Compounds for inhibiting EGFR kinase, preparation methods and uses thereof

Abstract

To develop TKIs with selectivity to exon 20 insertions over wild-type EGFR and to provide a new generation of TKIs that demonstrate superior biochemical and cellular activity towards T790M and exon 20 insertion mutations over wild-type EGFR.SOLUTION: The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, a preparation method and application thereof. The compounds can selectively inhibit the activity of epidermal growth factor receptor (EGFR) mutants, and shows good inhibitory effect towards mutant EGFR and anti-proliferative activity against cancer cells. Thus they can be used for treating tumors and related diseases.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] This application claims the benefit of Chinese Patent Application No. 201910600229.1, filed on July 4, 2019, which is hereby incorporated by reference in its entirety.

[0002] (Technical Field) The present invention relates to the field of pharmaceuticals, and more specifically, to a series of EGFR inhibitors, preparation methods and their uses.

Background Art

[0003] Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase of the ErbB family in the cell membrane. Other members of the ErbB family include ERBB2 (HER2), ERBB3 (HER3) and ERBB4 (HER4). EGFR promotes cell proliferation by activating the MAPK and PI3K signaling pathways. Overactivated EGFR due to mutation, amplification or overexpression has been identified in multiple solid tumors, particularly lung cancer.

[0004] The prevalence of EGFR mutations in non-small cell lung cancer (NSCLC) is 50% in East Asia and 15% in Europe and the United States. Most EGFR mutations occur in exons 18 to 21. First-generation EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib mainly target mutations in exons 18, 19 and 21. However, resistance inevitably occurs during the treatment process. The EGFR-T790M mutation accounts for more than 60% of the acquired resistance to first-generation TKIs. Afatinib, a second-generation irreversible EGFR inhibitor, is effective against T790M but is accompanied by substantial toxicity such as rash and diarrhea due to its activity against wild-type EGFR. AZD9291, a third-generation EGFR TKI, specifically targets T790M and has been approved as a therapeutic agent for patients with EGFR T790M mutation-positive non-small cell lung cancer.

[0005] In addition to the aforementioned classical EGFR mutations, exon 20 insertions constitute the third largest group of EGFR mutations, with an incidence of 4-10% among all EGFR mutations. They are more commonly seen in women, non-smokers, Asians, and adenocarcinoma patients and are associated with clinical characteristics similar to those of classical mutations.

Chem.

[0006] Mutations in exon 20 cluster at amino acids 762-823, all of which are insertions except for T790M. In addition to EGFR, approximately 2% of NSCLC patients carry a her2 mutation, 90% of which are exon 20 insertions. Exon 20 insertion mutations in Her2 occur at structurally similar positions to those in EGFR with similar molecular characteristics and drug sensitivities. That is, they are broadly classified into exon 20 insertions. 122 subtypes of EGFR exon 20 insertions have been identified to date, with Asp770_Asn771ins being the most common, followed by Va1769_Asp770ins, Ala767_Va1769ins, and Ser768_Asp770ins. On the other hand, the most common variant of exon 20 mutation in Her2 is A775_G776insYVM, accounting for 70% of cases. Exon 20 insertions in EGR and Her2 all promote ligand-independent activation.

Summary of the Invention

Problems to be Solved by the Invention

[0007] The majority of EGFR exon 20 insertions are naive, and some of them are acquired. Except for lung cancer, exon 20 insertions are also observed in a rare type of head and neck cancer known as sinonasal squamous cell carcinoma. Considering the presence of exon 20 insertions in a significant number of patients, drugs that can inhibit EGFR carrying the said exon 20 insertions may be particularly useful in this patient group. However, many studies have shown that exon 20 insertions, especially those after amino acid 764, are not sensitive to approved TKIs, and the available treatment options are limited. Two TKIs for exon 20 insertions, poziotinib and mobocertinib, are currently in clinical trials. Among them, poziotinib is probably related to serious adverse effects due to the simultaneous inhibition of wild-type EGFR. Therefore, the development of TKIs with selectivity for exon 20 insertions rather than wild-type EGFR is needed. The new generation of TKIs disclosed in this patent shows better biochemical and cellular activities against T790M and exon 20 insertion mutations than wild-type EGFR.

Means for Solving the Problems

[0008] (Summary of the Invention) The present invention provides a compound of general formula (I) and a pharmaceutically acceptable salt thereof.

Chemical formula

Chemical formula

[0009] In general formula (I), R 1 is preferably selected from the group consisting of hydrogen, halogen, C1-6 alkyl, -C(O)OR 8 or CN, and R 5 , R 6 and R 7 are preferably independently selected from the group consisting of hydrogen and halogen.

[0010] The present invention provides a compound of formula (I) that can inhibit one or more EGFR activation or drug-resistant mutants, such as the T790M drug-resistant mutant and the exon 20 insertion activation mutant. Therefore, such compounds can be used in cancer treatment regimens for patients who have acquired drug resistance to existing EGFR inhibitor-based therapies.

[0011] The present invention has a stronger inhibition of EGFR formed by activation or resistance mutants than wild-type EGFR due to reduced toxicity associated with wild-type EGFR inhibition. Therefore, the present invention provides a compound of general formula (I) that is particularly suitable for use as a therapeutic agent for cancer treatment.

[0012] The present invention provides a method for preparing a compound of general formula (I).

[0013] The present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, excipient or diluent.

[0014] The present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the treatment of diseases mediated by EGFR activation or drug-resistant mutants in mammals, particularly humans, especially humans during cancer treatment.

[0015] The present invention provides a method for treating a disease mediated by EGFR activation or a drug-resistant variant, particularly cancer, in a mammal, especially a human, which comprises administering to a patient a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) and a pharmaceutically acceptable carrier, excipient or diluent.

[0016] The present invention provides a method for selectively inhibiting an EGFR activation or drug-resistant variant as compared to wild-type EGFR, which comprises contacting or administering to a patient a biological sample of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0017] The cancers mentioned in the present invention may be selected from hepatocellular carcinoma, lung cancer, pancreatic cancer, breast cancer, cervical cancer, endometrial cancer, colorectal cancer, gastric cancer, lung cancer, nasopharyngeal cancer, ovarian cancer, prostate cancer, leukemia, lymphoma, non-Hodgkin lymphoma, myeloma, glioma, glioblastoma, melanoma, gastrointestinal stromal tumor (GIST), thyroid cancer, cholangiocarcinoma, kidney cancer, anaplastic large cell lymphoma, acute myeloid leukemia (AML), multiple myeloma or mesothelioma.

[0018] In the present invention, particularly preferred compounds of formula (I) or pharmaceutically acceptable salts thereof include the following.

[0019]

Table 1-1

Table 1-2

Table 1-3

Table 1-4

[0020] The present invention provides a process for preparing a compound of formula (I) comprising the following steps.

Chemical formula

Chemical formula

[0021] Using compounds (a) and (b) as starting materials, a substitution reaction is carried out under basic conditions to obtain intermediate 1. Using intermediate 1 and intermediate 2, a substitution or coupling reaction is carried out to obtain compound (c). Compound (c) is subjected to nucleophilic substitution to obtain compound (d). The nitro group of the said compound (d) is reduced to obtain compound (e). Further acylation of compound (e) is carried out to obtain compound (I), or intermediate 1 and intermediate 2' are directly subjected to a substitution or coupling reaction to obtain compound (I).

[0022] In one embodiment, when intermediate 1 is intermediate 1a, the compound of formula (I) is prepared as follows.

Chemical formula

[0023] In one embodiment, when intermediate 1 is intermediate 1b, the compound of formula (I) is prepared as follows.

Chemical formula

[0024] In one embodiment of the preparation of the compound of formula (I) according to the present invention, the process for the preparation of intermediate 2 and intermediate 2' comprises the following steps.

Chem.

[0025] Using 2,6-dichloro-3-nitropyridine as a starting material, an etherification reaction is carried out to obtain compound (g), which is then subjected to reduction of the nitro group of compound (g) to obtain compound (h), compound (h) is subjected to acylation to obtain compound (i), then compound (i) is subjected to a nitration reaction to obtain compound (j), and this is further deprotected to obtain intermediate 2.

[0026] Compound (j) reacts with R 3 H by substitution to obtain compound (k), compound (k) is protected with Boc to obtain compound (l), which is then subjected to deacetylation protection to obtain compound (m), the nitro group of compound (m) is reduced to obtain compound (n), compound (n) is further acylated to obtain compound (o), and finally compound (o) is deprotected to obtain intermediate 2'.

[0027] In the preparation methods of intermediates 2 and 2', the etherification reaction is carried out under the action of a strong base. Here, the strong base includes, but is not limited to, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium ethoxide and sodium methoxide. The reduction method of the nitro group includes, but is not limited to, using conventional reducing agents known in the art such as iron powder, zinc powder, sodium sulfide, H 2 / PtO 2 and the like. The upper protecting group or deprotecting group is carried out by a conventional method well-known in the art under suitable acidic or basic conditions.

[0028] "Halogen" (or "halo") refers to fluorine, chlorine, bromine or iodine.

[0029] "C1-6 alkyl" refers to a linear or branched alkyl group having 1 to 6 carbon atoms, preferably a linear or branched alkyl group having 1 to 4 carbon atoms. A branched chain means that one or more alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl or propyl, are bonded to the linear alkyl group. Preferred C1-6 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like.

[0030] "Deuterated alkyl" means that one or more hydrogen atoms in the alkyl group are replaced by deuterium. For example, by replacing all 3 hydrogen atoms in the methyl group with deuterium, a deuterated methyl group CD 3 is formed.

[0031] "C1-6 haloalkyl" refers to a C1-6 alkyl group as defined containing one or more halogen atom substituents.

[0032] "C1-6 heteroalkyl" means a C1-6 alkyl as defined containing one or more substituents selected from the group consisting of O, S, N, -(S=O)-, -(O=S=O)- and the like.

[0033] "C3-6 cycloalkyl" refers to a non-aromatic monocyclic or polycyclic group having 3 to 6 carbon atoms, preferably 3 to 6 carbon atoms. Preferred monocyclic C3-6 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl and the like.

[0034] "C1-6 alkoxy" refers to a C1-6 alkyl-O- group in which the parent moiety is bonded by oxygen, where C1-6 alkyl is as defined. Preferred C1-6 alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.

[0035] Any functional group of the present invention may be unsubstituted or substituted with a substituent described herein. The term "substituted" (or substituting) refers to the replacement of one or more hydrogen atoms at a particular atom with a group selected from a particular group, provided that the normal valence state of the particular atom is not exceeded and a stable compound is obtained as a result of the substitution. Such combinations of substituents and / or variables are only permitted when a stable compound is formed by the combination.

[0036] The present invention also includes pharmaceutically acceptable salts of the compounds of formula (I). The term "pharmaceutically acceptable salt" refers to relatively non-toxic acid addition salts or base addition salts of the compounds of the present invention. The acid addition salts are salts of the compounds of formula (I) according to the present invention with suitable inorganic or organic acids, and these salts can be prepared in the final separation and purification of the compounds, or by reacting the purified compound of formula (I) in the form of the free base with a suitable organic or inorganic acid. Representative acid addition salts include hydrobromide, hydrochloride, sulfate, bisulfate, sulfite, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, hydrogen phosphate, carbonate, bicarbonate, toluylate, citrate, maleate, fumarate, succinate, tartrate, benzoate, methanesulfonate, p-toluenesulfonate, gluconate, lactate, laurate, etc. The base addition salts are salts of the compounds of formula (I) of the present invention with suitable inorganic or organic bases, including salts with, for example, alkali metals, alkaline earth metals, quaternary ammonium cations, such as sodium, lithium, potassium, calcium, magnesium, tetramethylammonium, tetraethylammonium, etc., and salts formed with ammonia (NH 3 ) and primary, secondary or tertiary amines, such as amine salts including methylamine salt, dimethylamine salt, trimethylamine salt, triethylamine salt, ethylamine salt, etc.

[0037] Enzyme activity assays demonstrated that the compounds of the present invention have good activity against exon 20 insertion mutants. Cellular assays, namely in vitro anti-proliferation assays of activated mutant cells, i.e., exon 20 insertion type activated mutant cells, drug-resistant tumor cells, and wild-type EGFR human skin cells, showed that the compounds have good anti-proliferation activity against activated mutant cells or drug-resistant mutant tumor cells, but have weak anti-proliferation activity with good selectivity against wild-type EGFR cancer cells. The compounds of the present invention are useful for the treatment of diseases or conditions mediated by EGFR activation or the activity of resistant mutants, particularly for the treatment of cancer. Such cancers include, but are not limited to, hepatocellular carcinoma, lung cancer, head and neck cancer, pancreatic cancer, breast cancer, cervical cancer, endometrial cancer, colorectal cancer, gastric cancer, lung cancer, nasopharyngeal cancer, ovarian cancer, prostate cancer, leukemia, lymphoma, non-Hodgkin lymphoma, multiple myeloma, glioma, glioblastoma, melanoma, gastrointestinal stromal tumor (GIST), thyroid cancer, cholangiocarcinoma, kidney cancer, anaplastic large cell lymphoma, acute myeloid leukemia (AML), multiple myeloma, or mesothelioma. Particularly for the threonine to methionine mutation of epidermal growth factor receptor 790 (EGFR T790M), the thymol type and the activated type mutations, the exon 20 insertion type activated mutant tumor type is more preferably applicable.

[0038] It should be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the claimed invention.

[0039] It should be understood that various changes or modifications can be made by those skilled in the art without departing from the scope and spirit of the present invention, and it will be apparent to those skilled in the art that such equivalents can be included within the scope of the present invention as defined by the appended claims.

Brief Description of the Drawings

[0040]

Figure 1

Best Mode for Carrying Out the Invention

[0041] Hereinafter, embodiments of the present invention will be described in detail.

[0042] (Example) The present invention will be further described with specific examples. These examples are for illustrative purposes only and are not intended to limit the scope of the present invention. It should be understood that the present invention is not limited to these examples. Those skilled in the art will readily understand that these compounds can be prepared using the conditions of the following preparation methods and known variations of the processes. Starting materials used in the present invention without special description are commercially available.

[0043] Abbreviations: room temperature (RT, rt); aqueous solution (aq.); petroleum ether (PE); ethyl acetate (EA); dichloromethane (DCM); methanol (MeOH); ethanol (EtOH); tetrahydrofuran (THF); dimethylformamide (DMF); dimethyl sulfoxide (DMSO); triethylamine (TEA); diisopropylethylamine (DI(P)EA); 4-dimethylaminopyridine (DMAP); palladium on carbon (Pd / C); equivalent (eq.); gram / milligram (g / mg); mole / millimole (mol / mmol); liter / milliliter (L / mL); minute (s); hour (h, hr, hrs); nitrogen (N 2 ); nuclear magnetic resonance (NMR); thin layer chromatography (TLC).

[0044] General synthesis method: Unless otherwise specified, all reactions are carried out under an inert gas (e.g., argon or nitrogen) using commercially available reagents and anhydrous solvents without further treatment.

[0045] Mass spectra were recorded using a liquid chromatography-mass spectrometer (LC-MS) (Agilent 6120B single-stage and four-stage LC-MS). Nuclear magnetic resonance spectra (e.g., hydrogen ( 1 H), carbon (13 C), phosphorus ( 31 P), and fluorine ( 19 F)) were recorded using a Bruker AMX-400, Gemini-300, or AMX-600 NMR spectrometer in a deuterated solvent such as deuterated chloroform, deuterated methanol, heavy water, or deuterated dimethyl sulfoxide, with the deuterated solvent peak used as a reference standard. The unit of chemical shift δ is ppm, and the unit of coupling constant (j) is Hertz (Hz). Coupling splitting peaks in the NMR spectrum are represented as broad singlet peak (brs), singlet peak (s), doublet peak (d), double doublet peak (dd), triplet peak (t), quartet peak (q), and multiplet peak (m).

[0046] Detailed Description of the Invention

[0047] 1. Preparation Example of the Intermediate of the Present Invention

[0048] Intermediate 1a: Synthesis of 1-(2-Chloropyrimidin-4-yl)-8-fluoro-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one

Chemical formula

[0049] Step 1: Synthesis of 3-Chloro-N-(4-fluorophenyl)propenamide

Chemical formula

[0050] 3-Chloropropionyl chloride (653 g, 1 eq) was dissolved in 6.5 L of dichloromethane, and 4-fluoroaniline (783.6 g, 1.05 eq), the starting material, was added dropwise under a dry ice / ethanol bath while maintaining the internal temperature at 0 - 10 °C. A large amount of solid precipitated. After the addition, the mixture was stirred for an additional 0.5 h, and imidazole (405 g, 1.01 eq) was added in several portions (with an obvious temperature rise), while maintaining the internal temperature at 0 - 10 °C. After stirring for 1 h, the reaction was complete. The reaction solution was poured into dilute hydrochloric acid, separated, and the organic phase was concentrated until a large amount of solid precipitated. 800 mL of PE / EA (5 / 1) was added, stirred overnight, filtered, and washed with PE / EA (5 / 1) to obtain 950 g of 3-chloro-N-(4-fluorophenyl)propenamide as a white solid. MS (ESI): m / z = 202 [M+H] + , 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.16 (s, 1H), 7.71 - 7.60 (m, 2H), 7.23 - 7.13 (m, 2H), 3.91 (t, J = 6.3 Hz, 2H), 2.84 (t, J = 6.3 Hz, 2H).

[0051] Step 2: Synthesis of 6-fluoro-3,4-dihydroquinolin-2(1H)-one

Chemical Structure

[0052] In a 5 L three-necked flask, 3-chloro-N-(4-fluorophenyl)propionamide (820 g, 1 eq) was added, followed by the addition of aluminum trichloride anhydrous (1640 g, 3 eq) while stirring, and then nitrogen replacement was carried out three times. The external temperature was set to 60 °C, and the flask was stirred until it became molten (the internal temperature was raised to 70 °C). After lowering the internal temperature, the flask was heated to 100 °C (the internal temperature was 97 °C), and the mixture was stirred for 4 hours. LCMS showed that when 500 g of aluminum trichloride was added and the mixture was further stirred for 4 hours, the reaction convention was about 58%. LCMS showed that the reaction convention was about 73%. An additional 200 g of aluminum trichloride was added and stirred for 4 hours. LCMS showed that the unconverted starting material was very little. When the mixture was cooled to 40 °C, DCM (2 L) was added to the mixture, and then THF (6 L) was added dropwise to the mixture, resulting in intense heat generation. EA (3 L) was added, and water was continuously added to separate a large amount of precipitate. The organic phase was separated, the organic phase was concentrated, and the aqueous phase was filtered. The combined products were slurried with EA and water respectively to obtain 600 g of wet product as a white solid. MS (ESI): m / z = 166 [M+H] + , 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.16 (s, 1H), 7.71 - 7.61 (m, 2H), 7.23 - 7.13 (m, 2H), 3.92 (t, J = 6.3 Hz, 2H), 2.85 (t, J = 6.3 Hz, 2H).

[0053] Step 3: Synthesis of 6-fluoro-8-nitro-3,4-dihydroquinolin-2(1H)-one

Chemical Structure

[0054] 6-Fluoro-3,4-dihydroquinolin-2(1H)-one (700 g, 1 eq) was added to a 5 L three-necked flask, followed by 3.5 L of acetic anhydride. The internal temperature was controlled at 15 - 20 °C, and concentrated nitric acid (485 g, 1.2 eq) was slowly added dropwise. After the addition, the solution became clear. It was further stirred at 25 °C for 30 minutes, then a large amount of solid precipitated. The reaction solution was poured into water (20 L) and stirred until hydrolysis was complete. It was filtered, and the filter cake was washed with water until the washing solution became colorless, and then dried to obtain 700 g of the desired intermediate as a yellow solid. MS(ESI): m / z = 211 [M+H] + , 1H NMR: 1 1H NMR (400 MHz, DMSO-d 6 ) δ 9.84 (s, 1H), 7.91 (dd, J = 8.9, 2.9 Hz, 1H), 7.70 (dd, J = 8.2, 2.8 Hz, 1H), 3.15 - 3.04 (m, 2H), 2.63 (dd, J = 8.3, 6.7 Hz, 2H).

[0055] Step 4: Synthesis of 6-Fluoro-1,2,3,4-tetrahydroquinolin-8-amine

Chemical formula

[0056] LiAlH 4(48 g, 1.27 mol) was dissolved in THF (1 L), and a suspension of 6-fluoro-8-nitro-3,4-dihydroquinolin-2(1H)-one (89 g, 0.42 mol) in THF (100 mL) was added in portions, maintaining the internal temperature at 5 - 10 °C. After the addition was complete, the mixture returned to 12 °C naturally and was stirred for 0.5 h. Then, the mixture was cooled below 0 °C, and while maintaining the internal temperature below 5 °C, water (48 mL), 15% NaOH (48 mL), and water (144 mL) were successively quenched, and diatomaceous earth (90 g) was added. After stirring for 30 min below 5 °C, the mixture was filtered through diatomaceous earth, washed with THF, the filter cake was slurried again with THF, filtered, and the organic phase was concentrated. The residue was purified by column chromatography (the mobile phase PE / EA ratios were 1 / 10, 1 / 4, and 2 / 3 and contained 0.1% TEA) to obtain 57 g of the desired intermediate as a wine-red oily liquid. MS(ESI): m / z = 167 [M + H] + 。

[0057] Step 5: Synthesis of 8-fluoro-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one

Chemical Structure

[0058] 6-Fluoro-8-amino-1,2,3,4-tetrahydroquinoline (166 g, 1 mol) was dissolved in THF (1 L), and a suspension of triphosgene (118 g, 0.4 mol) in THF (300 mL) was added dropwise while maintaining the internal temperature at 5 - 10 °C. After the addition was complete, stirring was continued for 0.5 h, imidazole (160 g, 20 mol) was added dropwise, the internal temperature was maintained at 10 - 20 °C, and after the temperature was returned to room temperature, stirring was continued for 15 min. Under the monitoring of LCMS, after the starting material was consumed, 1 L of 13% NaCl solution was added, followed by THF (1 L), the organic phase was separated, extracted with THF (2 L * 2), dried, concentrated, the residue was slurried with EA overnight, and filtered to obtain 168 g of the desired intermediate as a light brown solid. MS(ESI): m / z = 193 [M + H].

[0059] Step 6: Synthesis of 1-(2-Chloropyrimidin-4-yl)-8-fluoro-5,6-dihydro-4H-imidazo-[4,5,1-ij]quinolin-2(1H)-one

Chem.

[0060] 8-Fluoro-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (36 g, 0.19 mol) and 2,4-dichloropyrimidine (34 g, 0.23 mol) were dissolved in DMF (400 mL), cesium carbonate (122 g, 0.37 mol) was added, and the mixture was stirred at room temperature for 4 h. Completion of the reaction was confirmed by LCMS. The mixture was diluted with water (250 mL), the solid was filtered, and the crude sample was further purified by column chromatography (DCM / EA, 100 / 1), concentrated to about 50 mL, slurried with PE (200 mL), filtered to give 45 g of the desired intermediate as a white solid. MS (ESI): m / z = 305 [M+H] + , 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.81 (d, J = 5.7 Hz, 1H), 8.42 (d, J = 5.8 Hz, 1H), 7.75 (d, J = 9.7 Hz, 1H), 7.00 (d, J = 9.6 Hz, 1H), 3.82 (t, J = 5.5 Hz, 2H), 2.85 (t, J = 5.6 Hz, 2H), 2.15 - 2.01 (m, 2H).

[0061] Intermediate 1b: Synthesis of 1-(2-Chloropyrimidin-4-yl)-5,6-dihydro-4H-imidazo-[4,5,1-ij]quinolin-2(1H)-one

Chem.

[0062] Step 1: Synthesis of N-Methoxy-3,4-dihydroquinoline-1(2H)-carboxamide

Chem.

[0063] Triphosgene (335 g, 1.13 mol) was dissolved in DCM (3 L), and a solution of 1,2,3,4-tetrahydroquinoline (300 g, 2.26 mol) and triethylamine (390 g, 3.86 mmol) in DCM (2 L) was added dropwise at 0 - 5 °C over 1.5 h. After the addition, the mixture was stirred at room temperature for 1 h. TLC (PE:EA = 5:1) showed that most of the 1,2,3,4-tetrahydroquinoline had been consumed. Triethylamine (800 g, 7.92 mol) and methoxyamine hydrochloride (375 g, 4.52 mol) were added, and the mixture was further stirred at room temperature (15 °C) for 16 h. TLC (PE:EA = 5:1) confirmed that a small part (about 20%) of the starting materials remained unconsumed, and then the reaction was heated to 30 °C (water bath) for an additional 3 h. The completion of the reaction was confirmed by TLC (PE:EA = 5:1), and the reaction solution was washed with hydrochloric acid (2 M, 3 L), the aqueous phase was extracted with DCM (1 L), the organic phases were combined, washed with saturated sodium bicarbonate solution (3 L) and saturated brine (2 L), dried over anhydrous sodium sulfate, filtered, and dried to obtain the desired intermediate (580 g) as a yellow solid.

[0064] Step 2: Synthesis of 1-methoxy-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one

Chemical Structure

[0065] N-Methoxy-3,4-dihydroquinoline-1(2H)-carboxamide (crude, 580 g, 1.13 mol) was dissolved in DCM (500 mL), and a solution of bis(trifluoroacetic acid)iodobenzene (1250 g, 2.91 mol) in DCM (1.2 L) was added dropwise at -3 °C to 2 °C. After addition, the mixture was warmed naturally to room temperature (15 °C) and stirred for an additional 1 hour. Completion of the reaction was confirmed by TLC (PE:EA = 1:1). Saturated sodium bicarbonate solution (8 L) was added to the mixture, the organic phase was separated, concentrated, and the residue was purified by column chromatography (PE:EA = 5:1 to 1:1) to obtain the desired intermediate (205 g, yield 44.5%) as a yellow solid.

[0066] Step 3: Synthesis of 5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one

Chemical Structure

[0067] 1-Methoxy-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (51.25 g, 251.22 mol) was dissolved in ethanol (500 mL), and Raney nickel (20 g) was added at room temperature (15 °C). Then the temperature was raised to 50 °C, and the mixture was stirred for an additional 16 hours under a hydrogen balloon. It was found by TLC (PE:EA = 1:1) that about 30% of the starting material was not consumed. The mixture was stirred at 50 °C for an additional 4 hours under a new hydrogen balloon, and TLC (PE:EA = 1:1) indicated that about 20% of the starting material was still not consumed. Additional Raney nickel (8 g) was added at room temperature, and the mixture was stirred at 50 °C for 16 hours under a new hydrogen balloon. Completion of the reaction was confirmed by TLC (PE:EA = 1:1). The reaction solution was cooled to room temperature, filtered through celite, and the filter cake was washed three times with methanol (150 mL). The filtrate was concentrated. The crude product (combining 4 batches) was slurried with PE / EA (1:1, 800 mL) and filtered to obtain the desired intermediate (155 g, yield 88.6%) as an off-white solid.

[0068] Step 4: Synthesis of 1-(2-Chloropyrimidin-4-yl)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one

Chem.

[0069] 5,6-Dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (155 g, 890.80 mol) was dissolved in DMF (1.5 L), 2,4-Dichloropyrimidine (158 g, 1.06 mol) and cesium carbonate (580 g, 1.78 mol) were added at room temperature (10 °C), then heated to 30 °C and stirred for an additional 16 hours. Completion of the reaction was confirmed by TLC (DCM:MeOH = 20:1), water (3 L) was added to the reaction and stirred for an additional 1 hour. Filtered and the filter cake was washed with water (1 L). The filter cake was slurried with PE:EA (1:1, 1.5 L), filtered and dried to obtain the desired intermediate (230 g, 90.2% yield) as an off-white solid.

[0070] Intermediate 2a: Synthesis of N-(5-Amino-2-((2-(dimethylamino)ethyl)-(methyl)-amino)-4-methoxyphenyl)acrylamide

Chem.

[0071] Step 1: N 1 -(2-(Dimethylamino)ethyl)-5-methoxy-N 1 -methyl-2-nitrobenzene-1,4-diamine synthesis

Chem.

[0072] 4-Fluoro-2-methoxy-5-nitroaniline (3 g, 16 mmol) and N 1 ,N 1 ,N 2-Trimethylethane-1,2-diamine (2.47 g, 24 mmol) was dissolved in DMF (30 mL), potassium carbonate (4.5 g, 32 mmol) was added, and the mixture was stirred at 80 °C for 2 hours. The completion of the reaction was confirmed by LCMS, cooled to room temperature, the mixture was diluted with water (60 mL), filtered, and the filter cake was slurried with EtOH / H 2 O (1 / 1), filtered, and dried to obtain the desired intermediate (3.1 g) as a yellow solid. MS (ESI): m / z = 269 [M+H] + .

[0073] Step 2: Synthesis of tert-butyl (4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)carbamate

Chemical formula

[0074] N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -methyl-2-nitrobenzene-1,4-diamine (3.1 g, 12 mmol) was dissolved in THF (40 mL), di-tert-butyl dicarbonate (3.8 g, 17 mmol) was added, and the mixture was stirred at 70 °C for 6 hours before the reaction was completed. It was then concentrated, and the residue was slurried with EA / PE (1 / 5) to obtain the desired intermediate (3.8 g) as a pale yellow solid. MS (ESI): m / z = 369 [M+H] + .

[0075] Step 3: Synthesis of tert-butyl (5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)carbamate

Chemical formula

[0076] (tert-Butyl (4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)carbamate (3.8 g, 10.3 mmol) was dissolved in MeOH (40 mL), purged with nitrogen three times, then Pd / C (0.4 g) was added, and purged with hydrogen three times. Next, the mixture was stirred at room temperature for 4 hours. After the reaction was complete, the mixture was filtered, concentrated, and the crude product was used directly in the next step without further purification. MS(ESI): m / z = 339 [M+H] + 。

[0077] Step 4: Synthesis of tert-Butyl (5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)carbamate

Chemical formula

[0078] (tert-Butyl (5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)carbamate (10.3 mmol) was dissolved in DCM (50 mL), acryloyl chloride (1.36 g, 15 mmol) was added dropwise continuously under an ice bath, and then the mixture was allowed to return to room temperature while stirring for 0.5 hour. The pH was adjusted to 8 by adding saturated sodium bicarbonate solution, the aqueous phase was separated, extracted with DCM (50 mL), the organic phases were combined, dried, concentrated, and the residue was purified by column chromatography (MeOH / DCM = 1 / 70 to 1 / 20) to obtain the desired intermediate (1.4 g) as a gray solid. MS(ESI): m / z = 393 [M+H] + 。

[0079] Step 5: Synthesis of N-(5-Amino-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

Chemical formula

[0080] (5 - Acrylamido - 4 - ((2 - (dimethylamino)ethyl)(methyl)amino)-2 - methoxy - phenyl)-carbamic acid tert - butyl (392 mg, 1 mmol) was dissolved in DCM (5 mL), TFA (1 mL) was added dropwise, and after stirring at room temperature for 1 hour, the reaction was completed. The pH was adjusted to 8 by adding saturated sodium bicarbonate solution under an ice bath. The aqueous phase was separated, extracted with DCM (50 mL), dried, concentrated, and the residue was purified by column chromatography (MeOH / DCM = 1 / 20 to 1 / 10) to obtain the desired intermediate (200 mg) as a brown syrupy solid. MS(ESI): m / z = 293[M + H] + 。

[0081] Intermediate 2b: Synthesis of N-(5 - amino - 2 - ((2 - (dimethylamino)ethyl)(methyl)-amino)-6 - methoxypyridin - 3 - yl)acrylamide

Chemical Structure

[0082] Step 1: Synthesis of 6 - chloro - 3 - nitro - 2-(2,2,2 - trifluoroethoxy)pyridine

Chemical Structure

[0083] 2,6 - Dichloro - 3 - nitropyridine (500 g, 2.6 mol) was dissolved in THF (1 L), cooled to below - 10 °C, sodium hydrogen (104 g, 2.6 mol) was added, trifluoroethanol (260 g, 2.6 mol) was added dropwise at - 15 °C, and after addition, the temperature was returned to room temperature and stirred overnight. The completion of the reaction was confirmed by TLC (PE / EA = 5 / 1), poured into ice water (1 L), stirred, and separated. The organic phase was concentrated to a small volume, extracted twice with EA, the organic phases were combined, washed with water and saturated salt solution, dried, and concentrated to obtain the desired intermediate (720 g) as a yellow oily solid. MS(ESI): m / z = 257[M + H] + 。

[0084] Step 2: Synthesis of 6-chloro-2-(2,2,2-trifluoroethoxy)pyridin-3-amine

Chemical formula

[0085] 6-Chloro-3-nitro-2-(2,2,2-trifluoroethoxy)pyridine (150 g, 0.58 mol) was dissolved in ethanol / water (1.2 L / 0.3 L), and ammonium chloride (160 g, 2.9 mol) was added. After the temperature was raised to 50 °C (internal temperature), iron powder (166 g, 2.9 mol) was slowly added in several batches, then stirred at 80 °C for 1 hour, and the completion of the reaction was confirmed by TLC (PE / EA = 5 / 1). The temperature was lowered to 40 °C (internal temperature), sodium carbonate (160 g) and diatomaceous earth (160 g) were added, followed by stirring for 20 minutes. The mixture was filtered using diatomaceous earth, the filter cake was slurried with DCM, and the ethanol-aqueous solution was concentrated to dryness. This was extracted twice with the DCM in which the filter cake was slurried. The organic phases were combined, washed with water and saturated salt solution, dried, and concentrated to obtain the desired intermediate (122 g) as a black oil. MS (ESI): m / z = 227 [M+H] + 。

[0086] Step 3: Synthesis of N-(6-chloro-2-(2,2,2-trifluoroethoxy)pyridin-3-yl)acetamide

Chemical formula

[0087] 6-Chloro-2-trifluoroethoxypyridin-3-amine (570 g, 2.5 mol) was dissolved in DCM (4.5 L), and DIPEA (540 mL, 3.8 mol) was added. After the temperature was lowered to 0 °C, acetyl chloride (200 mL, 3 mol) was added dropwise over about 1 hour while maintaining the temperature around 10 °C, and then stirred for 30 minutes. TLC (PE / EA = 5 / 1) indicated that the reaction was complete. Water (2 L) was added under an ice bath, the organic phase was separated, the aqueous phase was extracted with DCM, the organic phases were combined, washed with 1 M hydrochloric acid and saturated brine, dried, concentrated, and the residue was purified by column chromatography (PE / EA = 5 / 1) to obtain the desired intermediate (480 g) as a yellow solid-liquid mixture. MS (ESI): m / z = 269 [M+H] + 。

[0088] Step 4: Synthesis of N-(6-chloro-5-nitro-2-(2,2,2-trifluoroethoxy)pyridin-3-yl)acetamide

Chemical Structure

[0089] N-(6-Chloro-2-(2,2,2-trifluoroethoxy)pyridin-3-yl)acetamide (300 g, 1.1 mol) was suspended in anhydrous trifluoroacetic acid (1.5 L) and cooled to below -5 °C. Concentrated nitric acid (125 g, 1.2 mol) was added dropwise over 1 hour, then stirred at -5 °C for 3 hours. The completion of the reaction was confirmed by TLC (PE / EA = 2 / 1), then added to an ice-water mixture with stirring, followed by stirring for a short time, filtered, and the filter cake was successively leached with water and PE. The wet product (185 g) was slurried in PE / EA (400 mL) overnight, filtered, the filter cake was slurried again in PE / EA (5 / 1), filtered, and dried to obtain the desired intermediate (220 g) as a yellow solid. MS (ESI): m / z = 314 [M+H] + 。

[0090] Step 5: Synthesis of 6-chloro-5-nitro-2-(2,2,2-trifluoroethoxy)pyridin-3-amine [Chemical]

[0091] N-(6-chloro-5-nitro-2-(2,2,2-trifluoroethoxy)pyridin-3-yl)acetamide (220 g, 0.7 mol) was suspended in a mixed solvent of methanol / concentrated hydrochloric acid (900 / 220 mL), heated at 50 °C for about 4 hours. The reaction mixture became clear, and it was confirmed by TLC that the reaction was complete. The reaction solution was added to water with stirring, filtered, the filter cake was washed with water, then slurried with saturated sodium bicarbonate solution, filtered, the filter cake was successively leached with water and PE, and dried to obtain the desired intermediate (175 g) as a yellow solid. MS(ESI): m / z = 272 [M+H] + .

[0092] Step 6: N 2 -(2-(dimethylamino)ethyl)-N 2 -methyl-3-nitro-6-(2,2,2-trifluoroethoxy)pyridine-2,5-diamine synthesis [Chemical]

[0093] 6-chloro-5-nitro-2-(2,2,2-trifluoroethoxy)pyridin-3-amine (950 mg, 3.5 mmol) was dissolved in acetonitrile (15 mL), K 2 CO 3 (967 mg, 7 mmol) and N,N,N′-trimethylethylenediamine (643 mg, 6.3 mmol) were added at room temperature, and then the reaction mixture was stirred at 80 °C overnight. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain the desired intermediate (1.16 g) as a red oil. MS(ESI): m / z = 338.2 [M+H] + .

[0094] Step 7: N 2 -(2-(dimethylamino)ethyl)-N2 Synthesis of -Methyl-3-nitro-5-di-tert-butoxycarbonylamino-6-(2,2,2-trifluoroethoxy)-2-amine

Chemical formula

[0095] N 2 -(2-(Dimethylamino)ethyl)-N 2 -Methyl-3-nitro-6-(2,2,2-trifluoroethoxy)pyridine-2,5-diamine (1.01 g, 3.5 mmol) and DMAP (110 mg, 0.9 mmol) were dissolved in 1,4-dioxane (30 mL), di-tert-butyl dicarbonate (1.96 g, 10.5 mmol) was added, and then the mixture was stirred at 100 °C in an oil bath for 8 hours, concentrated, and the residue was purified by column chromatography to obtain the desired intermediate (680 mg) as a yellow oil. MS(ESI): m / z = 538 [M+H] + 。

[0096] Step 8: N 2 -(2-(Dimethylamino)ethyl)-N 2 Synthesis of -Methyl-5-di-tert-butoxycarbonylamino-6-(2,2,2-trifluoroethoxy)-2,3-diamine

Chemical formula

[0097] N 2 -(2-(Dimethylamino)ethyl)-N 2-Methyl-3-nitro-5-di-tert-butoxycarbonylamino-6-(2,2,2-trifluoroethoxy)-2-amine (680 mg, 1.3 mmol) was dissolved in MeOH (30 mL), 10% Pd-C (136 mg) was added, the air in the flask was replaced with hydrogen three times, and then stirred at room temperature for 1 hour. After the reaction was completed, it was filtered through celite, concentrated, and the residue was purified by column chromatography to obtain the desired intermediate (415 mg) as a brown oil. MS (ESI): m / z = 508.3 [M+H] + 。

[0098] Step 9: Synthesis of N-(5-di-tert-butoxycarbonylamino-2-((2-(dimethylamino)ethyl)(methyl)amino)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)acrylamide

Chemical formula

[0099] N in DCM (15 mL) 2 -(2-(dimethylamino)ethyl)-N 2 -methyl-5-di-tert-butoxycarbonylamino-6-(2,2,2-trifluoroethoxy)-2,3-diamine (415 mg, 0.8 mmol) and triethylamine (248 mg, 2.4 mmol) were added, stirred under an ice-water bath, acryloyl chloride (148 mg, 1.6 mmol) was added dropwise, then the temperature was returned to room temperature, stirring was continued for 10 minutes, then quenched with water, extracted with DCM (15 mL * 3), the combined organic phases were dried, concentrated, and the residue was purified by column chromatography to obtain the desired intermediate (318 mg) as a brown oil. MS (ESI): m / z = 562.3 [M+H] + 。

[0100] Step 10: Synthesis of N-(5-amino-2-((2-(dimethylamino)ethyl)(methyl)amino)-6-methoxypyridin-3-yl)acrylamide

Chemical formula

[0101] N-(5-Di-tert-butoxycarbonylamino-2-((2-(dimethylamino)ethyl)(methyl)amino)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)acrylamide (318 mg, 0.57 mmol) was dissolved in DCM (20 mL), methanesulfonic acid (1.63 g, 5.7 mmol) was added dropwise under an ice-water bath, and then, after the temperature returned to room temperature naturally, stirring was continued for 2.5 h. The pH was gradually adjusted to 8 by adding saturated sodium bicarbonate solution dropwise under an ice-water bath, extracted with DCM (25 mL * 3), the organic phases were combined, dried, concentrated, and the residue was purified by column chromatography to obtain the desired intermediate (176 mg) as a light brownish green solid. MS (ESI): m / z = 362.2 [M + H] + 。

[0102] Example 1: Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(8-fluoro-2-oxo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-1(2H)-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

Chemical formula

[0103] Intermediate 1a (152 mg, 0.2 mmol), Intermediate 2a (200 mg, 0.68 mmol), palladium acetate (45 mg, 0.2 mmol), Xanphos (116 mg, 0.2 mmol) and cesium carbonate (130 mg, 0.4 mmol) were added to 1,4-dioxane (5 mL) with stirring at 90 °C for 10 h. After the reaction was completed, it was filtered through celite, concentrated, and the residue was purified by column chromatography (MeOH / DCM = 1 / 10) to obtain the desired target compound (41 mg) as a light brown solid.

[0104] Compounds synthesized by the same method are shown in the following table.

Table 2-1

Table 2-2

Table 2-3

Table 2-4

Table 2-5

Table 2-6

Table 2-7

Table 2-8

Table 2-9

Table 2-10

Table 2-11

[0105] Regarding the synthesis of Compound 1, the compounds shown in the following table were obtained.

[0106]

Table 3-1

Table 3-2

Table 3-3

Table 3-4

Table 3-5

[0107] Examples of Biological Assays of the Compounds of the Present Invention

[0108] Assay 1: Biochemical Activity Assay of Wild-Type EGFR, HER2, and HER4, and Mutant EGFR 10 nL of serially diluted compound was transferred to an assay plate using a Labcyte Echo 550, followed by dispensing 5 uL of 2X enzyme in assay buffer. The assay plate was covered with an adhesive plate seal and spun at 1000 g for 30 s for a short time. 5 uL of 2X TK-substrate-biotin and ATP mixed in assay buffer were added.

[0109] After incubation at room temperature for 40 minutes, 10 uL of Sa-XL665 and TK-antibody-Cryptate mixed in HTRF assay buffer were added to initiate antibody binding.

[0110] After further incubation at room temperature for 60 minutes, the signal was measured at wavelengths of 615 nm (cryptate) and 665 nm (XL665) with an Envision 2104. The ratio of the signal at 665 nm to 615 nm was calculated, and the negative control value was used for normalization to calculate the percentage of inhibition. IC 50 was calculated and analyzed using a four-parameter logistic model.

[0111]

Table 4

[0112] As shown in the table, the compounds disclosed in the present invention exhibit higher activity against a wide range of EGFR variants including exon 20 insertions and point mutations than AZD9291. Excellent activity was also observed for compounds not shown in the table.

[0113] Assay 2: A431 (wild-type EGFR, skin cancer), H1975 (EGFR L858R / T790M, NSCLC) and Ba / F 3 (EGFR D770_N771insSVD or EGFR V769_D770insASV, pro-B) cell proliferation assay

[0114] A431 cells, H1975 and Ba / F3 cells expressing various mutant EGFRs were collected from logarithmic-phase cultures and seeded into 96-well plates at a cell density of 3000 cells per well for A431 and H1975, and 10000 cells per well for Ba / F3 cells. After overnight attachment, the compounds were serially diluted three-fold and applied to the cells in triplicate at 30 μM, 10 μM, 3 μM, 1 μM, 0.3 μM, 0.1 μM, 0.03 μM and 0.01 μM, and incubated for 3 days. Subsequently, 20 μL of 5 mg / mL MTT was added, followed by an additional 50 μL of 10% SDS in 5% isobutyl alcohol in 0.01 mol / L HCl. The plates were incubated overnight. The absorbance (A) at a wavelength of 570 nm was quantified. The inhibition rate (%) was used for the calculation of IC 50 for the purpose of the calculation. The results are shown in Table 5.

[0115]

Table 5

[0116] Compared with AZD9291, the compounds in Table 5 showed higher activity in inhibiting the proliferation of BaF 3 cells having EGFR D770_N771insSVD or EGFR V769_D770insAS and activity comparable to that against H1975 and A431, suggesting that the compounds of the present disclosure exhibit significantly improved activity against EGFR exon 20 insertions while maintaining potent activity against EGFR L858R / T790M with higher selectivity than wild-type EGFR. Other examples of the present application not described in the table also showed similar activity profiles as described above.

[0117] Assay 3 In Vivo Study in Cell Line-Derived (CDX) and Patient-Derived Xenograft (PDX) Mouse Models Cells (H1975) or tissue pieces (LU0493 and LU0426) were subcutaneously transplanted into the left axilla of nude mice. When the average tumor volume reached 100 - 150 mm 3 , the mice were randomized by tumor volume and treated with vehicle, Compound 1, or poziotinib respectively. Tumor volume and body weight were measured twice a week. The mice were sacrificed on Day 21 or Day 28, and tumor volume and final body weight were recorded. Relative tumor volume, the ratio of treatment / control value (%), and tumor growth inhibition were calculated, and statistics were performed.

[0118]

Table 6

[0119] *: P < 0.05 compared to the vehicle group; D1: Day 1 of drug treatment; RTV: Relative tumor volume; RTV = V t / V 0 ; T / C(%) = T RTV / C RTV ×100; T RTV : RTV of the treatment group; C RTV : RTV of the vehicle group; TGI(%): Tumor growth inhibition (%); T / C(%) > 60: Ineffective; T / C(%) ≤ 60 and P < 0.05: Effective. The final body weight change was calculated as the percentage of the body weight change from Day 1 to Day 21.

[0120] As shown in the table, compared with poziotinib, Compound 1 is more effective in blocking tumor growth with EGFR exon 20 insertion and T790M mutation, has less impact on body weight, and shows an increased safety margin.

[0121] Assay 4 In Vivo Orthotopic Brain PC9 Xenograft Mouse Model 3×10 expressing luciferase 5PC9 cells were injected into the mouse brain. The mice were randomized based on brain fluorescence intensity and body weight, and vehicle or Compound 1 was administered orally. Survival and body weight were monitored daily, and mice with more than 20% weight loss were euthanized.

[0122] As shown in Table 7 and Figure 1, all mice in the vehicle group died within 28 days after dosing, while all mice administered Compound 1 survived, suggesting that Compound 1 can enter the brain, inhibit tumor growth, and promote survival.

Table 7

[0123] From the results of Assays 1-4, it can be seen that the compounds of the present disclosure inhibit the activity of mutant EGFR with exon 20 insertion and point mutations, and the proliferation of Ba / F3 cells with different EGFR mutations, with better selectivity than wild-type EGFR. Compared with poziotinib, Compound 1 showed higher in vivo efficacy in a mouse PDX model with an improved safety window. It is also active in the PC9 orthotopic brain model and shows good brain permeability. Other compounds of the present disclosure are also effective in blocking tumor growth in vivo.

[0124] Although specific embodiments of the present invention have been described, these are merely examples, and those skilled in the art will understand that various changes and modifications can be made to these embodiments without departing from the principles and spirit of the present invention. Therefore, the scope of the present invention is defined by the appended claims.

Claims

1. A compound of formula (I) or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 (In the formula: X is selected from the group consisting of N and CH; R １ is hydrogen, halogen, C1-6 alkyl, C3-6 cycloalkyl, -C(O)OR ８ and CN; R ２ is selected from the group consisting of C1-6 alkyl, deuterated C1-6 alkyl, C3-6 cycloalkyl, and C1-6 haloalkyl; R ３ is -NR ９ (CH ２ ) ２ N.R. ９ 'R ９ ", 【Chemistry 2】 Selected from the group consisting of: R ４ teeth 【Chemistry 3】 That is, R ５ , R ６ and R ７ is independently selected from the group consisting of hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy and CN; R ８ is selected from the group consisting of hydrogen, C1-6 alkyl, and C1-6 haloalkyl; R ９ is selected from the group consisting of hydrogen, C1-6 alkyl, deuterated C1-6 alkyl, and C1-6 haloalkyl; R ９ ' and R ９ " is independently selected from the group consisting of hydrogen, C1-6 alkyl, C3-6 cycloalkyl, deuterated C1-6 alkyl and C1-6 haloalkyl, or R ９ ' and R ９ " taken together with the nitrogen to which they are attached form a heterocycle, said heterocycle being unsubstituted or optionally substituted with 1 to 3 groups selected from the group consisting of halogen, C1-6 alkyl, C1-3 alkoxy, methylthio, methanesulfonyl, and C1-6 haloalkyl; R １０ is hydrogen, halogen, C1-6 alkyl and -CH ２ N.R. １２ 'R １２ "selected from the group consisting of R １１ is selected from the group consisting of hydrogen, halogen and C1-6 alkyl, and R １２ and R １２ ' is independently selected from the group consisting of hydrogen, C1-6 alkyl and C1-6 haloalkyl, or R １２ ' and R １２ " taken together with the nitrogen to which they are attached form a heterocycle, which is unsubstituted or optionally substituted with 1 to 3 groups selected from the group consisting of halogen, C1-6 alkyl, and C1-6 haloalkyl.

2. R １ is hydrogen, halogen, C1-6 alkyl, -C(O)OR ８ and CN, R ５ , R ６ and R ７ A compound of general formula (I) according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein is independently selected from the group consisting of hydrogen and halogen.

3. The compound is 【Chemistry 4-1】 【Chemistry 4-2】 【Chemistry 4-3】 【Chemistry 4-4】 3. The compound of claim 2 having the general formula (I) or a pharma- ceutically acceptable salt thereof,

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