 8 (250 mg, 847. Mu. Mol), DMAP (21 mg, 169. Mu. Mol), DIPEA (766 mg,5.93 mmol) and DCM (10 mL) were added sequentially to a round bottom flask under nitrogen. Stirring was carried out at room temperature for 2h. After the reaction was completed, the reaction was quenched by adding 20mL of water, and the reaction was extracted with DCM. The organic solvent is distilled off under reduced pressure to obtain a crude product. The crude product was isolated by column chromatography to give 300mg of the title compound as a yellow oil. LC-MS (ESI): R T =4.12min,mass calcd.for C 16 H 21 BrN 2 O 3 S 400.05 m/z,found 401.0[M+H] + .
Intermediate 51: 5-bromo-2- (2-cyclopropylpropane-2-yl) -7-fluoroisoindol-1-one
The above compound was prepared by the method described with reference to intermediate 6, LC-MS (ESI): R T =0.85min mass calcd.For C 14 H 15 BrFNO 311.03 m/z found 311.9[M+H] + .
Intermediate 52:7- (benzylthio) -5-bromo-2- (2-cyclopropylpropane-2-yl) isoindol-1-one
The above compound was prepared by the method described with reference to intermediate 21, LC-MS (ESI): R T =0.97min mass calcd.For C 21 H 22 BrNOS 415.06 m/z found 415.9[M+H] + .
Intermediate 53: 6-bromo-2- (2-cyclopropylpropyl-2) -3-oxo-isoindoline-4-sulfonyl chloride
The above compound was prepared by the method described with reference to intermediate 22, LC-MS (ESI): R T =0.89min mass calcd.For C 14 H 15 BrClNO 3 S 390.96 m/z found 391.9[M+H] + .
Intermediate 54: 6-bromo-2- (2-cyclopropylpropane-2-yl) -N-methyl-3-oxoisoindoline-4-sulfonamide
The above compound is prepared by the method described with reference to intermediate 33, LC-MS (ESI): R T =0.86min mass calcd.For C 15 H 19 BrN 2 O 3 S 386.03 m/z found 386.9[M+H] + .
Intermediate 55: (S) -5-bromo-2- (3, 3-dimethylbut-2-yl) -7-fluoroisoindol-1-one
The above compound was prepared by the method described with reference to intermediate 6, LC-MS (ESI): R T =0.86min,mass calcd.For C 14 H 17 BrFNO 313.05 m/z found 313.9[M+H] + .
Intermediate 56: (S) -7- (benzylthio) -5-bromo-2- (3, 3-dimethylbut-2-yl) isoindol-1-one
The above compound was prepared by the method described with reference to intermediate 21, LC-MS (ESI): R T =0.96min,mass calcd.For C 21 H 24 BrNOS 417.08 m/z found 418.0[M+H] + .
Intermediate 57: (S) -6-bromo-2- (3, 3-dimethylbutan-2-yl) -3-oxoisoindoline-4-sulfonyl chloride
The above compound was prepared by the method described with reference to intermediate 22, LC-MS (ESI): R T =0.90min,mass calcd.For C 14 H 17 BrClNO 3 S 392.98 m/z found 393.9[M+H] + .
Intermediate 58: (S) -6-bromo-2- (3, 3-dimethylbut-2-yl) -N-methyl-3-oxoisoindoline-4-sulfonamide
The above compound is prepared by the method described with reference to intermediate 33, LC-MS (ESI): R T =0.86min,mass calcd.for C 15 H 21 BrN 2 O 3 S 388.05 m/z,found 388.9[M+H] + .
Intermediate 59: 5-bromo-2- (tert-butyl) -7-fluoroisoindol-1-one
The above compound was prepared by the method described with reference to intermediate 6, LC-MS (ESI): R T =0.81min,mass calcd.For C 12 H 13 BrFNO 285.02 m/z found 285.9[M+H] + .
Intermediate 60:7- (benzylthio) -5-bromo-2- (tert-butyl) isoindol-1-one
The above compound was prepared by the method described with reference to intermediate 21, LC-MS (ESI): R T =0.96min,mass calcd.For C 19 H 20 BrNOS 389.04 m/z found 389.9[M+H] + .
Intermediate 61: 6-bromo-2- (tert-butyl) -3-oxoisoindoline-4-sulfonyl chloride
The above compound was prepared by the method described with reference to intermediate 22, LC-MS (ESI): R T =0.92min,mass calcd.For C 12 H 13 BrClNO 3 S 364.95 m/z found 365.7[M+H] + .
Intermediate 62: 6-bromo-2- (tert-butyl) -N-methyl-3-oxoisoindoline-4-sulfonamide
The above compound is prepared by the method described with reference to intermediate 33, LC-MS (ESI): R T =0.82min,mass calcd.for C 13 H 17 BrN 2 O 3 S 360.01 m/z,found 360.9[M+H] + .
Intermediate 63: (S) -bromo-7-fluoro-2- (1, 1-trifluoropropan-2-yl) isoindol-1-one
The above compound was prepared by the method described with reference to intermediate 6, LC-MS (ESI): R T =0.82min,mass calcd.For C 11 H 8 BrF 4 NO 324.97 m/z found 325.8[M+H] + .
Intermediate 64: (S) - (benzylthio) -5-bromo-2- (1, 1-trifluoropropan-2-yl) isoindol-1-one
The above compound was prepared by the method described with reference to intermediate 21, LC-MS (ESI): R T =0.95min,mass calcd.For C 18 H 15 BrF 3 NOS 429.00 m/z found 429.9[M+H] + .
Intermediate 65: (S) -6-bromo-3-oxo-2- (1, 1-trifluoropropan-2-yl) isoindoline-4-sulfonyl chloride
The above compound was prepared by the method described with reference to intermediate 21, LC-MS (ESI): R T =0.85min,mass calcd.For C 11 H 8 BrClF 3 NO 3 S 404.90 m/z found 405.8[M+H] + .
Intermediate 66: (S) -6-bromo-N-methyl-3-oxo-2- (1, 1-trifluoropropan-2-yl) isoindoline-4-sulfonamide
The above compound is prepared by the method described with reference to intermediate 33, LC-MS (ESI): R T =0.82min,mass calcd.for C 12 H 12 BrF 3 N 2 O 3 S 399.97 m/z,found 400.9[M+H] + .
Intermediate 67: (S) -6-bromo-N- (3-cyanophenyl) -2- (1-cyclopropylethyl) -3-oxoisoindoline-4-sulfonamide
To a solution of intermediate 22 (300 mg, 792.25. Mu. Mol,1 eq), 3-aminobenzonitrile in dichloromethane (187 mg,1.58mmol,2 eq) in pyridine (6 mL) was added DMAP (290 mg,2.38mmol,3 eq). Stirring for 16h at 50 ℃. And cooling the reaction liquid to normal temperature after the reaction is completed. Ethyl acetate and water are used for extracting the reaction liquid, an organic phase is taken in layers, anhydrous sodium sulfate is dried, and the organic solvent is removed by reduced pressure distillation, so that a crude product is obtained. The crude product was isolated by column chromatography to give 330mg of the title compound as a white solid. LC-MS (ESI): R T =0.90min,mass calcd.For C 20 H 18 BrN 3 O 3 S 459.03 m/z found 460.0[M+H] + .
Intermediate 68: 6-bromo-N- (3-cyanophenyl) -2-isopropyl-3-oxoisoindoline-4-sulfonamide
The above compound was prepared by the method described with reference to intermediate 67, LC-MS (ESI): R T =0.85min,mass calcd.For C 18 H 16 BrN 3 O 3 S 433.01 m/z found 434.0[M+H] + .
Intermediate 69:3- (2, 5-dimethyl-1H-pyrrol-1-yl) -1-methyl-1H-pyrazole
A solution of methylpyrazol-3-amine (60 g,617.8mmol,1 eq) in toluene (600 mL) was added of hexane-2, 5-dione (70.5 g,618mmol,72.47mL,1 eq) and 4-methylbenzenesulfonic acid (5.32 g,30.89mmol,0.05 eq). Stirred at 135℃for 36h. After the reaction was completed, the organic solvent was distilled off under reduced pressure to obtain a crude product. Separating the crude product by column chromatography To 820mg of the title compound as yellow oil. LC-MS (ESI): R T =0.75min,mass calcd.for C10H13N3 175.11 m/z,found 175.8[M+H] + . 1 H NMR(400MHz,CDCl 3 )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).
Intermediate 70: (3- (2, 5-dimethyl-1H-pyrrol-1-yl) -1-methyl-1H-pyrazol-5-yl) boronic acid
To a solution of intermediate 69 (10 g,57.07mmol,1 eq) in tetrahydrofuran (300 mL) was slowly added dropwise n-butyllithium (27.39mL,2.5M in hexane,68.5mmol,1.2eq) under nitrogen at-75 ℃. After the completion of the dropwise addition, stirring at normal temperature for 3 hours. After completion of the reaction, the reaction was quenched with 1M HCl (10 mL) at 0 ℃ to adjust ph=6. The organic solvent was distilled off under reduced pressure. Ethyl acetate and water extraction, separating liquid, taking an organic layer, drying by anhydrous sodium sulfate, and removing the organic solvent by reduced pressure distillation to obtain a crude product. The crude product was isolated by column chromatography to give 11g of the title compound as a brown solid. LC-MS (ESI): rt= 0.69min,mass calcd.For C 10 H 14 BN 3 O 2 219.12 m/z,found 219.9[M+H]+. 1 H NMR(400MHz,CDCl 3 )δ6.75-6.39(m,1H),5.95-5.79(m,2H),4.25-3.88(m,3H),2.14-2.04(m,6H).
Intermediate 71: 4-bromo-2- (bromomethyl) -6-chlorobenzoic acid methyl ester
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The above compound is prepared by the method of reference intermediate 5, LC-MS (ESI): R T =0.97min,mass calcd.For C 9 H 7 Br 2 ClO 2 339.85 m/z found 341.2[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ7.91-7.84(m,1H),7.73-7.49(m,1H),3.97-3.86(m,3H),1.98(m,2H).
Intermediate 72: (S) -5-bromo-7-chloro-2- (1-cyclopropylethyl) isoindol-1-one
The above compound was prepared by the method described with reference to intermediate 6, LC-MS (ESI): R T =0.86min,mass calcd.For C 13 H 13 BrClNO 312.99 m/z found 313.8[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ7.84(s,1H),7.76(s,1H),4.52(s,2H),4.03(q,J=7.3Hz,1H),3.62-3.48(m,1H),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).
Intermediate 73: (S) -7-chloro-2- (1-cyclopropylethyl) -5- (3- (2, 5-dimethyl-1H-pyrrol-1-yl) -1-methyl-1H-pyrazol-5-yl) isoindolin-1-one
Intermediate 72 (860 mg,2.73mmol,1 eq), 1, 4-dioxane (8 mL), water (2 mL), na, were reacted in the order named under nitrogen 2 CO 3 (869 mg,8.20mmol,3 eq), intermediate 70 (898 mg,3.28mmol,80% purity,1.2 eq), pd (dppf) Cl 2 (200 mg, 273. Mu. Mol,0.1 eq) was added to a microwave tube. The reaction was carried out for 1 hour at 90℃with microwaves. After the reaction was completed, the reaction solution was cooled to room temperature. The organic solvent was distilled off under reduced pressure. Ethyl acetate and water extraction, separating the liquid, taking the organic layer, drying by anhydrous sodium sulfate, decompressing and distilling to remove the organic solvent to obtain a crude product. The crude product was isolated by column chromatography to give 780mg of the title compound as a white solid. LC-MS (ESI): R T =0.96min,mass calcd.For C 23 H 25 ClN 4 O 408.17 m/z found 409.1[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )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).
Intermediate 74: (S) -2- (1-cyclopropylethyl) -5- (3- (2, 5-dimethyl-1H-pyrrol-1-yl) -1-methyl-1H-pyrazol-5-yl) -7-vinylisoindolin-1-one
Intermediate 73 (580 mg,1.42mmol,1 eq), 1, 4-dioxane (8 mL), water (1 mL), 4, 5-tetramethyl-2-vinyl-1, 3, 2-dioxaborane (436.9 mg,2.84mmol,2 eq), cs are reacted in sequence under nitrogen 2 CO 3 (1.39g,4.26mmol,3eq),XPhos Pd G 3 (120 mg, 142. Mu. Mol,0.1 eq) was added to the microwave tube. The reaction was carried out for 1 hour at 120℃with microwaves. After the reaction was completed, the reaction solution was cooled to room temperature. The organic solvent was distilled off under reduced pressure. Ethyl acetate and water extraction, separating the liquid, taking the organic layer, drying by anhydrous sodium sulfate, decompressing and distilling to remove the organic solvent to obtain a crude product. The crude product was isolated by column chromatography to give 560mg of the title compound as a white solid. LC-MS (ESI): R T =0.95min,mass calcd.For C 25 H 28 N 4 O 400.23 m/z found 401.5[M+H] + .
Intermediate 75: (S) -2- (1-cyclopropylethyl) -5- (3- (2, 5-dimethyl-1H-pyrrol-1-yl) -1-methyl-1H-pyrazol-5-yl) -7-ethylisoindolin-1-one
To a solution of intermediate 74 (530 mg,1.32mmol,1 eq) in tetrahydrofuran (3 mL) under nitrogen was added dry PtO 2 (90 mg, 397. Mu. Mol,0.3 eq). The hydrogen was purged several times and the nitrogen in the reactor was replaced with hydrogen (15 psi). Stirring for 3h at room temperature. After the reaction was complete, the suspension was filtered through a pad of celite and the celite was washed with ethyl acetate. The filtrate was distilled to dryness under reduced pressure to give 480mg of a white solid product. LC-MS (ESI): R T =0.95min,mass calcd.For C 25 H 30 N 4 O 402.24 m/z found 403.1[M+H] + .
Intermediate 76: (S) -5- (3-amino-1-methyl-1H-pyrazol-5-yl) -2- (1-cyclopropylethyl) -7-ethylisoindol-1-one
To a solution of intermediate 75 (450 mg,1.12mmol,1 eq) in ethanol (4 mL) was added NH 2 OH HCl (1.17 g,16.8mmol,15 eq) and Et 3 N (260 mg,2.57mmol, 358. Mu.l, 2.3 eq). Stirring for 16h at 95 ℃. After the reaction was completed, the reaction solution was cooled to room temperature. The organic solvent was distilled off under reduced pressure. Ethyl acetate and water were extracted, and the organic layer was separated, dried over anhydrous sodium sulfate, and the organic solvent was distilled off under reduced pressure to obtain 450mg 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] + .
Intermediate 77: (S) -5-bromo-2- (1-cyclopropylethyl) -7-ethoxyisoindol-1-one
Intermediate 6 (400 mg,1.34mmol,1 eq), ethanol (8 mL), K 2 CO 3 (556 mg,4.02mmol,3 eq) was added to a round bottom flask. Stirring for 16h at 80 ℃. After the reaction was completed, the reaction solution was cooled to room temperature. The organic solvent was distilled off under reduced pressure. Ethyl acetate and water extraction, separating the liquid, taking the organic layer, drying by anhydrous sodium sulfate, decompressing and distilling to remove the organic solvent to obtain a crude product. The crude product was isolated by column chromatography to give 175mg of the title compound as a white solid. LC-MS (ESI): rt= 0.83min,mass calcd.For C 15 H 18 BrNO 2 323.05 m/z found 323.9[M+H] + .
Intermediate 78: (S) -5-bromo-2- (1-cyclopropylethyl) -7- (ethyl (4-methoxybenzyl) amino) isoindolin-1-one
The above compound was prepared by the method described with reference to intermediate 7, LC-MS (ESI): R T =0.88min,mass calcd.For C 23 H 27 BrN 2 O 2 442.13 m/z found 443.0[M+H] + .
Intermediate 79: (S) -N- (5- (2- (1-cyclopropylethyl) -7- (ethyl (4-methoxybenzyl) amino) -1-oxoisoindol-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide
The above compound was prepared by the method described with reference to intermediate 29, LC-MS (ESI): R T =0.69min,mass calcd.For C 29 H 35 N 5 O 3 501.27 m/z found 502.3[M+H] + .
Intermediate 80: (S) -N- ((4-Bromofuran-2-yl) methyl) -1-cyclopropylethylamine
To a solution of 4-bromofuran-2-carbaldehyde (863 mg,4.93mmol,1.2 eq), (S) -1-cyclopropylethylamine hydrochloride (500 mg,4.11mmol,1 eq) in methanol (10 mL) was added triethylamine (416 mg,4.11mmol,1 eq) and NaBH 3 CN (775 mg,12.3mmol,3 eq). Stirring was carried out at room temperature for 16h. After the completion of the reaction, the organic solvent was distilled off under reduced pressure. Ethyl acetate and water extraction, separating liquid, taking an organic layer, drying by magnesium sulfate, filtering, and distilling under reduced pressure to obtain a crude product. The crude product was isolated by column chromatography to give 670mg of the title 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] + . 1 H NMR(400MHz,DMSO-d 6 )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).
Intermediate 81: (3 aS, 6R) -5-bromo-2- ((S) -1-cyclopropylethyl) -1-oxo-1, 2,3,6,7 a-hexahydro-3 a, 6-epoxyisoindole-7-carboxylic acid
To a solution of intermediate 80 (640 mg,2.74mmol,1 eq) in toluene (10 mL) was added furan-2, 5-dione (292 mg,3.02mmol,1.1 eq). Stirring was carried out at room temperature for 16h. After the completion of the reaction, the organic solvent was distilled off under reduced pressure. Ethyl acetate and water extraction, separating liquid, taking an organic layer, drying by magnesium sulfate, filtering, and distilling under reduced pressure to obtain a crude product. The crude product was isolated by column chromatography to give 590mg of the title compound as a white solid. LC-MS (ESI): R T =0.72min,mass calcd.For C 14 H 16 BrNO 4 341.03 m/z found 341.9[M+H] + .
Intermediate 82: (S) -6-bromo-2- (1-cyclopropylethyl) -3-oxoisoindoline-4-carboxylic acid
To a solution of intermediate 81 (560 mg,1.72mmol,1 eq) in 1, 4-dioxane (8 mL) was added BF 3 ·Et 2 O (1.10 g,7.76mmol, 958. Mu.l, 4.5 eq). Stirring for 2h at 110 ℃. After the completion of the reaction, the organic solvent was distilled off under reduced pressure. Ethyl acetate and water extraction, separating liquid, taking an organic layer, drying by magnesium sulfate, filtering, and distilling under reduced pressure to obtain a crude product. The crude product was isolated by column chromatography to give 550mg of the title compound as a white solid. LC-MS (ESI): R T =0.82min,mass calcd.For C 14 H 14 BrNO 3 323.02 m/z found 323.9[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )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).
Intermediate 83: (S) -6-bromo-2- (1-cyclopropylethyl) -N-methyl-3-oxoisoindoline-4-carboxamide
Toward intermediate 82 (570 mg,1.76mmol,1 eq), methylamine hydrochloride (125 mg,1.85mmol,1.05 eq) in DMF (10 mL) was added DIPEA (909 mg,7.03mmol,1.23mL,4 eq) and HATU (730 mg,1.93mmol,1.1 eq). Stirring was carried out at room temperature for 16h. After the completion of the reaction, the organic solvent was distilled off under reduced pressure. Ethyl acetate and water extraction, separating liquid, taking an organic layer, drying by magnesium sulfate, filtering, and distilling under reduced pressure to obtain a crude product. The crude product was isolated by column chromatography to give 420mg of the title compound as a white solid. LC-MS (ESI): R T =0.86min,mass calcd.For C 15 H 17 BrN 2 O2 336.05 m/z found 337.4[M+H] + .
Intermediate 84:5- (3-amino-1-methyl-1H-pyrazol-5-yl) -2-methyl isoindolin-1-one
The above compound was prepared by the method described with reference to intermediate 76, mass calcd.for C 13 H 14 N 4 O 242.1 m/z,found 243.0[M+H] + .
Intermediate 85: 4-bromo-N- (6-bromopyridin-2-yl) butanamide
To a solution of 6-bromopyridin-2-amine (5 g,28.9mmol,1 eq), 4-bromobutyryl chloride (6.43 g,34.68mmol,4.02mL,1.2 eq) in acetonitrile (50 mL) was added pyridine (3.43 g,43.35mmol,3.50mL,1.5 eq) dropwise. After the completion of the dropwise addition, the reaction was carried out at room temperature for 16 hours. After the completion of the reaction, 3/4 of the organic solvent was distilled off under reduced pressure. Ethyl acetate and water were added to extract the filtrate, and the organic layer was separated, dried over anhydrous sodium sulfate, and the organic solvent was distilled off under reduced pressure to obtain a crude product. The crude product was isolated by column chromatography to give 7.1g of the title compound as a white solid. LC-MS (ESI): R T =0.79min,mass calcd.For C 9 H 10 Br 2 N 2 O 319.92 m/z found 320.7[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )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).
Intermediate 86:1- (6-bromopyridin-2-yl) pyrrolidin-2-one
To a solution of intermediate 85 (3.6 g,11.18mmol,1 eq) in DMF (20 mL) was added K 2 CO 3 (4.02 g,29.07mmol,2.6 eq). The reaction was carried out at 60℃for 4h. After the reaction was completed, the reaction solution was cooled to room temperature. 3/4 of the organic solvent was distilled off under reduced pressure. Ethyl acetate and water were added to extract the filtrate, and the organic layer was separated, dried over anhydrous sodium sulfate, and the organic solvent was distilled off under reduced pressure to obtain 2.6g of the title compound as a white solid. LC-MS (ESI): R T =0.80min,mass calcd.For C 9 H 9 BrN 2 O 239.99 m/z found 240.5[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )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).
Intermediate 87: (S) -N- (5- (7-amino-2- (1-cyclopropylethyl) -1-oxoisoindol-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide
The above compound was prepared by the method described with reference to intermediate 29, LC-MS (ESI): R T =0.69min,mass calcd.for C 19 H 23 N 5 O 2 353.19 m/z,found 354.4[M+H] + .
Intermediate 88: (S) -5- (3-amino-1-methyl-1H-pyrazol-5-yl) -2- (1-cyclopropylethyl) -7-methylisoindolin-1-one
The above-described formation is obtained by reference to intermediate 76Compound, mass calcd.for C 18 H 22 N 4 O 310.2 m/z,found 311.0[M+H] + .
Intermediate 89:5- (3-amino-1-methyl-1H-pyrazol-5-yl) -4-methylisoindol-1-one
The above compound was prepared by the method described with reference to intermediate 76, mass calcd.for C 13 H 14 N 4 O 242.1 m/z,found 242.9[M+H] + .
Intermediate 90:5- (3-amino-1-methyl-1H-pyrazol-5-yl) -2-ethylisoindolin-1-one
The above compound was prepared by the method described with reference to intermediate 76, mass calcd.for C 14 H 16 N 4 O 256.1 m/z,found 257.0[M+H] + .
Intermediate 91:5- (3-amino-1-methyl-1H-pyrazol-5-yl) -7-methyl isoindolin-1-one
The above compound was prepared by the method described with reference to intermediate 76, mass calcd.for C 14 H 16 N 4 O 242.1 m/z,found 242.9[M+H] + .
Intermediate 92:5- (3-amino-1-methyl-1H-pyrazol-5-yl) -2- (cyclopropylmethyl) isoindolin-1-one
The above compound was prepared by the method described with reference to intermediate 76, mass calcd.for C 18 H 22 N 4 O 282.1 m/z,found 283.0[M+H] + .
Intermediate 93: n- (5-bromo-1-methyl-1H-pyrazol-3-yl) acetamide
5-bromo-1-methyl-1H-pyrazol-3-amine (2.5 g,15 mmol), triethylamine (6 mL), toluene (15 mL) were added to the round bottom flask, followed by dropwise addition of acetic anhydride (2.1 mL,3.75 mmol) to the mixture. The reaction was carried out at 40℃for 2h. After the reaction was completed, the reaction mixture was cooled to room temperature, and the organic solvent was distilled off under reduced pressure. The reaction solution was added to 100mL of water, and the organic matter was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The organic solvent is distilled off under reduced pressure to obtain a crude product. The crude product was separated by column chromatography to give 1.9g of the title compound as a yellowish white solid. Mass calcd.for C 6 H 8 BrN 3 O 216.99 m/z,found 217.7[M+H] + 。
Intermediate 94: 6-bromo-8- ((4-methoxybenzyl) amino) -3, 4-dihydroisoquinolin-1 (2H) -one
6-bromo-8-fluoro-3, 4-dihydroisoquinolin-1 (2H) -one (480.0 mg,2 mmol) was added to (4-methoxyphenyl) methylamine (5 mL). Stirring at 100deg.C for 16 hr, adding ethyl acetate and water to extract reaction solution, separating organic layer, drying with magnesium sulfate, and distilling under reduced pressure to remove organic solvent to obtain crude product. The crude product was isolated by column chromatography to give 586mg of the title compound as a yellow oil. Mass calcd.for C 17 H 17 BrN 2 O 2 360.05 m/z,found 360.8[M+H] + 。
Intermediate 95: 8-amino-6-bromo-3, 4-dihydroisoquinolin-1 (2H) -one
Method of referencing intermediate 8Preparation of the above Compound from intermediate 94, mass calcd.for C 9 H 9 BrN 2 O 239.99 m/z,found 240.9[M+H] + 。
Intermediate 96: n- (6-bromo-1-oxo-1, 2,3, 4-tetrahydroisoquinolin-8-yl) ethanesulfonamide
The above compound was prepared from intermediate 95 by the method described for intermediate 9 11 H 13 BrN 2 O 3 331.98 m/z,found 332.7[M+H]+。
Intermediate 97: n- (1-oxo-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,2,3, 4-tetrahydroisoquinolin-8-yl) ethanesulfonamide
Intermediate 96 (332.0 mg,1 mmol), pinacol biborate (333.1 mg,1.3 mmol) ferrocene [1,1' -bis (diphenylphosphine) were reacted in sequence under nitrogen]Palladium dichloride (73.2 mg,0.1 mol) and potassium acetate (215.9 mg,2.2 mmol) were added to a tube sealer, dried dioxane (15 mL) was added, heated to 100deg.C, reacted for 3 hours, after the reaction was completed, concentrated, silica gel column chromatography, and separated to give 306mg of the objective compound, mass calcd.for C 17 H 25 BN 2 O 5 S 380.16 m/z,found 381.0[M+H]+。
Example 1
This example provides a compound named: (S) -N- (5- (2- (1-cyclopropylethyl) -7- (methylsulfonyl) -1-oxoisoindol-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide having the structure:
the preparation method comprises the following steps:
Intermediate 20 (150 mg, 419. Mu. Mol), intermediate 3 (111 mg, 419. Mu. Mol), cs are reacted in this order under Ar protection 2 CO 3 (477.48mg,1.47mmol)、Pd(dppf)Cl 2 (30.64 mg, 41.87. Mu. Mol), 1, 4-dioxane (4 mL) and H 2 O (1 mL) was added to a 40mL microwave tube. And carrying out microwave reaction for 2 hours under the protection of argon, wherein the reaction temperature is 110 ℃. And (5) distilling under reduced pressure to obtain a crude product. The crude product was isolated by column chromatography to give 31mg of product as a white solid. LC-MS (ESI): R T =2.47min,mass calcd.for C 20 H 24 N 4 O 4 S 416.15 m/z,found 416.8[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )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),3.63-3.58(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).
Example 2
This example provides a compound: (S) -N- (5- (2- (1-cyclopropylethyl) -7- (methylsulfonyl) -1-oxoisoindol-5-yl) -1H-pyrazol-3-yl) acetamide having the structure:
the preparation method comprises the following steps:
to a solution of intermediate 29 (390 mg, 732. Mu. Mol) in dichloromethane (6 mL) was added TFA (6.68 g,4.34mL,58.57 mmol) dropwise. After the completion of the dropwise addition, stirring was carried out at room temperature for 1 hour. Subsequently, the organic solvent was distilled off under reduced pressure. The crude product was isolated by column chromatography to give 143.6mg of the compound as a white solid. LC-MS (ESI): R T =1.96min,mass calcd.For C 19 H 22 N 4 O 4 S 402.14 m/z found 402.8[M+H]+. 1 H NMR(400MHz,DMSO-d 6 )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,3H),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).
Example 3
This example provides a compound: n- (5- (2-isopropyl-7- (methylsulfonyl) -1-oxoisoindol-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide has the following structure:
prepared by the method of reference example 1 using intermediate 3 and intermediate 12. LC-MS (ESI) R T =2.57min,mass calcd.for C 18 H 22 N 4 O 4 S 390.14 m/z,found 390.8[M+H] + .1H NMR(400MHz,CDCl 3 )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).
Example 4
This example provides a compound: (S) -N- (5- (2- (1-cyclopropylethyl) -1-oxo-7-sulfamoyl isoindol-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide having the structure:
prepared by the method of reference example 1 using intermediate 3 and intermediate 31. LC-MS (ESI): R T =0.68min,mass calcd.for C 19 H 23 N 5 O 4 S 417.15 m/z,found 418.1[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )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),3.70-3.59(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).
Example 5
This example provides a compound: (S) -N- (6- (3-acetamido-1-methyl-1H-pyrazol-5-yl) -2- (1-cyclopropylethyl) -3-oxoisoindol-4-yl) acetamide having the structure:
prepared by the method of reference example 1 using intermediate 3 and intermediate 32. LC-MS (ESI): R T =3.01min,mass calcd.for C 21 H 25 N 5 O 3 395.20 m/z,found 395.8[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )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).
Example 6
This example provides a compound: (S) -N- (5- (2- (1-cyclopropylethyl) -7- (N-methylsulfamoyl) -1-oxoisoindol-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide having the structure:
prepared by the method of reference example 1 using intermediate 3 and intermediate 33. LC-MS (ESI): R T =2.80min,mass calcd.For C 20 H 25 N 5 O 4 S 431.16 m/z found 431.9[M+H] + . 1 H NMR(400MHz,CDCl 3 )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).
Example 7
This example provides a compound: (S) -N- (5- (2- (1-cyclopropylethyl) -7- (N, N-dimethylsulfamoyl) -1-oxoisoindol-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide has the following structure:
prepared by the method of reference example 1 using intermediate 3 and intermediate 35. LC-MS (ESI): R T =0.70min,mass calcd.for C 21 H 27 N 5 O 4 S 445.18 m/z,found 446.1[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )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).
Example 8
This example provides a compound: (S) -N- (5- (2- (1-cyclopropylethyl) -7- (N-methylsulfamoyl) -1-oxoisoindol-5-yl) -1H-pyrazol-3-yl) acetamide having the structure:
The preparation method comprises the following steps: to a solution of intermediate 34 (350 mg, 639. Mu. Mol) in dichloromethane (2 mL) was added TFA (2 mL) dropwise. After the completion of the dropwise addition, stirring was carried out at room temperature for 2 hours. Subsequently, the organic solvent was distilled off under reduced pressure. 4M methanolic ammonia (3 mL) was added and dissolved, and stirring was continued for 1h at ambient temperature. After the reaction was completed, the organic solvent was distilled off under reduced pressure. The crude product was isolated by column chromatography to give 33mg of the title compound as a white solid. LC-MS (ESI): R T =2.31min,mass calcd.For C 19 H 23 N 5 O 4 S 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).
Example 9
This example provides a compound: (S) -N- (5- (2- (1-cyclopropylethyl) -7- (methylsulfonamide) -1-oxoisoindol-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide has the following structure:
the procedure of reference example 1 uses intermediates3 and intermediate 14. LC-MS (ESI): R T =3.07min,mass calcd.For C 20 H 25 N 5 O 4 S 431.16 m/z found 431.8[M+H] + . 1 H NMR(400MHz,CDCl 3 )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),3.73-3.65(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).
Example 10
This example provides a compound: (S) -N- (5- (7- (N-cyclobutylsulfamoyl) -2- (1-cyclopropylethyl) -1-oxoisoindol-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide has the following structure:
prepared by the method of reference example 1 using intermediate 3 and intermediate 36. LC-MS (ESI): R T =3.48min,mass calcd.for C 23 H 29 N 5 O 4 S 471.19 m/z,found 471.8[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )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).
Example 11
This example provides a compound: n- (5- (2-isopropyl-7- (N-methylsulfamoyl) -1-oxoisoindol-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide has the following structure:
Prepared by the method of reference example 1 using intermediate 3 and intermediate 37. LC-MS (ESI): R T =2.52min,mass calcd.For C 18 H 23 N 5 O 4 S 405.15 m/z found 406.1[M+H] + . 1 H NMR(400MHz,CDCl 3 )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).
Example 12
This example provides a compound: (S) -N- (5- (2- (1-cyclopropylethyl) -1-oxo-7-sulfamoyl isoindol-5-yl) -1H-pyrazol-3-yl) acetamide having the structure:
prepared by the method of reference example 8 using intermediate 38. LC-MS (ESI): R T =1.94min mass calcd.For C 18 H 21 N 5 O 4 S 403.13 m/z found 403.8[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )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).
Example 13
This example provides a compound: (S) -N- (5- (2- (1-cyclopropylethyl) -7- (N- (cyclopropylmethyl) sulfamoyl) -1-oxoisoindol-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide having the following structure:
prepared by the method of reference example 1 using intermediate 3 and intermediate 39. LC-MS (ESI): R T =3.36min,mass calcd.For C 23 H 29 N 5 O 4 S 471.19 m/z found 471.9[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )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).
Example 14
This example provides a compound: (S) -N- (5- (2- (1-cyclopropylethyl) -7- (N-cyclopropylsulfamoyl) -1-oxoisoindol-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide has the following structure:
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prepared by the method of reference example 1 using intermediate 3 and intermediate 40. LC-MS (ESI): R T =3.23min,mass calcd.For C 22 H 27 N 5 O 4 S 457.18 m/z found 457.9[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )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).
Example 15
This example provides a compound: (S) -N- (5- (2- (1-cyclopropylethyl) -7- (N-ethylsulfamoyl) -1-oxoisoindol-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide has the following structure:
prepared by the method of reference example 1 using intermediate 3 and intermediate 41. LC-MS (ESI): R T =3.12min,mass calcd.for C 21 H 27 N 5 O 4 S 445.18 m/z,found 445.8[M+H] + . 1 H NMR(400MHz,CDCl 3 )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).
Example 16
This example provides a compound: (S) -N- (5- (2- (1-cyclopropylethyl) -7- (N- (oxetan-3-yl) sulfamoyl) -1-oxoisoindol-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide has the following structure:
prepared by the method of reference example 1 using intermediate 3 and intermediate 42. LC-MS (ESI): R T =2.73min,mass calcd.For C 22 H 27 N 5 O 5 S 473.17 m/z found 473.8[M+H] + . 1 H NMR(400MHz,CDCl 3 )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).
Example 17
This example provides a compound: (S) -N- (5- (2- (1-cyclopropylethyl) -7- (N- (3, 3-difluorocyclobutyl) sulfamoyl) -1-oxoisoindol-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide, having the following structure:
prepared by the method of reference example 1 using intermediate 3 and intermediate 43. LC-MS (ESI): R T =4.67min,mass calcd.For C 23 H 27 F 2 N 5 O 4 S 507.18 m/z found 507.8[M+H] + . 1 H NMR(400MHz,CDCl 3 )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).
Example 18
This example provides a compound: (S) -N- (5- (2- (1-cyclopropylethyl) -7- (N- (2-methoxyethyl) sulfamoyl) -1-oxoisoindolin-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide, having the following structure:
the preparation method comprises the following steps: prepared using intermediate 3 and intermediate 44 as described with reference to example 1. LC-MS (ESI): rt= 2.96min,mass calcd.for C 22 H 29 N 5 O 5 S 475.19 m/z,found 475.9[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )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,3H),1.24-1.11(m,1H),0.66-0.55(m,1H),0.49-0.39(m,2H),0.34-0.24(m,1H).
Example 19
This example provides a compound: (S) -N- (5- (2- (1-cyclopropylethyl) -7- (N- ((1- (fluoromethyl) cyclopropyl) methyl) sulfamoyl) -1-oxoisoindol-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide having the following structure:
The above compound was prepared using intermediate 3 and intermediate 24 as described with reference to example 1. LC-MS (ESI): R T =3.59min,mass calcd.For C 24 H 30 FN 5 O 4 S 503.20 m/z found 503.9[M+H] + . 1 H NMR(400MHz,CDCl 3 )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).
Example 20
This example provides a compound: (S) -N- (5- (2- (1-cyclopropylethyl) -1-oxo-7- (N- (2, 2-trifluoroethyl) sulfamoyl) isoindolin-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide, the structure is as follows:
prepared using intermediate 3 and intermediate 45, as described with reference to example 1. LC-MS (ESI): R T =3.51min,mass calcd.for C 21 H 24 F 3 N 5 O 4 S 499.15 m/z,found 499.8[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )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).
Example 21
This example provides a compound: n- (5- (2-isopropyl-1-oxo-7-sulfamoyl isoindol-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide has the following structure:
prepared by the method of example 1 using intermediate 3 and intermediate 48. LC-MS (ESI): R T =3.50min,mass calcd.For C 17 H 21 N 5 O 4 S 391.13 m/z found 391.8[M+H] + . 1 H NMR(400MHz,CDCl 3 )δ8.14(s,1H),7.86(s,1H),7.76(s,1H),6.88(s,1H),6.63(s,2H),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).
Example 22
This example provides a compound: (S) -N- (5- (2- (1-cyclopropylethyl) -7- (methylsulfonamide) -1-oxoisoindol-5-yl) -1H-pyrazol-3-yl) acetamide has the following structure:
prepared by the method of reference example 8 using intermediate 29. LC-MS (ESI): R T =2.43min,mass calcd.For C 19 H 23 N 5 O 4 S 471.15 m/z found 471.8[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )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),3.72-3.51(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).
Example 23
This example provides a compound: (S) -N- (5- (7- (cyclopropanesulfonamide) -2- (1-cyclopropylethyl) -1-oxoisoindol-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide having the structure:
Prepared using intermediate 3 and intermediate 49 according to the method of example 1. LC-MS (ESI): R T =3.35min,mass calcd.for C 22 H 27 N 5 O 4 S 457.18 m/z,found 457.8[M+H] + . 1 H NMR(400MHz,CDCl 3 )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,1H),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).
Example 24
This example provides a compound: (S) -N- (5- (2- (1-cyclopropylethyl) -1-oxo-7- (propylsulfonylamino) isoindol-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide has the following structure:
prepared using intermediate 3 and intermediate 50 as described with reference to example 1. LC-MS (ESI): R T =2.98min,mass calcd.for C 22 H 29 N 5 O 4 S 459.19 m/z found 459.9[M+H] + . 1 H NMR(400MHz,CDCl 3 )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,1H),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).
Example 25
This example provides a compound: (S) -N- (5- (2- (1-cyclopropylethyl) -7- (ethylsulfonamide) -1-oxoisoindol-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide having the structure:
prepared using intermediate 3 and intermediate 9 as described with reference to example 1. LC-MS (ESI): R T =3.51min,mass calcd.for C 21 H 27 N 5 O 4 S 445.18 m/z,found 445.8[M+H] + . 1 H NMR(400MHz,CDCl 3 )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).
Example 26
This example provides a compound: (S) -N- (5- (2- (1-cyclopropylethyl) -7- (1, 1-dimethylethylsulfonamide) -1-oxoisoindol-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide having the structure:
prepared using intermediate 3 and intermediate 16 as described with reference to example 1. LC-MS (ESI): R T =3.70min,mass calcd.for C 23 H 31 N 5 O 4 S 473.21 m/z,found 473.9[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )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).
Example 27
This example provides a compound: (S) -N- (5- (2- (1-cyclopropylethyl) -7- (2-methoxyethylsulfonamide) -1-oxoisoindol-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide has the following structure:
Prepared using intermediate 3 and intermediate 17 as described with reference to example 1. LC-MS (ESI): R T =3.28min,mass calcd.for C 22 H 29 N 5 O 5 S 475.19 m/z,found 475.8[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ10.48(s,1H),9.63(s,1H),7.51(s,1H),7.44(s,1H),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).
Example 28
This example provides a compound: (S) -N- (5- (2- (1-cyclopropylethyl) -7- (cyclopropylmethylsulfonylamino) -1-oxoisoindolin-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide having the structure:
the preparation method comprises the following steps: to a solution of intermediate 87 (360 mg,1.02mmol,1 eq), cyclopropylmethylsulfonyl chloride (709 mg,4.58mmol,4.5 eq) in dichloromethane (6 mL) under nitrogen, DIPEA (480 mg,1.06mL,6.11mmol,6 eq), DMAP (49.8 mg, 407. Mu. Mol,0.4 eq), triethylamine (412 mg, 567. Mu.L, 4.07mmol,4 eq), pyridine (564 mg, 576. Mu.L, 7.13mmol,7 eq) were added dropwise in succession. After the completion of the dropwise addition, stirring was carried out at room temperature for 1 hour. After the reaction was completed, 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 distilled off under reduced pressure to give a crude product. The crude product was isolated by column chromatography to give 7mg of the title compound as a white solid. LC-MS (ESI): R T =2.96min,mass calcd.for C 23 H 29 N 5 O 4 S 471.19 m/z,found 472.0[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )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).
Example 29
This example provides a compound: (S) -N- (5- (2- (1-cyclopropylethyl) -7- (1, 3-dimethyl-1H-pyrazole-4-sulfonamide) -1-oxoisoindol-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide, having the structure:
Prepared using intermediate 3 and intermediate 18 as described with reference to example 1. LC-MS (ESI): R T =3.40min,mass calcd.for C 24 H 29 N 7 O 4 S 511.20 m/z,found 511.9[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )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).
Example 30
This example provides a compound: n- (5- (2- (2-cyclopropylprop-2-yl) -7- (N-methylsulfamoyl) -1-oxoisoindol-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide has the following structure:
prepared using intermediate 3 and intermediate 54 as described with reference to example 1. LC-MS (ESI): R T =3.43min,mass calcd.For C 21 H 27 N 5 O 4 S 445.18 m/z found 446.1[M+H] + . 1 H NMR(400MHz,CDCl 3 )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).
Example 31
This example provides a compound: (S) -N- (5- (2- (3, 3-dimethylbutan-2-yl) -7- (N-methylsulfamoyl) -1-oxi-isoindolin-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide, the structure is as follows:
prepared using intermediate 3 and intermediate 58 as described with reference to example 1. LC-MS (ESI): R T =2.82min,mass calcd.for C 21 H 29 N 5 O 4 S 447.19 m/z,found 447.8[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )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,CDCl 3 )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).
Example 32
This example provides a compound: n- (5- (2- (tert-butyl) -7- (N-methylsulfamoyl) -1-oxoisoindol-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide has the following structure:
prepared using intermediate 3 and intermediate 62 as described with reference to example 1. LC-MS (ESI): R T =2.31min,mass calcd.for C 19 H 25 N 5 O 4 S 419.16 m/z,found 419.9[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )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).
Example 33
This example provides a compound: (S) -N- (1-methyl-5- (7- (N-methylsulfamoyl) -1-oxo-2- (1, 1-trifluoropropan-2-yl) isoindolin-5-yl) -1H-pyrazol-3-yl) acetamide, the structure is as follows:
Prepared using intermediate 3 and intermediate 66 as described with reference to example 1. LC-MS (ESI): R T =2.31min,mass calcd.for C 18 H 20 F 3 N 5 O 4 S 459.12 m/z,found 459.8[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )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).
Example 34
This example provides a compound: (S) -N- (5- (7- (N- (3-cyanophenyl) sulfamoyl) -2- (1-cyclopropylethyl) -1-oxoisoindol-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide having the following structure:
prepared using intermediate 3 and intermediate 67 as described with reference to example 1. LC-MS (ESI): R T =3.23min,mass calcd.for C 26 H 26 N 6 O 4 S 518.17 m/z,found 518.8[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )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).
Example 35
This example provides a compound: n- (5- (7- (N- (3-cyanophenyl) sulfamoyl) -2-isopropyl-1-oxoisoindol-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide has the following structure:
prepared using intermediate 3 and intermediate 68 as described with reference to example 1. LC-MS (ESI): R T =2.84min,mass calcd.For C 24 H 24 N 6 O 4 S 492.16 m/z found 492.8[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )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).
Example 36
This example provides a compound: (S) -N- (5- (2- (1-cyclopropylethyl) -7-ethyl-1-oxoisoindol-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide has the following structure:
the preparation method comprises the following steps: to a dichloromethane solution (5 mL) of intermediate 76 was added acetic anhydride (706 mg,6.94mmol,650 μl,5 eq). Stirring was carried out at room temperature for 16h. 3/4 of the organic solvent was distilled off under reduced pressure. Dichloromethane and water were added to extract the filtrate, an organic layer was separated, dried over anhydrous sodium sulfate, and the organic solvent was distilled off under reduced pressure to obtain a crude product. The crude product was isolated by column chromatography to give the compound as a white solid (60.6 mg, 11.92%). LC-MS (ESI): R T =3.24min,mass calcd.For C 21 H 26 N 4 O2 366.21 m/z found 366.8[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )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).
Example 37
This example provides a compound: (S) -N- (5- (2- (1-cyclopropylethyl) -7-ethoxy-1-oxoisoindol-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide having the structure:
prepared using intermediate 3 and intermediate 77 as described with reference to example 1. LC-MS (ESI): R T =3.01min,mass calcd.For C 21 H 26 N 4 O 3 382.20 m/z found 382.8[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )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).
Example 38
This example provides a compound: (S) -N- (5- (2- (1-cyclopropylethyl) -7- (ethylamino) -1-oxoisoindol-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide has the structure:
the preparation method comprises the following steps: to a solution of intermediate 79 (190 mg, 379. Mu. Mol,1 eq) in dichloromethane (2 mL) was added TFA (4.32 g,37.9mmol,2.80mL,100 eq). Stirring for 3h at 50 ℃. After the completion of the reaction, the organic solvent was distilled off under reduced pressure. Ethyl acetate and water, the organic layer was separated, dried over magnesium sulfate, filtered and distilled under reduced pressure to give a crude product (70.5 mg, 49%). The crude product was separated by column chromatography to give the target compound as a white solid. LC-MS (ESI): R T =3.42min,mass calcd.For C 21 H 27 N 5 O 2 381.22 m/z found 381.8[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )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),1.14-1.05(m,1H),0.62-0.50(m,1H),0.45-0.31(m,2H),0.27-0.16(m,1H).
Example 39
This example provides a compound: (S) -6- (3-acetamido-1-methyl-1H-pyrazol-5-yl) -2- (1-cyclopropylethyl) -N-methyl-3-oxoisoindoline-4-carboxamide has the structure:
prepared using intermediate 3 and intermediate 83 as described with reference to example 1. LC-MS (ESI): R T =2.97min,mass calcd.For C 21 H 25 N 5 O 3 395.20 m/z found 395.8[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )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).
Example 40
This example provides a compound: (S) -2- (1-cyclopropylethyl) -5- (1-methyl-3- ((6- (2-oxopyrrolidin-1-yl) pyridin-2-yl) amino) -1H-pyrazol-5-yl) -7- (methylsulfonyl) isoindolin-1-one has the structure:
the preparation method comprises the following steps: to the compound of example 1: (S) -N- (5- (2- (1-cyclopropylethyl) -7- (methylsulfonyl) -1-oxoisoindol-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide (320 mg, 768.32. Mu. Mol,1 eq) in 4M HCl in 1, 4-dioxane (10 mL) was slowly added dropwise H 2 O (1 mL). The reaction was carried out at 70℃for 2h. After the reaction was completed, the reaction solution was cooled to room temperature, and the organic solvent was distilled off under reduced pressure to obtain a yellow solid compound. SubsequentlyUnder the protection of Ar gas, 1- (6-bromo-2-pyridyl) pyrrolidin-2-one (141 mg,584 mu mol,0.8 eq) Cs is continuously added into a reaction flask 2 CO 3 (833 mg,2.56mmol,3.5 eq), 1, 4-dioxane (8 mL), pd 2 (dba) 3 (67 mg, 73. Mu. Mol,0.1 eq) 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (84.5 mg, 146. Mu. Mol,0.2 eq) was placed in a lock tube. The reaction was carried out at 100℃for 16h. After the reaction was completed, the reaction solution was cooled to room temperature. The organic solvent was distilled off under reduced pressure to give a crude product. The crude product was isolated by column chromatography to give the title compound (29.3 mg, 7.4%) as a white solid. LC-MS (ESI): R T =3.69min,mass calcd.For C 27 H 30 N 6 O 4 S 534.20 m/z found 535.2[M+H] + . 1 H NMR(400MHz,CDCl 3 )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),3.85(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).
Example 41
This example provides a compound: (S) -N- (5- (2- (1-cyclopropylethyl) -7-methyl-1-oxoisoindolin-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide having the structure:
prepared using intermediate 3 and intermediate 88 as described in reference to example 36. Mass calcd.for C 20 H 24 N 4 O 2 352.2 m/z,found 353.1[M+H] + .
Example 42
This example provides a compound: n- (1-methyl-5- (4-methyl-1-oxoisoindol-5-yl) -1H-pyrazol-3-yl) acetamide has the following structure:
prepared using intermediate 3 and intermediate 89 by the methods described with reference to example 36. Mass calcd.for C 15 H 16 N 4 O 2 284.1 m/z,found 285.0[M+H] + .
Example 43
This example provides a compound: n- (5- (2-ethyl-1-oxoisoindolin-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide has the following structure:
prepared using intermediate 3 and intermediate 90 as described in reference to example 36. Mass calcd.for C 16 H 18 N 4 O 2 298.1 m/z,found 299.1[M+H] + .
Example 44
This example provides a compound: n- (1-methyl-5- (7-methyl-1-oxoisoindolin-5-yl) -1H-pyrazol-3-yl) acetamide has the following structure:
prepared using intermediate 3 and intermediate 91 as described in reference to example 36. Mass calcd.for C 15 H 16 N 4 O 2 284.1 m/z,found 284.8[M+H] + .
Example 45
This example provides a compound: n- (5- (2- (cyclopropylmethyl) -1-oxi-isoindolin-5-yl) -1-methyl-1H-pyrazol-3-yl) acetamide has the following structure:
Prepared using intermediate 3 and intermediate 92 as described in reference to example 36. Mass calcd.for C 18 H 20 N 4 O 2 324.1 m/z,found 325.0[M+H] + .
Example 46
This example provides a compound: n- (1-methyl-5- (2-methyl-1-oxoisoindol-5-yl) -1H-pyrazol-3-yl) acetamide has the following structure:
prepared using intermediate 3 and intermediate 84 as described in reference to example 36. Mass calcd.for C 15 H 16 N 4 O 2 284.1 m/z,found 285.0[M+H] + .
Example 47
This example provides a compound: n- (5- (8- (ethylsulfonamide) -1-oxo-1, 2,3, 4-tetrahydroisoquinolin-6-yl) -1-methyl-1H-pyrazol-3-yl) acetamide has the following structure:
intermediate 93 (109 mg,0.5 mmol), intermediate 97 (284 mg,0.75 mmol) and [1,1' -bis (diphenylphosphino) ferrocene were reacted under nitrogen]Palladium dichloride (36.6 mg,0.05 mol) and potassium phosphate (318.5 mg,1.5 mmol) were mixed, dioxane (3 mL) and water (0.5 mL) were added, heated to 90℃and reacted for 11 hours, after the reaction was completed, concentrated, and silica gel column chromatography was performed to separate 66mg of the objective compound. Mass calcd.for C 17 H 21 N 5 O 4 S 391.13 m/z,found 391.9[M+H]+.
Biological test evaluation
Test example 1-test of inhibition of Pi I3K alpha/beta/gamma/delta kinase Activity by Compounds of the examples
Experimental instrument: the centrifuge was purchased from Eppendorf corporation, the pipettor from Eppendor and Gilson corporation, and the microplate reader from US Thermo Fisher Scientific corporation under the model Varioskan LUX multifunctional microplate reader.
Experimental materials:
name of the name | Goods 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 |
MgCl 2 | Sigma#M2670-500g |
96well plate | Corning#3365 |
The experimental method comprises the following steps: the experiment adopts an ADP-Glo lipid kinase determination method of Promega company, lipid kinase Pi3K alpha/beta/gamma/delta is subjected to catalytic reaction in the presence of a 1:3 ratio mixture (Pi 2:3 PS) of substrate phosphoinositide-4, 5-diphosphate (Pi 2) and lipid-loaded Phosphatidylserine (PS) and ATP to generate ADP, the content of ADP in the reaction is determined to characterize the activity of the lipid kinase, and half inhibition concentration IC of a compound on inhibition of Pi3K alpha/beta/gamma/delta kinase activity is obtained 50 。
The specific experimental operation is as follows:
the kinase reaction was performed in white 96-well plates with 2. Mu.L of ddH in 1% DMSO per well 2 O diluted different concentrations of the compound of the present invention, positive control wells were added with 2. Mu.L of ddH containing 1% DMSO 2 O, then 2. Mu.L of 5 Xkinase buffer (HEPES 250mM, mgCl) was added to each well 2 15mM,NaCl 250mM,BSA 0.05%) diluted 0.1-2 nM PI3K kinase solution; negative control wells were added with 2. Mu.L of 5 Xkinase buffer, all wells were added with 4. Mu.L of 10 Xdilution buffer and ddH 2 O-formulated 50 μm substrate PIP2:3PS, and finally adding 2. Mu.L of 50-100. Mu.M ATP solution diluted with water, starting the reaction, reacting at room temperature for 90-120 min, and adding 10. Mu.L of ADP-Glo Reagent (containing 10mM MgCl) per well 2 ) And reacted at room temperature for 60min to remove excess ATP in the reaction, then 20. Mu.L of kinase assay reagent was added to each well, and after 20min of reaction at room temperature in the dark, the chemiluminescent value was measured by Varioskan LUX microplate reader.
The experimental data processing method comprises the following steps: % inhibition = 100- [ (test compound value-negative control value)]/(positive control value-negative control value) ×100. IC is calculated by using GraphPad prism to fit different concentration and corresponding percent inhibition rate data to a four-parameter nonlinear logic formula 50 Values. The results are shown in Table 1 (note: "-" represents undetected).
TABLE 1
Test example 2-determination of the inhibition of the phosphorylation of AKT protein by the Compounds of the examples in the mouse macrophage-like cell line Raw264.7
Experimental instrument: the cell counter was purchased from Counterstar (Countstar-IC-1000), the carbon dioxide incubator was purchased from ThermoFisher (MCO-15 AC), the pipettor was RAININ Multichannel, the microplate reader was purchased from Perkin Elmer (Envision multiple plate reader) U.S. A., the Centrifuge was purchased from Thermo (Centrifuge ST 40R), the water supply was purchased from Millipore (Milli-Q Reference system), the refrigerator was ultra-low Wen Bingxiang from sea, and the freezer storage box was Mr. Frosoty TM Gradient cooling box Cat#5100-0001.
The experimental method comprises the following steps: the inhibition of AKT protein phosphorylation reaction caused by Pi 3K gamma in Raw264.7 cell lines by each compound is detected by using a Phospho-AKT (ser 473) kit, and the inhibition is specifically as follows:
raw264.7 cell lines (institute of basic medicine, national academy of sciences, # TIB-71) were cultured in RPMI1640 medium (Invitrogen # 11875093) containing 10% Fetal Bovine Serum (FBS) (Gibco # 10091148) and l% double antibodies (penicillin and streptomycin) (P/S (Invitrogen # 15140122)), at 37℃and 5% CO 2 Is cultured under the condition of (2). Cells were collected prior to the experiment, and after cell counting, the cells were seeded at a density of 60,000 cells/45 μl/well in 96 well cell culture plates in RPMI-1640 medium without FBS. Cells were incubated at 5% CO 2 And incubated overnight at 37 ℃. After 18 hours of serum starvation, 45. Mu.L of pre-formulated compound solution of different concentrations was added to the cells to give a final DMSO concentration of 0.2% and at 5% CO 2 And incubated at 37℃for 60 minutes. Then in the presence of the compound a solution of C5a (R&D System, # 2150-C5/CF) stimulated cells for 5 min. The medium was aspirated and 50. Mu.L/well lysis buffer was added. At room temperature Shake for 45 min and then transfer 16 μl/well lysate to 384 well plates. In addition, a solvent control well is provided, and other treatments are unchanged except that no compound is added. Premixed Phospho-AKT antibody reagent (Cisbio, #64 AKSPEG) was added to the wells at a density of 4. Mu.L/well. Plates were centrifuged at 1000rpm for 1 min at room temperature and then incubated at 22℃for 4 hours, read by an Envision microplate reader.
The experimental data processing method comprises the following steps: % inhibition = 100- (test compound value/vehicle control value) ×100. IC is calculated by using GraphPad prism to fit different concentration and corresponding inhibition rate data to a four-parameter nonlinear logic formula 50 Values, results are shown in Table 2.
TABLE 2
Compounds of formula (I) | 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 |
Test example 3-test of the efficacy of example Compounds in syngeneic mouse tumor models
The experimental object: female Balb/c mice aged 6-8 weeks.
The experimental method comprises the following steps:
1) CT-26 tumor cells were placed in 1640 medium supplemented with 10% heat-inactivated fetal bovine serum, 100U/mL penicillin and 100. Mu.g/mL streptomycin at 37℃with 5% CO 2 Is cultured in the air. Tumor cells were subcultured twice a week in a conventional manner and cells growing in the exponential growth phase were harvested while counted for tumor inoculation.
3) CT-26 tumor cells obtained by subcutaneous inoculation and culture on the right side of mice, the number of cells inoculated per mouse is about 5×10 5 . A26 gauge needle was used for injection when the tumor volume reached about 100mm 3 At this time, 32 mice were randomly divided into 4 groups of 8 based on tumor volume (body weight also considered), each: control, PD-1 antibody (PD-1 antibody from Bioxcell, CAT No. be0146), compound (example 25) and combination of compound (example 25) and PD-1 antibody, each given by:
control group: physiological saline and sodium chloride are taken orally once daily, the concentration of sodium chloride is 0.9%, and the administration volume is 10mL/kg.
PD-1 antibody group: PD-1 antibody was injected intraperitoneally twice a week with an amount of 10mg/kg per injection.
Group of compounds: the compound of example 25 was administered orally once daily at a dose of 10mg/kg.
Combination of compound and PD-1 antibody: the compound of example 25 was administered orally at a dose of 10mg/kg once a day, while the PD-1 antibody was injected intraperitoneally, twice a week, at a dose of 10mg/kg each time.
During the experiment, care and use of the animals were performed as prescribed by the american society for laboratory animal care evaluation and approval (AAALAC, approval No. 001516). After grouping, animals were checked daily for morbidity and mortality. Mice were checked daily for general health during the experimental period. At routine monitoring, the animals will be examined for any effect of treatment on normal behavior, such as mobility, food and water consumption, weight gain/loss (daily weight measurement), eye/hair pads and any other abnormal effects. Any observed clinical symptoms or unexpected death will be recorded based on the number of animals in each subset. Tumor volumes were measured in two dimensions twice a week using calipers, the volumes would be in mm using the following formula 3 The representation is: v=0.5a×b 2 Wherein a and b are the major and minor diameters of the tumor, respectively. When the tumor volume of the mice exceeds 2000mm 3 Euthanasia was performed at this time, and the tumor-inhibiting effect of each group is shown in fig. 1. And (3) injection: in the experiments, once the tumor volume of the animals reached the maximum allowable value, euthanasia was performed as required, and none of the compound, control and PD-1 antibody groups had live animals at days 12, 14 and 16, respectively.
The test results above show that:
(1) Compared with Pi I3K alpha/beta/delta, the compounds of each embodiment have remarkable inhibition effect on the activity of Pi I3K gamma, and the compounds provided by the invention have the effect of highly selectively inhibiting the activity of Pi I3K gamma.
(2) The compounds have remarkable inhibition effect on AKT protein phosphorylation reaction caused by Pi 3K gamma in Raw264.7 cell lines, and further prove that the compounds provided by the invention have strong inhibition effect on the activity of Pi 3K gamma.
(3) The data of the homologous mouse CT26 tumor model (figure 1) show that the compound provided by the invention has better tumor inhibition effect when being combined with the PD-1 antibody than the PD-1 antibody alone.
The applicant states that the present invention is illustrated by the above examples as a compound inhibiting phosphatidylinositol-3-kinase gamma subtype activity and methods of making and using the same, but the present invention is not limited to, i.e., does not mean that the present invention must be practiced in dependence upon, the above examples. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of raw materials for the product of the present invention, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present invention and the scope of disclosure.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the specific details of the above embodiments, and various simple modifications can be made to the technical solution of the present invention within the scope of the technical concept of the present invention, and all the simple modifications belong to the protection scope of the present invention.
In addition, the specific features described in the above embodiments may be combined in any suitable manner, and in order to avoid unnecessary repetition, various possible combinations are not described further.
Claims (10)
1. A compound for inhibiting phosphatidylinositol-3-kinase gamma subtype activity, which is characterized by having a structure shown in a formula I;
wherein X is selected from-CH 2 -、-CH 2 -CH 2 -、-CH(CH 3 ) -or-C (CH) 3 ) 2 -any one of the following;
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 the group consisting ofH. Any one of C1-C3 alkanyl or C1-C3 alkoxy;
R 4 selected from the group consisting of
R 7 And R is 8 Each independently selected from any one of unsubstituted or substituted C1-C3 alkanyl, unsubstituted or halogenated C3-C5 cycloalkyl, C2-C4 oxacycloalkanyl, unsubstituted or cyano-substituted phenyl or H, wherein in the substituted C1-C3 alkanyl the substituted substituent is selected from any one of C1-C3 alkoxy, unsubstituted or substituted C3-C5 cycloalkyl or halogen, and wherein in the substituted C3-C5 cycloalkyl the substituted substituent is unsubstituted or halogenated C1-C3 alkanyl;
R 10 Selected from unsubstituted or substituted C1-C5-alkanyl, C3-C5-cycloalkyl orAny one of the substituents being 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 is 14 Each independently selected from H or C1-C3 alkanyl.
2. A compound for inhibiting phosphatidylinositol-3-kinase gamma subtype activity according to claim 1, wherein R 1 Any one selected from substituted or unsubstituted C1-C6 chain alkyl or H, wherein the substituted substituent is selected from cyclopropyl or fluorine;
preferably, R 1 Selected from the group consisting ofH、CH 3 Or CH (CH) 2 CH 3 Any one of them;
preferably, R 3 Selected from the group consisting ofH or CH 3 ;
Preferably, R 5 Selected from H or CH 3 ;
Preferably, R 6 Is CH 3 ;
Preferably, R 7 And R is 8 Each independently selected from H, CH 3 、CH 2 CH 3 、CH 2 CF 3 、 Any one of them;
preferably, R 9 Is CH 3 ;
Preferably, R 10 Selected from CH 3 、CH 2 CH 3 、Any one of them;
preferably, R 11 Is CH 2 CH 3 ;
Preferably, R 12 Is CH 3 ;
Preferably, R 13 Is CH 3 ;
Preferably, R 14 Is CH 3 ;
Preferably, R 2 Selected from any one of the following structures:
H、CH 3 、CH 2 CH 3 、OCH 2 CH 3 。
3. a compound for inhibiting phosphatidylinositol-3-kinase gamma subtype activity according to claim 1 or 2, wherein the compound for inhibiting phosphatidylinositol-3-kinase gamma subtype activity has any one of the following structures:
4. a process for the preparation of a compound inhibiting phosphatidylinositol-3-kinase gamma subtype activity according to any one of claims 1 to 3, which comprises mixing compound B with compound C and reacting to give compound I, of the formula:
Wherein Y is 1 Selected from the group consisting of
Y 2 Selected from any one of F, cl, br or I.
5. The process of claim 4 wherein said compound B is prepared by mixing an acid halide or anhydride with compound A and reacting to give compound B of the formula:
preferably, in the reaction of compound B with compound C, the temperature of the reaction is 15-150 ℃ and the time of the reaction is 1-20h;
preferably, in the reaction of the acid halide or anhydride with the compound A, the temperature of the reaction is 15-150 ℃, and the time of the reaction is 1-20h;
preferably, the reaction of the compound B and the compound C further comprises mixing with a base and/or a catalyst to perform the reaction, wherein the catalyst comprises any one or a combination of at least two of 1,1' -bis-diphenylphosphino ferrocene, palladium dichloride, palladium acetate, tetra (triphenylphosphine) palladium or tris (dibenzylideneacetone) dipalladium;
preferably, the base comprises an organic base and/or an inorganic base, the inorganic base comprises any one or a combination of at least two of a hydride, a hydroxide, an alkoxide, an acetate, a fluoride, a phosphate, a carbonate or a bicarbonate of alkali metal or alkaline earth metal, and the organic base comprises any one or a combination of at least two of an amine compound, a pyridine compound, a pyrrole compound, a quinoline compound, an imidazole compound, an amino-substituted naphthalene compound or an azacycloalkane compound;
Preferably, the inorganic base comprises 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 fluoride, cesium fluoride, sodium carbonate, potassium bicarbonate, sodium bicarbonate or cesium carbonate;
preferably, the organic base includes triethylamine, trimethylamine, N-diisopropylethylamine, tri-N-propylamine, tri-N-butylamine, tri-N-hexylamine, tricyclohexylamine, N-methylcyclohexylamine, N-methylpyrrolidine, N-methylpiperidine, N-ethylpiperidine, 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, any one or a combination of at least two of N, N, N-tetramethyl ethylenediamine, N, N-dimethyl-1, 4-diazacyclohexane, N, N-diethyl-1, 4-diazacyclohexane, 1, 8-bis (dimethylamino) naphthalene, diazabicyclooctane, diazabicyclononane, diazabicycloundecane or butylimidazole or methylimidazole;
preferably, the reaction of the acyl halide or anhydride with compound a and the reaction of compound B with compound C also optionally comprises mixing with a solvent, wherein the solvent comprises any one or a combination of at least two of an ether compound, an unsubstituted or halogenated hydrocarbon compound or an ester compound;
Preferably, the solvent comprises any one or a combination of at least two of ethyl propyl ether, n-butyl ether, anisole, phenetole, cyclohexylmethyl ether, dimethyl ether, diethyl ether, dimethylethylene glycol, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisoamyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, dioxane, dichloro diethyl ether, polyethers of ethylene oxide and/or propylene oxide, pentane, hexane, heptane, octane, nonane, methylene chloride, chloroform, 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.
6. Use of a compound inhibiting phosphatidylinositol-3-kinase gamma subtype activity as claimed in any one of claims 1-3 for the preparation of a phosphatidylinositol-3-kinase gamma subtype inhibitor.
7. Use of a compound inhibiting phosphatidylinositol-3-kinase gamma subtype activity as claimed in any one of claims 1-3 for the manufacture of a medicament for the prevention and/or treatment of cancer, respiratory diseases or immune diseases.
8. The use of claim 7, wherein the medicament for treating cancer comprises an immunotherapeutic medicament for cancer;
preferably, the cancer comprises pancreatic tumor, ductal cancer, lung cancer, head and neck cancer, rectal cancer, uterine cancer, prostate cancer, renal cancer or breast cancer;
preferably, the respiratory disease comprises asthma, rhinitis, bronchitis, emphysema, pulmonary fibrosis or chronic obstructive pulmonary disease;
preferably, the immune disorder comprises allergy, rheumatoid arthritis or systemic lupus erythematosus.
9. An immunotherapeutic agent for cancer, comprising a compound of any one of claims 1 to 3 that inhibits phosphatidylinositol-3-kinase gamma subtype activity, or a stereoisomer, racemate, tautomer, isotopic label, nitroxide, solvate, or a combination of at least two thereof.
10. The immunotherapeutic agent for cancer of claim 9, further comprising a combination comprising any one or a combination of at least two of a PD-1 antibody, a PD-L1 antibody, a CTLA4 antibody, a glucocorticoid receptor agonist, a β2 adrenergic receptor agonist, an antimuscarinic agent, a p38 inhibitor, a xanthine derivative, paclitaxel, docetaxel, albumin paclitaxel, cisplatin, carboplatin, nedaplatin, platinum oxalate, lobaplatin, etoposide, teniposide, 5-fluorouracil, capecitabine, tegafur, irinotecan, topotecan hydrochloride, gemcitabine, a xanthine derivative, a PDE4 antagonist, an AKT inhibitor, or an ER antagonist;
Preferably, the combination comprises a PD-1 antibody and/or a PD-L1 antibody;
preferably, the cancer comprises pancreatic tumor, ductal cancer, lung cancer, head and neck cancer, rectal cancer, uterine cancer, prostate cancer, renal cancer or breast cancer;
preferably, the immunotherapeutic agent for cancer further comprises pharmaceutically acceptable excipients;
preferably, the auxiliary material comprises any one or a combination of at least two of a disintegrating agent, a glidant, a lubricant, a colorant, a carrier, a diluent, a flavoring agent, a binder or a filler.
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