Aromatic heterocyclic pyrrolidone derivative and use thereof

Abstract

Disclosed in the present invention is an aromatic heterocyclic pyrrolidone derivative having a new structure, which can be developed as an inhibitor targeting small molecule PI3Kγ. The PI3Kγ inhibitor has a high selectivity and a siginificant biological activity, and also has considerable potential in the prevention or treatment of diseases related to abnormal expression of the PI3Kγ signaling pathway.

Description

[0001] Specification: Aryl heterocyclic fused pyrrolidone derivatives and their uses Technical Field The present invention belongs to the field of medicinal chemistry and relates to an aryl heterocyclic fused pyrrolidone compound, its preparation method and application. This kind of compound and its pharmaceutically acceptable salts, isotope derivatives, solvates or stereoisomers can be used as highly selective PI3Ky inhibitors for preventing or treating diseases related to abnormal expression of the PI3Ky signaling pathway, and have broad application prospects. Background Art 862 - 867 (see W02021004421 by Fangke Biotechnology Co., Ltd., Med. Chem. Lett. 2015, 58, 517 - 521 and Al:5 Med. Chem. Lett. 2021, 12, 129 - 135) and isoindolinone derivatives, etc. <W02017153527Al, W02020247496A1, W02020210379A1>. Currently, existing inhibitors often have many problems in terms of inhibitory activity and selectivity at the target, pharmacokinetic properties, and safety, which limit the further development of other drugs. In summary, how to provide a PI3Ky inhibitor with a brand - new structure, significant biological activity, and high selectivity is a technical problem that has not been solved by those skilled in the art yet. When the C1 - 6 alkyl group, C3 - 6 cycloalkyl group, or 4 - 10 - membered heterocyclic group has substituents, they can each independently be mono - substituted or multi - substituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C1 - 6 alkyl group, C2 - 5 alkenyl group, C1 - 6 alkoxy group, C1 - 6 alkylsulfonyl group, C1 - 6 alkylthio group, C1 - 6 alkylamino group, 4 - 10 - membered heterocyclic group, 5 - 14 - membered aryl group or heteroaryl group; or C1 - 6 alkoxy group, halo - C1 - 6 alkoxy group, or substituted or unsubstituted 4 - 10 - membered heterocyclic group; further when R 3 *, R* in the C1 - 6 alkyl group, C3 - 6 cycloalkyl Specification C1 - 6 alkylthio group or C1 - 6 alkylamino group; or When the C1 - 6 alkyl group, C3 - 6 cycloalkyl group, and 4 - 10 - membered heterocyclic group have substituents, they can each independently be mono - substituted or multi - substituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C b6Alkyl, C-alkenyl, C 2.6 ft alkyl, cycloalkyl, C 1-5 oxy, C 1-6 alkylsulfonyl, C 1-7 alkylthio, C 1-5 alkylamino, 4-10 membered heterocyclyl, 5-14 membered heterocyclic group or C 1-7 alkyl; or When R 3 When selected from -NR-, when selected from 10-15-16-17 ... 33 R 3c H'j , R 3 R, R, R-1, R-2, R-3, R-4, R-5, R-6, R-7, R-8, R-9, R-10, R-11, R-12, R-13, R-14, R-15, R-16, R-17, R-18, R-19, R-20, R-21, R-22, R-33, R-44, R-55, R-56, R-57, R-68, R-69, R-70, R-81, R-82, R-83, R-84, R-85, R-86, R-97, R-98, R-99, R-10, R-11, R-12, R-13, R-14, R-15, R-16, R-17, R-18, R-19, R-21, R-22, R-33, R-19, R-23, R-34, R-35, R-36, R-45, R-46, R-57, R-58, R-59, R-69, R-70, R-81, R-99, R-11, R-12, R-13, R-14, R-15, R-16, R-17, R-18, R-19, R-24, R-25, R-26, R-37, R-38, R-39, R-41, R-42, R-43, R-44, R-45, R-46, R-59, R-69, R-71, R-82, R-83, R-99, R-11, R-12, R-13, R-14, R-15, R-16 1-6 carbonyl, ... manual

[0002] - - with surface 'Sa and should stubborn open write involved qin common humor Cheng Gong '3 and Xue Zhen Fei stubborn tendon Sun; selected from hydrogen, halogen or Cw 'courtyard group;

[0003] R, R 5 Selected from hydrogen or C, C, alkyl;

[0004] R" is selected from alkyl substituted by cycloalkyl;

[0005] R 3 Select from -OR 3a or -NR 3a R 3cwherein, when R3 is selected from -0.1-3.5, R3, R1 is selected from a substituted or unsubstituted 4- to 10-membered heterocyclic group; further, when R3 is a 4- to 10-membered heterocyclic group, when substituents are present, they may be independently mono- or poly-substituted by one or more of the following substituents: halogen, hydrazine, hydroxyl, hydrogen, thiols, oxo, C1-6-alkyl, C1-6-alkenyl, thiols, cycloalkyl, C1-6-alkoxy, C1-6-sulfonyl, C1-6-alkylthio, or C1-6-alkylamino; or -P(O)R !s R ,b When C16-6 alkyl, C16-6 alkenyl, C16-6 alkynyl, C16-6 cycloalkyl, C16-6 aryl, C16-10 heterocyclic group and C16-14 heteroaryl have substituents, they may be mono- or poly-substituted independently by one or more of the following substituents: halogen, hydroxyl, chloro, thiazolyl, oxo, C16-6 alkyl, halogenated C16-6 alkyl, C16-6 alkenyl, C16-14 heteroaryl, C16-15 heteroaryl, C16-17 heteroaryl, C16-18 heteroaryl, C16-19 heteroaryl, C16-20 heteroaryl, C16-21 heteroaryl, C16-22 heteroaryl, C16-23 heteroaryl, C16-24 heteroaryl, C16-25 heteroaryl 2 6 C3-5 cycloalkyl, C6-4 aryl, 4-10 manual Mono- or poly-substituted: halogen, nitrogen, hydroxy, amino, mercapto, oxo, C alkyl, C alkene, C 2.s Rjb is a C1-6 alkyl, C1-7 cycloalkyl, C1-6 alkyl, C1-7 ...

[0006] R / is selected from hydrogen, halogen or alkyl;

[0007] R\RS is selected from hydrogen or alkyl; wherein is selected from C1-C1 alkyl substituted by cycloalkyl;

[0008] R 3 Select from -OR 33 or -NR 3a R 3c ; Wherein, when R3a is selected from -0-1, R* is selected from substituted or unsubstituted 0-membered heterocyclic group; further when R3a is 4... |0When a membered heterocyclic group has substituents, they may be mono- or poly-substituted independently by one or more of the following substituents: halogen, C1-4 alkyl, hydroxyl, amino-4-thiol, oxo, alkyl, C1-4 alkenyl, C1-6 alkyl, C1-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylthio, or amino; when R3 is selected from a C1-4 alkyl, C1-6 alkylthio, substituted or unsubstituted C1-6 alkyl, C1-6 alkylthio, or substituted or unsubstituted C1-6 alkyl. further, when the C1-6 alkyl, C1-6 cycloalkyl, or 4-10 membered heterocyclic group in R'' and R'' has a substituent, each of the substituents may be mono- or poly-substituted independently by one or more of the following substituents: halogen, thio, hydroxy, anthracene, mercapto, oxo, C1-6 alkyl, C1-6 alkenyl, C1-6 alkyl, C1-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino; More preferably, the aforementioned aromatic heterocyclic ring: and pyrrolidine derivative is a compound represented by the general structural formula (III) or a pharmaceutically acceptable salt thereof; Wherein, X is selected from N or 5;

[0009] R' is selected from W !a R ib ;

[0010] R' b Each is independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted C1-6 hydroxyl, substituted or unsubstituted C1-6 cycloalkyl, or substituted or unsubstituted 4-membered heterocyclic group; when R'e, R'e, C1-6 alkyl, C1-6 alkenyl, C1-6 hydroxyl, C1-6 cycloalkyl, or substituted or unsubstituted 4-membered heterocyclic group has a substituent, each may be independently substituted or polysubstituted by one or more of the following substituents: halogen, hydroxy, amino, oxo, C1-6 alkyl, C1-6 alkenyl, C1-6 hydroxyl, C1-6 cycloalkyl, C1-6 alkoxy, C1-6 alkyl ...alkyl, C1-6 b6 C-6 alkylsulfanyl, C-6 alkylthiol, C-6 alkylamino, 4-membered heterocyclic group, 5-14 membered heteroaryl or C-6 aryl;

[0011] R 2 、 R 2a# is independently selected from hydrogen, halogen or C1-alkyl; R is selected from hydrogen, halogen, C1-alkyl, substituted or unsubstituted C1-alkyl, substituted or unsubstituted C1-alkenyl, substituted or unsubstituted C1-alkyl, substituted or unsubstituted C3.8 cycloalkyl, substituted or unsubstituted C4.8 aryl, substituted or unsubstituted C5-10 membered heterocyclyl, substituted or unsubstituted 5-14 membered heteroaryl, -OR 3 -SR 3 \ -SO2-R 3a .-NH-R 3 \ -NHCO-R 3 -C(O)NH-R 3a . -C(O)-R 3 -NHSO2-R 3a or -P(O)R ia R ;b ; When R is alkyl, isocyanate, or alkenyl. 2 6 When a C1-C1 alkyl group, a C1-C1 cycloalkyl group, a C1-C1 aryl group, a 4- to 10-membered heterocyclic group, or a 5- to 14-membered heteroaryl group has a substituent, it may be monosubstituted or polysubstituted independently by one or more of the following substituents: halogen, alkyl, hydroxyl, When R3 is selected from -1-3, R:, a, R* are each independently selected from substituted or unsubstituted C1-1 alkyl, halogenated C1-1 alkyl, substituted or unsubstituted manual -NH802-R2, .C(0)NH-R3b or .C(O)-R 3b ; alkyl, hydroxyl, amino, mercapto, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 cycloalkyl, C1-6 cyclohexyl, C2-6 cyclohexyl, C3-6 cyclohexyl,

[0012] R 2 , R* are each independently selected from hydrogen, halogen or Ci fi K-based;

[0013] R\R' is selected from hydrogen or Cm alkyl; is selected from CsS alkyl substituted with Cm alkyl;

[0014] R 3 Select from -OR 3a or-N-RMR 3 .; in, manual Each of Rm is independently selected from hydrogen, C1_6 alkyl, halogenated C1_6 alkyl, C3_6 cycloalkyl, C1_6 alkoxy, halogenated C1_6 alkoxy or

[0015] 4-! () membered heterocyclic group; heteroaryl group, heterocyclic group contains at least one heteroatom, the heteroatom is selected from N, S ". More preferably, the aforementioned aromatic heterocyclic pyrrolidone derivative is a compound represented by the general structural formula or a pharmaceutically acceptable salt thereof: manual manual manual The "compounds" described herein include, but are not limited to, the following forms of compounds: free bases, stereoisomers, geometric isomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, prodrugs (esters), and the like. The "compounds" described herein may be asymmetric, for example, having one or more stereoisomers. Unless otherwise specified, all stereoisomers are inclusive, such as enantiomers and diastereomers. Compounds of the present invention containing asymmetric carbon atoms are isolated in optically pure or racemic forms. Optically pure forms can be obtained by resolution of racemic mixtures or synthesis using chiral starting materials or reagents. The "pharmaceutically acceptable salt" in the present invention refers to a salt of the compound of the present invention, wherein the compound having a specific substituent discovered by the present invention reacts with 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, glucose, glutamic acid, acetic acid, hydrochloric acid, iodide, hydroxybenzoic acid, isethionic acid, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, dihydroxyacetic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, aminosulfonic acid, p-aminobenzenesulfonic acid, sulfuric acid, When the compound is salted with one of tannin, tartaric acid, and p-tolueneic acid; or when it contains relatively acidic functional groups, a base addition salt is formed by contacting the neutral form of such compound with a sufficient amount of base in a purified aqueous solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium, arsenic, calcium, magnesium salts, arsenic, or organic amines. Examples include alkali metal salts, alkaline earth metal salts, other metal salts, inorganic base salts, organic base salts, inorganic acid salts, lower alkanesulfonates, arylsulfonates, organic acid salts, and amino acid salts. "Isotope" as used herein means, unless otherwise specified, that the compound of the present invention may exist in an isotopically traced or enriched form, containing one or more atoms whose atomic weight or mass number differs from the atomic weight or mass number of the largest atom found in nature. Isotopes may be radioactive or non-radioactive.The isotopes commonly used as isotope labels are: Hydrogen isotopes, including but not limited to H and C; Carbon isotopes: including but not limited to "O" and "C"; Chlorine isotopes: including but not limited to "C" and "N"; Fluorine isotopes: including but not limited to "F"; Iodine isotopes: including but not limited to "C" and "N"; Nitrogen isotopes: including but not limited to "N" and "N"; Oxygen isotopes: including but not limited to "O", "O" and "Qi". i8 0; Sulfur isotopes: including but not limited to * S. These isotope-labeled compounds can be used to investigate the distribution of medicinal molecules in tissues, especially 3 H !3 c, because they are easy to label and detect, they are more widely used. Some heavy isotopes, such as deuterium ( 2 11) Substitution can enhance metabolic stability and prolong half-life, thereby achieving the goal of reducing dosage and providing therapeutic advantages. Isotope-labeled compounds generally start from a labeled starting material and are synthesized using known synthetic techniques similar to those used for non-isotope-labeled compounds. 3-Methyl-1-pentylynyl, 4-methyl-1-pentyl, 3,3-dimethyl-1-butanyl, 3-ethyl-1-butanyl, 1,3-hexanediol, 1 / 1-hexanediol, 3-methyl-3,4-pentanediynyl, 1,5-hexanediol, and the like.

[0016] The term "alkylthio" refers to a straight or branched alkyl group connected through a sulfur atom, i.e., -S-:alkyl, such as a C1-6 thio group, including but not limited to methylthio, ethylthio, propylthio (including n-propylthio and isopropylthio), butylthio (including n-butylthio, isobutylthio, sec-butylthio, tert-butylthio), pentylthio (including n-pentylthio, isopentylthio, neopentylthio), hexylthio (n-hexylthio, 2-methylpentylthio, 3-methylpentylthio, 2,3-dimethylbutylthio, 2,2-dimethylbutylthio), and the like. The term "alkyl" refers to a straight-chain or long-chain alkyl group connected through a base, i.e., a -SO-alkyl group, such as a C-alkyl group, including but not limited to methylamino, ZrI-M®, propylamino (including n-propyliodo and isopropylamino), butylthio (including n-butylamino, isobutylamino, sec-butylamino, and tert-butylamino), pentylamino (including tert-pentylamino, isopentylamino, and tert-pentylamino), hexyl (tert-hexylamino, 2-methylpentylamino, 3-methylisothio, 2,3-dimethylbutylamino, and 2,2-dimethylbutylamino), and the like. * pyrazinyl, pyridazine, benzophenone, benzophenone, benzimidazolinone, benzophenone, benzophenone, benzophenone, benzophenone, etc. manual

[0017] !a-1 la-2 is where R"', R 2 , R 3 The definitions of R* and A are as described above. The reaction process is as follows:

[0018] 2-Amino hydroxyl compound Ia-1 and amine fragment are condensed under the action of CD1 to obtain hydroxyl intermediate Ia-2 : The intermediate la-2 and the isoquinone intermediate la-3 are coupled with the 5-position C-bond aromatic halide in the presence of an indium reagent and microwave reaction conditions to obtain the target product. The halogenated isoquinolinone derivative lb-1 was subjected to Miyaura boronation to generate the boronate intermediate Ib-2, which was then coupled with the adenine intermediate Ib-3 under indium catalysis to obtain the target product lb. manual With tin Under alkaline conditions, the target product Ilbo was obtained by reacting with methylaminoformyl chloride. where R i? \ R\ R ? \ R 4 The definitions of R and R are as mentioned above and the reaction process is as follows:

[0019] 2 - amino thiazolinyl compound IVa-l and chloroformate pseudo condensation to give a nitrocarboxylic acid ester intermediate IVa-2: Intermediate IVa-2 and intermediate IVa-3 in the presence of a reagent and microwave reaction conditions occur 5-position CH bond and aromatic halide coupling to give the target product IVa. Instructions The boron ester intermediate IVb-4 was coupled with the methyl carbamate intermediate IVb-2 under the catalysis of G to obtain the target product IVb. Among them, V R \ R\ R4 and R? are defined as above. The reaction process is as follows: Intermediate I¥e4 reacts with R under alkaline conditions laOH undergoes an ester exchange reaction to produce the target product Wco. In the aforementioned Routes 1-10, the tackifier reagent can be selected from one or more of tetrakistriphenylphosphine tackifier, bis(triphenylphosphine)indium chloride, tris(dibenzylideneacetone)dicarboxylic acid, [1,1'-bis(di-tert-butylphosphine)ferrocene]dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]dichloride. In Routes 1, 3, and 6, the reaction conditions for synthesizing the target compound can be microwave or oil bath. The present invention also provides a pharmaceutical composition comprising the aforementioned compound or a pharmaceutically acceptable salt thereof as an active ingredient. Furthermore, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers. In the present invention, a "pharmaceutical composition" refers to a formulation of one or more compounds of the present invention or their salts with a carrier commonly used in the art for delivering biologically active compounds to an organism (e.g., a human). The purpose of the pharmaceutical composition is to facilitate administration and delivery to an organism. As used herein, "pharmaceutically acceptable carrier" refers to a substance that is co-administered with an active ingredient and facilitates the administration of the active ingredient, including but not limited to any pharmaceutically acceptable glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier for human or animal (e.g., livestock) administration. Non-limiting examples of "pharmaceutically acceptable carriers" include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol. The pharmaceutical compositions provided herein can be manufactured using methods well known in the art, including, but not limited to, mixing, dissolution, granulation, sugar-coated pill production, grinding, emulsification, and cold drying. The pharmaceutical compositions provided herein can be formulated into solid, semisolid, liquid, or gaseous preparations, including, but not limited to, tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. The pharmaceutical composition provided by the present invention may be administered by routes including, but not limited to, oral administration, injection, inhalation, transmucosal administration, topical administration, and intracavitary administration. Administration sites include, but are not limited to, the oral cavity, sublingual cavity, intravenous, intramuscular, lung, gastrointestinal tract, epidermal, subcutaneous, intranasal, intraocular, intraauricular, intraperitoneal, intravaginal, rectal, and acupuncture points. The preferred route of administration is oral administration. Instructions BRIEF DESCRIPTION OF THE DRAWINGS FIG1 is a comparison of the inhibition rates of the compounds of the present invention on IL-17A secretion in lymphocytes derived from AD model mice, and FIG2 is a comparison of the inhibition rates of the compounds of the present invention on IL-17A secretion in lymphocytes derived from psoriasis model mice. Instructions: m-CPBA: m-chloroperbenzoic acid; HCl: benzoic acid; CataCxiumA: n-butyldi(1-adamantyl)phosphine; SeF: sodium fluoride; CuCN: cuprous chloride; Xplios: 2-dicyclohexyl R-2',4',6'-triisopropylbiphenyl; Pd ? (dba)3: tris(dibenzyleneacetone)_®; Toh: toluene; Cui: cuprous iodide; EA: ethyl acetate; RT: room temperature; DIPEA: N-diisopropylethylamine; SOC12: r-chloropropane; TFA: trifluoroacetic acid Step L 4 ■ Synthesis of 2-bromo-2-fluoro-6-methylbenzoate (A1-2) Dissolve 4-chloro-2-methyl-6-benzoic acid: A1-1 (1000 g, 4291 mmol) in AJV-dimethylformamide (100 nil) J ) were added to the reaction mixture, and the reaction mixture was stirred at 80°C for 1 hour. 200 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 (X) mL x 3). The combined organic phases were washed twice with water and once with saturated brine, then dried and concentrated to yield 10.20 g (crude) of a yellow oil, A 1-25, which was used in the next step.

[0020] ES1-MS: m / z = 247.0 [M+H].

[0021] ?H NMR (400 MHz, DMSO-a6): 57.56 (dd, J = - 9.6 Hz, J = 2.0 Hz, 1H), 7.47 (d, J = 0.8 Hz, 1H), 3.88 (s, 3H), 2.34 (s 3H). Step & Synthesis of methyl 4-bromo-2-(bromomethyl)-6-fluorobenzoate (A1-3): A1-2 (10.20 g, 4128 mmol) was dissolved in carbon tetrachloride (100 μL), and N-bromosuccinimide (8.08 g, 45.41 μM bd) and azobisisobutyronitrile (677.95 mg, 4.13 mmol) were added. The reaction was stirred at 85°C under nitrogen for 3 hours. The reaction solution was spin-dried to dryness. The residue was dissolved in petroleum ether, filtered, and the filtrate was dried to obtain 13.5 g (crude) of A1-3.

[0022] ESI-MS: ro / z = 325.0, 327.0 [M+H]L Step 3: Synthesis of (S)-5-bromo-2-(1H-cyclopropylethyl)-1-fluoroisoindole-1-one (13.05) & A mixture of (S)-1-cyclopropylethane-1-amine hydrochloride (4.87 g, 40.04 mmol), boric acid (49509 mg, 801 mmol), and potassium carbonate (1660 g, 12011 mmol) was added, and the mixture was stirred at 85°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 100 mL of ethyl acetate, washed once with water, once with saturated brine, dried, and concentrated. The residue was separated by column chromatography using a 1% to 20% ethyl acetate solution in petroleum aldehyde as the eluent to obtain 3.17 g of common intermediate A as a yellow solid. The total yield of steps 1 to 3 was 26.3%.

[0023] ESJ-MS: m / z = 2980 [M+His] 2. Preparation of Common Intermediate (5)-5-it-2-(1-cyclopropylethyl)-1-hydroxyisothiazolinone (A2) The common intermediate Al (3.17 g, 10.63 mmol) was dissolved in ethylene glycol dimethyl ether (30 mL). After nitrogen replacement three times, potassium trimethylsilanolate (4.09 g, 31.5 mmol) was added. The mixture was heated to 85°C and stirred for 1 hour. The reaction solution was poured into 1M HCl (30 mL) and extracted with ethyl acetate (30 mL, 3 mmol). The organic and organic phases were combined, washed once with water and once with saturated brine, dried, and concentrated to obtain 3.00 g of common intermediate A2 as a red solid with a yield of 952%.

[0024] ES1-MS: m / z = 296.0 3. Common intermediate (S>5 Step 1: Synthesis of (S)-5-bromo-2-(cyclopropyl)ethyl*7.7-dichloromethoxyisoquinoline-1-one (A3): Dissolve the common intermediate A2 (3.00 g, 1013 mmol) in N-methylpyrrolidone (30 ml, ), add sodium 2-chloro-2,2-difluoroacetate (1.85 g, 12.16 mmol) and potassium phosphate (430 g, 2026 mmol), and heat the mixture to 400 °C. Stir for 1 hour. The reaction mixture was cooled to room temperature, poured into 2 M HCl (40 ml), and extracted with ethyl acetate (30 ml). The organic phases were combined, washed twice with water, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by column chromatography using 0-10% diethyl acetate in ethanol as the eluent to obtain 1.50 g of common intermediate A3 as a light yellow solid in a 429% yield.

[0025] ES1-MS: Wz -3460 [M+H]L

[0026] 'H NNIR (400 WIz, DMSO-40: 8776 (s, 1H), 7.61 (■, J = 74.4 Hz, 1H) , 748 (s, IHj, 455 (s, 2H), 3.56-3.49 (m, 1H), 1.27 (d, J=6.8 Hz, 3H)„ 1 13-1.06 (m, 1H), 0.58-0.53 (m = 1H).0.43-034 (m, 2H).025-0.20 (m, 1H) C The common intermediate A3 (1.50 g, 433 mmol) was dissolved in 1,4-dioxane (15 inL), and pinacol diboronate (1.32 g, 5.20 mmol) was added. [Bis(diphenylphosphino)ferrocene] dichloride (157.22 ing5022 mmol) and potassium ferrate (128 g, 13. (X) mmol), and the reaction was stirred at 100 -Cg under nitrogen for 1 hour. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography and eluted with a 0.70% ethyl acetate solution in petroleum ether to obtain 1.70 g of the common intermediate link L as an off-white solid with an elution rate of 99.4%.

[0027] ESI-MS: in / z = 394.0 [M+H °

[0028] ] 11 miR (400 NHIz, DMSO- J6): 7.74 fs, 1H), 156 (t, J -74.4 Hz, ill), 736 (s, HI),.4.55 (s ; 2II), 357-3.50 (m„ 1H) ? 1.32 (s, ]2H), 1.28 (d, J = 68 Hz, 311), 1.12-1.08 (nr 1H) ; 0.61-0.53 (m, 1H), 0.43-033 (m, 2H), 0.25-0.18 (m, TH). Five% common middle body ⑶ point - chloro-2 "(1-cyclopropylethyl) 7-zhen isoluminol ■ ■ 1-ketone (A4) Preparation Instructions A4-2 (6.10 g, 20.57 mmol) was dissolved in 10 mL of dimethylformamide (MMDF). Potassium carbonate (4.27 g, 3086 mmol) was added and stirred at room temperature for 5 minutes. Methyl iodide (438 g, 30.86 mmol) was added and the system was stirred at room temperature overnight. The reaction solution was quenched with water and extracted three times with ethyl acetate (20 mL x 3). The organic phases were combined, washed three times with water (20 mL x 3) and once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using 7% ethyl acetate in petroleum ether as the eluent to obtain 60 g of KJ A4-3 as a yellow solid in a 93.3% yield.

[0029] ESI-MS: 1H / Z =: 311.0 [M+H]+

[0030] ; 1H NMR (400 MHz, DMSO-d6) δ 7.81 (dd, J1 = 2.0 Hz, J2 = 0.8 Hz, 1H), 7.46 (dd, J1 = 2.0 Hz, J2 = 0.8 Hz, 1H), 3.87 (s, 3H), 2.25 (t, J = 0.8 Hz, 3H). Step 3: Synthesis of methyl 2-methyl-4-chloro-4-iodobenzoate (A4-4). A4-3 (6.0 g, 19.32 mmol), N-bromosuccinimide (6.19 g, 34.78 mmol) and benzoyl peroxide (317 mg, 1.93 and potassium carbonate (1.06 g, 7.70 mmol) were dissolved in acetonitrile (10 mL), and the temperature was raised to 60 °C and reacted for 1 hour. After the mixture was cooled to room temperature, it was quenched with water, extracted twice with ethyl acetate (20 mL × 3), the organic phases were combined, the organic layer was washed once with water (20 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography, and the eluent was a petroleum ether solution of 5% ethyl acetate, obtaining 300 mg of the common intermediate A4, which was a yellow solid with a yield of 32.3%.

[0031] ESI-MS: m / z = 362.0

[0032] ! 1H NMR (400 MHz, DMSO-d6): δ 7.98 (d, J = 2.0 Hz, 1H), 7.76 (d, J = 2.0 Hz, 1H), 4.46 (s, 2H), 3.59 - 3.52 (br s, 1H), 1.27 (d, J = 6.8 Hz ; 3H), 1.16 - 1.06 (m, 1H), 0.61 - 0.53 (m, 1H), 0.43 - 0.34 (m, 2H) ; 0.25 - 0.16 (m, 1H). Description of the specification VI. Preparation of the common intermediate (5) 4,6-dichloro-2-(1-cyclopropylethyl)-1,2-dihydro-3H-pyrrolo[3,2-b]pyridin-3-one (A5) and potassium carbonate (1.8 g, 13.05 mmol) were dissolved in ethanol (10 mL), heated to 60° C., and reacted for 2 hours. The mixture was cooled to room temperature and quenched with water. It was extracted three times with ethyl acetate (20 mL*3\. The organic phase was washed three times with water: 20 mL*3), washed with saturated brine (<20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography. The eluent was 65% ethyl acetate in petroleum dilution solution to obtain 180 mg (crude) of the common intermediate A& as an oil. The total yield of the three-step reaction of steps 2 to 4 was 150%. o

[0033] ESI-MS: .n / z -2710

[0034] ! H NMR (400 MHz, DMSO-J6): 8789 (s. 1H), 462 (s, 2H) 358-351 (m, 1H) 127 (d, J = 68 Hz, 3H), 1.16- 1.07 (iih 1H), 0.61-0.54 (in, HI), 044-035 (m, 2H), 026-019 (m, old). manual Common intermediate A5 (100 mg, 0.37 mmol), morpholino (48 mg, 0.53 mmol) and triethylamine (56 mg, 0.53 mmol) were dissolved in dimethylformamide (3 mL). The reaction was heated to 60°C and quenched with water (15 mL) after cooling to room temperature. The mixture was extracted three times with ethyl acetate (10 mL x 3). The combined organic phases were washed three times with water (10 mL x 3), then dried over anhydrous sodium sulfate (10 mL), and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography using 1% ethyl acetate in petroleum ether as the developing solvent to obtain 66 mg of common intermediate A6 as a light green oil in a yield of 55.9%.

[0035] ESI-MS: m / z =<<220 [M+H

[0036] !H NMR (400 MHz, DMSO-;: / 6): S 706 (s„ 1H), 4.48 (s, 2H), 3.72-3.tS5 (m, 8H).3.57-3.46 (m, 1H), 123 (d ; J -68 Hz, 3HX 1 11-102 (m, 1H) ; 058-042 (m, 1H), 040-030 (m, 2H), 023-017 (m, 1H) VIII. Preparation of Common Intermediate 1-Methyl-3-(4-methyl-2-yl)-1-nitropropane (B0) Step L1: Synthesis of 2-(4-methylpurinan-2-yl)methylhydrazine (BS). Dissolve 2-amino-4-methylpurinan-2-yl hydrochloride (BM) (1.0 g, 6.69 mmol) in dichloromethane (10 mL). Add triethylamine (17 g, 1696 mmol) dropwise and stir at room temperature for 15 minutes. Add methylaminomethyl chloride (745 mg, 7.97 mmol) under ice-cooling, and heat to 40°C for 2 hours. Cool the mixture to room temperature, quench with water, and extract twice with dichloromethane (20 mL, approximately). The organic phases are combined, washed twice with water (20 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure. The residue is purified by column chromatography using a 50% ethyl acetate solution in petroleum ether as the eluent. 402 mg of common intermediate B1 was obtained as a white solid with an absorbance of 35.3%.

[0037] ESI-MS: Bi / z = 172.0 [M-

[0038] ] II NMR (400 MHz ; DMSO-J6): d 10.36 (s, irlj, 6.53 (q ; J- 12 Hz ; iH), 641 (d, J = 4.8 Hz ; IHj, 2.67 (d, J = 4.8 IIz, 311), 2.18 (d, J = 1.21 Iz, 311). IX. Preparation of the Common Intermediate Compound 1"(5-'';^-4"methylhydroxyl)-3-methylhydrazine (B2) Step L Synthesis of 1-(4-bromo-4-methylthiazol-2-yl)-3-methylthiazol-2-yl (B2): Dissolve 5-(4-bromo-4-methylthiazol-2-yl)-3-methylthiazol-2-yl (1.92 g, 10.0 mmol) in dichloromethane (10 mL), add triethylamine (2.02 g, 20.00 mmol), and heat for 1 h.

[0039] ESI-MS: ni / z = 250.0[lvRHf\ 10. Preparation Instructions for Common Intermediate (4-Methyl-5-(tributyltin-2-yl)tetrahydro-2-yl)carbamate (B3) Step n Synthesis of tert-butyl (4-methylpurine-Z-yl)carbamate (B3-2) Prepare tert-butyl amino-4-methyl-1-(60 g) ; The mixture was stirred at room temperature for 15 minutes. Di-tert-[2-(2-[2-(2-[2-(2-[2-(2-dimethylamino)methyl]-1-pyrrolidone)]-1-oxo ...

[0040] EST-MS: m / 7 = 5050 XI. Common intermediate (5 Step 1: Preparation of 5-bromo-4-methylpurin-2-ylcarbamate (B4-2): Dissolve 5-bromo-4-methylpurin-2-amine (B4-K, 1.92 g, 10.00 mmol) in dichloromethane (100 mL). Add triethylamine (2.02 × 20.00 mmol). Add phenyl Bn chloroformate (1.88 g, 12.00 mmol) dropwise in an ice bath. React at room temperature for 2 h. After completion of the reaction, quench with water (30 mL), extract twice with dichloromethane (10 mL x 2), and then wash with saturated brine (30 mL). The organic phases are combined and concentrated to yield 2.47 g of B3-2 as a yellow solid in a yield of 792%.

[0041] ESI-MS: m / z = 31.3.0, 315 Step A ◎-O-4-methyl-1,2-dimethoxy-1,2-dione B4-2 (265 mg, 0.85 mmol) was dissolved in methanol (10 mL), followed by the addition of sodium methoxide (92 mg, 1.71 mmol), and the reaction was carried out at 60°C for 1 h. After the reaction was completed, the temperature was cooled to room temperature, 30 mL of ethyl acetate was added to the reaction solution, and the reaction solution was washed three times with saturated brine (30 mL x 3). The organic phases were combined and concentrated, and the residue was purified by green column chromatography using a 3-12% ethyl acetate solution in petroleum acid as the eluent to obtain 20 mg of common intermediate 84 as a white solid in a yield of 94.7%.

[0042] ES1-MS: m / z = 25 i.0, 253.0 [M+Hf0 manual Step L: Synthesis of tert-butyl (tert-butyloxy) (4-methylpurinazine-2-yl)carbamate (C1-1): BM (10 g, 876 mmol) was dissolved in tetrahydrofuran (10 mL), followed by the addition of di-tert-butyl dicarbonate (478 ± 2190 mmol), sodium carbonate (2.32 g, 21.90 mmol), and 4-dimethylaminopyridine (107 mg, 0.88 mmol). The reaction was allowed to proceed at 60°C for 1 h. After the reaction was completed, the temperature was cooled to room temperature, and 30 mL of ethyl acetate was added to the reaction solution. The reaction solution was then washed three times with saturated brine (3 mL x 3). The organic phases were combined and concentrated, and the residue was purified by column chromatography using a 7% ethyl acetate solution in petroleum liquefaction as the solvent to obtain 297 g of a crude oil.

[0043] ESI-MS: in / z = 315.0 Step 2: (5 • Bromo-4-methyl Synthesis of tert-butyl (tert-butyloxy)carbamate (C1-2): C1-1 (10 g, 3.18 mmol) was dissolved in 4-dimethylformamide (10 mL), followed by the addition of N-halogenated succinimide (623 mg, 3.50 minol) and the reaction was carried out at (>°C for 1 h. After completion of the reaction, water (30 μL) was added to quench the reaction. The reaction solution was then extracted three times with ethyl acetate (00 mL*3). The organic phases were combined and concentrated, and the residue was purified by column chromatography using a 5% ethyl acetate solution in petroleum ether as the eluent to obtain 90 mg of become

[0044] C1-3 (287 g, 4.95 mmol) was dissolved in dichloromethane (20 mL), followed by the addition of trifluoroacetic acid (5 mL), and the reaction was allowed to react at room temperature overnight. After the reaction was complete, water (30 mL) was added to quench the mixture. The reaction solution was then extracted with dichloromethane (30 mL x 2). The organic phases were combined and concentrated, and the residue was purified by column chromatography using 0% to 5% methanol in dichloromethane as the eluent. 1.85 g of C1-4 was obtained as a yellow isoform in a 984% yield.

[0045] ESI-MS: in / z = 380.0

[0046] ] H NMR (400 MHz, DMSO-d' s δ): 88.47 (s, 2H), 7.62 (t, J = 74.8 Hz, 1H), 7.51 (d, J = -1.2 Hz, 1H), 7.17 (1H), 4.58 (s, 2H), 3.59-3.52 (m, 1H), 2.29 (s, 3H), 1.28 (d, J = 6.8 Hz, 3H), 1.15-1.07 (M, 1H), 0.60-0.53 (m, 1H), 0.44-0.35 (m, 2H), 0.26-0.20 (m, 1H). Step 5: (S)-(5-(2-(1-IFN-propylethyl)phenyl)-1-oxoisoindolyl)-5-methyl)-1H-[4-(2-(1-IFN-propylethyl)phenyl]-1-oxoisoindolyl)-5-methyl] ... Synthesis of phenyl chloroformate (C1): C1-4 (500 mg, 1.32 mmol) was dissolved in dichloromethane (20 mL), followed by the addition of triethylamine (200 mg, 1.98 mmol) and phenyl chloroformate (248 mg, 1.58 mmol). The reaction was allowed to react at room temperature for 1 hour. After completion, the reaction was quenched with water. The reaction solution was then extracted with dichloromethane (30 mL), and the combined organic phases were concentrated. The residue was purified by column chromatography using 0-5% methanol in dichloromethane as the eluent to obtain 350 mg of the common intermediate (I) as a white solid in a yield of 532%.

[0047] ESI-MS: m / z = 500.0 [M+H"L Step ]: Synthesis of Methyl 4-Bromo-2-(bromomethyl)-6-methylbenzoate (1-1-2) Dissolve methyl 4-bromo-2,6-dimethylbenzoate (1.21 g, 5.00 mmol) in carbon tetrachloride (10 mL), add N-bromosuccinimide (1.07 g, 6.00 mmol) and 2,2'-azobis(2-methylpropionitrile) (84 mg, 0.50 mmol). The reaction is stirred at 80 °C for 4 hours under nitrogen protection. The reaction solution is evaporated to dryness, and the residue is washed with petroleum ether. The filtrate is evaporated to dryness to obtain 1.71 g (crude product). 1-1-2 o

[0048] ESI-MS: m / z = 320.0, 3220 Step ㈤ -5-Fluoro-2-(cyclopropyl)isonicotinic acid

[0049] W 1-1-2 (17! g : 536 mmol) 0 ml,) 651 mg, (536 mmol), boric acid (66 mg, 1.07 mmol) and potassium carbonate (370 g, 2.680 mmol). The mixture is stirred at 85 °C for 15 hours. The reaction mixture The organic phase is washed three times with water (10 mL * 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure. The residue is purified by preparative liquid chromatography to obtain the target compound 1-1.

[0050] ESI-MS:.rt / z = 385.0 [M + H]. [[ID=二十ー]] Description of the Invention Synthesis Preparation of the target compound i-3 refers to step 3 in the preparation method of the target compound 1-1, only replacing the intermediate # 1-1-3 with the intermediate 1-3-1, and the rest of the preparation method remains unchanged to obtain the target compound 1-3.

[0051] ESI-MS: m / z = 456.0 [M + H]. Description of the Invention Example 4s (1V)-1-(5-(2-(1-3>Propylhexyl)-7-Methoxy-1-Oxoisonicotinoyl)-4-Methylthiazol-2-yl)-3-Methylurea C 1-4 ) The common intermediate A2 (295 mg, 1.00 mmol) was dissolved in acetonitrile (5 mL), potassium carbonate (276 mg, 2.00 mmol) and iodomethane (170 mg, 1.2 mmol) were added, and the reaction was stirred at 50°C for 4 hours. 20 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL x 3). 282 mg of the product was obtained.

[0052] ES1-MS: m / z = 310.0 Step 2 S Synthesis of (S)-1-(5-(2-(1-cyclopropylethyl)-7-methoxy-1-oxoisoindole)-4-methyl)-2-yl)-3-methylbenzene (1-4) Preparation of target compound 1-4: Reference target compound: In step 3 of the preparation method, only the intermediate 1-1-3 is replaced by the intermediate 1-4-1, and the rest of the preparation method remains unchanged to obtain the target compound 1-40.

[0053] ESI-MS: m / z = 40 i.0 [M+H]. Example 5. Preparation of 1-(5-(2-(1-propylethyl)-7-diazomethoxy-1-oxoisoindol-2-yl)-1-methylthiazole-2-yl)-3-methylhydrazone (1-5) Step 1: Synthesis of (S)-1-(5-(2-(1-cyclopropylethyl)-7-difluoromethoxyoxoisoindolyl)-4-methyl-2-yl)-3-methylhydrazine (1-5) The preparation of target compound 1-5 was carried out by referring to step 3 of the preparation method of target compound 1-1, except that intermediate 1-1-3 was replaced with common intermediate A3. The preparation method remained unchanged, and target compound 1-5 was obtained as a white solid in a yield of 182%. , J6):810.74 (s, HI), 7.63 (t J==== 748IIz, 1H), 752 (s, HI), 7.19 (s, 1H), 656 (s, HI), 4.59 (s, 2H) ; 359-3.51 (tn, UT) S 270 (d s J=44 Hz, 3H), 235 (s, 3H), 1.28 (d, J=6.8 Hz, 3H), 1.14-108 (m, 1H) :0.60-0.55 (m51H), 044-0.35 (m 2H), 0.27-022 (m, 1H), manual 1-6-1 (840 mg, 277 mL) was dissolved in dioxane (10 mL ± 1 mL), and 3 N aqueous hydrochloric acid was added dropwise. The mixture was stirred at room temperature for 1 hour. The mixture was quenched with water, and the pH was adjusted to 6-7 with saturated sodium bicarbonate. The mixture was extracted twice with ethyl acetate (20 mL ± 3). The organic phases were combined, washed once with water (20 mL), then with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using a 5% ethyl acetate solution in petroleum ether as the eluent to obtain 836 mg (crude) of 1-6-2 as a yellow solid.

[0054] ESI-MS: m / z = 278.0 \

[0055] ; 11 NN4R (400 WIz, DMSO- < / 6): 87.83 (d. J- 2.0 Hz, iH), 746 (d, J- 2.0 ITz.. 1H), 4.60 (s, 2II), 358-3.51 (m„ IH), 2.63 (s, 3H), 128 (d, J - 6.8 Hz, 3H), 1.16-1.07 (m, 1H), 0.60-053 (in. 1H\ 0.43-036 (m, 2¥l), The residue was purified by column chromatography using a 20% hexyl acetate in petroleum ether solution as the eluent to obtain 540 mg of R-3 as a yellow solid. The total yield of the three-step reaction was 61.1%.

[0056] ES1-MS: nVz = 294.0 [M+H]L L6-3 (250nig ?A mixture of 1,4-dimethylaminobenzoic acid (0.85 mL), the common intermediate amine (19 mg, 28 mmol), pyridine acetate (19 mg, 0.17 mmol), n-butyldi(1-adamantyl)phosphine (61 mg, 0.17 mmol), and tris(III) fluoride (259 mg, 0.70 mmol) was dissolved in N,N-dimethylformamide (2 mL). Nitrogen was purged for 30 seconds and microwaved at 90% RH for 2 h. The mixture was cooled to room temperature, quenched with water, and extracted twice with ethyl acetate (8 mL x 3). The organic phases were combined, washed three times with water (20 mL x 3) and once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography using a 70% ethyl acetate in petroleum ether solution as the eluent to obtain 5.0 mg of the target compound 1-6 as a yellow solid with a yield of 1.4%.

[0057] ESI-MS: -n / z = 429.0 manual Palladium (19 mg.0.03 inmol) and cesium carbonate (342 mg , 1.05 μmol) was dissolved in a mixed solvent of dioxane / water (10 μL / 1 mL), replaced with nitrogen three times, and reacted at 90°C for 2 hours. The mixture was cooled to room temperature, quenched with water, and extracted three times with ethyl acetate (20 μl / mL). The organic phases were combined (washed once with water <20 mL), washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography using 4% methanol in dichloromethane as the eluent to obtain the target compound 47 as a white solid. The total yield of Steps 2 and 3 was 24%.

[0058] ESLMS: nv'z = 396.0 [M+H] H NMR (400 MHz, DMSO-r / 6): 510.77 (s, 1H), 7.95 (s, 211), 655 (s, III), 464 (s, 2H), 3.62-3,55 (m, 1H), 270 (d, J = 44 Hz. 3H), 2.36 (s. 3H), 1.31 (d ; J = 6.8 Hz, 3H), 1.16-112 (m, 1H).0.60-0.56 (m; 1H), 0.45-0.39 (m, 2H), 028-023 (m, 1H) manual Step L 1: propyl 3 (4 -methyl quinazoline-2-yl)

[0059] # B1-1 (570 mg, 5.00 mmol) was dissolved in tetrahydrofuran Add in sequence

[0060] ® (1-9) The preparation of target compound A9 was carried out by referring to step 3 of the preparation method of target compound L4. Only the common intermediate 81 was replaced by intermediate

[0061] 1-9-1, intermediate 1-1-3 was replaced with common intermediate A3 to obtain the Japanese standard compound 1-9 =

[0062] ES1-MS: nVz = 463.0 [M+H] + o

[0063] ESI-MS: m / z -212 0 [M+H] Step 2 Synthesis of (S)-A "(5"(2"(1-propyl-2-difluoromethoxy-D-oxoisoquinoline)-4-methylthiophene)pyrrolidinecarboxamideew The preparation of the target compound 140 was carried out by referring to step 3 in the preparation method of the target compound 1, except that the intermediate 8 was replaced by the intermediate

[0064] 1-10-1, intermediate 1-1-3 is replaced with common intermediate A3 to obtain the target compound 1-10.

[0065] ES1-MS: m / z = 477.0 [M+H]-(difluoromethoxy-2-oxoisoindole-3-yl)-4-(2-methyl-2-oxo-3-indole)-1-nitropropane-1-yl)-4-nitropropane-2-yl]-1-nitropropane ...nitropropane-1- manual The common intermediate AS (200 mg ? (1.74 mmol) was dissolved in 4-dimethylformamide (mL), 4-methylpiperidinium (170 mg, 1.48 mmol) and triethylamine (224 mg, 2.21 mmol) were added, and the temperature was raised to 6U°C for 2 h. After the reaction was completed, water was added to quench the reaction, and the product was extracted with ethyl acetate.

[0066] Hl-1 (184 mg, 0.55 mmol) was dissolved in 1,4-dioxane (5 mL), and tert-butyl (4-methyl-5-(trimethyltinyl)indole-2-yl)carbamate (415 mg, 0.82 mmol) and lithium tetrakistriphenylphosphine (63 mg, 0.11 mmol) were added. N-substituted nitriles were then microwaved at 120°C for 1 h. After the reaction, the mixture was cooled to room temperature, and a 40% aqueous potassium fluoride solution (3 mL) was added to the reaction mixture. The mixture was stirred for 30 min and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, concentrated, and the residue was purified by column chromatography using a 1% to 5% methanol in dichloromethane solution as the eluent to obtain 6 mg of H-1-2 as a black oil in a yield of 21.3%.

[0067] ES1-MS: m / z = 513.0 [M+ Step 3: (S)-6-(2-Methyl-[3,4-trimethoxy-3-hydroxybenzoate)] hydrochloride (II- Ni-2 (60 mg, 0.117 mmol) was dissolved in a hydrochloric acid-ethyl acetate solution (5 mL, 4 M) and stirred at room temperature for 4 h. After the reaction, the hydrochloric acid and ethyl acetate were removed by concentration to obtain 52 mg of crude product H-1-3, which was used directly in the next step.

[0068] ES1-MS: m / z = 413.0 [M+]. Step 2: Synthesis of 3-(2-cyclopropylethyl)-4-(4-methylthiazine-L-yl)-3-oxo-2,3-dihydro-pyrrolo[4-nitro]pyrrolo[4-yl)-4-methylthiazine-2-yl)-3-methylhydrazine (114): The crude product of compound 1-1-3 obtained in the previous step was dissolved in dichloromethane (2 mL), and methylaminoformyl chloride (22 mg, 0.23 mmol) and triethylamine (SS rog / DJS mmol) were added. The reaction was carried out at room temperature. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by preparative liquid chromatography to obtain 4 mg of the target product 11-1 formate as a white solid. The total yield of the two-step reaction of step 3 and step 4 was 6.5%.

[0069] ESL-MS: r n / z = 470 0[M+H] + .,

[0070] !H NMR (400 MHz„ DMSO-d6): 5 10.64 (s, ! H), 8.19 (s„ 1H), 7.16 6.54 (d, J = 5.0 Hz, 1H), 4.50 (s,

[0071] δ 4.74 (s, 2H), 3.70 (s, 4H), 3.56-3.49 (m, 1H), 2.70 (d, J - 4.8 Hz, 3H), 2.52 (s, 3H), 2.49 (s, 4H), 2.24 (s, 3H), 1.24 (d, J - 6.8 Hz, 3H), 1.09-1.04 (m, 1H), 0.57-0.54 (m, 1H), 0.41-0.32 (m, 2H), 0.23-0.82 (ir, 1H). Example 13. (X(&(2-(1-methylpropylethyl)-3-oxo-4-(2-oxopyrrolidin-1-yl)-2,3-diazolyl)-1,4-py ... Preparation of 2-methyl-3-methylpyridine-2-yl)-3-methyladenosine (II-2) manual manual Instructions for the preparation of 4-methylamino-2-yl-3-methylhydrazone (II-4) 20 mg of the target product II-4 was obtained as a white solid. The total yield of steps 3 and 4 was 7.3%.

[0072] ESLMS: nvz = 485.0[M-iH]\

[0073] ! H NMR (400 MHz, DMSO-zfc): 8 10.61 (s, 1H), 7. 16 (s, 1H), 6.48 (s, HI), 4.50 (s ; 2H), 4.48 -4.41 (m, 2H), 3,73-3.66 (m, 2H), 3.56-3.52 (m, 1H), 2.70 (d, J = 4.4 Hz, 3H), 2.58^2.54 (m, 2H), 2.52 (s, 3H), 1.24 (d, J = 6.8 Hz, 3M), 1 14 (dd, J; = 6.0 Hz, J2- 1.6 Hz ;6H), 1.09-1 06 (m, 1H), 0.58-0.53 (m. 1H) S 0 42-0.32 (m s 2H), 0.25-0.20 (m, 1H). Example 16, pyridin-6-yl)-a-methyl manual manual The reaction mixture remained unchanged, yielding 203 mg of St; II-6-1 as a yellow oil in a yield of 78.2%.

[0074] ESI-MS: n / z = 352 0[M+Hf. Step 2: Synthesis of tert-butyl ((1-cyclopropylethyl)-4-(4-(4-methyl)-3-oxo-2,6-dihydropyrrolo[3,4-e] Hit®-6-yl)-4-methylpyrrolo[2,4-e] Hit®-6-yl)carbamate (11-6-2) The synthesis of the intermediate IM-2 in step 2 of reference example 12 was carried out, except that the intermediate IM-1 was replaced with II-6-L. The rest of the preparation method remained unchanged to obtain 220 mg of 11-6-2 as a black oil with a yield of 73.1%.

[0075] ES1-MS: m / z = 530.0[M+r-Ij\ 43 mg of the target product 11-6 was obtained as a white solid. The total yield of Steps 3 and 4 was 21.7%.

[0076] ESi-MS: m / z = 487 0[M+H] + „

[0077] ? H NMR (400 MHz, DMSO-a ? 6): § 10 63 (s. 1H), 7.16 (s, 1H), 6.50 (d, J = 4.8 Hz, 1H), 4 50 (s, 2H), 4.20 (d, J = 13 2 Hz. 2H\ 3.55-3.50 (m, 1H), 3.26-3 23 (m. 2H), 2.70 (d. J = 4.8 Hz, 3H). 2.52 (s, 3H) ; 1 85-1.77 (m, 4H) ,1.40 (d, J = 22.0 Hz, 3H), 1.24 (d, J = 6.8 Hz, 3H), l. l l-i.06 (m, ]H), 0.57-0.53 <m, 1H), 0.41-0.33 (m, 2H), 025-0.21 (m, IH).咯并 Specification Refer to the synthesis of Intermediate??-0 in Step 1 of Reference Example 12. Only replace methylpiperazine with 4,5,6,7 - tetrahydropyrido [i ; 5-Altazine dihydrochloride, and the rest of the preparation method remains unchanged. 270 mg of compound -74 is obtained as a yellow solid with a yield of 51.5%., Refer to the synthesis of Intermediate n」-3 in Step 3 of Reference Example 12. Only replace IIM-2 with n-7-2, and the rest of the preparation method remains unchanged. The crude product H-7-3 obtained is directly used in the next step.

[0078] ES1-MS: m / z = 436.0[M+IIl\ Step 4 S (^-1-(5-(2-(1-5F propyl ethyl S)-4-(6,7 - dihydropyrido [L5-a]trazine -辎理)-yl)。oxo -2# - dihydro -1H<pyrrolo 伐 4 - netdiazole 6 - yl}-4 - methyl pyrimidine -2 - yl)-3 - methyl urea (II-7) Synthesis Refer to the synthesis of the target compound 113 in Step 4 of Reference Example 12. Only replace 11-1-3 # with II-7-3, and the rest of the preparation method remains unchanged. 2() mg of the target product 11-7 is obtained as a white solid. The total yield of the two-step reactions of Step 3 and Step 4 is 18.8%o

[0079] ESi-MS: m / z = 493 0[M+H] + „

[0080] ? H NMR (400 MHz, DMSO-^g): 5 10.65 (s, 1H), 7.43 (d, J = 2.0 Hz. 1H), 7.27 (s. 1H), 6.48 (d., / = 4.8 Hz, 1H) ; 6.17 (d. J = 2.0 Hz. 1H), 4.89 (s_ 2H), 4.55 (s. 2H), 4.32-4.29 (m, 2H)„ 4 20-4.17 (m, 2H)S 3 59-3.55 (m, !H) = δ 2.71 (d, J = 4.4 Hz, 3H), 2.54 (s, 3H), 1.26 (d, 6.8 Hz, 3H), 1.10-1.08 (m, 1H), 0.58-0.55 (m, 1H), 0.42-0.35 (m, 2H). 0.25-0.21 (m, 1H). Example 19. Preparation of (S)-1-(5-(2-(1-cyclopropylethyl)-4-(2,2-difluoroethoxy)-3-oxo-2,3-dihydro-1-pyrrolo[3,4-e]pyrenesin-2-yl)-3-methyl)-1-[[(S)-1-(5-(2-(1-cyclopropylethyl)-4-(2,2-difluoroethoxy)-3-oxo-2,3-dihydro-1-pyrrolo[3,4-e]pyrenesin-2-yl)-3-methyl] ... Sodium hydride (66 mg, 278 mmol) was added to 2,2-difluoroethane alcohol (136 mg, 1.66 mmol) and stirred at room temperature for 15 minutes. Then, a dioxane solution (10 ml.) of the common intermediate AS (300 mg, 1.11 mmol) was added dropwise. The system was heated to 60 c The mixture was cooled to room temperature and quenched with water. The mixture was extracted three times with ethyl acetate (20 mL x 3). The organic phases were combined, washed three times with water (8 mL x 3), washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography using a 30% ethyl acetate solution in petroleum ether as the eluent.

[0081] ESI-MS: in / z = 317.0

[0082] NMR (400 MHz, DMSO-d;): 87.47 (s, 1H), 6.55 (tt, , / j = 54.4 Hz, J2= 3.6 Hz, IH)„ 473 (td„ J-. = 14.8 Hz,, = 36 Hz, 2H), 4.57 (s, 2H), 352-3.45 (m, ill), 1,25 (d, J - 6.8 Hz, 3H), 1,134.04 (dm 1H), 0.6C-0.52 (m, Dissolve II-8-2 (208 mg, 0.42 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (2 mL; >) dropwise, and stir at room temperature overnight. Quench the mixture with water, adjust the pH to 6-7 with saturated sodium bicarbonate, and extract three times with dichloromethane (3 mL x 3). Combine the organic phases, wash once with water (20 mL), once with saturated brine (50 mL), and dry over anhydrous sodium sulfate. Filter. Concentrate the filtrate under reduced pressure to obtain crude II-8-3, which is used directly in the next step.

[0083] ESI-MS: in / z - 395.0. Step 1: (S)-1-(5-(2-(2-[N-(2-ethoxy)-3-oxo-2-nitro-1,2-pyrrolo[2-(2-nitro-1,2-dihydro-1,2-pyrrolo[2-( ... The residue was purified by residual spectrum, and the developing solvent was 1-5% methanol in dichloromethane solution, and 45 mg of the target product n-8 was obtained as a yellow solid. The total yield of the two-step reaction was 238%.

[0084] ESI-MS: m / z = 4520

[0085] ; H NMR (400 MHz, DMSO-a fi ): 810.74 (s, 114), 7.44 (s, 1H), 6,59 (it,′ = 544 Hz,′ = 3.6 Hz, 1H), 6.52 (s, Instruction Manual

[0086] 1H), 475 (td, J; = 148 Hz, J2- 36 Hz, 2H), 4.58 (Wan 2H) , 3.54-3.47 (m ; 1H) ; 2 / 70 (d, J - 44 Hz, 3H) :2.55 (s, 3H): 1-25 (d, J- 6.8 Hz, 3H), 1.134.05 (m, 1H).0.58-053 (nx HI), 043-0.34 (m, 2H), 024^0.20 (m ; Example 2 Team 1 · (5. (2. ((1. Cyclopropylethyl) 3 oxo 4 ((tetrahydrofuran 3 yl) oxy) g dihydro-1H-pyridinium chloride and 4 can be sneezing

[0087] Preparation of 6'-methyl)-4-methylthiazol-2-yl)-3-methyladenine (II-9) 45 mg of target product II-9, a yellow solid. The total yield of Steps 3 and 4 was 22.4%. »

[0088] ESI-MS: nvz - 458.0 [M+H]L

[0089] ; H NMR (400 MHz, DMSO-d6): 810.69 (s, 1H), 7.38 (s, 1H), 650 (s, 1H) ; 559-5.55 (m, 1H), 454 (s, 2H) ; 405-401 (m, IH), 3.91-3.75 (m s 3H), 352-3.45 (in, 1H), 2.70 (d, J= 4.8 Hz, 311), 2.54 (s, 3H), 2.37-2.28 (rn, 1H), 208-203 (■«, 1H), 125 ( <i, 6.8 Hz, 3H).. 1.12-104 (nr 1H) ; 058-0 S3 (m. 1H).0.43-0.32 (tn, 2H), 0.24-0.20

[0090] (m, iH) Example 21 > (>V)-i-(5-(4 -cyclopropyloxy- Preparation instructions for hydroxy-2-methyl-3-nitro-1-nitropropane (11-10) manual 200 mg of II-11-2 was obtained as a yellow solid with a yield of 76.5%. 80 mg of II-12-2 was obtained, with a yield of 745%. 19 mg of target compound 11-12 was obtained as a yellow solid. The overall reaction yield of steps 3 and 4 was 11.7%.

[0091] ESI-MS: m / z = 430.0 [M+H]L

[0092] ! H NMR (400 MHz, DMSO-<76): 610.66 (s, 1H), 7.33 (s, 1H), 648 (s„ 1H), 543-5.37 (m, 1H), 452 (s„ 2H), 3.52-3.44 (m, HI), 2,70 (d, J - 4,8 Hz, 311), 2.54 (s, 311), 1.37 (dd, 6.4 Hz, 3.2 IIz, 611), 1.25 (d, J == 6.8 Hz, 3H), l l-105(m, 111),058-0.52 (ni, 1H), 04 i -0.33 (m, 2H)„ 0.23-019 (m ; Example 24, (5) -1- (5- (2- (1-cyclopropyl) -4 ■ (dimethylamino) -3 - oxo-2, 3 - dihydro-1 / 1 - pyrrolo [3,4-c] t ^ -6- ^) -4 - methyl sneeze azole-2 - base 1 -3 - methyl benzoate (11-13) Preparation Step L (5) Synthesis of 4-chloro-2-(1,2-cyclopropylethyl)-4-(dimethylamino)-1,2-dichloro-3-pyrrole-3-one (II-13-1): The common intermediate A5 (200 mg, 0.74 mmol) was dissolved in N-dimethylformamide (10 mL), and triethylamine (187 mg, 1.84 mmol) and dimethylamine hydrochloride (72 mg, 0.89 mmol) were added. The temperature was raised to "C" and the reaction was continued for 1 hour. The mixture was cooled to room temperature and quenched with water. The mixture was extracted three times with ethyl acetate (20 mL * 3). The organic phases were combined, washed three times with water (20 mL * 3^, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using an 18% ethyl acetate solution in petroleum ether as the eluent. 165 mg of EI43-L was obtained as a yellow solid, yield 801%.

[0093] ESI-MS: nvz = 280.0 [M+H

[0094] ; H NMR (600 MHz, DMSO-J6): 6691 (s, 1H), 444 ( s ; 2H) 353-348 (m, 1H), 316 (s, 6H), 1.2.2 (d. J = 6.8 Hz, 3H), 1.08-1.03 (m, 1H), 0.56-0.52 (m, 1H), 0.40-0.31 (m, 2H), 0.23-0.19 (m, 1H) Step 2: (,S)-1-(S-(2-(1-SF3propylethyl)-2-dimethyl-MS)-3-(4-hydroxy-2-[3-(2-(1-SF3propylethyl)-2-dimethyl-MS)-3-(4-hydroxy-2-[3-hydroxy-2-[3-hydroxy-2-[3-hydroxy-2-[3-hydroxy-2-[3-hydroxy-2-[3-hydroxy-2-[3-hydroxy-2-[3-hydroxy-2-[3-hydroxy-2-[3-hydroxy-2-[3-hydroxy-2-[3-hydroxy-2-[3-hydroxy-2-[3-hydroxy-2-[3-hydroxy-2-[3-hydroxy-2-[3-hydroxy-2-[3-hydroxy-2-[3-hydroxy-2-[3-hydroxy-2-[3-hydroxy-2-

[0095] ESI-MS: ni / z = 415.0 [M+H

[0096] ! II NMR (400 MHz, DMSO- < / 6): 810.54 (s, 1H), 7.07 (s, 1H) ;645 (s, 1H), 448 (s, 2H), 3.57-350 (m, 1H), 3.18 (s, 611), 2.70 (d,J-4.8Ilz, 311), 2.53 (s, 311), 1.24 (i, / -6.8Hz ; 31 n 1.10-104 (m, HI), 0.58-0.52 (m, 111), 0.41-0.32 (m, 2H), 0.25-0.21 (m, 1H) Example 25, Preparation of (S)-1-(5-(2-(1-cyclopropylethyl)-4-methoxy-3-oxo-2#-dihydro-1H-pyrrolo[2-(1-pyridyl)-4-methylthio[2-yl]-3 ... H NMR (400 M IIz, DMSO-64): 610.60 (s, 1H), 7.14 (s, 1H), 6.47 (s, 1H), 4.51 (s, 2H), 4.27 -4.17 (m, 2H) ; 3.97-3.92 (m, 2H), 3.57-350 (m, 1H)„ 2.70 (d, J = 4.8 Hz, 3H), 2.53 (s, 3H), 247 - 243 (ro, 2H)„ 125 (d, J = 6.8 Hz, 3H), 1 12-103 im, 1H), 058-053 (m, 1H), 042-033 (m, 2H), 02S-021 (m, 1H) Synthesis Synthesis

[0097] ; H NMR (400 N HIz, DMSO- <f fi ): 610.63 (s, iH), 716 (s, 1H), 652 (d, J = 5.2 Hz, LH), 477 (d, J = 7.2 Hz, 1H), 4.51 (s, 2H), 4.09-4.06 (m, 1H), 392 (d, J = 10.8 Hz, 1H), 3.72-3.49 (m, 5H), 2.69 (d, J = 4.8 Hz, 3H), 2.52 Instruction Manual

[0098] (s, 3H). 1.25 (d, J - 6.4 Hz, 3H) , 1.19 (d ; J = 6.4 Hz, 3H), 1.09 - 1.05 (m, 1H), 0.58 - 0.52 (m : 1H) , 0.40 - 0.32 (m : 2H), 0.30 - 0.19 (m ; 1H).

[0099] ESIMS: m / z = 441.0 [M + H]+

[0100] 1H NMR (400 MHz, DMSO-d6): δ 10.58 (s, 1H), 6.98 (s, 1H), 6.49 (d, J = 5.2 Hz, 1H), 4.46 (s, 2H), 3.75 - 3.68 (m, 4H), 3.56 - 3.48 (m, 1H), 2.69 (d, J = 4.4 Hz, 3H), 2.52 (s, 3H), 1.90 - 1.84 (m, 4H), 1.23 (d, J = 6.8 Hz, 3H), 1.09 - 1.02 (m, 1H), 0.58 - 0.52 (m, 1H), 0.41 - 0.31 (m, 2H), 0.24 - 0.19 (m, 1H). Example 30. Preparation of (S)-α-(5-(2-(5-cyclopropylethyl)-2-(diethylamino)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-4-methylsulfanyl-2-methyl)-3-methylbutanamide (III-19-1) Step 1: Synthesis of 6-chloro-2-(5-cyclopropylethyl)-4-(diethylamino)-1,2-dihydro-3-oxo-1H-pyrrolo[3,4-c]pyridine-3-carboxylate (II-19-1) Refer to the synthesis of the target compound II-13-1 in Step 1 of Reference Example 24, and only replace dimethylamine hydrochloride with diethylamine hydrochloride, and the rest Description (s, 3H). 1.25 (d, J - 6.4 Hz, 3H) Step 1: Synthesis of (chloro-2-(1-cyclopropylethyl)-2-oxa-or-2-chlorospiro[4.5]decane-2-yl)-dihydro-3-pyrrolo[4.5]-3-one (H-2J-1). The synthesis of target compound II-13-1 in step 1 of Example 24 was performed with the exception of replacing dimethylamine hydrochloride with oxa-2-azaspiro[4.5]decane. The remaining preparation method remained unchanged, yielding 260 mg of II-21-1 in a 93.7% yield.

[0101] ESI-MS: nvz = 376.0[M+HR Step 2: N-(5-(2-(1-cyclopropylethyl)-3-oxo-4-(8-methyl-2-[4.5]-1-decan-2-yl)-2-[ ... 20 mg of target compound 11-22, / g S-colored solid, yield 70% (1

[0102] ES1-MS: nVz = 512.0[M+H]\

[0103] JI NMR (400 MHz, DMSO- J6): 6 10 57 (s, 1H), 7.16 (s, 1H) S 6 48 (s ; 1H), 4.57 (t, J = 6 4 Hz, 2H), 4.50 (s, 2H), 4.48-4.47 (m, 2H), 3.71 (s, 4H), 3.54-3.50 fm, iH), 3.47-3.42 (m, 1H), 2.69 (d, J - 4 4 Hz, 3H) S 2.52 (s, 3H), 2 41 (d ; J = 5.2 Hz, 4IT), 1.2.4 (d, J = 6 8 Hz, 3H), 1.09- 1.04 (:n ; LIT), 0.57-0.52 (m, 1H), 0.40-0.32 (m, 2H), 0.23-0.19 (m, III). Example 34, Preparation of (4-(5-(2-(1-cyclopropylethyl)-4-(4-methyl-1-yl)-1-oxo-23-211^,-1 / / -1-pyrrolido[3,4-c]pyrrolidone-6-yl)-4-methylpurin-2-yl)-3-methylpyrrolidone (H-23) manual 398-3.94 (m, 2H), 3.54-3.50 (m, 1H), 3.44-3.33 (m, 2H), 2.70 (d, J= 4.4 Hz, 3H), 2.52 (s, 3H), 1.60-1.53 ​​(ni, 4H), 124 (d, J - 68 Hz, 3H) ; δ 1.16 (s, 3H), 1.09- 1.04 (m, 1H), 0.57-0.54 (m, II T), 0.41-0.32 (m, 2H), 0.23-0.20 (m, 1H) Example 35, GM-C]pyridin-6-yl} Step 1: Synthesis of (S-chloro-2-(1-cyclopropylethyl)-4-(2-oxa-6-azaspiro[3.3]heptane)-1,2-dihydro-3H-pyrrolo[3H]pyrrol-3-one (n-24-n) The synthesis of the target compound II-13-1 in step 1 of Example 24 was carried out with the exception that dimethylamine hydrochloride was replaced with oxa-6-azaspiro[3.3]heptane. The rest of the preparation method remained unchanged to obtain 400 mg of n-24-1 as a yellow, slurry-like substance. The yield was 64.9%. 3H), 440-4.34 (m, 4H), 3.52-3.48 (m, 1H), 2.70 (d, J = 4 / 1 Hz, 3H), 253 (s, 3H), 124 (d, J = 6.8 Hz, 3H), 1.07-1.05 (m, 4H), 0.57-0.52 (m, 1H), 0.40-0.32 (m, 2H), 0.23-0.19 (m, 1H) Example 36, (S)-1-(5-(2-(1-cyclopropyl)-2-nitropropane)-1-nitropropane Preparation instructions for 2-methyl-3-methyl-1-nitropropene (11-25) The target compound n-25 was prepared by synthesizing 1-1-3-methyladenine (11-25) according to step 3 of the preparation method of the target compound 1-1 in Example 1. Only the intermediate 1-1-3 was replaced with the common intermediate A6. The rest of the preparation method remained unchanged to obtain the target compound 11-25 as a white solid in a yield of 32%.

[0104] ESI-MS: m / z = 457 0 [M+H .

[0105] ; H NMR (400 MHz, OMSO-t / s): 8.45 (s, 1H)„ 7 19 (s. 1H)_ 6 79 (d. J = 5 2 Hz, 1H), 4.52 (s_ 2H), 3.75 (t. J = 4.4 Hz, 4H), 3.68 ft, J = 4 0 Hz, 4H), 3 56-3.49 (m, 1H), 2.69 (d, J - 4.8 Hz. 3H), 2.53 (s, 3H), 1.25 (d. J = 6.8 Hz, 3H) : 1 11 -J .04 (m, HI), 0.60-0.53 (m, 1H), 0.43-0.31 (m, 2H), 0.24-0. S9 (m, 1H) = Preparation of target compound II-26 K1: Referring to step 3 of the preparation method of target compound II in Example 1, only intermediate 1-1-3 was replaced with common intermediate A6, and common intermediate B1 was replaced with intermediate PM. The rest of the preparation method was changed to obtain target compound II-26.

[0106] ES1-MS: m / z =483.0 [M+H | + . manual Step 1: Synthesis of 11-29- (4-Ep-yl warm-thaw-2-yl 1-M2-morpholino-4-tomb (11-29- O) Referring to the synthesis of the intermediate ear-9-i in Step 1 of Example 9, only the intermediate cyclopropylamine was replaced with 2-morpholinoethanolamine, CB was replaced with methylaminocarbonyl chloride, and the solvent was replaced by tetrahydrofuran with dichloromethane. The rest of the preparation method remained unchanged to prepare the intermediate 11-29-! =

[0107] ESL-MS: m / z -271.0 [M+H manual

[0108] EST-MS: m / z = 497 0 [M+H hl NMR (600 MIlz, DMSO-CM): 8 10.77 (s :ill), 7.20 (s, HI), 4.52 (s, 211), 3.75 (LJ = 4.8 Ilz, 411), 3.68 (t, J = 4.8 Hz, 4H), 3 55-3.50 (m 1H) ; 3 39 (s, 4H), 2.56 (s, 3H), 1.85 (s, 4H) ; 1.24 (d, J - 4.4 Hz, 311), 1.10-1.05 (m, 1H), 0.58-0.54 (m, 1H), 0.42-0.37 (m, 2H), 0.36-0.32 (m, 1H). Example 42. Preparation of (A)-(5-(2-(1-propylethyl)-7-(difluoromethoxy)-1-hydroxyisoquinolin-2-yl)-4-methyl)carbamate (1V4) Step L: Synthesis of (S)-2,2-difluoroethyl(5-(2-(1-(5-propylethyl)-7-(difluoromethoxy)-1-oxoisonaphthalene-4-yl)methyl)carbamate (IV4): Sodium hydride (14 mg, 0.60 mmol) was added to 2,2-dioxoethane-1-ol (1 mL) and stirred at room temperature for 15 minutes. Subsequently, the common intermediate #-C1 (100 mg, 0.20 mmol) was dissolved in dioxane (5 mL) and added dropwise to the mixture. The system was heated to 50°C and the reaction was allowed to proceed for 1 hour. After the reaction, the mixture was cooled to room temperature and quenched with water. The reaction solution was then extracted with ethyl hexanoate (30 ml, 3 × 3). The organic phases were combined and concentrated. The residue was purified by column chromatography using a 0-3% methanol in dichloromethane solution as the eluent to obtain 193 mg of the target compound, N-L, as a white solid in a yield of 20.4%.

[0109] ES1-MS: nVz = 488.0 [M+H]L

[0110] 5H NMR (400 MHz, DMSO-tZ6): 8 12 23 (s, 1H). 7.64 (t, J = 74.8 Hz, 1H), 7.57 (d, J - 1,2 Hz, 1H>, 7.24 ( s, 1H), 6.48 (it, J = 54.0 Hz, J2= 3.2 Hz, 1H), 4.60 (s, 2H), 4.54 (Ed, % = 15.2 Hz, J2= 3.2 Hz, 2H), 3.59-3.52 (m, 1H), 2.38 (s, 3H), 1.28 (d, J = 6.8 Hz, 3H), 1.16-1.07 (m, 1H), 0.60-0.54 (m, 1H). 0.44-0.35 (m, 2H), 0.26-0.22 (m, 1H) Example 43s Preparation of Tetrahydroxanthan-3-yl (5-(2-((>S)-1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisothiazolinyl)-2-methylthiazolin-2-yl)carbamate (IV-2) manual , , , , , , , , , , J- 08 Hz, 1H) S 460 (s, 2H), 3.97 (d, J -6.4 Hz, 2H), 3.59-352 (in, 1H), 2.37 (s ; 3H), 2.00489 (m, 1H), 1.28 (d, J -6.8 Hz, 3H), 1.15-1.07 (m, 1H), 0.93 (d, J = 6.4 Hz, 6H) S 0.60-0.54 (m, 1H), 0.44-0.35 (m, 2H), 0.27-0.22 (m, 1H) Example 47. Preparation of 2-methoxyethyl (S)-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-e.g., ... Step 1: Preparation of 2-methoxyethyl-cyclopropylethyl-7-(difluoromethoxy-1-oxoisoxazolidin-2-yl)-1-methyl-1-ol. The reaction mixture of step 1 of Example 42 of target compound IV-6 was prepared by replacing 2,2-difluoroethane-1-ol with ethylene glycol carboxylate to obtain 25 mg of target compound I as a solid in a yield of 28.1%.

[0111] ESI-MS: m / z = 482.0

[0112] ! II NMR (400 MHz, D 11.94 (s s IH), 763 (t, J = 74.8 Hz. 1H), 7.56 (d, J = 12 Hz ; HI), 7.22 (d. J = 12 Hz. 1H), 460 (s, 2H), 431-429 (m, 2H), 359-357 (m, 2H), 356-352 (m, 1H), 328 (s, 3H), 23? (s, 3H), 1.28 (d, . / =6.8Hz, 3H). i.15- 107 (m, 1H), 060-054 (m, HD, 044-.035 (m, 2H), 027 - 022 (m, iH) Instructions for the preparation of 2-amino-1,2-dimethylamino)carbamate (IV-7)

[0113] ESI-MS: m / z = 551.0 [M+H Sink NMR (400 MHz. DMSO-J6): 311.85 (s, 1H), 7.63 (t ; J = 74.8 Hz, 1H), 7.55 (d, J - 12 Hz, 1H) : 7.22 (d, .1= i 2Jfz. 1H) , 459 (s.2H\ 422 (t..7 = 64 Hz, 2H)„ 359-352 (m, 5H) ;δ 2.38-2.33 (m.9H), 1.58 (d, J = 68 Hz, 2H), 1.28 (d, J = 6.8 Hz, 3H), 1.16-1.07 (m, 1H), 0.60-0.54 (m, 1H), 0.44-0.35 (m, 2H), 0.27-0.22 (m, 1H). Example 50, Methyl (5-(2-a-propylethyl)-7-(difluoromethoxy-7-oxoisoquinoline-5-yl-3-methylchloroformate (IV-). Purchased and prepared Step L (3) -(5-(2-cyclopropylethyl)-7-(dimethoxy)-4-oxoisoindole-5-ylmethylpiperazine-2-yl)carbamate rv-io-1 Step h (5) Synthesis of (2,0-cyclopropylethyl)-3-hydroxypropane-2-yl)-5-tetramethyl-L-3,2-dioxaborolane-2-yl)isoquinoline-4-one (IV-iO-D) The preparation of compound IV-W-1 can refer to the preparation method of compound 1-7-2 in step 2 of Example 7, except that intermediate L7-1 is replaced by compound 1-7-2. The rest of the preparation method remains unchanged to obtain 610 mg of IV-W-1 as a white solid with a yield of 93.0%.

[0114] ESl-MS(nVz): 386.0 [M+HJ + t Step 2: Synthesis of (S)-(5-(2-(1-propylethyl)-7-(2-methylpropan-2-yl)-1-oxoisopropyl-5-yl)-4-methyl-1-hydroxy-2-yl)carbamate (WW) The preparation of target compound IV-10 can refer to the preparation method of target compound L7 in Step 3 of Example 7, except that intermediate 1-7-2 is replaced by compound IV-10-1. The rest of the preparation method remains unchanged to obtain 2 mg of target compound IV-10 as a white solid with a yield of 1.2%.

[0115] ESl-MS(nVz): 430.0 [M+H

[0116] 'H NMR (400 ?vnIz ;DMSO-cfe): 6 1 1 .89 (s, ill), 7 57 (d, J = 1.2 Hz„ III), 7 43 (d, J = 1.6 Hz, 1H) 7.17 (s, 1H), 4.66 (s, 2H), 3 75 (s, 3H) t 3.67-3.60 (m, 1H), 2.37 (s, 3H), 1 56 (i J - 2.0 Hz, 6H) S 1.32 (d t J - 6 8 Hz, 3H) ; 1 18-1 1 i (m, IH), 0.62-0.56 (m, 1H), 0.46-0.37 (m, 2H) ; 0 29-0.24 (m, 1H). Example 52. Preparation of (.S)-(5-(2-(l-5F propylethyl)-7-morpho-X-oxoisopropyl-X-oxoisopropyl-4-methyl-2-methyl ... Step h (V) Synthesis of 2-(1-cyclopropylethyl)-7-morpholinoisonalvinyl-1-ol (IV-H-1) The common intermediate 4 (400 mg, 1.48 mmol) was dissolved in diisocyanate (60 mL), followed by the addition of morpholino (578 mg, 1.48 mmol). g> 2,96 mmol) and triethylamine (597 mg ; The reaction mixture was stirred for 1 h at 130°C in a microwave oven. After the reaction was complete, the temperature was cooled to room temperature, and 30 mL of ethyl acetate was added. The reaction mixture was then washed with saturated brine (30 mL x 3). The organic phases were combined and concentrated, and the residue was purified by column chromatography using a 25% ethyl acetate in petroleum ether solution as the eluent. 180 mg of IV-ML was obtained as a yellow solid, with a yield of 735%.

[0117] ESI-MS: m / z = 365.0[M+Hr h =

[0118] 'HNMR (400 IvflIz, DMSO<4) 8 H 88 (s, III), 7.16 (d, J= 1.2 Hz, HI), 6.84 (d, J - i 2 Hz, HI).448 (s, 2H), 3.77-3.75 (m, TH), 3.58-3.51 (m, IH), 3.27-320 (m, 4H), 2.37 (s, 3H), 1.25 (d, J= 6.8 Hz, 3H), 1.12-1.04 (m, nT), 060-053 (m ; ilT), 042-031 (m, 2H) ; 024-019 (n\ 1H) Example 53, Preparation of (S)-(5-(2-(1-SF-propylethyl)-4-fluoro-5-nitro-2-yl)-5-nitro-2-nitro-3-oxo-2,3-dihydro-1-pyrrolo-4-pyrido-4-yl)-4-methylpyridin-2-yl)carbamic acid methyl ester (IV-12) Step h: IH-1 (200 mg, 0.85 mmol) was reacted with 2-(2-methyl-2-thiazol-2-yl)amino group for 1 h. After the reaction was completed, the temperature was cooled to room temperature and the mixture was stirred for 1 h. The organic phases were combined and concentrated, and the residue was purified by column chromatography using a 10-12% ethyl acetate solution in petroleum ether as eluent to obtain 130 mg of 1V-12-1 as a white solid with a yield of 88.4%.

[0119] EST-MS: rn / z = 1730 [M+] Step 2: Synthesis of (S)-(5-(2-(1-nitroethyl)-1-oxo-2,3-dihydro-1-pyrrolo-2-yl)-4-(1-nitromethyl)-2-carbamate (IV-12) IV-4- ...methyl)-1-oxo-2,3-dihydro-1-pyrrolo-2-yl)-4-(1-nitromethyl)-2-carbamate (IV-12) IV-4-2-(1-nitromethyl)-1-oxo-2,3-dihydro-1-pyrrolo-2-yl)-4-(1-nitromethyl)-2-carbamate (IV-12) IV-4-2-(1-nitromethyl)-1-ox The temperature was lowered to room temperature, and the reaction solution was extracted with ethyl acetate (30 mL*3). The organic phases were combined, concentrated, and the residue was purified by preparative liquid chromatography to obtain 40 mg of the target compound IV-12 as a white solid with a yield of 28.2%. Reference compound 2 GP1-549): Refer to the preparation method of compound 4 in Example 1 of WO2015051244A1. Example 55: PI13Ky Inhibitory Activity of the Compounds of the Present Invention The compounds of the present invention were tested for their ability to bind to and inhibit PI13K in vitro using ADP Gio assay, using IPI-549 as a control. yActivity. Compound solution preparation: First, dissolve the compound in DMSO. Then, serially dilute the test compound three-fold with sterile deionized ultrapure water to create eight compound solution concentrations. Experimental method: Prepare 2xPI3Ky enzyme solution in activating buffer. Prepare substrate solution containing 2xPIP2:3PS and ATP in substrate buffer. Add 1 μL of each gradient compound solution to a 384-well plate and centrifuge. Then, add 5 μL of 2xPI3Ky solution and alcohol-free kinase buffer. Centrifuge. Add 5 μL of 2xPIP2:3PS and ATP substrate solution to each well. Mix well, centrifuge, and incubate at room temperature for 90 minutes. Add 10 μL of ADP-Glo ​​reagent to each well to stop the reaction. Mix well, centrifuge, incubate at room temperature for 60 minutes, and then add 20 μL of ADP-Glo ​​Kinase Detection Reagent to each well. Centrifuge. After averaging, the results were read on a microplate reader and the inhibition rate of each compound was determined. The final results were input into Stratagem Prism for plotting. The results are shown in the following table: Table L PI3Ky Inhibitory Activity of Aromatic Alkanone Compounds manual The ADP Gio assay was used to test the ability of compounds to bind and inhibit the in vitro activity of PI3Kα, PI3Kβ, and PI3Kβ. A 2xPI3Kα / β enzyme solution was prepared in kinase buffer, and a substrate solution containing 2xPIP2:3PS and ATP was prepared in substrate buffer. Each gradient concentration of compound solution was added to a 384-well plate and centrifuged. Five microliters of 2xPI3Kα enzyme solution and enzyme-free kinase buffer (i.e., 1 L) were then added. 5 μL of the substrate solution containing 2xPIP2:3PS and ATF was added to each well. The mixture was mixed thoroughly and incubated at room temperature for 9 minutes. The reaction was stopped by adding 10 μL of DP-Glo ​​reagent to each well, mixed thoroughly, and centrifuged. After incubation at room temperature for 60 minutes, 20 μL of ADP-Glo ​​Kinase Detection Reagent was added to each well and centrifuged. The plate was then equilibrated for 6 minutes. After 1 minute, the enzyme was read on a microplate reader and the inhibition rate of each compound was determined. Table 2. PI3Ka, PI3Kps, and PI3K8 Inhibitory Activities of the Compounds of the Invention As can be seen from the data in Table 2, the compounds provided by the present invention have significantly stronger selectivity for H3Ky isoforms than PI3Ka, PI3K3, and PI3K5, indicating that the compounds provided by the present invention have reduced off-target effects compared to IPI-549.

[0120] (1) A 96-well plate was pre-coated with 100 μL of CD3 antibody at a concentration of 3 μg / ml and incubated overnight at 4°C. Afterwards, the plate was washed twice with sterile PBS to remove the free CD3 antibody in the plate for later use.

[0121] (2) Control and AD mice were sacrificed by cervical dislocation and immersed in 75% ethanol solution for 5 minutes. Lymph nodes were then removed from the ear in a clean bench. According to the instructions, an appropriate amount of RPMI-1640 blank medium was used to grind the cells into a single cell suspension using a 200-mesh sieve. Lymphocytes were obtained by centrifugation at 4°C and 1200 rpm after sieving the cells through a 70-mesh sieve.

[0122] (3) Grind and separate single lymphocytes using a 70 μM cell sieve. Centrifuge at 300 g for 5 min. Resuspend in complete medium and count. The Oueway-ANOWs method was used for statistical analysis, and P < 0.05 was considered statistically significant. Example 58. The inhibitory activity of the compounds of the present invention on the secretion of cytokine II-17A by lymphocytes derived from psoriasis mice induced by oxazolidinone cream

[0123] (3) Grind and separate single lymphocytes using a 70-μm IFFI cell sieve. Centrifuge at 300 g for 5 min. Resuspend in complete medium and count. The results and data of the measurements and observations required by the protocol were recorded in appropriate tables and analyzed uniformly in Excel. Quantitative data were expressed as mean ± standard error. All data were analyzed using Pnsm statistical software. Oneway-ANOVA was used for statistical analysis. P < 0.05 was considered statistically significant. The experimental results are shown in Figure 2. As shown in Figure 2, the compounds of the present invention have a potent inhibitory effect on the secretion of IL-37A in lymphocytes derived from psoriasis mice induced by vinblastine cream and can be used to prevent or treat psoriasis. Example 4: Pharmacokinetic test method for the compounds of the present invention: Male SD rats weighing approximately 200 g were randomly divided into two groups, each containing three rats. Group 1 received a single intravenous injection of 0.5 mg / kg of vinblastine. The experimental results show that compared with IPL549, the plasma exposure and oral bioavailability of some compounds of the present invention after oral administration are significantly improved. Data were collected and analyzed using pCLAMP 10 (Molecular Devices, Union City, CA), and the analysis results were reviewed by the experimenter. The results of the inhibitory effect of the compounds of the present invention on human bERG ion channels are shown in the following table: Table 4. Blocking rate of the compounds of the present invention on hERG ion channels The experimental results show that some compounds of the present invention have good safety after oral administration.

Claims

The claim book ~ two supplements beside chrysanthemum * hernia thin collar rattan cloth car - mine Yu Jiabiao I cloud W two factory truth stubborn and I Ji or color Jin E humorous hill blessing; In the formula, Ring A is selected from a 5-16-membered aromatic ring or heteroaromatic ring, and Ring A contains at least one substituent R 2 ; B Selected from NR ,a R !b OR ,a ; R i2 > R lb R', R'' are each independently selected from hydrogen, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted C1-4 alkenyl, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted C1-4 cycloalkyl or substituted or unsubstituted 4-10 membered heterocyclyl; 2 6 When substituents are present in alkenyl, C16-4-diene, C16-6-cycloalkyl and 4-10 membered heterocyclic groups, they can be independently substituted by one or more of the following substituents: halogen, hydroxyl, hydroxyl, oxo, C16-4-alkyl, C16-4-diene, C16-6-cycloalkyl, C16-6-cycloalkyl. R\R\R\ are each independently selected from hydrogen, halogen, oxy, hydroxy, amino, alkyl, C-6 alkyl, halogenated C-6 alkyl, C-6 alkenyl, C-6 alkyl, Halogenated C1-6 alkoxy, C1-6 alkylthio or C1-6 alkylamino; X and Y are each independently selected from N or CR% Hwanyl, substituted or unsubstituted 3.6 cycloalkyl, substituted or unsubstituted L-aryl, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted 5-14 membered heteroaryl, -OR 3 \-SR 3 \ -SO2-R 3 \ -NR 3n R 3 . 、 -NH-R 3 \ -NHCO-R 3a , -C(O)NH-R 3 \ -C(O)-R 3 \ -NHSO2-R 3a or (0)21: When the alkyl, alkenyl, C1-6-alkyl, C2-4-alkyl, C3-6-aryl, C4-6-membered heterocyclic group and 5-14-membered heteroaryl have substituents, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, oxo, hydroxyl, amino, 9-hydroxy, oxo, C1-6-alkyl, halogenated C1-6-alkyl, C1-6-alkenyl, C1-6-heptyl, C1-6-cycloalkyl, C1-2-aryl, 4-3-membered heterocyclic group, 5-14-membered heteroaryl, -OR 3 \ -SR 3 \ -SO2-R 3 \ -NH-R 3 \ -NHCO-R 3 \ -NHSO,-R 3 \ When a cycloalkyl 4-10 membered heterocyclic group has a substituent, it may be independently substituted or polysubstituted by one or more of the following substituents: halogen, halogen, hydroxyl, amino, mercapto, oxo, C16-alkyl, C16-alkenyl, C12-alkyl, C14-cycloalkyl, C16-alkoxy, C16-alkylthio, C16-alkylamino or C12-alkylamino; R\ R 5 Each is independently selected from hydrogen, halogen, oxy, hydroxy, amino, substituted or unsubstituted. C 2.6 The alkyl and C1-6-cycloalkyl groups may be independently substituted or polysubstituted by one or more of the following substituents: halogen, hydrazine, hydroxyl, amino, thiocyanate, oxo, C1-6-alkyl, C1-6-alkenyl, alkynyl, C1-6-cycloalkyl, C1-6-hydroxyl, C1-6-alkylthio, C1-6-alkylthio or C1-6-amino; or they may be connected to each other with R' and form a 3-8 membered saturated or unsaturated aliphatic ring or heterocyclic ring together with the C atoms on the ring: Claims R6 is selected from substituted or unsubstituted C2-alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted C2-M2-alkyl or substituted or unsubstituted One or more may be substituted or polysubstituted: halogen, alkyl, C & alkyl, C 2.6 B group, C* phenyl group or Ms cycloalkyl group; the heterocyclic ring, heteroaryl group, heterocyclic group contains at least one heteroatom, and the heteroatom is selected from one or more of N, S, and O.

2. The aromatic heterocyclic pyrrolidone derivative according to claim 1, characterized in that: The compound or its pharmaceutically acceptable salt represented by the general structural formula: Ring A is selected from a 5- to 16-membered aromatic ring or heteroaromatic ring, and contains at least one substituent R 2 ; R [Selected from I\R l a R ib OR 13 ; R ia , R'b are each independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C1-6 alkynyl, substituted or unsubstituted C1-6 cycloalkyl or substituted or unsubstituted 4-10 membered heterocyclyl; when R; a . R ib wherein the C16 alkyl, C M Alkenyl, C 2.6 When the 4-10 membered heterocyclic group has a substituent, it can be independently substituted or polysubstituted by one or more of the following substituents: carnitine, hydroxyl, hydroxyl, thiophene, oxo, C6 alkyl, C7 alkenyl, C8 alkenyl, C9 alkenyl, C12 alkenyl, C16 cycloalkyl, C12 alkoxy, C16 alkoxy ...2 alkoxy, C12 alkoxy, C12 alkoxy, C12 alkoxy, For example, R and R' are connected to each other and together with the N atom form a 3-8 membered saturated or unsaturated heterocyclic ring; R, R' are each independently selected from hydrogen, halogen, oxy, hydroxy, amino, alkyl, C_6 alkyl, halogenated C_6 alkyl (benzene, C_6 alkyl, C_3-6 cycloalkyl, C_6 alkoxy, halogenated C_6 alkoxy, C_6 alkylthio or C_6 alkylamino; and R and Y are each independently selected from N or CR 2a - or -P(O)R iB R :b ; When R, C alkyl, C 2 6 B base, C 2 6 ^ Base, (, Beijing When there are substituents in the heteroaryl group, they can be independently substituted by one or more of the following substituents: halogen, nitrogen, C4-6 alkyl, C6-6 alkyl, C3-6 cycloalkyl, C4-6 alkyl, C6 ... alkyliodo, G<alkylthio or G<alkylamino; or Claims R? and R? are connected to each other and together with the C atoms on the ring to form a 3-8 membered saturated or unsaturated aliphatic ring or heterocyclic ring: R6 is selected from substituted or unsubstituted C1_4 alkyl, substituted or unsubstituted C1_6 alkenyl, substituted or unsubstituted C1_7 alkenyl or substituted or unsubstituted C1_8 alkenyl. It is mono- or poly-substituted by one or more of the following substituents: halogen, oxo, C1-6 alkyl, C2-6 alkenyl, C1-6 alkyl or C2-6 cycloalkyl: the heterocyclic ring, heteroaryl. The heterocyclic group contains at least one heteroatom, and the heteroatom is selected from one or more of N, S.O.

3. The aromatic heterocyclic pyrrolidone derivative according to claim 1, characterized in that: The compound represented by the general structural formula (I) or a pharmaceutically acceptable salt thereof: In the formula, ring A is selected from a 5-16-membered aromatic ring or heteroaromatic ring, and ring A contains at least one substituent R 2 ; R' is selected from NR^R'b or OR 13 : When there are substituents on alkenyl, C1-6-alkynyl, C2-6-cycloalkyl and 4-10-membered heterocyclic groups, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, alkyl, hydroxyl, nitrogen, C",'alkynyl' C:"*cycloalkyl, Cm alkoxy, halogenated Cm hydroxyl, Cm alkylthio or G-alkylamino; X and Y are each independently selected from N or CR 2a ; R\ R 5 Each independently selected from hydrogen, halogen, hydroxyl, nitrogen, substituted or unsubstituted alkyl, substituted or unsubstituted (When the C3-6 alkynyl and C4-6 cycloalkyl groups have substituents, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, hydroxyl, hydroxyl, amino, hydroxyl, oxo, C6-alkyl, C7-6 alkenyl, C8-alkynyl, C12-cycloalkyl, C16-alkoxy, C18-alkynyl, C12-alkynyl, C12-cycloalkyl, C18-alkoxy, C18-alkynyl ... It is monosubstituted or polysubstituted by one or more of the following substituents: halogen, nitrogen group, CL alkyl, C 2.6 B group, C16-6 alkyl group or C16-6 cycloalkyl group; R 3 Select from -OR & or -NR 3a R 3C ; wherein, when R3 is selected from -O-, 20 is selected from substituted or unsubstituted 4-membered heterocyclic group; wherein the 4-10-membered heterocyclic group is present Claims when R3 is selected from C 60 -C 64 -R 3., R 3 \ R ,C Each is independently selected from substituted or unsubstituted C1-6 alkyl, halogenated C1-6 alkyl, substituted or When there are substituents in the C6-alkyl, C7-cycloalkyl and C4-10-membered ring groups, they can be independently substituted or polysubstituted by one or more of the following substituents: hematoxylin, oxyl, hydroxyl, oxyl, mercapto, oxo, C6-hydroxyl, C1-alkenyl, C2-6-hydroxyl, C16-cycloalkyl, C2-alkoxy, C3-alkylthio, C1-alkylthio or C16-alkylamino; the heterocyclic ring, heteroaryl and heterocyclic group contain at least one heteroatom, and the heteroatom is selected from one or more of N, S and C.

4. The aromatic heterocyclic pyrrolidone derivative according to any one of claims 1 to 3, characterized in that: In the general structural formula (I), ring A is selected from 2-hydroxy-1, 2-hydroxy-1, 2-hydroxy-2, 2-hydroxy-1 or 2-hydroxy-1.

5. The aromatic heterocyclic polyols according to claim 4, characterized in that: It is a compound represented by the general structural formula I or a pharmaceutically acceptable salt thereof: Alkenyl, C 2 6 When there are substituents in the alkynyl, (C1-6-cycloalkyl) and 4-10 membered heterocyclic groups, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, fluoro, hydroxy, nitrogen, carbonyl, oxo, C1-6-alkyl, C2-6-alkenyl, (C1-6-cycloalkyl), C2-6-cycloalkyl, C3-6-cycloalkyl, C4-6-cycloalkyl, C5-6-cycloalkyl, C6-6-cycloalkyl, C7-6-cycloalkyl, C8-6-cycloalkyl, C9-6-cycloalkyl, C1 ...2-6-cycloalkyl, C3-6-cycloalkyl, C5-6-cycloalkyl, C8-6-cycloalkyl, C9-6-cycloalkyl, C1-6-cycloalkyl, C alkyl, substituted or unsubstituted C3.8 cycloalkyl, substituted or unsubstituted C4.8 aryl, substituted or unsubstituted K4-10 membered: heterocyclic group, substituted or unsubstituted 5-14 membered heteroaryl, -eR%, -SR 3 \ -SO2-R; , \ -NH-R 3 \ -NHCO-R 3,1 , -C(O)NH-R 3 \ -C(O)-R 3,1 .-NHSO2-R 3a or -P((J)R"RE; when R° is Gy alkyl, Cz-ij is alkynyl, Cz-ij is 3-cycloalkyl, Ce-i2 J When there are substituents for the alkyl, 4-10 membered heterocyclic group and 5-14 membered heteroaryl group, they may be substituted independently by one or more of the following substituents: halogen, alkyl, hydroxyl, amino, alkyl, oxo, alkyl, C1-6 alkyl, C2-6 cycloalkyl, C6-7 alkyl, 4-10 membered heterocyclic group, 5-14 membered heteroaryl, -OR 3b , -S NHCO-R 3b , -NHSO2-R 3b > -C((:))NH-R 3b or -C:(O)-R 3h ; R" and R" are each independently selected from hydrogen, C1-6 alkyl, halogenated C1-5 alkyl, C2-6 cycloalkyl, C1-6 alkoxy or halogenated C1-6 alkoxy; Claim 1__ The mineral paste is hydrogen or is selected from a C16 alkyl group substituted by a C12 cycloalkyl group; the heterocycle, heteroaryl group, and heterocyclic group contain at least one heteroatom, and the heteroatom is selected from one or more of N, S, and O.

6. The aromatic heterocyclic pyrrolidone derivative according to claim 4, characterized in that: It is a compound represented by the general structural formula I or a pharmaceutically acceptable salt thereof: In the formula, R' is selected from W l a R ib ; R ia , R ,b R'a. R* is independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 cycloalkyl or substituted or unsubstituted 4-membered heterocyclic group; when R'a. R* is C1-6 alkyl, C2-6 alkenyl, C 2.fi When a C34-alkyl group, a C34-alkyl group, and a 4-membered heterocyclic group have substituents, they can be replaced by one or more of the following substituents independently: R2 is selected from hydrogen, halogen or Ci% alkyl; R*, R? are selected from hydrogen or C1-6 alkyl; Electrolyte C1-alkyl; R 3 Select from -OR 3 ' 1 or -NR& R% wherein, when R& is selected from -OR&, R& is selected from a substituted or unsubstituted 4-10 membered heterocyclic group; further, when the 4-10 membered heterocyclic group in R& has a substituent, each of them may be independently substituted or polysubstituted by one or more of the following substituents: halogen, hydrazine, hydroxyl, nitrogen group, Alkylamino; When R3 is selected from -NR 3a When R*, R%, R* are independently selected from substituted or unsubstituted C-5 alkyl, halogenated C-5 alkyl, substituted or unsubstituted C-5 cycloalkyl, C-5 alkoxy, halogenated alkoxy or substituted or unsubstituted 4-10 membered heterocyclic group; further when R*, R 3C When the C1-6 alkyl, C1-6 cycloalkyl, and 4-10 membered heterocyclic group have substituents, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, oxy, hydroxy, amino, mercapto, oxo, C1-6 alkyl, C1-6 alkenyl, C1-6 cycloalkyl ... The heterocycle, heteroaryl, and heterocyclic group contain at least one heteroatom, and the heteroatom is selected from one or more of N, S, and O.

7. The aromatic heterocyclic pyrrolidone derivative according to claim 4, characterized in that: It is a compound represented by the general structural formula II or a pharmaceutically acceptable salt thereof: Claims R', R'-4'-alkyl, R'-5'-alkyl, R'-6'-alkyl, R'-7'-alkyl, R'-8'-alkyl, R'-9'-alkyl, R'-10'-alkyl, R'-11'-alkyl, R'-12'-alkyl, R'-13'-alkyl, R'-14'-alkyl, R'-15'-alkyl, R'-16'-alkyl, R'-17'-alkyl, R'-18'-alkyl, R'-19'-alkyl, R'-20'-alkyl, R'-21'-alkyl, R'-22'-alkyl, R'-23'-alkyl, R'-24'-alkyl, R'-25'-alkyl, R'-26'-alkyl, R'-30'-alkyl, R'-31'-alkyl, R'-32'-alkyl, R'-33'-alkyl, R'-34'-alkyl, R'-35' R 2 is selected from hydrogen, halogen or Cm-alkyl; R3 is selected from hydrogen, halogen, alkyl, substituted or unsubstituted C2-6 alkyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C4-10 membered heterocyclyl, substituted or or -cro)-R 3b : The heterocycle, heteroaryl, or heterocyclic radical contains at least one heteroatom selected from one or more of N, S, and O.

8. The aromatic heterocyclic pyrrolidone derivative according to claim 4, characterized in that: It is a compound represented by the general structural formula II or a pharmaceutically acceptable salt thereof: The claims include: the at least one alkyl group is substituted with one or more of the following: alkyl, alkyl, hydroxyl, alkyl, sulfhydryl, oxo, C6-6-alkenyl, C6-6-cycloalkyl, C6-6-cyclohexyl ... R¹ is selected from hydrogen, halogen, or C₁₋₆ alkyl; R"、R 5 Selected from hydrogen or C1<alkyl; R² is selected from C₁₋₆ alkyl substituted with C₃₋₆ cycloalkyl; R3 is selected from -OR 33 or -NR* 1 henry; wherein, when R* is selected from -0-R*, R* is selected from a substituted or unsubstituted 4-10 membered heterocyclic group; further, when the 4-10 membered heterocyclic group in R* has a substituent, each of them can be independently substituted or polysubstituted by one or more of the following substituents: halogen, oxy, hydroxyl, amino, unsubstituted C-6 cycloalkyl, C-1 alkoxy, halogenated C-1 alkoxy or substituted or unsubstituted 4-10 membered heterocyclic group; further when R 5 \ R 3C When the G1-6 alkyl, G2-cycloalkyl, or 4-10 membered heterocyclic group has a substituent, it may be independently substituted or polysubstituted by one or more of the following substituents: halogen, hydrazine, hydroxyl, isocyanate, oxo, G2-6 alkyl, C4-alkenyl, C5-alkyl, C6-cycloalkyl, C7-alkoxy, C8-alkyl, G2-6 alkylthio, or G6-alkylamino; the heterocyclic ring, heteroaryl, or heterocyclic group contains at least one heteroatom, and the heteroatom is selected from one or more of N, S, and O.

9. The aromatic heterocyclic pyrrolidone derivative according to claim 4, characterized in that: It is a compound represented by the general structural formula III or a pharmaceutically acceptable salt thereof: In the formula, X is selected from N or CR 2a : R' is selected from NR ,a R lb : R 1 % R?' are each independently selected from hydrogen, substituted or unsubstituted G-& alkyl, substituted or unsubstituted. 2-6 alkenyl, substituted or unsubstituted Gw; alkynyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted 4-10 membered heterocyclyl; when R, ! \ R" is a C alkyl group, C 2.6 When substituents are present in alkenyl, C1-6-yl, C2-6-cycloalkyl and 4-(4-)-membered heterocyclic groups, one or more of the substituents may be independently added to the substituents. alkynyl, substituted or unsubstituted C₃₋₆ cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted 4 - 10 - membered heterocyclic radical, substituted or Claims When the membered heteroaromatic group has substituents, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, nitrogen group, hydroxyl group, amino group, mercapto group, oxo group, C1-C12 alkyl group, halogenated C12 alkyl group, C13 alkenyl group, C14-C16 cycloalkyl group, C14-C16 aryl group, 4-1. membered heterocyclic group, 5-14 membered heteroaryl group, C14-C16 ... 3l \ -SR 3 \ -SO,-R 3 \ -NH-R 3 \ -NHCO-R 3 \ -NHS02-R 3b . -C(O)NH-R 3b or -C(O)-R 3b : R 3 \ R 3b Each is independently selected from hydrogen, C1-C1 alkyl, halogenated C1-C1 alkyl, C1-C1 cycloalkyl, C1-C1 alkoxy or halogenated C1-C1 alkoxy; R³ is selected from C₁₋₆ alkyl substituted with C₃₋₆ cycloalkyl; the heterocycle, heteroaryl, or heterocyclic radical contains at least one heteroatom selected from one or more of N, S, and O.

10. The aromatic heterocyclic pyrrolidine derivative according to claim 4, characterized in that: It is a compound represented by the general structural formula HI or a pharmaceutically acceptable salt thereof: When there are substituents, the alkenyl, C2 / heptyl, C6-cycloalkyl and 4-10 membered heterocyclic groups may be independently substituted or polysubstituted by one or more of the following substituents: halogen, C6-hydroxyl, amino, C6-base, oxo, C6-alkyl, C6-alkenyl, C6-cycloalkyl ... R⁴ and R⁵ are each independently selected from hydrogen or C₁₋₆ alkyl; R⁶ is selected from C₁₋₆ alkyl substituted with C₃₋₆ cycloalkyl; R 3 Select from -OR 3a or -NI* R 3C ; wherein, when R3 is -OR, R* is selected from a substituted or unsubstituted 4- to 10-membered heterocyclic group; further, when the 4- to 10-membered heterocyclic group described in the preceding paragraph has a substituent, each of the substituents may be independently substituted or polysubstituted by one or more of the following substituents: halogen, oxy, hydroxy, amino, S1-1, oxo, C2-6 alkyl, C3-6 alkenyl, C4-6 alkyl, C5-6 cycloalkyl, C1-6 alkoxy, C2-6 alkylthio, C2-6 alkylamino; when R 3 Select i-NR 3a When, R, R are each independently selected from substituted or unsubstituted alkyl, halogenated alkyl, substituted or When the C₁₋₆ alkyl, C₃₋₆ cycloalkyl, or 4 - 10 - membered heterocyclic radical has a substituent, it may each independently be substituted with one or more of the following substituents halogen, nitro, cyano, amino, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylamino; the heterocycle, heteroaryl, or heterocyclic radical contains at least one heteroatom selected from one or more of N, S, and O.

11. The aromatic cyclophilic pyrrolidone derivative according to claim 4, characterized in that: The compound or its pharmaceutically acceptable salt is represented by the general structural formula: alkynyl, C₁₋₆ alkylthio, C₁₋₆ alkylamino, 4 - 10 - membered heterocyclic radical, 5 - 14 - membered heteroaryl, or aryl; R 2 , R 2 ] are each independently selected from hydrogen, halogen or C 6-alkyl; ] are each independently selected from hydrogen, halogen, cyclopentyl, substituted or unsubstituted C 6-alkyl, substituted or unsubstituted C 6-alkyl 2.6 t group, substituted or unsubstituted C?,6 or -P(O)R ia R, b ; When R" is J; alkyl, C CM alkenyl, C 2 6 When a C1-6-alkyl, ... R⁶ is selected from C₁₋₆ alkyl substituted with C₃₋₆ cycloalkyl; the heterocycle, heteroaryl, or heterocyclic radical contains at least one heteroatom selected from one or more of N, S, and O.

12. The aromatic heterocyclic pyrrole:alkanone derivative according to claim 4, characterized in that: is a compound of the general structural formula W or a pharmaceutically acceptable salt thereof: 73 Claims In the formula, X is selected from N or CR 2a : wherein is selected from OR"; silicon is selected from hydrogen, substituted or unsubstituted C 1 -alkyl Wood substituted C 3 6 Cycloalkyl or substituted or unsubstituted 4-10 membered heterocyclic group; When R'a is described in C; e When alkyl, alkenyl, 2-6-alkynyl, 3-6-cycloalkyl and 4-3 membered heterocyclic groups have substituents, they may be independently substituted or polysubstituted by one or more of the following substituents: Alkyl, CH alkylthio, C ; 6 Alkylamino, 4-1. membered heterocyclic group, 5-14 membered heteroaryl or C&12 aryl; R\R are each independently selected from hydrogen, halogen or G-<, alkyl; R⁷ is selected from C₁₋₆ alkyl substituted with C₃₋₆ cycloalkyl; R 3 is selected from -OR* or -N-RE R3. Wherein, when R? is selected from -. -1, R 3 ® is selected from substituted or unsubstituted 4-10 membered heterocyclic groups: Further, when the 4-10 membered heterocyclic group in R& has substituents, they can be independently substituted or polysubstituted by one or more of the following substituents: halogen, nitrogen, hydroxyl, amino, the heterocycle, heteroaryl, or heterocyclic radical contains at least one heteroatom selected from one or more of N, S, and O.

13. The aromatic heterocyclic pyrrolidone derivative according to claim II or 12, characterized in that: It is a compound represented by the general structural formula N-1 or a pharmaceutically acceptable salt thereof: In the formula, R is selected from substituted or unsubstituted C® alkyl or -OR 3a When the G* alkyl group in R3 has a substituent, it can be independently substituted by one or more of the following substituents: halogen, alkyl, hydroxyl, amino, alkyl, oxo, C / C alkyl, halogenated Claims 8 - dichloro, 6 - dichloro, "two - something", "1; '- '3 - something EM1TEZ; ; side - something", "element - free forest - set - something MTT - element", "table - side - something: two - something?'叮 3:1? house -SO2-R 3b , -NH-R 3 \ -NHCO-R 3b , -NHSO2-R 3b , -C(O)NH-R 3b jS-C(O)-R 3b ; R 3 R is independently selected from hydrogen, C1-6 alkyl, C2-6 halogenated C1-6 alkyl, C2-6 cycloalkyl, C3-6 alkoxy, C4-6 halogenated C6-6 alkoxy or 4 - 10 - membered heterocyclic radical; the heteroaryl or heterocyclic radical contains at least one heteroatom selected from one or more of N, S, and O.

14. ® The aromatic heterocyclic pyrrolidone derivative according to claim 7 or 8, A compound or a pharmaceutically acceptable salt thereof: When the 4-10 membered heterocyclic group has substituents, they may be independently substituted by one or more of the following substituents: halogen, nitrogen group, hydroxyl group, nitrogen group, or a 4-1 membered heterocyclic group; 15. The aromatic heterocyclic pyrrolidone derivative according to any one of claims 1 to 14, The invention is characterized in that D is selected from the following characteristic compounds or their isomers or pharmaceutically acceptable salts: Claims 76 Claims Claims 15. A pharmaceutical composition comprising at least one active ingredient as described in any one of claims 1 - 14 and at least one pharmaceutically acceptable carrier or excipient.

16. Use of a compound as described in any one of claims 1 - 14 or the pharmaceutical composition as described in claim 15 for the prevention or treatment of diseases related to the PDK1 signaling pathway. 1" The use according to claim 16, characterized in that The diseases include but are not limited to: 1) chronic inflammatory diseases, such as gout, nephritis, atherosclerosis, non-alcoholic fatty hepatitis, hepatitis, diabetes, enteritis, etc.; 2) acute inflammatory diseases, such as traumatic brain injury, wounds, toothache, acute nephritis, viral infection, sepsis, burns, septic shock; 3) cardiovascular diseases, such as myocardial ischemia, heart failure, etc.; 4) nervous system diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, meningitis, headache, neuropathic pain, etc.; 5) autoimmune diseases, such as atopic dermatitis, rheumatoid arthritis, systemic analgesia; 6) respiratory diseases, such as COPD, asthma, pneumonia, tuberculosis, etc.; 7) metabolic syndrome, such as obesity, hyperglycemia, hyperlipidemia, local uric acid, 8) Digestive system, such as viral hepatitis, liver cirrhosis, liver fibrosis, enteritis, etc.; 9) Tumors, tumor metastasis, tumor complications, etc.

18. The use according to claim 0, characterized in that The disease is selected from atopic dermatitis.