Compounds that inhibit EGFR kinase, methods of preparation, and uses thereof

Abstract

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, its preparation method, and use. The compound can selectively inhibit the activity of epidermal growth factor receptor (EGFR) mutants, and exhibits good inhibitory effect on mutant EGFR and antiproliferative activity against cancer cells. Therefore, they can be used to treat tumors and related diseases. [Formula 1] TIFF2022539224000072.tif49169

Description

[Technical field]

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

[0002] (Technical field) The present invention relates to the field of medicine, more specifically to a series of EGFR inhibitors, preparation methods and uses thereof. [Background technology]

[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. Hyperactivated EGFR due to mutation, amplification or overexpression has been identified in several solid tumors, especially 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 inhibitors (TKIs), including gefitinib and erlotinib, primarily target mutations in exons 18, 19, and 21. However, resistance inevitably develops during the course of treatment. EGFR-T790M mutations account for more than 60% of acquired resistance to first-generation TKIs. Afatinib, a second-generation irreversible EGFR inhibitor, is effective against T790M, but is associated with substantial toxicity, including rash and diarrhea, due to its activity against wild-type EGFR. AZD9291, a third-generation EGFR TKI, is specific for T790M and has been approved for the treatment of patients with EGFR T790M mutation-positive NSCLC.

[0005] In addition to the aforementioned classical EGFR mutations, exon 20 insertions constitute the third largest group of EGFR mutations, accounting for an incidence of 4–10% of all EGFR mutations, are more common in women, non-smokers, Asians, and patients with adenocarcinoma, and are associated with clinical features similar to those of the classical mutations. [ka]

[0006] Mutations in exon 20 are clustered at amino acids 762-823, all of which are insertions, except for T790M. In addition to EGFR, nearly 2% of NSCLC patients carry her2 mutations, 90% of which are exon 20 insertions. Exon 20 insertion mutations in Her2 occur at structurally similar positions to those in EGFR, which have similar molecular characteristics and drug sensitivity; that is, they are broadly classified as exon 20 insertions. 122 subtypes of EGFR exon 20 insertions have been identified so far, with Asp770_Asn771ins being the most common, followed by Va1769_Asp770ins, Ala767_Va1769ins, and Ser768_Asp770ins. Meanwhile, the most common variant of exon 20 mutations in Her2 is A775_G776insYVM, accounting for 70% of cases. EGR and the exon 20 insertion in Her2 all promote ligand-independent activation. Summary of the Invention [Problem to be solved by the invention]

[0007] The majority of EGFR exon 20 insertions are naive, and some of them are acquired. Apart from lung cancer, exon 20 insertions are also observed in a rare type of head and neck cancer known as sinonasal squamous cell carcinoma. Given the presence of exon 20 insertions in a significant number of patients, drugs capable of inhibiting EGFR carrying said exon 20 insertions may be particularly useful in this patient group. However, many studies have found that exon 20 insertions, especially those after amino acid 764, are not sensitive to approved TKIs, and available treatment options are limited. Two TKIs against exon 20 insertions, poziotinib and mobocertinib, are currently in clinical trials. Among them, poziotinib is associated with serious adverse effects, possibly due to simultaneous inhibition of wild-type EGFR. Thus, there is a need to develop TKIs with selectivity for exon 20 insertions over wild-type EGFR. The new generation TKIs disclosed in this patent show superior biochemical and cellular activity against T790M and exon 20 insertion mutations over wild-type EGFR. [Means for solving the problem]

[0008] (Summary of the invention) The present invention provides compounds of general formula (I) and pharma- ceutically acceptable salts thereof. [ka] 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 -NR 9 (CH 2 ) 2 NR 9 ′R 9 ", [ka] is selected from the group consisting of R 4 teeth [ka] and 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 NR 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, C alkyl and C haloalkyl, or R 12 ′ and R 12" 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, and C1-6 haloalkyl.

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

[0010] The present invention provides compounds of formula (I) that can inhibit one or more EGFR activating or drug-resistant mutations, such as the T790M drug-resistant mutation, the exon 20 insertion activating mutation, and therefore such compounds can be used in cancer treatment regimens for patients who have acquired drug resistance to existing therapies based on EGFR inhibitors.

[0011] The present invention provides compounds of general formula (I) that have more potent inhibition of EGFR formed by activating or resistant mutants than wild-type EGFR due to the reduced toxicity associated with wild-type EGFR inhibition and are therefore more suitable for use as therapeutic agents, particularly for the treatment of cancer.

[0012] The present invention provides a process for the preparation of compounds of general formula (I).

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

[0014] The present invention provides the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the treatment of a disease mediated by EGFR activation or drug resistance mutations in a mammal, particularly a human, especially a human undergoing cancer treatment.

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

[0016] The present invention provides a method for selectively inhibiting activated or drug-resistant mutants of EGFR relative to wild-type EGFR, comprising contacting or administering to a patient a biological sample of a compound of formula (I) or a pharma- ceutical acceptable salt thereof or a pharmaceutical composition thereof.

[0017] The cancer referred to 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's lymphoma, myeloma, glioma, glioblastoma, melanoma, gastrointestinal stromal tumor (GIST), thyroid cancer, cholangiocarcinoma, renal 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 pharma- ceutically 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: [ka] or [ka] In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 has the same definition as defined in general formula (I).

[0021] Starting from compounds (a) and (b), a substitution reaction is carried out under basic conditions to obtain intermediate 1, intermediate 1 and intermediate 2 are used to carry out a substitution or coupling reaction to obtain compound (c), compound (c) is subjected to nucleophilic substitution to obtain compound (d), the nitro group of compound (d) is reduced to obtain compound (e), and compound (e) is further acylated 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: [ka]

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

[0024] In one embodiment of the present invention for the preparation of compounds of formula (I), the process for the preparation of intermediate 2, intermediate 2' comprises the following steps: [ka] In the formula, R 2 , R 3 and R 4 has the same definition as defined in general formula (I).

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

[0026] Compound (j) is substituted with R 3 Reacting with H to obtain compound (k), protecting compound (k) with Boc to obtain compound (l), subjecting this to deacetylation protection to obtain compound (m), reducing the nitro group of compound (m) to obtain compound (n), further acylation to obtain compound (o), and finally subjecting compound (o) to deprotection to obtain intermediate 2'.

[0027] In the preparation of intermediates 2 and 2', the etherification reaction is carried out under the action of a strong base, which 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 iron powder, zinc powder, sodium sulfide, H 2 / PtO 2 Conventional reducing agents known in the art are used, including: The upper protecting or deprotecting groups are carried out under suitable acidic or basic conditions by conventional methods well known in the art.

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

[0029] "C1-6 alkyl" refers to a straight or branched alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Branched means that one or more alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl or propyl, are bonded to a straight 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 an alkyl group have been replaced with deuterium. For example, all three hydrogen atoms in a methyl group are replaced with deuterium to form a deuterated methyl group, CD 3 is formed.

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

[0032] "C1-6 heteroalkyl" means a C1-6 alkyl as defined above including 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 attached to the parent moiety through an 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 can be unsubstituted or substituted with the substituents described herein. The term "substituted" (or substituted) refers to the replacement of one or more hydrogen atoms at a specified atom with a group selected from the specified groups, provided that the substitution does not exceed the normal valence state of the specified atom and results in a stable compound. Combinations of such substituents and / or variables are permissible only if such combinations result in stable compounds.

[0036] The present invention also includes pharma- ceutically acceptable salts of the compounds of formula (I). The term "pharma- ceutically acceptable salts" refers to relatively non-toxic acid 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, which can be prepared upon final isolation and purification of the compounds, or by reacting the purified compounds of formula (I) in the form of a free base with suitable organic or inorganic acids. 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, toluate, citrate, maleate, fumarate, succinate, tartrate, benzoate, methanesulfonate, p-toluenesulfonate, gluconate, lactate, laurate, and the like. The base addition salts include salts of the compounds of formula (I) of the present invention with suitable inorganic or organic bases including, for example, salts of alkali metals, alkaline earth metals, quaternary ammonium cations such as sodium, lithium, potassium, calcium, magnesium, tetramethylammonium, tetraethylammonium, and the like, ammonia (NH 3 ), salts formed with primary ammonia, secondary ammonia, or tertiary amines, such as amine salts including methylamine salts, dimethylamine salts, trimethylamine salts, triethylamine salts, ethylamine salts, and the like.

[0037] Enzyme activity assay showed that the compounds of the present invention have good activity against exon 20 insertion mutants. Cell assay, i.e., in vitro anti-proliferation assay of activated mutant cells, i.e., activated mutant cells of exon 20 insertion type, 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 the activity of EGFR activated or 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's lymphoma myeloma, glioma, glioblastoma, melanoma, gastrointestinal stromal tumor (GIST), thyroid cancer, bile duct cancer, renal cancer, anaplastic large cell lymphoma, acute myeloid leukemia (AML), multiple myeloma or mesothelioma, and in particular, epidermal growth factor receptor 790 threonine to methionine mutation (EGFR T790M) timor type and activating mutation, exon 20 insertion type activating mutation tumor type is more applicable.

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

[0039] It should be understood that various changes or modifications may 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 may be included within the scope of the present invention as defined by the appended claims. [Brief description of the drawings]

[0040] [Figure 1] FIG. 1 shows the effect of Compound 1 on the viability of PC9 brain in situ in nude mice. BEST MODE FOR CARRYING OUT THEINVENTION

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

[0042] (Example) The present invention will be further described in specific examples. It should be understood that these examples are merely illustrative of the present invention and are not intended to limit the scope of the present invention, and the present invention is not limited to these examples. Those skilled in the art will easily understand that these compounds can be prepared using known variations of the conditions and processes of the following preparation methods. Starting materials used in the present invention that are not specifically described 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); dimethylsulfoxide (DMSO); triethylamine (TEA); diisopropylethylamine (DI(P)EA); 4-dimethylaminopyridine (DMAP); palladium on carbon (Pd / C); equivalent (eq.); grams per milligram (g / mg); moles per millimole (mol / mmol); liters per milliliter (L / mL); minutes (s); time (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 (eg, argon or nitrogen) using commercially available reagents and anhydrous solvents without further conduction.

[0045] Mass spectra were recorded using liquid chromatography-mass spectrometry (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 deuterated solvents such as deuterated chloroform, deuterated methanol, deuterium oxide, or deuterated dimethyl sulfoxide, using the deuterated solvent peak as the reference standard. Chemical shifts δ are in ppm and coupling constants (j) are in Hertz (Hz). Coupling splitting peaks in NMR spectra are represented as broad singlet peaks (brs), singlet peaks (s), doublet peaks (d), double doublet peaks (dd), triplet peaks (t), quartet peaks (q), and multiplet peaks (m).

[0046] Detailed Description of the Invention

[0047] 1. Preparation examples of intermediates of the present invention

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

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

[0050] 3-Chloropropionyl chloride (653 g, 1 eq) was dissolved in 6.5 L of dichloromethane, and the starting material 4-fluoroaniline (783.6 g, 1.05 eq) was added dropwise under a dry ice / ethanol bath while maintaining the internal temperature at 0-10 °C, and a large amount of solid precipitated. After the addition, the mixture was stirred for another 0.5 h, and imidazole (405 g, 1.01 eq) was added in several batches (with obvious temperature increase) to maintain the internal temperature at 0-10 °C. After stirring for 1 h, the reaction was completed, and the reaction solution was poured into dilute hydrochloric acid, separated, and the organic phase was concentrated until a large amount of solid precipitated, and 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 (400MHz, DMSO-d 6 )δ 10.16(s,1H),7.71-7.60(m,2H),7.23-7.13(m,2H),3.91(t,J=6.3Hz,2H),2.84(t,J=6.3Hz,2H).

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

[0052] In a 5L three-neck flask, 3-chloro-N-(4-fluorophenyl)propionamide (820 g, 1 eq) was added, followed by anhydrous aluminum trichloride (1640 g, 3 eq) with stirring, followed by nitrogen purge three times. The external temperature was set to 60° C. and the flask was stirred until molten (internal temperature increased to 70° C.). After the internal temperature was lowered, the flask was heated to 100° C. (internal temperature was 97° C.) and the mixture was stirred for 4 hours. LCMS showed that the reaction convention was about 58% when 500 g of aluminum trichloride was added and the mixture was further stirred for 4 hours, 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 there was very little unconvented starting material. Once the mixture was cooled to 40° C., DCM (2 L) was added to the mixture, followed by dropwise addition of THF (6 L) to the mixture, resulting in a strong exotherm. EA (3 L) was added, followed by successive addition of water, resulting in the separation of a large amount of precipitate. The organic phase was separated, concentrated, and the aqueous phase was filtered. The combined products were slurried with EA and water, respectively, to give 600 g of wet product as a white solid. MS (ESI): m / z=166 [M+H] + , 1 H NMR (400MHz, DMSO-d 6 )δ 10.16(s,1H),7.71-7.61(m,2H),7.23-7.13(m,2H),3.92(t,J=6.3Hz,2H),2.85(t,J=6.3Hz,2H).

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

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

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

[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 addition was complete, the mixture returned to 12 °C spontaneously and was stirred for 0.5 h. The mixture was then cooled to <0 °C and quenched successively with water (48 mL), 15% NaOH (48 mL) and water (144 mL) while maintaining the internal temperature below 5 °C, followed by the addition of diatomaceous earth (90 g). After stirring for 30 min below 5 °C, the mixture was filtered through diatomaceous earth, washed with THF, the filter cake was reslurried with THF, filtered, and the organic phase was concentrated. The residue was purified by column chromatography (mobile phase PE / EA ratios were 1 / 10, 1 / 4, and 2 / 3, containing 0.1% TEA) to give 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 [ka]

[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, maintaining the internal temperature at 10-20 °C, and stirring was continued for 15 min after the temperature was returned to room temperature. Under LCMS monitoring, after the starting material was completed, 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 in EA overnight and filtered to give 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 [ka]

[0060] 8-Fluoro-5,6-dihydro-4H-imidazol[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), and filtered to give 45 g of the desired intermediate as a white solid. MS (ESI): m / z=305 [M+H] + , 1 H NMR (400MHz, DMSO-d 6 )δ 8.81(d,J=5.7Hz,1H),8.42(d,J=5.8Hz,1H),7.75(d,J=9.7Hz,1H),7.00(d,J =9.6Hz,1H),3.82(t,J=5.5Hz,2H),2.85(t,J=5.6Hz,2H),2.15-2.01(m,2H).

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

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

[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 over 1.5 h at 0-5 °C. After 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 further stirred at room temperature (15 °C) for 16 h. TLC (PE:EA=5:1) showed that only a small portion (approximately 20%) of the starting material had not been consumed, then the reaction was warmed to 30 °C (water bath) for another 3 h. Completion of the reaction was confirmed by TLC (PE:EA=5:1), the reaction solution was washed with hydrochloric acid (2M, 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 salt solution (2 L), dried over anhydrous sodium sulfate, filtered and dried to give 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 [ka]

[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(trifluoroacetate)iodobenzene (1250 g, 2.91 mol) in DCM (1.2 L) was added dropwise at -3°C to 2°C, and after addition, the mixture was allowed to warm to room temperature (15°C) and further stirred for 1 h. 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 and concentrated, and the residue was purified by column chromatography (PE:EA=5:1 to 1:1) to give the desired intermediate (205 g, 44.5% yield) as a yellow solid.

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

[0067] 1-Methoxy-5,6-dihydro-4H-imidazol[4,5,1-ij]quinolin-2(1H)-one (51.25 g, 251.22 mol) was dissolved in ethanol (500 mL), Raney Nickel (20 g) was added at room temperature (15° C.), then the temperature was raised to 50° C., and the mixture was further stirred under a hydrogen balloon for 16 h. TLC (PE:EA=1:1) showed that about 30% of the starting material was not consumed. The mixture was further stirred under a fresh hydrogen balloon at 50° C. for 4 h, TLC (PE:EA=1:1) showed 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 under a fresh hydrogen balloon at 50° C. for 16 h. Completion of the reaction was confirmed by TLC (PE:EA=1:1). The reaction solution was cooled to room temperature, filtered through Celite, the filter cake was washed three times with methanol (150 mL), and the filtrate was concentrated. The crude product (4 lots combined) was slurried with PE / EA (1:1, 800 mL) and filtered to give the desired intermediate (155 g, 88.6% yield) 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 [ka]

[0069] 5,6-Dihydro-4H-imidazol[4,5,1-ij]quinolin-2(1H)-one (155 g, 890.80 mol) was dissolved in DMF (1.5 L) and 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 further stirred for 16 h. Completion of the reaction was confirmed by TLC (DCM:MeOH=20:1), water (3 L) was added to the reaction and further stirred for 1 h. 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 give 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 [ka]

[0071] Step 1: 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 Synthesis of 1,4-methyl-2-nitrobenzene-1,4-diamine [ka]

[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, stirred at 80° C. for 2 h, the reaction was confirmed to be complete by LCMS, cooled to room temperature, the mixture was diluted with water (60 mL), filtered, and the filter cake was diluted with EtOH / H 2 Slurrying with O (1 / 1), filtering and drying gave 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 [ka]

[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 bicarbonate (3.8 g, 17 mmol) was added, and the mixture was stirred at 70° C. for 6 h, after which the reaction was complete. It was then concentrated and the residue was slurried with EA / PE (1 / 5) to give 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 [ka]

[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. The mixture was then stirred at room temperature for 4 h. 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 [ka]

[0078] tert-Butyl (5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)-carbamate (10.3 mmol) was dissolved in DCM (50 mL) and acryloyl chloride (1.36 g, 15 mmol) was added dropwise successively under ice bath, then allowed to warm to room temperature with stirring for 0.5 h. The pH was adjusted to 8 by adding saturated sodium bicarbonate solution, the aqueous phase was separated and extracted with DCM (50 mL), the organic phases were combined, dried and concentrated, and the residue was purified by column chromatography (MeOH / DCM=1 / 70 to 1 / 20) to give the desired intermediate (1.4 g) as a grey 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 [ka]

[0080] tert-Butyl (5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-phenyl)-carbamate (392 mg, 1 mmol) was dissolved in DCM (5 mL), TFA (1 mL) was added dropwise, and the reaction was completed after stirring at room temperature for 1 h. The pH was adjusted to 8 by adding saturated sodium bicarbonate solution under 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 give 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 [ka]

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

[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, after addition the temperature was allowed to return to room temperature and stirred overnight. The reaction was confirmed to be complete 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 give the desired intermediate (720 g) as a yellow oil-solid. MS (ESI): m / z=257 [M+H] + .

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

[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 (166g, 2.9mol) was slowly added in several batches, then stirred at 80°C for 1 hour, the reaction was confirmed to be complete by TLC (PE / EA=5 / 1), the temperature was lowered to 40°C (internal temperature), sodium carbonate (160g) and diatomaceous earth (160g) were added, followed by stirring for 20 minutes, filtered through diatomaceous earth, the filter cake was slurried with DCM, and the ethanol-water mother liquor was concentrated to dryness, which was extracted twice with DCM, the filter cake was slurried, the organic phases were combined, washed with water and saturated salt solution, dried and concentrated to give the desired intermediate (122g) 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 [ka]

[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 for about 1 h to maintain the temperature around 10° C., then stirred for 30 min, TLC (PE / EA=5 / 1) showed the reaction was complete. Water (2 L) was added under ice bath, the organic phase was separated, the aqueous phase was extracted with DCM, the organic phase was combined, washed with 1 M hydrochloric acid and saturated salt solution, dried, concentrated, and the residue was purified by column chromatography (PE / EA=5 / 1) to give 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 [ka]

[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 for 1 h, then stirred at -5°C for 3 h, the reaction was confirmed to be complete by TLC (PE / EA=2 / 1), then added to ice-water mixture with stirring, followed by short stirring, filtering, leaching the filter cake with water and PE successively, slurried the wet product (185 g) with PE / EA (400 mL) overnight, filtered, reslurried the filter cake with PE / EA (5 / 1), filtered and dried to give 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 [ka]

[0091] N-(6-chloro-5-nitro-2-(2,2,2-trifluoroethoxy)pyridin-3-yl)acetamide (220 g, 0.7 mol) was suspended in a mixture of methanol / concentrated hydrochloric acid (900 / 220 mL) and heated to 50° C. for about 4 hours, the reaction became clear and was confirmed to be complete by TLC, 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 give 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 Synthesis of -methyl-3-nitro-6-(2,2,2-trifluoroethoxy)pyridine-2,5-diamine [ka]

[0093] 6-Chloro-5-nitro-2-(2,2,2-trifluoroethoxy)pyridin-3-amine (950 mg, 3.5 mmol) was dissolved in acetonitrile (15 mL) and K 2 CO 3 (967 mg, 7 mmol) and N,N,N′-trimethylethylenediamine (643 mg, 6.3 mmol) were added at room temperature, and the reaction was then 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 give 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 1-methyl-3-nitro-5-di-tert-butoxycarbonylamino-6-(2,2,2-trifluoroethoxy)-2-amine [ka]

[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 bicarbonate (1.96 g, 10.5 mmol) was added, and the mixture was stirred in an oil bath at 100° C. for 8 hours, concentrated, and the residue was purified by column chromatography to give 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 5-methyl-5-di-tert-butoxycarbonylamino-6-(2,2,2-trifluoroethoxy)-2,3-diamine [ka]

[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 h. After the reaction was completed, it was filtered through Celite, concentrated, and the residue was purified by column chromatography to give 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 [ka]

[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), triethylamine (248 mg, 2.4 mmol) were added, stirred under 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 phase was dried and 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 [ka]

[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 ice-water bath, and then stirring was continued for 2.5 h after the temperature naturally returned to room temperature. The pH was gradually adjusted to 8 by adding saturated sodium bicarbonate solution dropwise under ice-water bath, extracted with DCM (25 mL*3), the organic phases were combined, dried and concentrated, and the residue was purified by column chromatography to give 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 [ka]

[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 give the desired target compound (41 mg) as a light brown solid.

[0104] Compounds synthesized in the same manner are shown in the table below. [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] Biological Assay Examples of Compounds of the Invention

[0108] Assay 1: Wild-type EGFR, HER2 and HER4, and mutant EGFR biochemical activity assays 10 nL of serially diluted compounds were transferred to the assay plate using a Labcyte Echo 550 and 5 uL of 2X enzyme in assay buffer was subsequently dispensed. The assay plate was covered with an adhesive plate seal and briefly spun at 1000 g for 30 s. 5 uL of 2X TK-substrate-biotin and ATP mixed in assay buffer were added.

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

[0110] After a further 60 min incubation at room temperature, the signal was measured at wavelengths of 615 nm (crypate) and 665 nm (XL665) in an Envision 2104. The ratio of the 665 nm to 615 nm signal was calculated and the negative control value was used for normalization to calculate the percentage 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 show higher activity against a broad range of EGFR mutations, including exon 20 insertions and point mutations, than AZD9291. Superior 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, H1975 and Ba / F3 cells expressing various mutant EGFR were harvested from log phase cultures and seeded in 96-well plates at a cell density of 3000 per well for A431 and H1975 and 10000 per well for Ba / F3 cells. After overnight attachment, compounds were serially diluted 3-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. Then, 20 μL of 5 mg / mL MTT was added, followed by further addition of 50 μL of 10% SDS with 5% isobutyl alcohol in 0.01 mol / L HCl. Plates were incubated overnight. Absorbance (A) was quantified at a wavelength of 570 nm. The inhibition percentage (%) was calculated as IC based on the Bliss method. 50 The results are shown in Table 5.

[0115] [Table 5]

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

[0117] Assay 3: In vivo studies in cell line-derived (CDX) and patient-derived xenograft (PDX) mouse models Cells (H1975) or tissue fragments (LU0493 and LU0426) were subcutaneously transplanted into the left axilla of nude mice. The average tumor volume was 100-150 mm. 3 Once tumor volume reached 100 mg / kg, mice were randomized according to tumor volume and treated with vehicle, Compound 1, or poziotinib, respectively. Tumor volumes and body weights were measured twice weekly. Mice were sacrificed on days 21 or 28, and tumor volumes and final body weights were recorded. Relative tumor volumes, percentages of treated / control values, and tumor growth inhibition were calculated and statistics were performed.

[0118] [Table 6]

[0119] *: P<0.05 vs. vehicle group; D1: first day of drug treatment; RTV: relative tumor volume; RTV=V t / V 0 ;T / C(%)=T RTV / C RTV ×100;T RTV : RTV of treatment group; C RTV : RTV of vehicle group; TGI(%): tumor growth inhibition(%); T / C(%)>60: no effect; T / C(%)≦60 and P<0.05: effective. The final body weight change was calculated as the percentage of body weight change from day 1 to day 21.

[0120] As shown in the table, compared to poziotinib, compound 1 is more effective at blocking tumor growth with EGFR exon 20 insertions and T790M mutations, has less effect on body weight, and demonstrates an increased margin of safety.

[0121] Assay 4. In vivo orthotopic brain PC9 xenograft mouse model Luciferase expressing 3 x 10 5PC9 cells were injected into mouse brains. Mice were randomized based on brain fluorescence intensity and body weight and orally administered vehicle or Compound 1. Survival and body weight were monitored daily, and mice with more than 20% weight loss were culled.

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

[0123] The results of assays 1-4 show that the compounds of the present disclosure inhibit the activity of mutant EGFR with exon 20 insertions and point mutations, as well as the proliferation of Ba / F3 cells with different EGFR mutations, with better selectivity than wild-type EGFR. Compared to poziotinib, compound 1 showed higher in vivo efficacy in mouse PDX models with an improved safety window. It is also active in the PC9 orthotopic brain model, showing good brain penetration. 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, it will be understood by those skilled in the art that these are merely examples and that various changes and modifications can be made to these embodiments without departing from the principles and spirit of the present invention. Accordingly, 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, -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】 R 10 is hydrogen and R 11 is hydrogen; R ５ , R ６ and R ７ is independently selected from the group consisting of hydrogen and halogen; 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, which is 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.

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

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