Patent Description:
The invention relates to the fields of pharmaceuticals, and more specifically, relates to a series of EGFR inhibitors, the preparation methods and the uses thereof.

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase of the ErbB family at the plasma membrane. Other members of the ErbB family include ERBB2 (HER2), ERBB3 (HER3) and ERBB4 (HER4). EGFR promotes cell growth through the activation of MAPK and PI3K signaling transduction pathway. Overactivated EGFR via mutation, amplification or ovexpression has been identified in multiple solid tumors especially lung cancer.

The prevalence of EGFR mutation in non-small cell lung cancer (NSCLC) is <NUM>% in east Asia and <NUM>% in Europe and America. Most EGFR mutations occur in exon <NUM> through exon <NUM>. The first generation EGFR tyrosine inhibitors (TKIs) including Gefitinib and Erlotinib mainly target mutations at exon <NUM>, <NUM> and <NUM>. Resistance, however, inevitably develops during the course of the treatment. EGFR-T790M mutation accounts for over <NUM>% of the acquired resistance to the first generation TKIs. Afatinib, a second generation irreversible EGFR inhibitor, is active against T790M, however, is associated with substantial toxicity including rash and diarrhea due to its activity towards wild type EGFR. The third generation of EGFR TKI, AZD9291, specifically tackles T790M, and is approved as treatments for patients with EGFR T790M mutation positive non-small cell lung cancer.

In addition to the aforementioned classical EGFR mutations, exon <NUM> insertions constitute the third largest group of EGFR mutations with a frequency of <NUM>-<NUM>% among all EGFR mutations, more common in women, non-smokers, asian population, and adenocarcinoma patients, and are associated with similar clinical characteristics to those of classical mutations.

Mutations in exon <NUM> clustered between amino acid <NUM> and <NUM> and all of them are insertions except T790M. In addition to EGFR, around <NUM>% of NSCLC patients carry her2 mutations, <NUM>% of which are exon <NUM> insertions. Exon <NUM> insertion mutations in Her2 occur in a structurally analogous position as those in EGFR with similar molecular features and drug sensitivity. Together, they are broadly categorized as exon <NUM> insertions. <NUM> subtypes of EGFR exon <NUM> insertions were identified so far, with Asp770_Asn771ins being the most prevalent followed by Va1769_Asp770ins, A1a767_Va1769ins and Ser768_Asp770ins. Whereas, the most common variant for exon20 mutation in Her2 is A775_G776insYVM, representing <NUM>% of the cases. Exon <NUM> insertions in EGR and Her2 all promote ligand-independent activation.

A majority of EGFR exon <NUM> insertions are naïve and some of them are acquired. Aside from lung cancer, exon <NUM> insertions are also observed in a rare form of head and neck cancer known as sinonasal squamous cell carcinoma. In view of the presence of exon <NUM> insertions in a significant number of patients, agents that can inhibit EGFR harboring the exon <NUM> insertions may be especially useful for this group of patients. Many studies show, however, exon <NUM> insertions, particularly those after amino acid <NUM> are not sensitive to the approved TKIs, and there are limited therapeutic options available. Poziotinib and Mobocertinib, two TKIs against exon <NUM> insertions, are now under clinical investigation. Among them, Poziotinib is associated with severe adverse effects possibly due to concomitant inhibition of wild-type EGFR. Therefore, development of TKIs with selectivity to exon <NUM> insertions over wild-type EGFR is warranted, a new generation of TKIs disclosed in this patent demonstrate superior biochemical and cellular activity towards T790M and exon <NUM> insertion mutations over wild type EGFR.

<CIT>, <CIT> and <CIT> disclose EGFR TKIs.

The present invention provides a compound of general formula (I), a pharmaceutically acceptable salt thereof:
<CHM>.

In the general formula (I), R<NUM> is preferably selected from the group consisting of hydrogen, halogen, Cl-<NUM> alkyl, -C(O)OR<NUM> or CN; and R<NUM>, R<NUM>; and R<NUM> are preferably independently selected from the group consisting of hydrogen and halogen.

The present invention provides compounds of formula (I) capable of inhibiting one or more EGFR-activated or drug-resistant mutants, e. , a T790M drug-resistant mutant, an exon <NUM> insertion-activated mutant, and thus such compounds can be used in cancer therapy regimens for patients who have gotten drug resistance to existing therapies based on EGFR inhibitors.

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

The invention provides a preparation method of a compound of the general formula (I).

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.

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of diseases mediated by EGFR-activated or drug-resistant mutants in mammals, particularly humans, and particularly in cancer treatment.

Also disclosed but not part of the invention is a method of treating disease, particularly cancer, mediated by EGFR-activated or drug-resistant mutants in mammal, particularly humans, comprising 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 a compound of formula (I) and a pharmaceutically acceptable carrier, excipient or diluent.

Also disclosed but not part of the invention is a method for selectively inhibiting EGFR-activated or drug-resistant mutants compared to wild-type EGFR, comprising 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.

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 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.

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

The present invention provides a process for preparing a compound of formula (I) comprising the following steps:
<CHM>
<CHM>
<CHM>
or
<CHM>.

Wherein, R<NUM>, R<NUM>, R<NUM>, R<NUM>, R<NUM>, R<NUM> and R<NUM> have the same definitions as defined in the above general formula (I).

Taking compounds (a) and (b) as starting materials, carrying out substitution reaction under basic condition to obtain intermediate <NUM>, conducting substitution or couple reaction using intermediate <NUM> and the intermediate <NUM> to obtain compound (c), compound (c) is carried out nucleophilic substitution to obtain compound (d), reduction the nitro group of the compound (d) to obtain compound (e), compound (e) is further conducted to acylation to obtain a compound (I); Or intermediate <NUM> and intermediate <NUM>' are directly conducted to substitution or coupling reaction to obtain compound (I).

In one embodiment, when intermediate <NUM> is intermediate 1a, the compound of formula (I) is prepared as following:
<CHM>.

In one embodiment, when intermediate <NUM> is intermediate 1b, the compound of formula (I) is prepared as following:
<CHM>.

In one embodiment of that present invention for the preparation of a compound of formula (I), the process for the preparation of intermediate <NUM>, intermediate <NUM>' includes the following steps:
<CHM>
<CHM>.

Wherein R<NUM>, R<NUM> and R<NUM> have the same definitions as defined in the above general formula (I).

Taking <NUM>,<NUM>-dichloro-<NUM>-nitropyridine as starting materials, carrying out etherification reaction to obtain compound (g), which is conducted to reduction nitro group of the compound (g) to obtain compound (h), the compound (h) is carried out acylation to obtain compound (i), then compound (i) is conducted to nitration reaction to obtain compound (j), which is further deprotected to obtain intermediate <NUM>.

The compound (j) reacts with R<NUM>H by substitution to obtain compound (k), compound (k) is protected by Boc to obtain compound (l), which is carried out deacetylation protection to obtain compound (m), the nitro group of the compound (m) is reduced to obtain compound (n), compound (n) is further acylated to obtain compound (o), and finally compound (o) is conducted to deprotection to obtain intermediate <NUM>'.

In the preparation method of the intermediates <NUM> and <NUM>', the etherification reaction is carried out under the action of strong base, wherein the strong base is including but is not limited to sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium ethoxide and sodium methoxide; Methods of reduction the nitro group use the conventional reductants known in the art, including but not limited to iron powder, zinc powder, sodium sulfide, H<NUM>/PtO<NUM>; The upper protecting group or the deprotecting group is carried out by conventional methods well known in the art under suitable acidic or basic conditions.

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

"C1-<NUM> alkyl" refers to a linear or branched alkyl group having <NUM> to <NUM> carbon atoms, preferably a linear or branched alkyl group having <NUM> to <NUM> carbon atoms. Branched chain means that one or more alkyl groups of <NUM> to <NUM> carbon atoms such as methyl, ethyl or propyl, etc. are attached to the linear alkyl group. Preferred C1-<NUM> alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like.

"Deuterated alkyl" means that one or more hydrogen atoms in the alkyl group are replaced by deuterium. For example, three hydrogen atoms in the methyl group are all replaced by deuterium to form deuterated methyl group CD<NUM>.

"C1-<NUM> haloalkyl" refers to a C1-<NUM> alkyl group as defined above containing one or more halogen atom substituents.

"C1-<NUM> heteroalkyl" means that C1-<NUM> alkyl as defined above containing one or more substituents selected from the group consisting of O, S, N, -(S=O)-, -(O=S=O)- and the like.

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

"C1-<NUM> alkoxy" refers to a C1-<NUM> alkyl-O- group bonding to the parent moiety by oxygen, wherein C1-<NUM> alkyl is as described above. Preferred C1-<NUM> alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.

Any of the abovementioned functional groups of the present invention may be unsubstituted or substituted by substituents described herein. The term "substituted" (or substitute) refers to the replacement of one or more hydrogen atoms at a specified atom with a group selected from the specified group, provided that the normal valence state of the specified atom is not exceeded, and the substitution results in a stable compound. Combination of that substituents and/or variable are permitted only when the combination forms a stable compound.

The invention also includes pharmaceutically acceptable salt of a compound of formula (I). The term "pharmaceutically acceptable salt" refers to a relatively non-toxic acid addition salt or base addition salt of a compound of the present invention. The acid addition salt is a salt of that a compound of formula (I) according to the invention with suitable inorganic or organic acid, which salt can be prepared in the final separation and purification of the compound or can be prepared by reacting the purified compound of formula (I) in its free base form with suitable organic or inorganic acid. Representative acid addition salt includes 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 that like. The base addition salt is a salt of that a compound of formula (I) of the present invention with suitable inorganic or organic base, including, for example, salt with alkali metal, alkaline earth metals, quaternary ammonium cation, such as sodium, lithium, potassium, calcium, magnesium, tetramethylammonium, tetraethylammonium and the like; Amine salt, including salt formed with ammonia (NH<NUM>), primary ammonia, secondary ammonia or tertiary amine, such as methylamine salt, dimethylamine salt, trimethylamine salt, triethylamine salt, ethylamine salt and the like.

The enzyme activity assays showed that the compound of the invention has good activity against exon <NUM> insertion mutant; Cell assays, namely in vitro antiproliferation assays of activated mutant cells, i.e., exon <NUM> insertion-type activated mutant cells, drug-resistant tumor cells and wild-type EGFR human skin cells showed that the compound has good antiproliferative activity on activated mutant cells or drug-resistant mutant tumor cells, but weak antiproliferative activity on wild-type EGFR cancer cells with good selectivity. The compound of the invention is useful for the treatment of disease or conditions mediated by the activity of EGFR-activated or resistant mutants, in particular treatment of cancer. Such cancer includes, but are not limited to, such as 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, cholangiocarcinoma, renal cancer, anaplastic large cell lymphoma, acute myeloid leukemia (AML), multiple myeloma or mesothelioma, especially for epidermal growth factor receptor <NUM> threonine-to-methionine mutation (EGFR T790M) timor type and activatied type mutation, exon <NUM> insertion type activated mutation tumor types have better application.

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

<FIG> shows the effects of compound <NUM> on the survival rate of PC9 brain in-situ nude mice.

The invention is further illustrated below with specific examples. It should be understood that these examples are only for illustrating 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 readily understand that these compounds can be prepared using known variations of the conditions and processes of the following preparation methods. The starting materials used in the present invention without particular description are commercially available.

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); <NUM>-dimethylaminopyridine (DMAP); palladium on carbon (Pd/C); equivalent (eq. ); gram/milligram (g/mg); mole/millimole (mol/mmol); Litre/millitre (L/mL); min (s)); hours (h, hr, hrs); nitrogen (N<NUM>); nuclear magnetic resonance (NMR); thin layer chromatography (TLC).

Unless otherwise specified, all reactions are conducted under inert gas (e.g., argon or nitrogen) using commercially available reagents and anhydrous solvents without further conduct.

The mass spectra were recorded using a liquid chromatography-mass spectrometer (LC-MS) (Agilent 6120B single-and four-stage LC-MS). Nuclear magnetic resonance spectra (such as hydrogen (<NUM>H), carbon (<NUM>C), phosphorus (<NUM>P), and fluorine (<NUM>F) were recorded using a BrukerAMX-<NUM>, Gemini-<NUM>, or AMX-<NUM> NMR spectrometer in a deuterated solvent such as deuterated chloroform, deuterated methanol, deuterated water, or deuterated dimethylsulfoxide with the deuterated solvent peak as the reference standard. The chemical shift δ is in ppm, and the coupling constant (j) is in Hertz (Hz). The coupling splitting peaks in the NMR spectrum are expressed as wide single peak (brs), single peak (s), double peaks (d), double double double peaks (dd), triple peak (t), quadruple peak (q) and multiple peaks (m).

<NUM>-Chloropropionyl chloride (<NUM>, <NUM> eq) was dissolved in <NUM> of dichloromethane, and the starting material <NUM>-fluoroaniline (<NUM>, <NUM> eq) was added dropwise under a dry ice/ ethanol bath while maintaining the internal temperature between <NUM> to <NUM>, a large amount of solids were precipitated. After the dropwise addition, the mixture was further stirred for <NUM>, and imidazole (<NUM>, <NUM> eq) was added in batches (with obvious temperature rise) to maintain the internal temperature between <NUM>-<NUM>. The reaction was completed after stirring for <NUM>, the reaction solution was poured into diluted hydrochloric acid, separated, the organic phase was concentrated until a large amount of solids were precipitated, <NUM> of PE/EA(<NUM>/<NUM>) was added, stirred overnight, filtered, and washed with PE/EA(<NUM>/<NUM>) to obtain <NUM> of <NUM>-chloro-N-(<NUM>-fluorophenyl)propenamide as a white solid. MS(ESI): m/z = <NUM> [M+H]+, <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

In a <NUM> three-necked flask, <NUM>-chloro-N (<NUM>-fluorophenyl)propionamide (<NUM>, <NUM> eq) was added, followed by the addition of anhydrous aluminum trichloride (<NUM>, <NUM> eq) under stirring, followed by nitrogen replacement for three times. The external temperature was set at <NUM>, and the flask was stirred until molten state (the internal temperature was increased to <NUM>). After the internal temperature was decreased, the flask was heated to <NUM> (the internal temperature was <NUM>), and the mixture was stirred for <NUM>. LCMS showed the reaction convention was about <NUM>%, while <NUM> of aluminum trichloride was added, and the mixture was further stirred for <NUM>, LCMS showed the reation convention was about <NUM>%, and additional <NUM> of aluminum trichloride was added and stirred for <NUM>, LCMS showed only litter unconvented starting material. When the mixture was cooled to <NUM>, DCM (<NUM>) was added into the mixture, then THF (<NUM>) was dropwise added into the mixture with intense exotherm. EA (<NUM>) was added and water was added continuously to separate out a large amount of precipations. the organic phase was separated out, the organic phase was concentrated, and the aqueous phase was filtered, the combined products were respectively slurried with EA and water to obtain <NUM> wet product as a white solid. MS(ESI): m/z = <NUM> [M+H]+, <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

<NUM>-Fluoro-<NUM>,<NUM>-dihydroquinoline-<NUM>(<NUM>H)-one (<NUM>, <NUM> eq) was added into a <NUM> three-neck flask, then <NUM> of acetic anhydride was added, controlling the internal temperature to be <NUM>-<NUM>, concentrated nitric acid (<NUM>, <NUM> eq) was slowly added dropwise, the solution became clear after the addition, further stirring at <NUM> for <NUM>, then a large amount of solids were precipated, pouring the reaction solution into water (<NUM>), stirring until the hydrolysis was completed, filtered, washed the filter cake with water until the washing solution became colorless, and dried to obtain <NUM> of desired intermediate as a yellow solid; MS(ESI): m/z = <NUM> [M+H]+, HNMR: <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J= <NUM>, <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (dd, J= <NUM>, <NUM>, <NUM>).

LiAlH<NUM> (<NUM>, <NUM> mol) was dissolved in THF (<NUM>) and a suspension of <NUM>-fluoro-<NUM>-nitro-<NUM>,<NUM>-dihydroquinoline-<NUM>(<NUM>H)-one (<NUM>, <NUM> mol) in THF (<NUM>) was added portionwise, maintaining the internal temperature between <NUM> to <NUM>. After the dropwise addition was completed, the mixture was naturally restored to <NUM> and stirred for <NUM>. Then the mixture was cooled to below <NUM>, water (<NUM>), <NUM>% NaOH (<NUM>) and water (<NUM>) were successively quenched while maintaining the internal temperature below <NUM>, and diatomaceous earth (<NUM>) was added. After stirring for <NUM> below <NUM>, the mixture was filtered with diatomaceous earth, washed with THF, the filter cake was slurried with THF again, filtered, and the organic phase was concentrated. The residual was purified by column chromatography (the mobile phase PE/EA ratio was <NUM>/<NUM>, <NUM>/<NUM>, and <NUM>/<NUM> contained <NUM>% TEA) to obtain <NUM> desired intermediate as wine-red oily liquid; MS (ESI): m/z = <NUM> [M+H]+.

<NUM>-Fluoro-<NUM>- amino-<NUM>,<NUM>,<NUM>,<NUM>-tetrahydroquinoline (<NUM>, <NUM> mol) was dissolved in THF (<NUM>) and a suspension of triphosgene (<NUM>, <NUM> mol) in THF (<NUM>) was added dropwise while maintaining the internal temperature between <NUM> to <NUM>. After the completion of addition, stirring was continued for <NUM>, imidazole (<NUM>, <NUM> mol) was added dropwise, the internal temperature was maintained between <NUM>-<NUM>, and the stirring was continued for <NUM> after the temperature was restored to room temperature. Under the supervision of LCMS, after the starting materials was completed, <NUM> of <NUM>% NaCl solution was added, followed by addition of THF (<NUM>), separated the organic phase, extracted with THF (<NUM>*<NUM>), dried and concentrated, the residual was slurried with EA overnight, and filtrated to obtain <NUM> of the desired intermediate as a light-brown solid MS(ESI): m/z = <NUM> [M+H].

<NUM>-Fluoro-<NUM>,<NUM>-dihydro-<NUM>H-imidazole[<NUM>,<NUM>,<NUM>-ij]quinoline-<NUM>(<NUM>H)-one (<NUM>, <NUM> mol) and <NUM>,<NUM>-dichloropyrimidine (<NUM>, <NUM> mol) were dissolved in DMF (<NUM>), cesium carbonate (<NUM>, <NUM> mol) was added, and the mixture was stirred for <NUM> at room temperature. The reaction was completed determined by LCMS. The mixture was diluted with water (<NUM>), solid was filtered, and the crude sample was further purified by column chromatography (DCM/EA, <NUM>/<NUM>), concentrated to about <NUM>, slurried with PE (<NUM>) and filtered to obtain <NUM> of desired intermediate as a white solid; MS (ESI): m/z = <NUM> [M+H]+, <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (d, J= <NUM>, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (d, J= <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J= <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>).

Triphosgene (<NUM>, <NUM> mol) was dissolved in DCM (<NUM>), the solution of <NUM>,<NUM>,<NUM>,<NUM>-tetrahydroquinoline (<NUM>, <NUM> mol) and triethylamine (<NUM>, <NUM> mmol) in DCM (<NUM>) was added dropwise over a period of <NUM> hours between <NUM> to <NUM>. After the addition, the mixture was stirred at room temperature for <NUM> hour. TLC (PE:EA = <NUM>:<NUM>) detected that most of the <NUM>,<NUM>,<NUM>,<NUM>- tetrahydroquinoline was consumed. Triethylamine (<NUM>, <NUM> mol) and methoxyamine hydrochloride (<NUM>, <NUM> mol) were added and further stirring at room temperature (<NUM>) for <NUM> hours. TLC (PE:EA = <NUM>:<NUM>) determined that a small portion (about <NUM>%) of the starting material was unconsumed, then the reaction was warmed to <NUM> (water bath) for additional <NUM> hours. The reaction was completed determined by TLC (PE:EA = <NUM>:<NUM>), the reaction solution was washed with hydrochloric acid (<NUM>, <NUM>), the aqueous phase extracted with DCM (<NUM>), combined the organic phases, washed with saturated sodium bicarbonate solution (<NUM>) and saturated salt solution (<NUM>), dried over anhydrous sodium sulfate, filtrated and dried to give the desired intermediate (<NUM>) as a yellow solid.

N-methoxy-<NUM>,<NUM>-dihydroquinoline-<NUM>(<NUM>H)-carboxamide (crude, <NUM>, <NUM> mol) was dissolved in DCM (<NUM>), the solution of bis(trifluoroacetic acid)iodobenzene (<NUM>, <NUM> mol) in DCM (<NUM>) was added dropwise between -<NUM> to <NUM>, after the addition, naturally warmed to room temperature (<NUM>) and further stirred for <NUM>. The reation was completed determined by TLC (PE:EA = <NUM>:<NUM>), saturated sodium bicarbonate solution (<NUM>) was added to the mixture, separated the organic phase, concentrated, the residual was purified by column chromatography (PE:EA = <NUM>:<NUM> to <NUM>:<NUM>) to give the desired intermediate (<NUM>, yield <NUM>%) as a yellow solid.

<NUM>-Methoxy-<NUM>,<NUM>-dihydro-<NUM>H-imidazole[<NUM>,<NUM>,<NUM>-ij]quinoline-<NUM>(<NUM>H)-one (<NUM>, <NUM> mol) was dissolved in ethanol (<NUM>), raney nickel (<NUM>) was added at room temperature (<NUM>), then the temperature was raised to <NUM> and the mixture was further stirred for <NUM> hours under a hydrogen balloon. TLC (PE:EA = <NUM>:<NUM>) detected that about <NUM>% of the starting material was unconsumed. The mixture further stirred at <NUM> for <NUM> hours under a new hydrogen balloon, TLC (PE:EA= <NUM>: <NUM>) showed that about <NUM>% of the starting material was still uncomsumed. Additional raney nickel (<NUM>) was added at room temperature, and the mixture was stirred at <NUM> for <NUM> hours under a new hydrogen balloon. The reaction was completed determined by TLC (PE:EA = <NUM>:<NUM>). The reaction solution was cooled to room temperature, filtered through celite, the filter cake was washed three times with methanol (<NUM>), and the filtrate was concentrated. The crude product (four lots combined) was slurried with PE/EA (<NUM>:<NUM>, <NUM>), filtered to afford the desired intermediate (<NUM>, yield <NUM>%) as an off-white solid.

<NUM>,<NUM>-dihydro-<NUM>H-imidazole [<NUM>,<NUM>,<NUM>-ij]quinoline-<NUM>(<NUM>H)-one (<NUM>, <NUM> mol) was dissolved in DMF (<NUM>), <NUM>,<NUM>-dichloropyrimidine (<NUM>, <NUM> mol) and cesium carbonate (<NUM>, <NUM> mol) was added at room temperature (<NUM>), then heated to <NUM> and further stirred for <NUM> hours. The reaction was completed determined by TLC (DCM:MeOH = <NUM>:<NUM>), water (<NUM>) was added to the reaction and further stirred for <NUM> hour. Filtered, the filter cake was washed with water (<NUM>). The filter cake was slurried with PE:EA (<NUM>: <NUM>, <NUM>), filtered and dired to obtain the desired intermediate (<NUM>, yield <NUM>%) as an off-white solid.

<NUM>-Fluoro-<NUM>-methoxy-<NUM>-nitroaniline (<NUM>, <NUM> mmol) and N<NUM>,N<NUM>,N<NUM>-trimethylethane-<NUM>,<NUM>-diamine (<NUM>, <NUM> mmol) were dissolved in DMF (<NUM>), potassium carbonate (<NUM>, <NUM> mmol) was added, stirred at <NUM> for <NUM>, the reaction was completed determined by LCMS, cooled to room temperature, the mixture was diluted with water (<NUM>), filtered, the filter cake was slurried with EtOH/H<NUM>O (<NUM>/<NUM>), filtered and dried to obtain the desired intermediate (<NUM>) as a yellow solid; MS(ESI): m/z = <NUM> [M+H]+.

N<NUM>-(<NUM>-(Dimethylamino)ethyl)-<NUM>-methoxy-N<NUM>-methyl-<NUM>-nitrobenzene-<NUM>,<NUM>-diamine (<NUM>, <NUM> mmol) was dissolved in THF (<NUM>), di-tert-butyl dicarbonate (<NUM>, <NUM> mmol) was added, and the mixture was stirred at <NUM> for <NUM> before the reaction was completed. Then concentrated, the residual was slurried with EA/PE (<NUM>/<NUM>) to obtain the desired intermediate (<NUM>) as a pale yellow solid, MS(ESI): m/z = <NUM> [M+H]+.

Tert-butyl (<NUM>-((<NUM>-(dimethylamino)ethyl)(methyl)amino)-<NUM>-methoxy-<NUM>-nitrophenyl) carbamate (<NUM>, <NUM> mmol) was dissolved in MeOH (<NUM>), replacement with nitrogen for three times, then Pd/C (<NUM>) was added and replacement with hydrogen for three times. Then the mixture was stirred at room temperature for <NUM>. After the reaction was completed, the mixture was filtered and concentrated, the crude product was directly used in the next step without further purification. MS (ESI): m/z = <NUM> [M+H]+.

Tert-butyl (<NUM>-amino-<NUM>-((<NUM>-(dimethylamino)ethyl)(methyl)amino)-<NUM>-methoxyphenyl)-carbamate (<NUM> mmol) was dissolved in DCM (<NUM>), acryloyl chloride (<NUM>, <NUM> mmol) was sequentially added dropwise under an ice bath, then stirred for <NUM> while naturally recoveried to room temperature. The pH was adjusted to <NUM> by adding a saturated sodium bicarbonate solution, the aqueous phase was separated and extracted with DCM (<NUM>), combined the organic phases, dired and concentrated, the residual was purified by column chromatography (MeOH/DCM = <NUM>/<NUM> to <NUM>/<NUM>) to give the desired intermediate (<NUM>) as a gray solid; MS (ESI): m/z = <NUM> [M+H]+.

Tert-butyl (<NUM>-acrylamido-<NUM>-((<NUM>-(dimethylamino)ethyl)(methyl)amino)-<NUM>-methoxyphenyl)-carbamate (<NUM>, <NUM> mmol) was dissolved in DCM (<NUM>), TFA (<NUM>) was added dropwise, and the reaction was completed after stirring at room temperature for <NUM>. The pH was adjusted to <NUM> by adding a saturated sodium bicarbonate solution under an ice bath. The aqueous phase was separated, extracted with DCM (<NUM>), dried and concentrated, the residual was purified by column chromatography (MeOH/DCM = <NUM>/<NUM> to <NUM>/<NUM>) to obtain the desired intermediate (<NUM>) as a brown and syrupy solid; MS (ESI): m/z = <NUM> [M+H]+.

<NUM>,<NUM>-Dichloro-<NUM>-nitropyridine (<NUM>, <NUM> mol) was dissolved in THF (<NUM>), cooled to below -<NUM>, sodium hydrogen (<NUM>, <NUM> mol) was added, trifluoroethanol (<NUM>, <NUM> mol) was added dropwise at -<NUM>, after the addition, recoveried the temperature to room temperature and stirred overnight. The reaction was completed determined by TLC (PE/EA = <NUM>/<NUM>), poured into iced water (<NUM>), stirred and separated. The organic phases were concentrated to a small volume, extracted with EA twice, combined organic phases, washed with water and saturated salt solution, dried and concentrated to give the desired intermediate (<NUM>) as a yellow oil-solid; MS (ESI): m/z = <NUM> [M+H]+.

<NUM>-Chloro-<NUM>-nitro-<NUM>-(<NUM>,<NUM>,<NUM>-trifluoroethoxy)pyridine (<NUM>, <NUM> mol) was dissolved in ethanol/water (<NUM>/<NUM>), ammonium chloride (<NUM>, <NUM> mol) was added. After the temperature was raised to <NUM> (the internal temperature), iron powder (<NUM>, <NUM> mol) was slowly added in batches, then stirred at <NUM> for <NUM>, the reaction was completed determined by TLC (PE/EA= <NUM>/<NUM>), the temperature was reduced to <NUM> (the internal temperature), sodium carbonate (<NUM>) and diatomite (<NUM>) were added, followed by stirring for <NUM>, filtrated with the aid of diatomite, the filter cake was slurried with DCM, and the ethanol-water mother solution was concentrated to dryness, which was extracted twice with the DCM in which the filter cake was slurried, the organic phases were combined, washed with water with saturated salt solution, dried and concentrated to give the desired intermediate (<NUM>) as black oil; MS (ESI): m/z = <NUM> [M+H]+.

<NUM>-Chloro-<NUM>-trifluoroethoxypyridine-<NUM>-amine (<NUM>, <NUM> mol) was dissolved in DCM (<NUM>), DIPEA (<NUM>, <NUM> mol) was added. After the temperature was reduced to <NUM>, acetyl chloride (<NUM>, <NUM> mol) was added dropwise for about <NUM> to maintaina the temperature around <NUM>, then stirred <NUM> and TLC (PE/EA= <NUM>/<NUM>) showed the reaction was completed. Water (<NUM>) was added under an ice bath, separated the organic phase, and the aqueous phase was extracted with DCM, combined organic phases, washed with <NUM> hydrochloric acid and saturated salt solution, dried and concentrated, the residual was purified by column chromatography (PE/EA = <NUM>/<NUM>) to obtain the desired intermediate (<NUM>) as a yellow solid-liquid mixture; MS (ESI): m/z = <NUM> [M+H]+.

N-(<NUM>-Chloro-<NUM>-(<NUM>,<NUM>,<NUM>-trifluoroethoxy)pyridin-<NUM>-yl)acetamide (<NUM>, <NUM> mol) was suspended in trifluoroacetic anhydride (<NUM>) and cooled to below -<NUM>. Concentrated nitric acid (<NUM>, <NUM> mol) was added dropwise for <NUM>, then stirred at -<NUM> for <NUM>, the reaction was completed determined by TLC (PE/EA = <NUM>/<NUM>), then added into the iced water mixture under stirring, followed by stirring a while, filtrated, the filter cake was leached with water and PE sequently, the wet product (<NUM>) was slurried with PE/EA (<NUM>) overnight, filtered and the filter cake was slurried with PE/EA (<NUM>/<NUM>) again, filtered and dried to obtain the desired intermediate (<NUM>) as a yellow solid; MS (ESI): m/z = <NUM> [M+H]+.

N-(<NUM>-Chloro-<NUM>-nitro-<NUM>-(<NUM>,<NUM>,<NUM>-trifluoroethoxy)pyridin-<NUM>-yl)acetamide (<NUM>, <NUM> mol) was suspended in a mixed solvent of methanol/concentrated hydrochloric acid (<NUM>/<NUM>), heated to <NUM> for reaction about <NUM>, the reaction became clear, the reaction was completed determined by TLC, added the reaction solution into water under stirring, filtrated, the filter cake was washed with water, then slurried with a saturated sodium bicarbonate solution, filtered, and the filter cake was leached with water and PE sequently, dried to obtain the desired intermediate (<NUM>) as a yellow solid; MS (ESI): m/z = <NUM> [M+H]+.

<NUM>-Chloro-<NUM>-nitro-<NUM>-(<NUM>,<NUM>,<NUM>-trifluoroethoxy)pyridin-<NUM>-amine (<NUM>, <NUM> mmol) was dissolved in acetonitrile (<NUM>), K<NUM>CO<NUM> (<NUM>, <NUM> mmol) and N,N,N'-trimethylethylenediamine (<NUM>, <NUM> mmol) were added at room temperature, then the reaction was stirred at <NUM> onvernight. The reaction solution was filtered, the filtrate was concentrated, the residual was purified by silica gel column chromatography to obtain the desired intermediate (<NUM>) as red oil; MS (ESI): m/z = <NUM> [M+H]+.

N<NUM>-(<NUM>-(Dimethylamino)ethyl)-N<NUM>-methyl-<NUM>-nitro-<NUM>-(<NUM>,<NUM>,<NUM>-trifluoroethoxy)pyridine-<NUM>,<NUM>-diamine (<NUM>, <NUM> mmol) and DMAP (<NUM>, <NUM> mmol) were dissolved in <NUM>,<NUM>-dioxane (<NUM>), di-tert-butyl dicarbonate (<NUM>, <NUM> mmol) was added, then stirred in an oil bath at <NUM> for <NUM>, concentrated, the residual was purified by column chromatography to obtain the desired intermediate (<NUM>) as yellow oil; MS (ESI): m/z = <NUM> [M+H]+.

N<NUM>-(<NUM>-(Dimethylamino)ethyl)-N<NUM>-methyl-<NUM>-nitro-<NUM>-di-tert-butoxycarbonylamino-<NUM>-(<NUM>,<NUM>,<NUM>-trifluoroethoxy)-<NUM>-amine (<NUM>, <NUM> mmol) was dissolved in MeOH (<NUM>), <NUM>% Pd-C (<NUM>) was added, and the air within the flask was replaced by hydrogen for three times, then stirred at room temperature for <NUM>. After the reaction was completed, filtered through celite, concentrated and the residual was purified by column chromatography to obtain the desired intermediate (<NUM>) as brown oil; MS (ESI): m/z = <NUM> [M+H]+.

N<NUM>-(<NUM>-(dimethylamino)ethyl)-N<NUM>-methyl-<NUM>-di-tert-butoxycarbonylamino-<NUM>-(<NUM>,<NUM>,<NUM>-trifluoroethoxy)-<NUM>,<NUM>-diamine (<NUM>, <NUM> mmol) in DCM (<NUM>), triethylamine (<NUM>, <NUM> mmol) was added, stirred under an ice-water bath, acryloyl chloride (<NUM>, <NUM> mmol) was added dropwise, then recoveried the temperature to room temperature, stirring was continued for <NUM>, then quenched with water, extracted with DCM (<NUM>*<NUM>), the combined organic phases were dried and concentrated, the residual was purified by column chromatography to yield the desired intermediate (<NUM>) as brown oil; MS (ESI): m/z = <NUM> [M+H]+.

N (<NUM>-Di-tert-butoxycarbonylamino-<NUM>-((<NUM>-(dimethylamino)ethyl) (methyl)amino)-<NUM>-(<NUM>,<NUM>,<NUM>- trifluoroethoxy)pyridine-<NUM>-yl)acrylamide (<NUM>, <NUM> mmol) was dissolved in DCM (<NUM>), methanesulfonic acid (<NUM>, <NUM> mmol) was added dropwise under an ice-water bath, then stirring continued for <NUM> after the temperature naturally recoveried to room temperature. Gradually adjusted the pH to <NUM> by dropwise addition of saturated sodium bicarbonate solution under an ice-water bath, extracted with DCM (<NUM>*<NUM>), combined the organic phases, dried and concentrated, the residual was purified by column chromatography to obtain the desired intermediate (<NUM>) as a pale brownish-green solid; MS (ESI): m/z = <NUM> [M+H]+.

Intermediate 1a (<NUM>, <NUM> mmol), intermediate 2a (<NUM>, <NUM> mmol), palladium acetate (<NUM>, <NUM> mmol), Xanphos (<NUM>, <NUM> mmol) and cesium carbonate (<NUM>, <NUM> mmol) were added to <NUM>,<NUM>-dioxane (<NUM>) with stirring at <NUM> for <NUM>. After the reaction was completed, filtered through celite, concentrated and the residual was purified by column chromatography (MeOH/DCM = <NUM>/<NUM>) to give dsired target compound (<NUM>) as a pale brown solid.

The compounds synthesized in the same method are shown in the following table:.

Referring to the synthesis of compound <NUM>, the compounds shown in the following table were obtained:.

<NUM> nL of Serially diluted compounds were transferred to assay plates using the labcyte Echo <NUM>, and <NUM> uL of 2X enzymes in assay buffer were subsequently dispensed. The assay plate was covered with an adhesive plate seal, and briefly spinned for <NUM> at <NUM>. <NUM> uL of 2X TK-substreate-biotin and ATP mixed in assay buffer were added.

After <NUM> minutes of incubation at room temperature, <NUM> uL of Sa-XL <NUM> and TK-antibody-Cryptate mixed in HTRF assay buffer were added to start the antibody binding.

After an additional of <NUM> incubation at room temperature, the signals were measured with Envision <NUM> at wavelengths of <NUM> (crypate) and <NUM> (XL665). The ratio of signals at <NUM> to <NUM> were calculated, and negative control values were used for normalization to calculate the percentage of inhibition. IC<NUM> was calculated and analyzed using a <NUM> parametric logistic model.

As shown in the table above, compounds disclosed in this patent exhibits greater activity towards a broad spectrum of EGFR mutants including exon <NUM> insertions and point mutations than AZD9291. Superior activity was also observed with compounds not shown in the table.

A431 cells, H1975 and Ba/F3 cells expressing various mutant EGFR were harvested from exponential phase cultures and seeded in <NUM>-well plates at a cell density of <NUM> per well for A431 and H1975, and <NUM> per well for Ba/F3 cells. After overnight attachment, compounds were <NUM>-fold serially diluted and applied to cells at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> with triplicates, and incubated for three days. <NUM>µL of <NUM>/mL MTT was added afterwards followed by the further addition of <NUM>µL <NUM>% SDS together with <NUM>% isobutyl alcohol in <NUM> mol/L HCl. The plates were incubated overnight. Absorbance (A) at a wavelength of <NUM> was quantified. Percentage of inhibition was used for the calculation of IC<NUM> based on the bliss method. The results were shown in Table <NUM>.

In comparison with AZD9291, compounds in table <NUM> exhibit greater activity in inhibiting the proliferation of BaF<NUM> cells harboring EGFR D770_N771insSVD or EGFR V769_D770insAS, and comparable activity towards H1975 and A431, suggesting that compounds of the present disclosure demonstrate greatly improved activities towards EGFR exon <NUM> insertions, while maintaining potent activities towards EGFR L858R/T790M together with high selectivities over wild-type EGFR. Other examples of this application not listed in the table also showed similar activity profiles as described above.

Cells (H1975) or tissue pieces (LU0493 and LU0426) were implanted subcutaneously into the left armpit of nude mice. When the average tumor volume reached <NUM>-<NUM><NUM>, mice were randomized by tumor volume and treated with vehicle, compound <NUM> or poziotinib respectively. Tumor volume and body weight were measured twice per week. Mice were sacrificed on day <NUM> or day <NUM>, and tumor volume and terminal body weight were recorded. The relative tumor volume, percent of treatment/control values and tumor growth inhibition were calculated and statistics was performed.

As shown in the table above, compared to poziotinib, compound <NUM> is more effective in blocking tumor growth with EGFR exon <NUM> insertions and T790M mutations with less impacts on body weight, indicative of an increased safety margin.

<NUM>×<NUM><NUM> PC9 cells expressing luciferase were injected to the mouse brain. Mice were randomized based on brain flurorescence intensity and body weight, and were orally administered vehicle or compound <NUM>. Survival and body weights were monitored every day and mice with more than <NUM>% body weight loss were sacrificed.

As shown in table <NUM> and <FIG>, all mice in the vehicle group succumbed to death within <NUM> days after dosing, whereas, all mice receiving compound <NUM> survived, suggesting that compound <NUM> can enter the brain and inhibits tumor growth to promote survival.

The results of Assays <NUM>-<NUM> show that the compound of this disclosure inhibits activity of mutant EGFR with exon <NUM> insertions and point mutations, and the proliferation of Ba/F3 cells harboring different EGFR mutations with a good selectivity over wild type EGFR. Compared to poziotinib, compound <NUM> showed greater in vivo efficacy in mouse PDX models with improved safety window. It is also active in PC9 orthotopic brain model indicative of a good brain penetration. Other compounds of the present disclosure are also efficacious in vivo in blocking tumor growth.

Claim 1:
A compound of general formula (I) or a pharmaceutically acceptable salt thereof:
<CHM>
wherein:
X is selected from the goup consisting of N and CH;
R<NUM> is selected from the group consisting of hydrogen, halogen, C1-<NUM> alkyl, C3-<NUM> cycloalkyl, -C(O)OR<NUM> and CN;
R<NUM> is selected from the group consditing of C1-<NUM> alkyl, deuterated C1-<NUM> alkyl, C3-<NUM> cycloalkyl and C1-<NUM> haloalkyl;
R<NUM> is selected from the group consisting of -NR<NUM>(CH<NUM>)<NUM>NR<NUM>'R<NUM>",
<CHM>
<CHM>
R<NUM> is
<CHM>
R<NUM>, R<NUM> and R<NUM> are independently selected from the group consisting of hydrogen, halogen, C1-<NUM> alkyl, C1-<NUM> haloalkyl, C1-<NUM> alkoxy and CN;
R<NUM> is selected from the group consisting of hydrogen, C1-<NUM> alkyl and C1-<NUM> haloalkyl;
R<NUM> is selected from the group consitins of hydrogen, C1-<NUM> alkyl, deuterated C1-<NUM> alkyl and C1-<NUM> haloalkyl;
R<NUM>' and R<NUM>" are independently selected from the group consisting of hydrogen, C1-<NUM> alkyl, C3-<NUM> cycloalkyl, deuterated C1-<NUM> alkyl and C1-<NUM> haloalkyl, or R<NUM>' and R<NUM>" together with the nitrogen connected thereto form a heterocycle, the heteroclcle is unsubstituted or optionally substituted with <NUM>-<NUM> groups selected from the group consisting of halogen, Cl-<NUM> alkyl, C1-<NUM> alkoxy, methylthio, methanesulfonyl and C1-<NUM> haloalkyl;
R<NUM> is selected from the group consisting of hydrogen, halogen, C1-<NUM> alkyl and - CH<NUM>NR<NUM>'R<NUM>";
R<NUM> is selected from the group consisting of hydrogen, halogen and C1-<NUM> alkyl; and
R<NUM> and R<NUM>' are independently selected from the group consisting of hydrogen, C1-<NUM> alkyl and Cl-<NUM> haloalkyl, or R<NUM>' and R<NUM>" together with the nitrogen connected thereto form a heterocycle, the heteroclcle is unsubstituted or optionally substituted with <NUM>-<NUM> groups selected from the group consisting of halogen, C1-<NUM> alkyl and C1-<NUM> haloalkyl.