CN108250187B - Indole-1-carbonate compound, its preparation method and application - Google Patents

Abstract

The invention belongs to the field of pharmaceutical synthesis, in particular to a class of indole-1-carbonate compounds represented by general formula (I), pharmaceutically acceptable salts, deuterated compounds or solvates thereof, and preparation methods thereof and use in the preparation of a medicament for selectively inhibiting active EGFR resistance mutation T790M and activating mutation.

Description

Indole-1-carbonate compound, its preparation method and application

technical field

The invention belongs to the field of drug synthesis, and in particular relates to a class of indole-1-carbonate compounds, a preparation method thereof, and use thereof in the preparation of antitumor drugs.

Background technique

Epidermal Growth Factor Receptor (EGFR), also known as ErbB1 or HER1, is an important member of the ErbB receptor family. It can polymerize or heterodimerize with other members of the ErbB family (such as HER2, HER3, HER4), and activate downstream pathways through the phosphorylation of key tyrosine residues at the intracellular end to regulate cell proliferation and survival.

P.A.；Carnaghi,C.；Calandri,C.；Bencardino,K.；Ligorio,C.；Ciardiello,F.；Pressiani,T.；et al.EGFR FISH assaypredicts for response to cetuximab in chemotherapy refractory colorectalcancerpatients.Ann.Oncol.2008,19,717–723.)；在胶质细胞癌和头颈癌中也具有显著的过度表达或激活现象。所以EGFR是重要的肿瘤治疗靶标之一。肺癌死亡是恶性肿瘤中的第一杀手，在我国，肺癌发病率逐年上升，每年新发病数高达70万，伴有EGFR激活性突变的比例高达40-60％，即中国对EGFR第三代抑制剂具有更大的需求。因此，开发高活性、高选择性和安全性的第三代EGFR抑制剂具有重要的意义。Epidemiological findings show that overexpression or overactivation of EGFR is closely related to the occurrence and development of many tumors, such as EGFR overexpression in 40-80% of non-small cell lung cancers (NSCLC) (Fujino, S.; Enokibori, T. Tezuka, N.; Asada, Y.; Inoue, S.; Kato, H.; Mori, AA comparison of epidermal growthfactor receptor levels and otherprognostic parameters in non-small celllungcancer. Eur. J. Cancer 1996, 32, 2070–2074 .); 50% of rectal cancers have 3- to 5-fold amplification of the EGFR gene (Cappuzzo, F.; Finocchiaro, G.; Rossi, E.;

Pa; Carnaghi, C.; Calandri, C.; Bencardino, K.; Ligorio, C.; Ciardiello, F.; Pressiani, T.; et al. EGFR FISH assaypredicts for response to cetuximab in chemotherapy refractory colorectalcancerpatients.Ann.Oncol . 2008, 19, 717–723.); also have significant overexpression or activation in glioblastoma and head and neck cancer. Therefore, EGFR is one of the important tumor therapeutic targets. Lung cancer death is the number one killer of malignant tumors. In my country, the incidence of lung cancer is increasing year by year. The number of new cases is as high as 700,000 each year, and the proportion of EGFR activating mutations is as high as 40-60%. agents have greater demand. Therefore, it is of great significance to develop third-generation EGFR inhibitors with high activity, selectivity and safety.

Currently approved drugs that selectively target EGFR include Gefitinib, Erlotinib, Afatinib, Dacomitinib and Osimertinib. Among them, gefitinib and erlotinib are first-generation EGFR inhibitors, which are non-covalent binding inhibitors; afatinib and Dacomitinib are second-generation EGFR covalent binding inhibitors; The resistance mutation T790M and the activating mutation (L858R, delE746-A750 or Exon19 deletion) have higher activity and are significantly better than the activity of EGFR wild type (EGFRWT), reducing the effect of strong inhibition of EGFRWT by first- and second-generation inhibitors Skin and gastrointestinal toxicity, is a third-generation inhibitor. Osimertinib has achieved great clinical success, with an objective response rate of 61% and a post-administration tumor control rate of 91%. Its important metabolite, AZ5104, was more active (nearly 10-fold difference) and also had a significant >10-fold selectivity difference for EGFR WT and mutation, but itself had poor oral exposure.

In order to better improve the druggability of the third-generation EGFR inhibitor and possibly have a better therapeutic effect in the human body, this patent is designed and synthesized on the basis of AZD9291 and related compounds, and innovatively introduced on the nitrogen of indole. Carbonate structure, which is extremely rare in drug research (only THOMSON REUTERS CORTELLISTM retrieved only 2 compounds containing indole-1-carbonate for the treatment of advanced melanoma, the search time was November 2017).

SUMMARY OF THE INVENTION

The object of the present invention is to provide a class of indole-1-carbonate compounds, pharmaceutically acceptable salts, deuterated compounds or solvates thereof.

Another object of the present invention is to provide a method for preparing the indole-1-carbonate compounds, pharmaceutically acceptable salts, deuterated compounds or solvates thereof,

Another object of the present invention is to provide a pharmaceutical composition comprising the indole-1-carbonate compounds, pharmaceutically acceptable salts, deuterated compounds or solvates thereof.

Another object of the present invention is to provide the indole-1-carbonate compound, its pharmaceutically acceptable salt, deuterated compound or solvate; or the indole-1-carbonate compound, Use of the composition of its pharmaceutically acceptable salts, deuterated compounds or solvates in the preparation of antitumor drugs.

The first aspect of the present invention provides an indole-1-carbonate compound represented by general formula (I), a pharmaceutically acceptable salt, deuterated compound or solvate thereof,

in,

R is selected from substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₆ -C ₁₂ aryl, substituted or unsubstituted benzyl ; The substituted substituent is selected from halogen, nitro, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ acyloxy, C ₁ -C ₆ alkoxy or C ₂ -C ₆ alkenyl ;

R' is selected from C ₁ -C ₆ alkyl or C ₁ -C ₆ deuterated alkyl; preferably methyl or deuterated methyl.

In a preferred embodiment of the present invention, the compound of general formula (I) is selected from indole-1-carbonate compounds represented by the following general formula (I-A), pharmaceutically acceptable salts thereof, deuterium Substitute compounds or solvates,

wherein R is as defined above.

Preferably,

R is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, phenyl, benzyl, methylbenzyl, acetoxybenzyl or allyl; more preferably methyl, ethyl, propyl, isopropyl, cyclopropyl, phenyl, benzyl, o-methylbenzyl, o-acetoxybenzyl or 2-allyl;

R' is methyl or deuterated methyl.

More preferably, the indole-1-carbonate compound represented by the formula (I), its deuterated compound, pharmaceutically acceptable salt or solvate is selected from the compounds of the following formula:

"C ₁ -C ₆ alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms in the chain, including, without limitation, methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, sec-butyl, tert-butyl, etc.

"C ₁ -C ₆ deuterated alkyl" refers to a C ₁ -C ₆ alkyl group in which one or more hydrogen atoms on the alkyl group have been replaced with deuterium atoms.

"C ₁ -C ₆ acyloxy" refers to a straight or branched chain alkyl acyloxy group having 1 to 6 carbon atoms in the alkyl moiety, eg, methyl acyloxy, ethyl acyloxy , n-propylacyloxy, isopropylacyloxy, n-butylacyloxy, isobutylacyloxy or tert-butylacyloxy.

"C ₁ -C ₆ alkoxy" refers to a straight or branched chain O-alkyl group containing 1 to 6 carbon atoms in the alkyl moiety, eg, methoxy, ethoxy, n-propyl oxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy.

"C3 _{- C6cycloalkyl} " refers to a group containing one or more saturated and/or partially saturated rings, all ring-forming atoms being carbon atoms, including 3 to 6 carbon atoms; for example, cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, etc.

"C ₆ -C ₁₂ aryl group" refers to an aromatic ring group containing 6-12 ring atoms but no heteroatoms in the ring atoms, preferably a 6-10 membered aryl group (that is, the number of carbon atoms is 6-10). aryl), such as phenyl, naphthyl.

"Halogen" refers to fluorine, chlorine, bromine and iodine.

In the second aspect of the present invention, there is provided a method for preparing an indole-1-carbonate compound represented by the general formula (I), the method comprising acylating the compound of the formula II with an acylating reagent to obtain a general formula The compound step shown in formula (I) is shown in the following reaction formula:

Wherein, R, R' are defined identically with the definition in general formula (I);

或碳酸酯

其中X为卤素；Described acylating reagent is selected from haloformate XCOOR, dicarbonate

or carbonate

wherein X is halogen;

Preferably, the haloformate XCOOR is selected from chloroformate or bromoformate.

In a preferred embodiment, the described method for preparing the indole-1-carbonate compound shown in formula (I) comprises one of the following methods:

method 1:

Wherein, R, R' are defined identically with the definition in general formula (I);

The compound of formula II is reacted with chloroformate ClCOOR under basic conditions to obtain the compound represented by the general formula (I);

Described alkali is selected from one or more in sodium hydride, potassium tert-butoxide, potassium carbonate, triethylamine, preferably sodium hydride;

The solvent used in the reaction is selected from one or more of tetrahydrofuran, dichloromethane, N,N-dimethylformamide, acetonitrile, dioxane, and toluene, preferably tetrahydrofuran;

The temperature of the reaction is 0-50°C;

Method 2:

Wherein, R, R' are defined identically with the definition in general formula (I);

反应获得通式(I)所示化合物；The compound of formula II reacts with dicarbonate under basic conditions

The reaction obtains the compound represented by the general formula (I);

Described alkali is selected from one or more in sodium hydride, potassium tert-butoxide, potassium carbonate, triethylamine, 4-dimethylaminopyridine, preferably triethylamine and dimethylaminopyridine,

The solvent used in the reaction is selected from one or more of tetrahydrofuran, dichloromethane, N,N-dimethylformamide, acetonitrile, dioxane, and toluene, preferably dichloromethane;

The temperature of the reaction is 0-40°C;

Method 3:

Wherein, R, R' are defined identically with the definition in general formula (I);

在离子液体为催化剂的条件下，反应获得通式(I)所示的化合物；The compound of formula II and carbonate

Under the condition that the ionic liquid is a catalyst, the reaction obtains the compound represented by the general formula (I);

The ionic liquid is 1-butyl-3-methylimidazole hydroxide [Bmim]OH or tetrabutylammonium hydroxide;

The temperature of the reaction is 0-90°C.

In a preferred embodiment, the method for preparing the indole-1-carbonate compound shown in general formula (I) comprises the following steps:

Preparation of intermediate 3: intermediate 1 is reacted with deuterated iodomethane or iodomethane under alkaline conditions to obtain intermediate 2, and then the Boc protecting group is removed by acid catalysis to obtain intermediate 3;

Described alkali is selected from one or more in sodium hydride, potassium carbonate, triethylamine, preferably potassium carbonate or triethylamine;

Described acid is selected from one or more in hydrochloric acid, hydrobromic acid or trifluoroacetic acid, is preferably hydrochloric acid;

In a preferred embodiment, the method for preparing the indole-1-carbonate compound represented by the general formula (I) comprises the following steps 1-5:

Wherein, R, R' are defined identically with the definition in general formula (I);

Step 1: Intermediate 4 and intermediate 5 are subjected to nucleophilic substitution under acid-catalyzed conditions to obtain intermediate 6;

The acid is selected from one or more of p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid or hydrochloric acid, preferably p-toluenesulfonic acid;

The reaction solvent is selected from one or more of 2-pentanol, tert-butanol, 1,4-dioxane or tetrahydrofuran, preferably 2-pentanol;

The reaction temperature is selected from 80-150°C;

Step 2: Intermediate 6 and intermediate 3 undergo nucleophilic substitution under alkaline conditions to obtain intermediate 7;

Described alkali is selected from one or more in triethylamine, diisopropylethylamine, potassium carbonate or sodium carbonate, preferably diisopropylethylamine;

The reaction solvent is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone, preferably N,N-dimethylacetamide;

The reaction temperature is 80-180°C;

Step 3: The nitro group of 7 is reduced by iron powder or metal catalyzed hydrogen reduction to obtain intermediate 8;

Described iron powder reduction is selected from and reacts in the presence of iron powder and acetic acid or in the presence of iron powder, ammonium chloride and ethanol;

The reaction temperature of described iron powder reduction is 60-100 ℃;

The metal for the metal catalyzed hydrogen reduction is selected from Pd/C, Pd(OH) ₂ , RaneyNi or PtO ₂ , preferably Pd/C;

The solvent for the metal-catalyzed hydrogen reduction is selected from one or more of ethanol, ethyl acetate, tetrahydrofuran or dioxane, preferably ethanol;

The reaction temperature of the metal-catalyzed hydrogen reduction is 20-60°C;

Step 4: 8 is reacted with acryloyl chloride in a solvent to obtain intermediate 9;

The solvent of the reaction is selected from one or more of dichloromethane, tetrahydrofuran, ethyl acetate or N,N-dimethylformamide, preferably dichloromethane;

The temperature of the reaction is -10-50°C;

Step 5: Intermediate 9 is reacted with an acylating reagent to obtain an indole-1-carbonate compound represented by formula (1),

The solvent of the reaction is selected from one or more of dichloromethane, tetrahydrofuran, ethyl acetate or N,N-dimethylformamide, preferably dichloromethane;

The temperature of the reaction is -10-50°C.

In the third aspect, the present invention also provides a pharmaceutical composition, which comprises a safe and effective amount selected from the above-mentioned indole-1-carbonate compounds, deuterated compounds, pharmaceutically acceptable salts or solvates thereof One or more of them are used as active ingredients, and a pharmaceutically acceptable carrier.

Preferably, the pharmaceutical composition further includes other pharmaceutically acceptable therapeutic agents, especially other antitumor drugs. The therapeutic agents include but are not limited to: drugs that act on the chemical structure of DNA, anti-tumor drugs such as cisplatin, anti-tumor drugs that affect nucleic acid synthesis, such as methotrexate (MTX), 5-fluorouracil (5FU), etc., affect nucleic acid transcription. Anti-tumor drugs such as doxorubicin, epirubicin, aclarithromycin, fucoidin, etc., anti-tumor drugs that act on tubulin synthesis such as paclitaxel, vinorelbine, etc., aromatase inhibitors such as aminolu Mitre, Lantron, Letrozole, Arinide, etc. Cell signaling pathway inhibitors such as epidermal growth factor receptor inhibitors Imatinib, Gefitinib, Erlotinib ), Lapatinib, etc.

"Pharmaceutically acceptable salt" refers to a relatively non-toxic inorganic or organic acid salt. Suitable inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, and suitable organic acids include trifluoromethanesulfonic acid, methanesulfonic acid, trifluoroacetic acid, citric acid, maleic acid, fumaric acid, succinic acid or tartaric acid.

In the fourth aspect, the present invention also provides indole-1-carbonate compounds represented by the general formula (I), their deuterated compounds, pharmaceutically acceptable salts or solvates in the preparation for selectively inhibiting active EGFR antibodies. Use of the sex mutation T790M and the activating mutation in medicine.

Said selective inhibitory active EGFR resistance mutation T790M and activating mutations include: lung cancer, breast cancer, ovarian cancer, liver cancer, melanoma, prostate cancer, colon cancer, rectal cancer, glial cell cancer, head and neck cancer, gastric cancer etc.; the compounds of general formula (I) and pharmaceutically acceptable salts thereof provided by the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds, and the route of administration can be selected from oral, rectal, gastrointestinal External (intravenous, intramuscular or subcutaneous).

beneficial effect

The compound of the general formula (I) provided by the present invention innovatively introduces a carbonate structure on the indole nitrogen in design, the obtained compound exhibits good activity and selectivity at the cellular level, and the exposure in animals is significantly better than Osimertinib has the characteristics of excellent druggability. In conclusion, this patent innovatively obtains a more druggable new structure of small molecule entities that selectively inhibit active EGFR resistance mutation T790M and activating mutation.

One of the significant advantages of the preparation method of the compound of general formula (I) provided by the present invention is that it is obtained by one-step reaction of commercially available raw materials, the operation is simple, and the reaction efficiency is high (the reaction of some compounds only takes 10 minutes). At the same time, this kind of compound can also be synthesized by de novo method, and the synthetic route has better flexibility and wider applicability.

Description of drawings

Figure 1 shows the effect of compound I-1 on the phosphorylation levels of L858R/T790M mutated EGFR and its downstream signals AKT and ERK.

Detailed ways

The present invention will be further described below in conjunction with specific embodiments. These examples are only used to illustrate the present invention, but not to limit the present invention. The specific experimental method is not indicated in the specific embodiment, and it is usually operated under normal conditions.

N-(5-((4-(1H-Indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)- Raw materials such as 4-methoxyphenyl)acrylamide were purchased from Yaodu Jingwei Information Technology (Beijing) Co., Ltd. or prepared with reference to literature (J.Med.Chem.2014,57,8249-8267);

¹ H NMR was recorded by Varian Mercury-500 or Varian Mercury-400 nuclear magnetic resonance instrument, chemical shifts were expressed in δ (ppm); mass spectra were obtained by Finnigan/MAT-95 (EI) and Finnigan LCQ/DECA and Micromass UltraQ-TOF (ESI) Mass spectrometer records; solvents and reagents used were purchased from Sinopharm Chemical Reagent Co., Ltd. and Beijing Bailingwei Technology Co., Ltd.

" ¹ H-NMR (CDCl ₃ , 400 MHz)" described below refers to the nuclear magnetic resonance of hydrogen nuclei measured at 400 MHz with deuterated chloroform as a solvent, and δ is a chemical shift, and its unit is ppm.

(1) Example of compound preparation

Example 1

2-(2-((5-Acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl) -1H-Indole-1-methylcarbonate (I-1)

Synthesis method 1:

N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino) -4-Methoxyphenyl)acrylamide (ie AZ5104, 3.0g, 6.18mmol) was dissolved in 200mL of anhydrous tetrahydrofuran, and slowly sodium hydride (encapsulated in mineral oil, 60%, 740mg, 18.53mmol) was added under ice bath conditions. After stirring for 2min, slowly add methyl chloroformate (1.75g, 18.53mmol) dissolved in 50mL tetrahydrofuran dropwise, remove the ice bath, slowly pour the reaction solution into 200mL saturated ammonium chloride solution after 10min, add 200mL ethyl acetate to extract organic phase, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, spin-dried the solvent, and purified by column chromatography to obtain 2-(2-((5-acrylamido-4-((2-(dimethylamino)ethyl) (methyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-1H-indole-1-carbonate methyl ester, 2.61 g, 77.0% yield.

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.11 (s, 1H), 9.65 (s, 1H), 8.52 (d, J=5.2 Hz, 1H), 8.46 (s, 1H), 8.32 (d, J= 7.8Hz,1H),8.26(d,J=8.1Hz,1H),7.62(s,1H),7.36(dt,J=20.0,7.2Hz,2H),7.12(d,J=5.2Hz,1H) ,6.80(s,1H),6.41(d,J＝16.5Hz,1H),6.31(dd,J＝16.9,10.0Hz,1H),5.67(d,J＝10.6Hz,1H),4.06(s, 3H), 3.89(s, 3H), 2.88(t, J=5.4Hz, 2H), 2.71(s, 3H), 2.31–2.28(m, 2H), 2.26(s, 6H).

LR-Mass (ESI): _544.3 (M _{+ 1} , _C29H34N7O4 ).

Synthesis method 2:

N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino) -4-Methoxyphenyl)acrylamide (ie AZ5104, 3.0 g, 6.18 mmol) was dissolved in 100 mL of anhydrous dichloromethane, followed by adding triethylamine (1.88 g, 18.53 mmol), 4-dimethylaminopyridine (0.15 g, 1.24 mmol) and dimethyl dicarbonate (1.08 g, 8.03 mmol), react at room temperature for 6 h, add 100 mL of dichloromethane and 100 mL of water to the reaction solution to dilute, separate the layers, dry the organic phase with anhydrous sodium sulfate, spin Dry solvent, 2-(2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxybenzene (yl)amino)pyrimidin-4-yl)-1H-indole-1-carbonic acid methyl ester, 2.40 g, 71.6% yield. NMR and mass spectrometry were the same as before.

Synthesis method 3:

N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino) -4-Methoxyphenyl)acrylamide (ie AZ5104, 3.0 g, 6.18 mmol) was dissolved in 30 mL of dimethyl carbonate, [Bmim]OH (88 mg, 0.618 mmol) was added, heated to 90 °C and reacted for 1 h, the reaction solution was Slowly pour into 200 mL of saturated ammonium chloride solution, add 200 mL of ethyl acetate to extract the organic phase, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, spin dry the solvent, and purify by column chromatography to obtain 2-(2-((5 -Acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-1H-indole-1- Methyl carbonate, 2.12 g, yield 63.2%. NMR and mass spectrometry were the same as before.

Example 2

2-(2-((5-Acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl) -1H-Indole-1-ethyl carbonate (I-2)

Except replacing methyl chloroformate with ethyl chloroformate, the synthetic method is the same as that of synthetic method 1 in Example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.08 (s, 1H), 9.64 (s, 1H), 8.53 (d, J=5.2 Hz, 1H), 8.42 (s, 1H), 8.38 (d, J= 7.5Hz, 1H), 8.26(d, J=8.1Hz, 1H), 7.64(s, 1H), 7.37(ddd, J=15.1, 14.0, 6.7Hz, 2H), 7.14(d, J=5.2Hz, 1H), 6.81(s, 1H), 6.41(d, J=2.8Hz, 2H), 5.72–5.64(m, 1H), 4.53(q, J=7.1Hz, 2H), 3.90(s, 3H), 2.94–2.86 (m, 2H), 2.72 (s, 4H), 2.36 (s, 2H), 2.31 (s, 8H), 1.49 (d, J=7.1 Hz, 3H).

LR-Mass (ESI): _558.8 (M _{+ 1} , _C30H36N7O4 ).

Example 3

2-(2-((5-Acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl) -1H-Indole-1-propyl carbonate (I-3)

Except replacing methyl chloroformate with propyl chloroformate, the synthetic method is the same as that of synthetic method 1 in Example 1.

¹ H NMR (500MHz, CDCl ₃ ) δ 9.91 (s, 1H), 9.50 (s, 1H), 8.73 (d, J=14.8Hz, 1H), 8.55 (dd, J=14.8, 3.1Hz, 1H) ,8.11(dd,J=14.9,3.1Hz,1H),7.43–7.06(m,4H),6.43(s,1H),6.17(ddd,J=26.6,24.4,12.2Hz,2H),5.69(dd ,J=33.3,4.6Hz,1H),4.69(s,1H),4.21(t,J=14.7Hz,2H),3.86(s,3H),3.53(dt,J=21.9,14.6Hz,2H) , 2.75(s, 3H), 2.50(t, J=14.6Hz, 2H), 2.21(s, 6H), 1.91–1.49(m, 2H), 1.01(t, J=13.4Hz, 3H).

LR-Mass (ESI): _572.8 (M _{+ 1} , _C31H38N7O4 ).

Example 4

2-(2-((5-Acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl) -1H-Indole-1-isopropyl carbonate (I-4)

Except replacing methyl chloroformate with isopropyl chloroformate, the synthetic method is the same as that of synthetic method 1 in Example 1.

¹ H NMR (400MHz, DMSO-d ₆ )δ10.08(s,1H),8.63(s,1H),8.59(s,1H),8.46(d,J=8.0Hz,1H),8.43-8.35( m, 2H), 8.15(d, J=8.3Hz, 1H), 7.43(d, J=5.3Hz, 1H), 7.38(t, J=7.3Hz, 1H), 7.23(t, J=7.4Hz, 1H), 7.04(s, 1H), 6.45(s, 1H), 6.19(dd, J=16.9, 1.9Hz, 1H), 5.77-5.69(m, 1H), 5.29-5.15(m, 1H), 3.81 (s, 3H), 2.95 (s, 2H), 2.74 (s, 3H), 2.40 (s, 2H), 2.28 (s, 6H), 1.45 (d, J=6.2 Hz, 6H).

LR-Mass (ESI): _572.8 (M _{+ 1} , _C31H38N7O4 ).

Example 5

2-(2-((5-Acrylamido-4-((2-(deuterated dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidine-4- yl)-1H-indole-1-methylcarbonate (I-5)

step 1:

N-methyl-N-tert-butoxycarbonylethylenediamine (1.74g, 10mmol) was dissolved in 50mL of anhydrous dichloromethane, potassium carbonate (4.15g, 30mmol) and deuterated iodomethane ( _CD3I , 3.19g, 22mmol), react at room temperature for 12h, spin dry the solvent, and purify by column chromatography to obtain N-methyl-N-tert-butoxycarbonyl-N',N'-bis(deuteromethyl) - Ethylenediamine, 1.5 g, 72% yield.

¹ H NMR (500MHz, CDCl ₃ ) δ 3.38 (t, J=14.6Hz, 1H), 3.23 (s, 3H), 3.20-3.10 (m, 1H), 2.53 (t, J=14.6Hz, 2H) , 1.42(s, 9H).

LR _- Mass (ESI): 209.3 (M _{+ 1} , _{C10H17D6N2O2 )} .

Dissolve N-methyl-N-tert-butoxycarbonyl-N',N'-bis(deuteromethyl)-ethylenediamine (1.5g, 7.2mmol) in 30mL of 1M hydrogen chloride solution in dioxane, room temperature The reaction was performed for 1 h, and the solvent was spin-dried to obtain 1.3 g of the dihydrochloride salt of N,N-bis(deuteromethyl)-N'-methyl-ethylenediamine, with a yield of 100%.

¹ H NMR (500 MHz, CDCl ₃ ) δ 3.25 (s, 3H), 2.54-2.45 (m, 2H), 2.45-2.33 (m, 2H).

LR _- Mass (ESI): 109.2 (M _{+ 1} , _C5H9D6N2 ).

Step 2:

Intermediate 4 (23 g, 100 mmol) was dissolved in 500 mL of 2-pentanol, p-toluenesulfonic acid (1.72 g, 10 mmol) was added, heated at 105° C. for 4 h, cooled the reaction solution, a yellow solid was precipitated, filtered, and the filter cake was used 50 mL 2-pentanol was washed and dried to obtain 635 g of the intermediate in a yield of 92%.

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.65-8.50 (m, 2H), 8.23-8.06 (m, 3H), 7.59 (dd, J=11.1, 7.0 Hz, 1H), 7.33 (ddd, J=18.1 , 13.0, 5.7Hz, 4H), 5.02(s, 1H), 3.86(s, 3H).

LR-Mass (ESI): _380.4 ( _M + ₁ , _C19H15N5O3 ).

Intermediate 6 (19 g, 50 mmol) was dissolved in 200 mL of trifluoroethanol, diisopropylethylamine (25.9 g, 200 mmol) and intermediate 3 (9 g, 50 mmol) were added successively, the reaction was refluxed for 12 h, the solvent was spin-dried, and the column layer was Analytical purification afforded intermediate 7 (15 g, pale yellow solid, 64%).

¹ H NMR (500MHz, CDCl ₃ ) δ 8.65-8.44 (m, 2H), 8.27-8.06 (m, 2H), 7.94 (s, 1H), 7.59 (dd, J=11.1, 7.0Hz, 1H), 7.43–7.20(m, 3H), 6.59(s, 1H), 5.04(s, 1H), 3.86(s, 3H), 3.63(t, J=14.6Hz, 1H), 3.49(t, J=14.6Hz) , 1H), 2.75 (s, 3H), 2.50 (t, J=14.5Hz, 2H).

LR _- Mass (ESI): 468.4 ( _M + ₁ , _{C24H22D6N7O3 )} .

Intermediate 7 (10 g, 21.4 mmol), iron powder (11.9 g, 214 mmol) and ammonium chloride (11.44 g, 214 mmol) were dissolved in 200 mL of a mixed solution of ethanol/water (ethanol/water=3:1, v/v ), heated under reflux for 4 h, the reaction solution was diluted with 200 mL of ethyl acetate, filtered through celite, the filtrate was spin-dried, and purified by column chromatography to obtain Intermediate 8 (8.3 g, pale yellow viscous liquid, yield 88%).

¹ H NMR (500MHz, CDCl ₃ ) δ 8.64-8.46 (m, 2H), 8.14 (q, J=6.5Hz, 2H), 7.66-7.19 (m, 4H), 6.15 (d, J=20.1Hz, 2H), 5.01(s, 1H), 3.84(d, J=22.3Hz, 5H), 3.50(dt, J=20.7, 14.6Hz, 2H), 2.75(s, 3H), 2.50(t, J=14.6 Hz, 2H).

LR _- Mass (ESI): 438.7 ( _M + ₁ , _C24H24D6N7O ).

The intermediate 8 (4.4 g, 10 mmol) was dissolved in 100 mL of anhydrous dichloromethane, and acryloyl chloride (0.9 g, 10 mmol) dissolved in 50 mL of anhydrous dichloromethane was slowly added dropwise under ice bath conditions. The reaction was quenched with 100 mL of 1M sodium carbonate solution, the organic phase was separated, dried over anhydrous sodium sulfate, the solvent was spin-dried, and purified by column chromatography to obtain Intermediate 9 (3.5 g, pale yellow solid, 71%).

¹ H NMR (500MHz, CDCl ₃ ) δ 9.89 (s, 1H), 8.73-8.51 (m, 2H), 8.19-8.03 (m, 2H), 7.59 (dd, J=11.1, 7.0Hz, 1H), 7.41–7.24 (m, 3H), 7.12 (s, 1H), 6.49–6.18 (m, 2H), 6.05 (dd, J=20.0, 4.6Hz, 1H), 5.69 (dd, J=33.3, 4.6Hz, 1H), 5.15(s, 1H), 3.86(s, 3H), 3.56(dt, J=28.9, 14.7Hz, 2H), 2.75(s, 3H), 2.50(t, J=14.7Hz, 2H).

LR _- Mass (ESI): _492.8 (M _{+ 1} , _C27H26D6N7O2 ).

Example 5 can be obtained by using the synthetic method 1 in Example 1 with intermediate 9 and methyl chloroformate.

¹ H NMR (500 MHz, CDCl ₃ ) δ 9.90 (s, 1H), 9.46 (s, 1H), 8.68–8.38 (m, 2H), 8.10 (dd, J=15.0, 3.1 Hz, 1H), 7.41– 7.01(m, 4H), 6.42(s, 1H), 6.11(ddd, J=26.4, 24.9, 12.5Hz, 2H), 5.68(dd, J=32.8, 4.9Hz, 1H), 4.98(s, 1H) , 3.86(s, 3H), 3.74–3.48(m, 5H), 2.75(s, 3H), 2.50(t, J=14.6Hz, 2H).

LR _- Mass (ESI): _550.8 (M _{+ 1} , _C29H28D6N7O4 ).

Example 6

2-(2-((5-Acrylamido-4-((2-(deuterated dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidine-4- base)-1H-indole-1-ethyl carbonate (I-6)

Except that methyl chloroformate was replaced with ethyl chloroformate, other synthetic routes were the same as in Example 5.

¹ H NMR (500 MHz, CDCl ₃ ) δ 9.83 (s, 1H), 8.80-8.59 (m, 2H), 8.51 (dd, J=14.8, 3.1 Hz, 1H), 8.07 (dd, J=14.9, 3.1 Hz, 1H), 7.42–7.01 (m, 4H), 6.40 (s, 1H), 6.10 (ddd, J=26.5, 24.9, 12.5Hz, 2H), 5.66 (dd, J=32.9, 4.9Hz, 1H) ,4.98(s,1H),4.19(q,J=11.8Hz,2H),3.84(s,3H),3.55(dt,J=38.8,14.3Hz,2H),2.74(s,3H),2.49( t, J=14.1 Hz, 2H), 1.26 (t, J=11.8 Hz, 3H).

LR _- Mass (ESI): _564.8 (M _{+ 1} , _C30H30D6N7O4 ).

Example 7

2-(2-((5-Acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl) -1H-Indole-1-cyclopropyl carbonate (I-7)

Except replacing methyl chloroformate with cyclopropyl chloroformate, the synthetic method is the same as the synthetic method 1 in Example 1.

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.80-8.42 (m, 3H), 8.11 (dd, J=14.9, 3.0 Hz, 1H), 7.48-7.06 (m, 4H), 6.49-6.24 (m, 2H) ),6.05(dd,J＝20.0,4.4Hz,1H),5.69(dd,J＝33.3,4.4Hz,1H),4.92(s,1H),4.20(p,J＝16.5Hz,1H),3.86 (s, 3H), 3.58(dd, J=45.2, 35.1Hz, 2H), 2.75(s, 3H), 2.50(t, J=10.1Hz, 2H), 2.21(s, 6H), 0.93–0.54( m, 2H), 0.39–0.20 (m, 2H).

LR-Mass (ESI): _570.7 (M _{+ 1} , _C31H36N7O4 ).

Example 8

2-(2-((5-Acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl) -1H-Indole-1-phenyl carbonate (I-8)

The synthesis method is the same as the synthesis method 1 in Example 1, except that methyl chloroformate is replaced with phenyl chloroformate.

¹ H NMR (400MHz, CDCl ₃ ) δ 9.97(s,1H), 9.63(s,1H), 8.60(s,1H), 8.53(d, J=5.2Hz,1H), 8.40-8.34(m, 1H), 8.34–8.29 (m, 1H), 7.67 (s, 1H), 7.47 (ddd, J=5.5, 2.9, 1.3Hz, 2H), 7.40 (td, J=7.4, 1.5Hz, 2H), 7.37 –7.30(m,4H),7.17(d,J=5.2Hz,1H),6.79(s,1H),6.42(dd,J=16.5,9.3Hz,1H),6.32(dd,J=16.9,1.9 Hz, 1H), 5.58(dd, J=9.8, 2.0Hz, 1H), 3.89(s, 3H), 3.00–2.89(m, 2H), 2.70(s, 3H), 2.45(s, 2H), 2.33 (s, 7H).

LR-Mass (ESI): _606.7 (M _{+ 1} , _C34H36N7O4 ).

Example 9

2-(2-((5-Acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl) -1H-Indole-1-benzyl carbonate (I-9)

The synthesis method is the same as that of synthesis method 1 in Example 1, except that methyl chloroformate is replaced with benzyl chloroformate.

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.08 (s, 1H), 9.63 (s, 1H), 8.54 (d, J=5.2 Hz, 1H), 8.39 (dd, J=9.7, 2.0 Hz, 2H) ,8.26(d,J=8.0Hz,1H),7.64(s,1H),7.57–7.50(m,2H),7.48–7.33(m,5H),7.12(d,J=5.2Hz,1H), 6.82(s, 1H), 6.48-6.29(m, 2H), 5.68(dd, J=9.3, 2.6Hz, 1H), 5.51(s, 2H), 3.91(s, 3H), 2.95-2.89(m, 2H), 2.73(s, 3H), 2.36(s, 2H), 2.31(s, 6H).

LR-Mass (ESI): _620.7 (M _{+ 1} , _C35H38N7O4 ).

Example 10

2-(2-((5-Acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl) -1H-Indole-1-carbonate-2'-methylbenzyl ester (I-10)

The synthesis method is the same as the synthesis method 1 in Example 1, except that methyl chloroformate is replaced with o-methyl benzyl chloroformate.

¹ H NMR (500 MHz, CDCl ₃ ) δ 9.88 (s, 1H), 8.78-8.69 (m, 2H), 8.55 (dd, J=14.8, 3.1 Hz, 1H), 8.11 (dd, J=14.9, 3.0 Hz, 1H), 7.47–6.99 (m, 8H), 6.43 (s, 1H), 6.12 (dd, J=53.0, 19.0Hz, 2H), 5.69 (dd, J=33.0, 4.9Hz, 1H), 5.13 (s, 2H), 4.92(s, 1H), 3.86(s, 3H), 3.55(dt, J=25.1, 14.6Hz, 2H), 2.75(s, 3H), 2.50(t, J=14.6Hz, 2H), 2.29(s, 3H), 2.21(s, 6H).

LR-Mass (ESI): _634.8 (M _{+ 1} , _C36H40N7O4 ).

Example 11

2-(2-((5-Acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl) -1H-Indole-1-carbonic acid-2'-acetoxybenzyl ester (I-11)

The synthesis method is the same as that of synthesis method 1 in Example 1, except that methyl chloroformate is replaced with o-acetoxybenzyl chloroformate.

¹ H NMR (500 MHz, CDCl ₃ ) δ 9.81 (s, 1H), 9.10 (s, 1H), 8.80–8.37 (m, 2H), 8.11 (dd, J=15.0, 3.1 Hz, 1H), 7.42– 7.01(m, 8H), 6.43(s, 1H), 6.30–5.95(m, 2H), 5.69(dd, J=33.2, 4.8Hz, 1H), 5.13(s, 2H), 4.94(s, 1H) , 3.86(s, 3H), 3.53(dt, J=16.1, 14.5Hz, 2H), 2.75(s, 3H), 2.55–2.26(m, 5H), 2.21(s, 6H).

LR _- Mass (ESI): _678.8 (M+ ₁ , _C37H40N7O6 ).

Example 12

2-(2-((5-Acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl) -1H-Indole-1-allyl carbonate (I-12)

The synthesis method is the same as the synthesis method 1 in Example 1, except that methyl chloroformate is replaced with allyl chloroformate.

¹ H NMR (400MHz, CDCl ₃ ) δ 9.56(s, 1H), 9.54-9.40(m, 1H), 8.52(d, J=5.2Hz, 1H), 8.42(s, 1H), 8.38(d, J=6.8Hz, 1H), 8.27(d, J=8.3Hz, 1H), 7.63(s, 1H), 7.46–7.35(m, 2H), 7.15(d, J=5.2Hz, 1H), 6.74( s, 1H), 6.42 (dd, J=16.9, 1.9Hz, 1H), 6.18–6.05 (m, 1H), 6.20–6.05 (m, 1H), 5.72 (d, J=12.0Hz, 1H), 5.51 (dd,J＝17.1,1.3Hz,1H),5.40(d,J＝10.3Hz,1H),4.98(d,J＝5.9Hz,2H),3.92(s,3H),3.25(s,2H) , 2.75(s, 4H), 2.72(s, 4H).

LR-Mass (ESI): _570.8 (M _{+ 1} , _C31H36N7O4 ).

(2) Examples of biological activity detection

Test Example 1: Cell Level Inhibition Experiment

experimental method:

The in vitro proliferation inhibitory effect of the compounds on human epidermal carcinoma A431 cell line with high expression of EGFR WT and human non-small cell lung cancer cell line with high expression of EGFRT790M/L858R mutation was detected. A431 cells and NCI-H1975 cell line were purchased from American Standard Biological Collection Center (ATCC). The sulforhodamine B (SRB) method was used for detection, as follows: a certain number of different tumor cells in the logarithmic growth phase were inoculated into a 96-well culture plate, and after culturing for 24 hours, the cells adhered to the wall, and then different concentrations of the present invention were added. Three replicate wells were set for each concentration of test compounds, and the corresponding concentration of DMSO solution control and cell-free zero wells were set. After the cells were treated with drugs for 72 h, the culture medium was poured out, and 100 μL of ice-cold 10% trichloroacetic acid solution was added to fix the cells. Then 100 μL of SRB (4 mg/mL) (Sigma, St Louis, MO, USA) solution was added, stained at room temperature for 15 min, removed the staining solution, washed with 1% glacial acetic acid for 5 times, and air-dried. Finally, 150 μL of 10 mM Tris solution (pH 10.5) was added, and the OD value was measured at a wavelength of 515 nm by a tunable wavelength microplate reader (VERSAmax ^™ , Molecular Device Corporation, Sunnyvale, CA, USA). The inhibition rate of drug on cell growth was calculated by the following formula: inhibition rate (%)=(OD control-OD added drug)/OD control×100%.

According to the growth inhibitory effect of the compound on cells, its half inhibitory concentration (IC ₅₀ ) value was calculated, as shown in Table 1.

The results of the analysis of the growth inhibitory effect of the compounds in Table 1

Experimental conclusion: In parallel experiments, some indole-1-carbonate compounds and AZD9291 (purchased from Yaodu Jingwei Information Technology (Beijing) Co., Ltd.) have comparable IC ₅₀ to the EGFR mutant cell line NCI-H1975. At the same time, they all show good selectivity and may have better safety in animals.

Test Example 2: Effects of I-1 and I-12 on EGFR and its downstream signal phosphorylation

experimental method:

Detection was performed using conventional immunoblotting (Western Blot). A431 cells and NCI-H1975 cells in logarithmic growth phase were seeded in 6-well plates according to a certain number, and after adherent culture in the incubator overnight, the serum-free medium was changed to starvation for 24 hours, and a certain concentration of compounds was added for 2 hours. EGF-stimulating factor 50ng/mL was acted on for 10min, and the cells were lysed with lysis buffer to collect samples. Then take an appropriate amount of samples for SDS-PAGE electrophoresis. After electrophoresis, the protein is transferred to a nitrocellulose membrane using a semi-dry electrotransfer system, and the nitrocellulose membrane is placed in a blocking solution (5% skimmed milk powder diluted in 0.1 wt. The membranes were blocked for 2 h at room temperature in TBS with temperature of 20, and then the membranes were respectively placed in primary antibody solution (1:500 diluted in TBS containing 0.1 wt.% Tween 20) and incubated overnight at 4°C. The cells were washed three times with triethanolamine buffered saline (TBS) containing 0.1 wt.% Tween 20 for 15 min each. The membrane was placed in a secondary antibody solution (horseradish peroxidase-labeled goat anti-rabbit IgG, diluted 1:2000 in TBS containing 0.1 wt.% Tween 20) for 1 h at room temperature. After washing three times with TBS containing 0.1 wt.% Tween 20, after 15 min each time, color was developed with ECLplus reagent and photographed with Image Quant LAS 4000, as shown in Figure 1.

Experimental conclusion: In parallel experiments, I-1 can significantly inhibit the phosphorylation of EGFRL858R/T790M double mutation at 10nM and 100nM concentrations, and also has a significant inhibitory effect on the phosphorylation of AKT and ERK in downstream signaling pathways. The effect is similar to AZD9291.

Test Example 3: Pharmacokinetic Test of I-1 in Beagle Dogs

Mode of administration: single gavage administration.

Dosage: 2 mg/5 mL/kg.

Preparation formula: It is formulated into a suspension with 0.5% CMC-Na.

Experimental animals: strain: Beagle; sex: male; body weight: 8-11Kg; fasting for 12 hours before the test, free drinking water. 4h after the administration of unified food.

Sample collection: 0.6 mL of blood was collected from the extremity veins before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h after administration.

Before blood sample collection, 20 μL of 1M esterase inhibitor (BNPP) was added to the labeled EDTA anticoagulation tube in advance, and stored in a refrigerator at 4°C. When the sample is collected, collect 600 μL of whole blood into an anticoagulant tube that has added 20 μL of 1M esterase inhibitor (BNPP), and gently invert the tube as soon as possible to mix 5-6 times (do not shake vigorously to avoid hemolysis). , Complete centrifugation at 4°C for 10min (3500rpm) within 1h to obtain plasma, and store in -70°C refrigerator. (Note: The preparation method of 1M dinitrophenol phosphate diester (BNPP) solution: after weighing 1.36g of BNPP, fully dissolve it in 4mL of acetonitrile:water (1:1, v/v), that is, it is obtained.)

Plasma sample pretreatment: add 25.0 μL internal standard solution (50.0 ng/mL verapamil internal standard solution) and 150 μL acetonitrile to 25.0 μL plasma sample, vortex for 1 min, centrifuge for 5 min (14000 rpm, 4 °C), take the supernatant for LC-MS/MS analysis.

LC-MS analysis:

1. Instruments

Liquid chromatography system: WatersACQUITYI Class system, Waters Corporation

Autosampler WatersACQUITYFTN Autosampler, Waters Corporation

MS/MS system: Triple Quad 5500 triple quadrupole tandem mass spectrometer equipped with electrospray ionization source (ESI source), Applied Biosystems, USA

Data processing: Analyst 1.6.2 quantitative processing software (AppliedBiosystems, USA)

2. Chromatographic conditions and mass spectrometry conditions

Chromatographic conditions

Analytical column: YMC-Triat C ₁₈ column, 2.0×50mm, 5.0μM, YMC Corporation, Japan

Pre-column: C ₁₈ guard column, 4.0×3.0mm ID, Philomon Corporation, USA

Column temperature: 40℃

Mobile phase: Phase A: 5mM ammonium acetate aqueous solution (containing 0.1% formic acid); Phase B: acetonitrile

Flow rate: 0.600mL/min

Injection volume: 2μL

Gradient elution:

MS conditions

The ion source is electrospray ionization source (ESI source), positive ion detection; ion spray voltage 5500V; ion source temperature 500°C; ion source gas 1 (N ₂ ) 50 psi; ion source gas 2 (N ₂ ) 50 psi; N ₂ ) 30 psi.

Table 2 Metabolic kinetics analysis of compounds in beagle dogs

Experimental conclusion: The results of pharmacokinetics test in beagle dogs showed that the plasma exposure Cmax of I-1 in beagle dogs was 1.7 times that of AZD9291, the AUC was 1.6 times that of AZD9291, the half-life was 7h, and the pharmacokinetics was 7h. The parameters are reasonable, see Table 2. Compared with AZD9291, the drugability is better.

According to the above description, without departing from the basic technical idea of the present invention, according to common technical knowledge or conventional means in the field, various modifications and substitutions can be made to the embodiments of the above invention.

Claims (6)

1. Indole-1-carbonate compounds shown in a general formula (I) or pharmaceutically acceptable salts thereof,

wherein,

r is selected from methyl, ethyl, propyl and isopropyl;

r' is methyl.

2. The method for preparing the indole-1-carbonate compound shown in the general formula (I) or the pharmaceutically acceptable salt thereof comprises the step of subjecting the compound shown in the formula II and an acylation reagent to acylation reaction to obtain the compound shown in the general formula (I), which is shown in the following formula:

wherein R, R' is as defined in claim 1;

the acylating agent is selected from haloformate XCOOR and dicarbonate

Or carbonates

Wherein X is halogen.

3. A pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the indole-1-carbonate compounds or pharmaceutically acceptable salts according to claim 1 as an active ingredient, and optionally a pharmaceutically acceptable carrier.

4. A pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the indole-1-carbonate compounds or pharmaceutically acceptable salts according to claim 1 as an active ingredient together with other pharmaceutically acceptable therapeutic agents, and optionally a pharmaceutically acceptable carrier.

5. Use of the indole-1-carbonate compound or pharmaceutically acceptable salt according to claim 1 or the pharmaceutical composition according to claim 3 or 4 for the preparation of a medicament for selectively inhibiting the active EGFR resistance mutation T790M and the activating mutation.

6. The use of claim 5, wherein said selective inhibitory activity of EGFR resistant mutation T790M and activating mutation is selected from lung cancer, breast cancer, ovarian cancer, liver cancer, melanoma, prostate cancer, colon cancer, rectal cancer, glial cell carcinoma, head and neck cancer and gastric cancer.

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