A synthetic method of N-heterocyclic BET bromodomain inhibitor and its intermediates

Abstract

The present application provides compound III, compound IV and compound VI and their use in preparing an N-heterocyclic BET bromodomain inhibitor (compound VII). The starting materials for the reaction are simple and easy to purchase, the cost is low, the reaction conditions for each step are mild, the operation is simple, the yield is high, and it is conducive to industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemical synthesis, and specifically relates to compound III, compound IV and compound VI and use thereof in preparing an N-heterocyclic BET bromodomain inhibitor (compound VII). Background Art

[0002] Histone acetylation is an important part of epigenetic research. Acetylated histones can activate gene transcription through the action of DNA polymerase, RNA polymerase and transcription factors. The bromodomain and extra-terminal domain (BET) family belongs to the bromodomain protein family (BRDs), which is a class of evolutionarily highly conserved proteins that can recognize and bind to acetylated lysine residues in the tail of histones, recruit chromatin regulatory proteins, transcription factors, chromatin remodeling factors, etc., and thus play an important role in regulating gene transcription and chromatin remodeling. It is related to various biological processes such as cell growth, proliferation and differentiation, apoptosis and necrosis, and is an important epigenetic "reader".

[0003] So far, it has been found that the human genome encodes a total of 61 bromodomains, which are distributed in 46 different proteins. The BRDs family consists of four subtypes: BRD2, BRD3, BRD4, and BRDT, all of which contain two tandem bromodomains (BD1, BD2) and an extra-terminal (ET) domain. The two bromodomains are mainly responsible for recognizing and binding to acetylated lysine residues, while the ET domain interacts with auxiliary factors. Abnormal expression of BET proteins is associated with a variety of diseases. Although the four members of the BET family have similar structures, their biological functions are still different, especially BRD4 is closely related to a variety of diseases such as cancer and inflammation (Jung M et al., Epigenomics, 2015, 7(3): 487-501.).

[0004] Targeting BET proteins is beneficial for developing new therapeutic strategies targeting cancer, inflammation and viruses. Currently, small molecule inhibitors targeting BET proteins have entered the preclinical and clinical research stages, which are mainly used in the treatment of cancer and autoimmune diseases.

[0005] In summary, BET protein inhibitors have great application prospects as drug research and development. The applicant Chengdu Yuandong Biopharmaceutical Co., Ltd. has developed an epigenetic-related bromo-binding domain protein BRD4 inhibitor, whose chemical name is: N-ethyl-4-(5-(2-hydroxypropyl-2-yl)-3-(indolyl-1-yl)thiophene-2-yl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide, and its structural formula is shown in Formula VII. The applicant's prior patent PCT / CN2021 / 134454 (application date 2021.11.30, domestic application number 202180005165.6) reported that the compound has good BET protein inhibitory activity and good pharmacokinetic properties, and can also exhibit good in vivo anti-tumor activity and low risk of hERG cardiotoxicity. It is a new generation of high-efficiency and low-toxic BET protein inhibitors.

[0006]

[0007] Therefore, it is of great practical significance to develop a preparation method for the compound of formula VII that has a simple process, low production cost, low environmental pollution, and is suitable for industrial production. Summary of the invention

[0008] The first object of the present invention is to provide a compound III having the following structure:

[0009]

[0010] Wherein, R is selected from C1-C6 alkyl;

[0011] Preferably, R is selected from C1-C4 alkyl;

[0012] Further preferably, R is selected from methyl or ethyl;

[0013] More preferably, R is selected from methyl.

[0014] The second object of the present invention is to provide a compound IV having the following structure:

[0015]

[0016] Wherein, R is selected from C1-C6 alkyl;

[0017] Preferably, R is selected from C1-C4 alkyl;

[0018] Further preferably, R is selected from methyl or ethyl;

[0019] More preferably, R is selected from methyl.

[0020] The third object of the present invention is to provide a compound VI having the following structure:

[0021]

[0022] Wherein, R is selected from C1-C6 alkyl;

[0023] Preferably, R is selected from C1-C4 alkyl;

[0024] Further preferably, R is selected from methyl or ethyl;

[0025] More preferably, R is selected from methyl.

[0026] The fourth object of the present invention is to provide a method for preparing compound VII, which comprises the following steps: reacting compound VI with a methyl metal reagent in a solvent D to prepare compound VII

[0027]

[0028] Wherein, the methyl metal reagent is selected from methyl lithium, methyl magnesium bromide, methyl magnesium chloride, methyl magnesium iodide, methyl zinc or methyl aluminum, preferably methyl lithium or methyl magnesium bromide;

[0029] Wherein, the molar ratio of compound VI to methyl metal reagent is 1:4.0-4.5;

[0030] Wherein, solvent D is selected from tetrahydrofuran and 2-methyltetrahydrofuran, preferably tetrahydrofuran;

[0031] The reaction temperature is 0 to 30°C, preferably 10 to 20°C.

[0032] In some specific embodiments, the method for preparing compound VII of the present invention comprises the following steps:

[0033] (1) Compound IV reacts with compound V in the presence of catalyst B, base 2 and solvent C to prepare compound VI

[0034]

[0035] In some specific embodiments, the reaction further includes a ligand of catalyst B, wherein the ligand of catalyst B is selected from X-Phos, S-Phos, AsPh3, n-Bu3P, (MeO)3P, PPh3, and bidentate ligand Ph2P(CH2)2PPh2(dppe) or Ph2P(CH2)3PPh2(dppp), preferably PPh3, AsPh3 or bidentate ligand Ph2P(CH2)2PPh2(dppe), Ph2P(CH2)3PPh2(dppp), more preferably PPh3;

[0036] Wherein, the molar ratio of catalyst B to catalyst B ligand is 1:1.0-4.0, preferably 1:1.0-1.5;

[0037] Wherein, the molar ratio of compound IV to compound V is 1.0:0.9-1.2, preferably 1.0:1.0;

[0038] Wherein, the catalyst B is selected from the palladium catalyst tetrakis(triphenylphosphine)palladium, palladium acetate, bis(triphenylphosphine)palladium dichloride or 1,1-bis(diphenylphosphine)diferronickel dichloride, preferably tetrakis(triphenylphosphine)palladium, palladium acetate, and more preferably tetrakis(triphenylphosphine)palladium;

[0039] Wherein, the molar ratio of compound IV to catalyst B is 1:0.05-0.3, preferably 1:0.05-0.10;

[0040] Wherein, base 2 is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, preferably potassium carbonate;

[0041] Wherein, the molar ratio of compound IV to base 2 is 1:2.0-3.5;

[0042] Wherein, the reaction solvent C is a mixed solvent composed of an organic solvent and water, and the organic solvent is selected from 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone, preferably 1,4-dioxane and N,N-dimethylacetamide, and more preferably 1,4-dioxane;

[0043] Wherein, the mass ratio of organic solvent to water in the mixed solvent is 1:0.05-0.20;

[0044] Wherein, the reaction temperature is 60-120°C, preferably 80-120°C, more preferably 80-90°C;

[0045] (2) Compound VI reacts with a methyl metal reagent in solvent D to prepare compound VII

[0046]

[0047] Wherein, the methyl metal reagent is selected from methyl lithium, methyl magnesium bromide, methyl magnesium chloride, methyl magnesium iodide, methyl zinc or methyl aluminum, preferably methyl lithium or methyl magnesium bromide;

[0048] Wherein, the molar ratio of compound VI to methyl metal reagent is 1:4.0-4.5;

[0049] Wherein, solvent D is selected from tetrahydrofuran and 2-methyltetrahydrofuran, preferably tetrahydrofuran;

[0050] The reaction temperature is 0 to 30°C, preferably 10 to 20°C.

[0051] In some specific embodiments, the method for preparing compound VII of the present invention comprises the following steps:

[0052] (1) Compound III reacts with a brominating agent in solvent B to prepare compound IV

[0053]

[0054] Wherein, the bromination reagent is selected from bromine, NBS, tribromopyridine or dibromohydantoin, preferably NBS or dibromohydantoin, more preferably NBS;

[0055] Wherein, the molar ratio of compound III to the brominating agent is 1.0:0.9-1.2, preferably 1.0:1.0;

[0056] Wherein, solvent B is an organic solvent, and the organic solvent is selected from acetonitrile, ethyl acetate, acetone, N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone, preferably acetonitrile and acetone, and more preferably acetonitrile;

[0057] Wherein, the reaction temperature is -10 to 30°C, preferably 0 to 20°C, more preferably 0 to 10°C;

[0058] (2) Compound IV reacts with compound V in the presence of catalyst B, base 2 and solvent C to prepare compound VI

[0059]

[0060] In some specific embodiments, the reaction further includes a ligand of catalyst B, wherein the ligand of catalyst B is selected from X-Phos, S-Phos, AsPh3, n-Bu3P, (MeO)3P, PPh3, and bidentate ligand Ph2P(CH2)2PPh2(dppe) or Ph2P(CH2)3PPh2(dppp), preferably PPh3, AsPh3 or bidentate ligand Ph2P(CH2)2PPh2(dppe), Ph2P(CH2)3PPh2(dppp), more preferably PPh3;

[0061] Wherein, the molar ratio of catalyst B to catalyst B ligand is 1:1.0-4.0, preferably 1:1.0-1.5;

[0062] Wherein, the molar ratio of compound IV to compound V is 1.0:0.9-1.2, preferably 1.0:1.0;

[0063] Wherein, the catalyst B is selected from the palladium catalyst tetrakis(triphenylphosphine)palladium, palladium acetate, bis(triphenylphosphine)palladium dichloride or 1,1-bis(diphenylphosphine)diferronickel dichloride, preferably tetrakis(triphenylphosphine)palladium, palladium acetate, and more preferably tetrakis(triphenylphosphine)palladium;

[0064] Wherein, the molar ratio of compound IV to catalyst B is 1:0.05-0.3, preferably 1:0.05-0.10;

[0065] Wherein, base 2 is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, preferably potassium carbonate;

[0066] Wherein, the molar ratio of compound IV to base 2 is 1:2.0-3.5;

[0067] Wherein, the reaction solvent C is a mixed solvent composed of an organic solvent and water, and the organic solvent is selected from 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone, preferably 1,4-dioxane and N,N-dimethylacetamide, and more preferably 1,4-dioxane;

[0068] Wherein, the mass ratio of organic solvent to water in the mixed solvent is 1:0.05-0.20;

[0069] Wherein, the reaction temperature is 60-120°C, preferably 80-120°C, more preferably 80-90°C;

[0070] (3) Compound VI reacts with a methyl metal reagent in solvent D to prepare compound VII

[0071]

[0072] Wherein, the methyl metal reagent is selected from methyl lithium, methyl magnesium bromide, methyl magnesium chloride, methyl magnesium iodide, methyl zinc or methyl aluminum, preferably methyl lithium or methyl magnesium bromide;

[0073] Wherein, the molar ratio of compound VI to methyl metal reagent is 1:4.0-4.5;

[0074] Wherein, solvent D is selected from tetrahydrofuran and 2-methyltetrahydrofuran, preferably tetrahydrofuran;

[0075] The reaction temperature is 0 to 30°C, preferably 10 to 20°C.

[0076] In some specific embodiments, the method for preparing compound VII of the present invention comprises the following steps:

[0077] (1) Compound I reacts with Compound II under the action of Catalyst A, Base 1 and Solvent A to prepare Compound III

[0078]

[0079] X is Cl, Br or I;

[0080] In some specific embodiments, the reaction further includes a ligand of catalyst A;

[0081] Wherein, the ligand of catalyst A is selected from P(o-tolyl)3, P(t-Bu)3, CyPF-t-Bu, JosiPhos, Binap, XantPhos, DPPF, Brett-Phos, Ru-Phos, X-Phos, S-Phos, Bippy-Phos, preferably JosiPhos, XantPhos, Brett-Phos, Ru-Phos, X-Phos, S-Phos, Bippy-Phos or Binap; more preferably S-Phos or Binap;

[0082] Wherein, the molar ratio of compound I to compound II is 1:1.0 to 2.0, preferably 1:1.2;

[0083] Wherein, the catalyst A is selected from one of tetrakis(triphenylphosphine)palladium, tris(bisbenzylideneacetone)dipalladium, palladium acetate and 1,1-bis(diphenylphosphine)diferropalladium dichloride, preferably tris(bisbenzylideneacetone)dipalladium, palladium acetate, and more preferably tris(bisbenzylideneacetone)dipalladium;

[0084] Wherein, the molar ratio of compound I to catalyst A is 1:0.025-0.05;

[0085] Wherein, the molar ratio of catalyst A to catalyst A ligand is 1:1.0-1.5;

[0086] Wherein, base 1 is selected from potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, potassium phosphate, potassium hydroxide, sodium hydroxide, preferably potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, potassium phosphate, more preferably sodium tert-butoxide, cesium carbonate;

[0087] Wherein, the molar ratio of compound I to base 1 is 1:2.0 to 3.5, preferably 1:2.0;

[0088] Wherein, the reaction solvent A is an organic solvent, and the organic solvent is selected from toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran or 1,4-dioxane, preferably toluene, xylene, tetrahydrofuran or 2-methyltetrahydrofuran, more preferably toluene or tetrahydrofuran;

[0089] Wherein, the reaction temperature is 60-120°C, preferably 60-80°C, more preferably 60-75°C;

[0090] (2) Compound III reacts with a brominating agent in solvent B to prepare compound IV

[0091]

[0092] Wherein, the bromination reagent is selected from bromine, NBS, tribromopyridine or dibromohydantoin, preferably NBS or dibromohydantoin, more preferably NBS;

[0093] Wherein, the molar ratio of compound III to the brominating agent is 1.0:0.9-1.2, preferably 1.0:1.0;

[0094] Wherein, solvent B is an organic solvent, and the organic solvent is selected from acetonitrile, ethyl acetate, acetone, N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone, preferably acetonitrile and acetone, and more preferably acetonitrile;

[0095] Wherein, the reaction temperature is -10 to 30°C, preferably 0 to 20°C, more preferably 0 to 10°C;

[0096] (3) Compound IV reacts with compound V under the action of catalyst B, base 2 and solvent C to prepare compound VI

[0097]

[0098] In some specific embodiments, the reaction further includes a ligand of catalyst B, wherein the ligand of catalyst B is selected from X-Phos, S-Phos, AsPh3, n-Bu3P, (MeO)3P, PPh3, and bidentate ligand Ph2P(CH2)2PPh2(dppe) or Ph2P(CH2)3PPh2(dppp), preferably PPh3, AsPh3 or bidentate ligand Ph2P(CH2)2PPh2(dppe), Ph2P(CH2)3PPh2(dppp), more preferably PPh3;

[0099] Wherein, the molar ratio of catalyst B to catalyst B ligand is 1:1.0-4.0, preferably 1:1.0-1.5;

[0100] Wherein, the molar ratio of compound IV to compound V is 1.0:0.9-1.2, preferably 1.0:1.0;

[0101] Wherein, the catalyst B is selected from the palladium catalyst tetrakis(triphenylphosphine)palladium, palladium acetate, bis(triphenylphosphine)palladium dichloride or 1,1-bis(diphenylphosphine)diferronickel dichloride, preferably tetrakis(triphenylphosphine)palladium, palladium acetate, and more preferably tetrakis(triphenylphosphine)palladium;

[0102] Wherein, the molar ratio of compound IV to catalyst B is 1:0.05-0.3, preferably 1:0.05-0.10;

[0103] Wherein, base 2 is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, preferably potassium carbonate;

[0104] Wherein, the molar ratio of compound IV to base 2 is 1:2.0-3.5;

[0105] Wherein, the reaction solvent C is a mixed solvent composed of an organic solvent and water, and the organic solvent is selected from 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone, preferably 1,4-dioxane and N,N-dimethylacetamide, and more preferably 1,4-dioxane;

[0106] Wherein, the mass ratio of organic solvent to water in the mixed solvent is 1:0.05-0.20;

[0107] Wherein, the reaction temperature is 60-120°C, preferably 80-120°C, more preferably 80-90°C;

[0108] (4) Compound VI reacts with a methyl metal reagent in solvent D to prepare compound VII

[0109]

[0110] Wherein, the methyl metal reagent is selected from methyl lithium, methyl magnesium bromide, methyl magnesium chloride, methyl magnesium iodide, methyl zinc or methyl aluminum, preferably methyl lithium or methyl magnesium bromide;

[0111] Wherein, the molar ratio of compound VI to methyl metal reagent is 1:4.0-4.5;

[0112] Wherein, solvent D is selected from tetrahydrofuran and 2-methyltetrahydrofuran, preferably tetrahydrofuran;

[0113] The reaction temperature is 0 to 30°C, preferably 10 to 20°C.

[0114] In some specific embodiments, the method for preparing compound VII of the present invention comprises the following steps:

[0115]

[0116] (1) Compound I, Compound II, cesium carbonate, tris(bis(benzylideneacetone)dipalladium, and S-Phos are reacted in toluene at 75° C. to generate Compound III;

[0117] (2) Compound III reacts with NBS in acetonitrile at 0-10°C to generate compound IV;

[0118] (3) Compound IV and compound V undergo Suzuki reaction to obtain compound VI;

[0119] (4) Compound VI reacts with methyl lithium in tetrahydrofuran at 10-20°C to generate compound VII.

[0120] Beneficial effects achieved by the present invention:

[0121] The method of the invention adopts compound I (methyl 4-bromothiophene-2-carboxylate), compound II (indoline) and compound V (2-(ethylaminocarbonyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-boronic acid pinacol ester) as raw materials, and obtains the target compound VII through four steps of reaction. The starting raw materials of the invention are simple and easy to purchase, with low cost, mild reaction conditions in each step, simple operation, high yield, and no need to use column chromatography and freeze-drying technology. Meanwhile, the purity of the product obtained by the preparation method of the invention is greater than 99%, and the total yield is high, so it is conducive to realizing industrial production. DETAILED DESCRIPTION

[0122] The present invention is further described in detail below in conjunction with the embodiments, but the present invention is not limited thereto. Any equivalent substitutions in the art made according to the disclosure of the present invention shall fall within the protection scope of the present invention.

[0123] The structures of compounds were determined by mass spectrometry (MS) or nuclear magnetic resonance (NMR). 1 HNMR, 13 C NMR).

[0124] Nuclear magnetic resonance (NMR) 1 HNMR, 13 C NMR) shifts (δ) are given in parts per million (ppm); nuclear magnetic resonance ( 1 HNMR) was measured using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO) as the solvent and tetramethylsilane (TMS) as the internal standard. The chemical shift was calculated based on 10 -6 (ppm) is given as the unit.

[0125] Mass spectrometry (MS) was performed using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Therm, model: Finnigan LCQ advantage MAX).

[0126] Unless otherwise specified in the present invention, the solution mentioned in the reaction of the present invention is an aqueous solution.

[0127] The term "room temperature" in the present invention refers to a temperature between 10°C and 25°C.

[0128] In the present invention, unless otherwise specified, the term "Cm-Cn" used means that the part modified by the term has mn carbon atoms (n is greater than m, and both are integers). For example, C1-C6 means that the part modified by it has 1-6 carbon atoms, such as 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.

[0129] In the invention, unless otherwise specified, the term "alkyl" used refers to a saturated hydrocarbon group consisting only of carbon atoms and hydrogen atoms, including, but not limited to, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl and C1 alkyl. As non-limiting examples of alkyl, the following straight-chain or branched saturated hydrocarbon groups can be cited: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and its other seven isomers, n-hexyl and its other sixteen isomers. For example, C1-C7 alkyl includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and all isomers thereof.

[0130] The words "include", "comprising" and "containing" and their equivalents should be understood as an open, non-exclusive meaning, i.e., "including but not limited to", meaning that in addition to the listed elements, components and steps, other unspecified elements, components and steps may also be included.

[0131] Example 1 Preparation of Compound III 4-(indolin-1-yl)thiophene-2-carboxylic acid methyl ester

[0132]

[0133] At room temperature, add 1L of toluene, 100g of compound I, 64.5g of compound II, and 221.15g of cesium carbonate to the reaction bottle, replace with nitrogen, then add 9.25g of S-Phos and 10.35g of tris(bisbenzylideneacetone)dipalladium, replace with nitrogen again, and heat to 75°C for reaction for 20 hours. Cool to room temperature, add 1L of water, filter with suction, and separate the liquids. The organic phase is washed twice with 1.2L of 1M hydrochloric acid, then washed with saturated brine, separated, and the organic solvent is concentrated under reduced pressure. Add 400ml of methanol to the residue, stir at room temperature for 2 hours, and filter with suction to obtain the crude product of compound III. Purify by recrystallization with acetonitrile and dry to obtain 74.8g of pure compound III (HPLC purity 99.50%, yield 64%).

[0134] MS + [M+1]260.2.

[0135] 1H NMR (400MHz, DMSO-d6) δ7.77(d,J=1.9Hz,1H),7.31(d,J=1.9Hz,1H),7.16(dd,J=7.2,1.4Hz,1H),7.09(td,J=7.6,1 .4Hz,1H),7.05–6.97(m,1H),6.74(td,J=7.3,1.1Hz,1H),3.92(t,J=8.5Hz,2H),3.84(s,3H),3.09(t,J=8.5Hz,2H).

[0136] 13 C NMR (101MHz, DMSO-d6) δ161.80,146.10,142.88,131.42,130.51,127.29,125.26,124.95,119.05,110.93,110.89,107.73,52.30,51.98,27.35.

[0137] Example 2 Preparation of Compound III 4-(Indolin-1-yl)thiophene-2-carboxylic acid methyl ester

[0138] At room temperature, tetrahydrofuran 100mL, compound I10g, compound II 6.45g, cesium carbonate 22.12g were added to the reaction bottle, nitrogen replacement, then S-Phos 0.93g and tris (bisbenzylideneacetone) dipalladium 1.04g were added, nitrogen replacement was performed again, and the temperature was raised to 75°C for reaction for 20 hours. Cooled to room temperature, ethyl acetate 100mL and water 100mL were added, filtered, and separated. The organic phase was washed twice with 120mL 1M hydrochloric acid, then washed with saturated brine, separated, and the organic solvent was concentrated under reduced pressure. Methanol 40ml was added to the residue, stirred at room temperature for 2 hours, and filtered to obtain a crude product of compound III. Purified by recrystallization with acetonitrile and dried to obtain pure compound III 6.25g (HPLC purity 99.17%, yield 53.3%).

[0139] Example 3 Preparation of Compound III 4-(indolin-1-yl)thiophene-2-carboxylic acid methyl ester

[0140] At room temperature, 100 mL of toluene, 10 g of compound I, 10.78 g of compound II, and 22.12 g of cesium carbonate were added to the reaction bottle, replaced with nitrogen, and then 0.93 g of S-Phos and 1.04 g of tris(bisbenzylideneacetone)dipalladium were added, replaced with nitrogen again, and the temperature was raised to 75 ° C for reaction for 20 hours. Cool to room temperature, add 100 mL of water, filter with suction, and separate the liquids. The organic phase was washed twice with 120 mL of 1M hydrochloric acid, then washed with saturated brine, separated, and the organic solvent was concentrated under reduced pressure. 40 ml of methanol was added to the residue, stirred at room temperature for 2 hours, and filtered with suction to obtain a crude product of compound III. Purified by recrystallization with acetonitrile and dried to obtain 7.54 g of pure compound III (HPLC purity 99.68%, yield 64.3%).

[0141] Example 4 Preparation of Compound III 4-(Indolin-1-yl)thiophene-2-carboxylic acid methyl ester

[0142] At room temperature, tetrahydrofuran 100mL, compound I10g, compound II 6.45g, cesium carbonate 22.12g were added to the reaction bottle, nitrogen purged, and then Binap 1.42g and tris (bisbenzylideneacetone) dipalladium 1.04g were added, nitrogen purged again, and the temperature was raised to 75°C for reaction for 20 hours. Cooled to room temperature, ethyl acetate 100mL and water 100mL were added, filtered, and separated. The organic phase was washed twice with 120mL 1M hydrochloric acid, then washed with saturated brine, separated, and the organic solvent was concentrated under reduced pressure. Methanol 40ml was added to the residue, stirred at room temperature for 2 hours, and filtered to obtain a crude product of compound III. Purified by recrystallization with acetonitrile and dried to obtain pure compound III 4.32g (HPLC purity 99.36%, yield 36.9%).

[0143] Example 5 Preparation of Compound III 4-(indolin-1-yl)thiophene-2-carboxylic acid methyl ester

[0144] At room temperature, 100 mL of toluene, 10 g of compound I, 10.78 g of compound II, and 6.5 g of sodium tert-butoxide were added to the reaction flask, replaced with nitrogen, and then 0.93 g of S-Phos and 1.04 g of tris(bisbenzylideneacetone)dipalladium were added, replaced with nitrogen again, and the temperature was raised to 75 ° C for reaction for 20 hours. The temperature was lowered to room temperature, 100 mL of water was added, filtered, and separated. The organic phase was washed twice with 120 mL of 1M hydrochloric acid, then washed with saturated brine, separated, and the organic solvent was concentrated under reduced pressure. Column chromatography purification was performed to obtain 4.17 g of pure compound III (HPLC purity 98.57%, yield 35.6%).

[0145] Example 6 Preparation of Compound III 4-(indolin-1-yl)thiophene-2-carboxylic acid methyl ester

[0146] At room temperature, 100 mL of toluene, 10 g of compound I, 6.45 g of compound II, and 22.12 g of cesium carbonate were added to the reaction bottle, replaced with nitrogen, and then 1.85 g of S-Phos and 2.07 g of tris(bisbenzylideneacetone)dipalladium were added, replaced with nitrogen again, and the temperature was raised to 75 ° C for reaction for 14 hours. Cool to room temperature, add 100 mL of water, filter with suction, and separate the liquids. The organic phase was washed twice with 120 mL of 1M hydrochloric acid, then washed with saturated brine, separated, and the organic solvent was concentrated under reduced pressure. 40 ml of methanol was added to the residue, stirred at room temperature for 2 hours, and filtered with suction to obtain a crude product of compound III. Purified by recrystallization with acetonitrile and dried to obtain 7.31 g of pure compound III (HPLC purity 99.08%, yield 62.3%).

[0147] Example 7 Preparation of Compound III 4-(indolin-1-yl)thiophene-2-carboxylic acid methyl ester

[0148] At room temperature, 100 mL of toluene, 10 g of compound I, 6.45 g of compound II, and 38.70 g of cesium carbonate were added to the reaction bottle, replaced with nitrogen, and then 0.93 g of S-Phos and 1.04 g of tris(bisbenzylideneacetone)dipalladium were added, replaced with nitrogen again, and the temperature was raised to 75 ° C for reaction for 20 hours. Cool to room temperature, add 100 mL of water, filter with suction, and separate the liquids. The organic phase was washed twice with 120 mL of 1M hydrochloric acid, then washed with saturated brine, separated, and the organic solvent was concentrated under reduced pressure. 40 ml of methanol was added to the residue, stirred at room temperature for 2 hours, and filtered with suction to obtain a crude product of compound III. Purified by recrystallization with acetonitrile and dried to obtain 7.68 g of pure compound III (HPLC purity 99.34%, yield 65.4%).

[0149] Example 8 Preparation of Compound III 4-(indolin-1-yl)thiophene-2-carboxylic acid methyl ester

[0150] At room temperature, 100 mL of toluene, 10 g of compound I, 6.45 g of compound II, and 22.12 g of cesium carbonate were added to the reaction bottle, replaced with nitrogen, and then 0.93 g of S-Phos and 1.04 g of tris(bisbenzylideneacetone)dipalladium were added, replaced with nitrogen again, and the temperature was raised to 60 ° C for reaction for 41 hours. Cool to room temperature, add 100 mL of water, filter with suction, and separate the liquids. The organic phase was washed twice with 120 mL of 1M hydrochloric acid, then washed with saturated brine, separated, and the organic solvent was concentrated under reduced pressure. 40 ml of methanol was added to the residue, stirred at room temperature for 2 hours, and filtered with suction to obtain a crude product of compound III. Purified by recrystallization with acetonitrile and dried to obtain 5.83 g of pure compound III (HPLC purity 99.42%, yield 49.7%).

[0151] Example 9 Preparation of Compound III 4-(indolin-1-yl)thiophene-2-carboxylic acid methyl ester

[0152] At room temperature, 100 mL of toluene, 10 g of compound I, 6.45 g of compound II, and 22.12 g of cesium carbonate were added to the reaction bottle, replaced with nitrogen, and then 0.93 g of S-Phos and 1.04 g of tris(bisbenzylideneacetone)dipalladium were added, replaced with nitrogen again, and the temperature was raised to 120 ° C for reaction for 10 hours. Cool to room temperature, add 100 mL of water, filter with suction, and separate the liquids. The organic phase was washed twice with 120 mL of 1M hydrochloric acid, then washed with saturated brine, separated, and the organic solvent was concentrated under reduced pressure. 40 ml of methanol was added to the residue, stirred at room temperature for 2 hours, and filtered with suction to obtain a crude product of compound III. Purified by recrystallization with acetonitrile and dried to obtain 6.17 g of pure compound III (HPLC purity 98.93%, yield 52.6%).

[0153] Example 10 Preparation of Compound IV 4-(Indolin-1-yl)-5-bromothiophene-2-carboxylic acid methyl ester

[0154]

[0155] At room temperature, 675 ml of acetonitrile and 45 g of compound III were added to the reaction bottle, stirred, cooled to 5°C, and then a solution of 29.2 g of NBS dissolved in 450 ml of acetonitrile was added, and reacted at 5°C for 1 hour. The mixture was filtered, dried under reduced pressure at 30°C for 4 hours, and then recrystallized from acetonitrile to obtain 45.6 g of pure compound IV (HPLC purity 99.21%, yield 77.6%).

[0156] MS + [M+1]338.0 / 340.0.

[0157] 1 H NMR(400MHz, DMSO-d6)δ7.76(s,1H),7.17(dd,J=7.2,1.3Hz,1H),7.01(td,J=7.7,1.3Hz,1H),6.73 (t,J=7.5Hz,1H),6.37(d,J=7.8Hz,1H),3.87(t,J=8.4Hz,2H),3.82(s,3H),3.10(t,J=8.4Hz,2H).

[0158] 13 C NMR (101MHz, DMSO-d6) δ160.65,148.12,143.60,131.93,129.63,129.13,126.98,124.84,119.15,111.76,108.51,53.16,52.58,28.18.

[0159] Example 11 Preparation of Compound IV 4-(Indolin-1-yl)-5-bromothiophene-2-carboxylic acid methyl ester

[0160] At room temperature, 675 ml of acetonitrile and 45 g of compound III were added to a reaction bottle, stirred, cooled to 5°C, and then a solution of 49.6 g of dibromohydantoin dissolved in 450 ml of acetonitrile was added, and reacted at 5°C for 1 hour. The mixture was filtered, dried under reduced pressure at 30°C for 4 hours, and then recrystallized from acetonitrile to obtain 32.6 g of pure compound IV (HPLC purity 98.43%, yield 55.5%).

[0161] Example 12 Preparation of Compound IV 4-(Indolin-1-yl)-5-bromothiophene-2-carboxylic acid methyl ester

[0162] At room temperature, 675 ml of acetonitrile and 45 g of compound III were added to the reaction bottle, stirred, cooled to 5°C, and then 35.04 g of NBS dissolved in 450 ml of acetonitrile was added, and reacted at 5°C for 1 hour. Filtered, dried under reduced pressure at 30°C for 4 hours, and then recrystallized from acetonitrile to obtain 40.08 g of pure compound IV (HPLC purity 98.67%, yield 68.3%).

[0163] Example 13 Preparation of Compound IV 4-(Indolin-1-yl)-5-bromothiophene-2-carboxylic acid methyl ester

[0164] At room temperature, 675 ml of acetone and 45 g of compound III were added to the reaction bottle, stirred, cooled to 5°C, and then a solution of 29.2 g of NBS dissolved in 450 ml of acetone was added, and the mixture was reacted at 5°C for 1 hour. 100 ml of water was added, stirred for 30 min, filtered, dried at 30°C for 4 h, and then recrystallized from acetonitrile to obtain 43.9 g of pure compound IV (HPLC purity 99.17%, yield 74.8%).

[0165] Example 14 Preparation of Compound IV 4-(Indolin-1-yl)-5-bromothiophene-2-carboxylic acid methyl ester

[0166] At room temperature, 675 ml of acetonitrile and 45 g of compound III were added to a reaction bottle, stirred, cooled to 0°C, and then a solution of 29.2 g of NBS dissolved in 450 ml of acetonitrile was added, and reacted at 0°C for 1 hour. The mixture was filtered, dried under reduced pressure at 30°C for 4 hours, and then recrystallized from acetonitrile to obtain 44.6 g of pure compound IV (HPLC purity 99.59%, yield 76.0%).

[0167] Example 15 Preparation of Compound IV 4-(Indolin-1-yl)-5-bromothiophene-2-carboxylic acid methyl ester

[0168] At room temperature, 675 ml of acetonitrile and 45 g of compound III were added to the reaction bottle, stirred, cooled to 10°C, and then a solution of 29.2 g of NBS dissolved in 450 ml of acetonitrile was added, and reacted at 10°C for 1 hour. The mixture was filtered, dried under reduced pressure at 30°C for 4 hours, and then recrystallized from acetonitrile to obtain 46.1 g of pure compound IV (HPLC purity 98.86%, yield 78.5%).

[0169] Example 16 Preparation of Compound VI N-ethyl-4-[5-methoxycarbonyl-3-(indolyl-1-yl)thiophen-2-yl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

[0170]

[0171] At room temperature, 405 ml of 1,4-dioxane, 45 ml of water, 15.0 g of compound IV, 18.3 g of compound V, 18.3 g of potassium carbonate and 3.06 g of tetrakis(triphenylphosphine)palladium were added to the reaction bottle, replaced with nitrogen, and heated to 80°C for reaction for 8 hours. Cooled to room temperature, 300 ml of ethyl acetate and 300 ml of water were added to extract the liquid, and the aqueous phase was extracted once with 300 ml of ethyl acetate; the organic phases were combined, washed with saturated brine, and the organic solvent was concentrated under reduced pressure. 100 ml of methanol was added to the residue, and the temperature was raised to 65°C for slurrying for 1 hour, cooled to room temperature, filtered, and dried to obtain 17.32 g of compound VI (HPLC purity 99.36%, yield 82.0%). MS + [M+1]477.2.

[0172] 1 H NMR(400MHz,DMSO-d6)δ12.39(s,1H),8.38(t,J=5.4Hz,1H),7.90(s,1H),7.54(s,1 H),7.06(dd,J=7.2,1.2Hz,1H),6.99(d,J=1.7Hz,1H),6.86(td,J=7.7,1.3Hz,1H),6 .60(td,J=7.4,1.0Hz,1H),6.31(d,J=7.8Hz,1H),3.85(s,3H),3.76(t,J=8.5Hz,2H) ,3.47(s,3H),3.26(qd,J=7.3,5.3Hz,2H),2.98(t,J=8.4Hz,2H),1.14–1.06(m,3H).

[0173] 13C NMR(101MHz,DMSO-d6)δ161.49,159.16,154.02,147.82,139.79,133.90,131.99,130.76,129.66,129.09,1 27.79,126.79,124.60,124.15,118.53,107.93,106.14,104.64,52.99,52.39,35.88,33.73,28.07,14.52.

[0174] Example 17 Preparation of Compound VI N-ethyl-4-[5-methoxycarbonyl-3-(indolyl-1-yl)thiophen-2-yl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

[0175] At room temperature, 40.5 ml of 1,4-dioxane, 4.5 ml of water, 1.5 g of compound IV, 2.2 g of compound V, 1.83 g of potassium carbonate and 0.31 g of tetrakis(triphenylphosphine)palladium were added to the reaction flask, replaced with nitrogen, and heated to 80 ° C for 8 hours. Cooled to room temperature, 30 ml of ethyl acetate and 30 ml of water were added to extract the liquid, and the aqueous phase was extracted once with 30 ml of ethyl acetate. The organic phases were combined, washed with saturated brine, and the organic solvent was concentrated under reduced pressure. 10 ml of methanol was added to the residue, heated to 65 ° C for 1 hour, cooled to room temperature, filtered and dried to obtain 1.80 g of compound VI (HPLC purity 99.68%, yield 85.4%). Example 18 Preparation of Compound VI N-ethyl-4-[5-methoxycarbonyl-3-(indolyl-1-yl)thiophen-2-yl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

[0176] At room temperature, 40.5 ml of 1,4-dioxane, 4.5 ml of water, 1.5 g of compound IV, 2.2 g of compound V, 1.83 g of potassium carbonate, 0.06 g of palladium acetate and 0.28 g of triphenylphosphine were added to the reaction bottle, replaced with nitrogen, and heated to 80 ° C for 8 hours. Cooled to room temperature, 30 ml of ethyl acetate was added, 30 ml of water was extracted and separated, and the aqueous phase was extracted once with 30 ml of ethyl acetate. The organic phases were combined, washed with saturated brine, and the organic solvent was concentrated under reduced pressure. 10 ml of methanol was added to the residue, heated to 65 ° C for 1 hour, cooled to room temperature, filtered and dried to obtain 1.72 g of compound VI (HPLC purity 98.74%, yield 81.5%). Example 19 Preparation of Compound VI N-ethyl-4-[5-methoxycarbonyl-3-(indolyl-1-yl)thiophen-2-yl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

[0177] At room temperature, 40.5 ml of 1,4-dioxane, 4.5 ml of water, 1.5 g of compound IV, 2.2 g of compound V, 1.22 g of potassium carbonate and 0.31 g of tetrakis(triphenylphosphine)palladium were added to the reaction flask, replaced with nitrogen, and heated to 80 ° C for 8 hours. Cooled to room temperature, 30 ml of ethyl acetate was added, 30 ml of water was extracted and separated, and the aqueous phase was extracted once with 30 ml of ethyl acetate. The organic phases were combined, washed with saturated brine, and the organic solvent was concentrated under reduced pressure. 10 ml of methanol was added to the residue, heated to 65 ° C for 1 hour, cooled to room temperature, filtered and dried to obtain 1.62 g of compound VI (HPLC purity 99.15%, yield 76.8%). Example 20 Preparation of Compound VI N-ethyl-4-[5-methoxycarbonyl-3-(indolyl-1-yl)thiophen-2-yl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

[0178] At room temperature, 40.5 ml of 1,4-dioxane, 4.5 ml of water, 1.5 g of compound IV, 2.2 g of compound V, 2.14 g of potassium carbonate and 0.31 g of tetrakis(triphenylphosphine)palladium were added to the reaction flask, replaced with nitrogen, and heated to 80 ° C for 8 hours. Cooled to room temperature, 30 ml of ethyl acetate was added, 30 ml of water was extracted and separated, and the aqueous phase was extracted once with 30 ml of ethyl acetate. The organic phases were combined, washed with saturated brine, and the organic solvent was concentrated under reduced pressure. 10 ml of methanol was added to the residue, heated to 65 ° C for 1 hour, cooled to room temperature, filtered and dried to obtain 1.82 g of compound VI (HPLC purity 99.03%, yield 86.3%). Example 21 Preparation of Compound VI N-ethyl-4-[5-methoxycarbonyl-3-(indolyl-1-yl)thiophen-2-yl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

[0179] At room temperature, 40.5 ml of N, N-dimethylacetamide, 4.5 ml of water, 1.5 g of compound IV, 2.2 g of compound V, 1.83 g of potassium carbonate and 0.31 g of tetrakis(triphenylphosphine)palladium were added to the reaction bottle, replaced with nitrogen, and heated to 80°C for 8 hours. Cooled to room temperature, 30 ml of ethyl acetate was added, and 30 ml of water was used to extract the liquid, and the aqueous phase was extracted once with 30 ml of ethyl acetate. The organic phases were combined, washed with saturated brine, and the organic solvent was concentrated under reduced pressure. 10 ml of methanol was added to the residue, and the temperature was raised to 65°C for 1 hour, cooled to room temperature, filtered, and dried to obtain 1.57 g of compound VI (HPLC purity 99.72%, yield 74.4%). Example 22 Preparation of Compound VI N-ethyl-4-[5-methoxycarbonyl-3-(indolyl-1-yl)thiophen-2-yl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

[0180] At room temperature, 40.5 ml of 1,4-dioxane, 4.5 ml of water, 1.5 g of compound IV, 2.2 g of compound V, 1.83 g of potassium carbonate and 0.31 g of tetrakis(triphenylphosphine)palladium were added to the reaction flask, replaced with nitrogen, and heated to 60 ° C for 24 hours. Cooled to room temperature, 30 ml of ethyl acetate was added, 30 ml of water was extracted, and the aqueous phase was extracted once with 30 ml of ethyl acetate. The organic phases were combined, washed with saturated brine, and the organic solvent was concentrated under reduced pressure. 10 ml of methanol was added to the residue, heated to 65 ° C for 1 hour, cooled to room temperature, filtered and dried to obtain 1.42 g of compound VI (HPLC purity 98.77%, yield 67.3%). Example 23 Preparation of Compound VI N-ethyl-4-[5-methoxycarbonyl-3-(indolin-1-yl)thiophen-2-yl]-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

[0181] At room temperature, 40.5 ml of 1,4-dioxane, 4.5 ml of water, 1.5 g of compound IV, 2.2 g of compound V, 1.83 g of potassium carbonate and 0.31 g of tetrakis(triphenylphosphine)palladium were added to the reaction flask, replaced with nitrogen, and heated to 120 ° C for 4 hours. Cooled to room temperature, 30 ml of ethyl acetate was added, 30 ml of water was extracted, and the aqueous phase was extracted once with 30 ml of ethyl acetate. The organic phases were combined, washed with saturated brine, and the organic solvent was concentrated under reduced pressure. 10 ml of methanol was added to the residue, heated to 65 ° C for 1 hour, cooled to room temperature, filtered and dried to obtain 1.79 g of compound VI (HPLC purity 99.16%, yield 84.8%). Example 24 Preparation of Compound VII (N-ethyl-4-(5-(2-hydroxypropyl-2-yl)-3-(indolyl-1-yl)thiophene-2-yl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide)

[0182]

[0183] At room temperature and under the protection of inert gas, 600 ml of tetrahydrofuran and 20 g of compound VI were added to the reaction bottle, the temperature was lowered to 10°C, 11.1 ml of 1.6 M methyl lithium was added dropwise, and the reaction was carried out for 30 min. Saturated ammonium chloride was added to quench the reaction, the pH was adjusted to 8-9, and 120 ml of water was added, the liquid was separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. 160 ml of dichloromethane and 30 ml of 1,4-dioxane were added to the residue, crystallized at 20°C for 6 hours, filtered, and dried to obtain 15.2 g of compound VII (HPLC purity 99.18%, yield 76.0%).

[0184] MS+ [M+1]477.3,

[0185] 1 H NMR (400MHz, DMSO-d6) δ12.28(s,1H),8.36(t,J=5.4Hz,1H),7.34(s,1H),7.05(s,1H),7.01(dd,J= 7.2,1.2Hz,1H),6.92(d,J=1.2Hz,1H),6.90–6.79(m,1H),6.54(td,J=7.4,1.0Hz,1H),6.34(d,J=7. 7Hz,1H),5.53(s,1H),4.02(q,J=7.1Hz,1H),3.70(t,J=8.5Hz,2H),3.47(s,3H),3.25(qd,J=7.2,5. 3Hz,2H),3.02–2.83(m,2H),1.99(s,1H),1.53(s,6H),1.17(t,J=7.1Hz,1H),1.11(t,J=7.2Hz,3H).

[0186] 13 C NMR (101MHz, DMSO-d6) δ170.33,159.27,154.00,153.91,148.56,138.11,133.59,129.65,129.27,128.75,126.84,124. 39,124.16,121.69,117.73,117.25,107.66,107.50,105.12,105.07,69.93,52.87,35.75,33.72,32.16,28.01,14.50.

[0187] Example 25 Preparation of Compound VII (N-ethyl-4-(5-(2-hydroxypropyl-2-yl)-3-(indolyl-1-yl)thiophene-2-yl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide)

[0188] At room temperature and under the protection of inert gas, 60 ml of tetrahydrofuran and 2.0 g of compound VI were added to the reaction bottle, the temperature was lowered to 10°C, 5.9 ml of 3M methylmagnesium bromide was added dropwise, and the reaction was carried out for 30 min. Saturated ammonium chloride was added to quench the reaction, the pH was adjusted to 8-9, and 12 ml of water was added, the liquid was separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. 16 ml of dichloromethane and 3 ml of 1,4-dioxane were added to the residue, crystallized at 20°C for 6 hours, filtered, and dried to obtain 1.48 g of compound VII (HPLC purity 98.56%, yield 74.0%).

[0189] Example 26 Preparation of Compound VII (N-ethyl-4-(5-(2-hydroxypropyl-2-yl)-3-(indolyl-1-yl)thiophene-2-yl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide)

[0190] At room temperature and under the protection of inert gas, 60 ml of tetrahydrofuran and 2.0 g of compound VI were added to the reaction bottle, cooled to 10°C, 11.8 ml of 1.6 M methyl lithium was added dropwise, and the reaction was carried out for 30 min. Saturated ammonium chloride was added to quench the reaction, the pH was adjusted to 8-9, and 12 ml of water was added, the liquid was separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. 16 ml of dichloromethane and 3 ml of 1,4-dioxane were added to the residue, crystallized at 20°C for 6 hours, filtered, and dried to obtain 1.46 g of compound VII (HPLC purity 97.21%, yield 73.0%).

[0191] Example 27 Preparation of Compound VII (N-ethyl-4-(5-(2-hydroxypropyl-2-yl)-3-(indolyl-1-yl)thiophene-2-yl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide)

[0192] At room temperature and under the protection of inert gas, 60 ml of 2-methyltetrahydrofuran and 2.0 g of compound VI were added to a reaction bottle, cooled to 10°C, 11.1 ml of 1.6 M methyl lithium was added dropwise, and the reaction was carried out for 30 min. Saturated ammonium chloride was added to quench the reaction, the pH was adjusted to 8-9, and 12 ml of water was added, the liquid was separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. 16 ml of dichloromethane and 3 ml of 1,4-dioxane were added to the residue, crystallized at 20°C for 6 hours, filtered, and dried to obtain 1.55 g of compound VII (HPLC purity 97.94%, yield 77.5%).

[0193] Example 28 Preparation of Compound VII (N-ethyl-4-(5-(2-hydroxypropyl-2-yl)-3-(indolyl-1-yl)thiophene-2-yl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide)

[0194] At room temperature and under the protection of inert gas, 60 ml of tetrahydrofuran and 2.0 g of compound VI were added to the reaction bottle, cooled to 20°C, 11.1 ml of 1.6 M methyl lithium was added dropwise, and the reaction was carried out for 30 min. Saturated ammonium chloride was added to quench the reaction, the pH was adjusted to 8-9, and 120 ml of water was added, the liquid was separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. 16 ml of dichloromethane and 3 ml of 1,4-dioxane were added to the residue, crystallized at 20°C for 6 hours, filtered, and dried to obtain 1.49 g of compound VII (HPLC purity 98.99%, yield 74.5%).

Claims

1. A compound IV having the following structure: in, R is a C1-C6 alkyl group.

2. Compound IV according to claim 1, characterized in that The R is a C1-C4 alkyl group.

3. Compound IV according to claim 2, characterized in that The R is a methyl group or an ethyl group.

4. A method for preparing compound VII, characterized in that: Compound VI reacts with a methyl metal reagent in solvent D to obtain compound VII wherein R is as defined in any one of claims 1 to 3.

5. The method according to claim 4, characterized in that The steps include: (1) Compound IV reacts with compound V in the presence of catalyst B, base 2 and solvent C to obtain compound VI; (2) Compound VI reacts with a methyl metal reagent in solvent D to obtain compound VII 6. The method according to claim 4, characterized in that The steps include: (1) Compound III reacts with a brominating agent in solvent B to prepare compound IV (2) Compound IV reacts with compound V under the action of catalyst B, base 2 and solvent C to obtain compound VI (3) Compound VI reacts with a methyl metal reagent in solvent D to obtain compound VII 7. The method according to claim 4, characterized in that The steps include: Wherein, X is Cl, Br or I; (1) Compound I reacts with Compound II under the action of Catalyst A, Base 1 and Solvent A to prepare Compound III; (2) Compound III reacts with a brominating agent in solvent B to obtain compound IV; (3) Compound IV reacts with compound V in the presence of catalyst B, base 2 and solvent C to obtain compound VI; (4) Compound VI is reacted with a methyl metal reagent in solvent D to obtain compound VII.

8. The method according to any one of claims 4 to 7, characterized in that: The methyl metal reagent is selected from methyl lithium, methyl magnesium bromide, methyl magnesium chloride, methyl magnesium iodide, methyl zinc or methyl aluminum; the solvent D is selected from tetrahydrofuran or 2-methyltetrahydrofuran.

9. The method according to any one of claims 5 to 7, characterized in that: The catalyst B is selected from tetrakis(triphenylphosphine)palladium, palladium acetate, bis(triphenylphosphine)palladium dichloride or 1,1-bis(diphenylphosphine)ferro-nickel dichloride; The base 2 is selected from potassium carbonate, sodium carbonate, cesium carbonate or potassium phosphate; The solvent C is a mixed solvent consisting of an organic solvent and water, wherein the organic solvent is selected from one or more of 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or N-methylpyrrolidone, and the mass ratio of the organic solvent to water in the mixed solvent is 1:0.05-0.

20.

10. The method according to any one of claims 6-7, characterized in that: The bromination reagent is selected from bromine, NBS, pyridinium tribromide or dibromohydantoin; The solvent B is an organic solvent, and the organic solvent is selected from acetonitrile, ethyl acetate, acetone, N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone.

11. The method according to claim 7, characterized in that: The catalyst A is selected from tetrakis(triphenylphosphine)palladium, tris(bisbenzylideneacetone)dipalladium, palladium acetate or 1,1-bis(diphenylphosphine)diferroni-palladium dichloride; The base 1 is selected from potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, potassium phosphate, potassium hydroxide or sodium hydroxide; The reaction solvent A is an organic solvent, and the organic solvent is selected from toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran or 1,4-dioxane.

12. The method according to claim 7, characterized in that: In step (1), the reaction further contains a catalyst A ligand, wherein the ligand is selected from PPh3, P(o-tolyl)3, P(t-Bu)3, CyPF-t-Bu, JosiPhos, Binap, XantPhos, DPPF, Brett-Phos, Ru-Phos, X-Phos, S-Phos or Bippy-Phos; the molar ratio of catalyst A to catalyst A ligand is 1:1.0-1.5; the molar ratio of compound I to catalyst A is 1:0.025-0.05; the molar ratio of compound I to compound II is 1:1.0-2.0; the molar ratio of compound I to base is 1:2.0-3.5; the reaction temperature is 60-120°C; In step (2), the molar ratio of compound III to the bromination reagent is 1.0:0.90-1.2; the reaction temperature is -10 to 30°C; In step (3), the reaction further contains a catalyst B ligand, wherein the ligand is selected from X-Phos, S-Phos, AsPh3, n-Bu3P, (MeO)3P, PPh3, bidentate ligand Ph2P(CH2)2PPh2(dppe) or Ph2P(CH2)3PPh2(dppp); the molar ratio of catalyst B to catalyst B ligand is 1:1.0-4.0; the molar ratio of compound IV to compound V is 1:0.9-1.2; the molar ratio of compound IV to catalyst B is 1:0.05-0.30; the molar ratio of compound IV to base 2 is 1:2.0-3.5; the reaction temperature is 60-120°C; In step (4), the molar ratio of compound VI to methyl metal reagent is 1:4.0-4.5; and the reaction temperature is 0-30°C.

13. The method according to claim 12, characterized in that: In step (1), the molar ratio of compound I to compound II is 1:1.

2.

14. The method according to claim 12, characterized in that: In step (1), the molar ratio of compound I to base is 1:2.

0.

15. The method according to claim 12, characterized in that: The reaction temperature in step (1) is 60-80°C.

16. The method according to claim 12, characterized in that: In step (2), the molar ratio of compound III to the bromination reagent is 1.0:1.0; and the reaction temperature is 0-20°C.

17. The method according to claim 16, characterized in that: The reaction temperature is 0-10°C.

18. The method according to claim 12, characterized in that: In step (3), the molar ratio of catalyst B to catalyst B ligand is 1:1.0-1.5; the molar ratio of compound IV to compound V is 1.0:1.0; the molar ratio of compound IV to catalyst B is 1:0.05-0.10; and the reaction temperature is 80-120°C.

19. The method according to claim 18, characterized in that: The reaction temperature is 80-90°C.

20. The method according to claim 12, characterized in that: The reaction temperature in step (4) is 10-20°C.

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