5,6-dihydropyrazino[2,3-c]isoquinoline compounds

Abstract

A compound represented by the general formula (1) and a method for preparing the same, and the use of the compound represented by the general formula (1), its various isomers, each crystal form, pharmaceutically acceptable salt, hydrate or solvate as an EGFR inhibitor in the preparation of drugs for treating EGFR-related diseases such as anti-tumor diseases.

Description

[0001] This application claims the priority of Chinese Application CN202010690210.3 with an application date of July 17, 2020. This application incorporates the entire text of the above-mentioned Chinese application by reference. Technical Field

[0002] The present invention relates to the field of medicinal chemistry. More specifically, it relates to a class of 5,6-dihydropyrazino[2,3-c]isoquinoline compounds, their preparation methods, and the use of such compounds as EGFR inhibitors in the preparation of anti-tumor drugs. Background Art

[0003] Lung cancer is one of the common malignant tumors. The number of newly diagnosed lung cancer cases globally each year is approximately 1.6 million, and the number of deaths caused by lung cancer each year is approximately 1.4 million. Among them, non-small cell lung cancer (NSCLC) accounts for about 80%-85% of the total number of lung cancers (Nature, 2018, 553, 446-454).

[0004] The EGFR protein family is a class of protein kinases that are responsible for transmitting mitogenic signals and play an important role in growth and development. Analyses and studies of a large number of in vitro tumor cells, animal models, and human tumor samples have shown that mutations in the EGFR family proteins lead to the development of human tumors and are one of the important inducements for the occurrence and development of various cancers. Therefore, targeting and inhibiting the activity of EGFR mutant proteins is an important means for treating related tumors.

[0005] Studies have shown that EGFR gene mutations can be found in approximately 12 to 47% of non-small cell lung cancers. In non-small cell lung cancer, the two most common EGFR gene mutations are exon 19 deletion (del19) and the L858R missense mutation in exon 21. These two mutations lead to the constitutive activation of the EGFR protein independent of ligand. Although NSCLC patients with EGFR protein Del19 or L858R mutations are more sensitive to targeted therapy with EGFR protein kinase inhibitors (EGFR TKIs) such as erlotinib, gefitinib, afatinib, or osimertinib and can achieve a relatively high (around 60 - 85%) objective response rate (ORR) clinically, this response usually does not last long, and most patients using first-generation or second-generation EGFR TKIs will experience disease progression at approximately 11 months. Resistance analysis has shown that in approximately 50 - 70% of resistant patients, the molecular mechanism of resistance is the acquisition of a second mutation in the EGFR gene, called the T790M mutation (T790M+)(Cancer Discov. 2012, 2, 872 - 5). This secondary mutation renders first-generation and second-generation EGFR TKIs inactive against mutant tumor cells.

[0006] Osimertinib, as a third-generation covalent EGFR TKI, has been developed to treat tumors with EGFR del19 and L858R mutations, with or without T790M mutations. Although osimertinib has a high response rate to resistance caused by the T790M mutation, however, approximately 70% of patients will eventually develop resistance, and the disease will progress again after about 10 months (Lung Cancer. 2017, 108, 228 - 231). Molecular mechanism studies on resistance to third-generation EGFR TKIs have shown that in approximately 20 - 40% of patients who experience osimertinib treatment and relapse, a major resistance mechanism is the acquisition of a third mutation in the EGFR gene, namely the C797S mutation. Moreover, after treatment with third-generation EGFR TKIs, patients with the EGFR del19 / L858R T790M C797S mutant can no longer respond to first-generation, second-generation, or third-generation EGFR TKIs. In 2015, Thress et al. first reported a resistance analysis of 15 patients to osimertinib and found that approximately 40% of the resistance was due to the C797S mutation (Nature Medicine, 2015, 21, 560 - 562). At the 2017 ASCO, Piotrowska and Zhou Caicun each reported resistance analyses of 23 and 99 patients, respectively, and the results of both analyses showed that approximately 22% of the resistance was caused by the C797S mutation. Therefore, targeted inhibition of the EGFR del19 / L858R T790M C797S mutation can overcome osimertinib resistance, but currently there is no marketed EGFR TKI that can inhibit the EGFR del19 / L858R T790M C797S mutant. Therefore, it is very urgent to research and discover a fourth-generation EGFR TKI to meet this unmet clinical need.

[0007] The EGFR del19 / L858R T790M C797S mutant, as a newly emerged EGFR mutant after treatment with third-generation EGFR TKIs, has not been extensively studied yet. Currently, only a few fourth-generation EGFR TKIs have been reported to be able to inhibit the EGFR del19 / L858R T790M C797S mutant. For example, Boehringer Ingelheim reported that a class of macrocyclic compounds, BI-4020, has anti-EGFR del19 / L858R T790M C797S mutant activity and anti-tumor activity in vivo (J MedChem. 2019, 62, 10272-10293). In patent WO2019 / 015655, a class of arylphosphine oxides was reported to have anti-EGFR del19 / L858R T790M C797S mutant activity and anti-tumor activity in vivo. The general formula A and the representative compound B (Example 41 in the patent) are structured as follows (for the definitions of the symbols in the formula, please refer to the patent):

[0008]

[0009] Currently, there is an urgent need to research and discover compounds with good activity against the EGFR del19 / L858R T790M C797S mutant and high safety. Summary of the Invention

[0010] The present invention aims to provide a compound represented by the general formula (1) or its various isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

[0011]

[0012] In the general formula (1):

[0013] Ring A is a (3-11 membered) heteroalkylidene, (C6-C14) arylidene or (5-10 membered) heteroarylidene, wherein the heteroalkylidene, arylidene and heteroarylidene may each independently be optionally substituted by one or more of the following groups: -H, halogen, -NO2, -R 4 、-OR 4 、-(CH2) n OR 4 、-(CH2) n NR 4 R 5 、-NR 4 R 5 、-CN、-C(O)NR 4 R 5 、-NR 5 C(O)R 4 、-NR 5S(O)2R 4 、-S(O) p R 4 and -S(O)2NR 4 R 5 ;

[0014] Y is -O-、-N(R 4 )- or chemical bonds;

[0015] Z is -C(=O)-, -C=N(R 4 )-, -C(=CH2)- or

[0016] L 1 is -O- or -NH-;

[0017] X is (C6-C14)arylene or (5-11 membered)heteroarylene, wherein the arylene and heteroarylene groups are each independently optionally substituted with one or more of the following groups: -H, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, and (C1-C6)haloalkoxy;

[0018] R 1 -H, halogen, -(CH2) n NR 6 R 7 、-NR 6 R 7 、-O(CH2) m NR 6 R 7 、-N(R 5 )(CH2) m NR 6 R 7 , (C1-C6) alkoxy, -CH2-(3-15 membered) heterocycloalkyl or (3-15 membered) heterocycloalkyl, wherein the alkoxy and heterocycloalkyl may each independently be optionally substituted with one or more of the following groups: -H, -R 4 、-(CH2) n NR 6 R 7 、-NR 6 R 7 、-O(CH2) m NR 6 R 7 、-N(R 5 )(CH2) m NR 6 R 7 and -R 3 ;

[0019] R2 is -H, (C1-C6) alkyl, (C3-C14) cycloalkyl, (C6-C14) aryl, (3-11 membered) heterocycloalkyl; wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl may each independently be optionally substituted with one or more of the following groups: halogen, -R 4 , -OH, -(CH2) n OR 4 , -(CH2) n NR 4 R 5 , -OR 4 , -NR 4 R 5 , -CN, -C(O)NR 4 R 5 , -NR 5 C(O)R 4 , -NR 5 S(O)2R 4 , -S(O) p R 4 , -S(O)2NR 4 R 5 ;

[0020] R 3 is (3-11 membered) heterocycloalkyl, wherein the heterocycloalkyl may each independently be optionally substituted with one or more of the following groups: -H, -CD3, -R 4 , -OR 4 and -NR 4 R 5 ;

[0021] R 4 and R 5 are each independently -H, (C1-C6) alkyl, (C1-C6) haloalkyl or (C3-C14) cycloalkyl;

[0022] R 6 and R 7 are each independently -H, (C1-C6) alkyl or (C3-C14) cycloalkyl, or R 6 and R 7 together with the N atom to which they are attached can form a (3-11 membered) heterocycloalkyl, which heterocycloalkyl may each independently be optionally substituted with one or more of the following groups: -H, -CD3, halogen, -R 4 and -OR 4 ;

[0023] R 8 and R 9 are each independently -H, -D, -OR 4, (C1-C6) alkyl or (C3-C14) cycloalkyl, or R 8 and R 9 The C atom to which it is attached can together with it form a (C3-C6) cycloalkyl; and

[0024] p is an integer of 0, 1 or 2, n is an integer of 0, 1, 2 or 3, and m is an integer of 1, 2 or 3.

[0025] In another preferred example, in the general formula (1), the A ring is a (5-7 membered) heteroalkylidene, phenylene or (5-10 membered) heteroarylidene, wherein the heteroalkylidene, phenylene and heteroarylidene can each independently be optionally substituted by one or more of the following groups: -H, -NO2, -F, -Cl, -Br, -CN, -OH, -OCH3, -NH2, -N(CH3)2, -NHCOCH3, -NHSO2CH3, -SO2CH3, -CH3, -CF3, -CHF2, -CONH2 and -CH2OH.

[0026] In another preferred example, in the general formula (1), the A ring is:

[0027]

[0028]

[0029]

[0030] In another preferred example, in the general formula (1), Y is -CH2-, -O-, -NH-, -N(CH3)- or a chemical bond.

[0031] In another preferred example, in the general formula (1), Z is -C(=O)-, -C(=NH)-, -C(=CH2)-, -CH2-, -CH(CH3)-, -CH(OH)-, -C(CH3)2-, -CD(CH3)-, -CD2-, -CH(CF3)- or -CH(CHF2)-.

[0032] In another preferred example, in the general formula (1), X is phenylene or 6-membered heteroarylidene, wherein the phenylene and heteroarylidene can each independently be optionally substituted by one or more of the following groups: -H, -F, -CH3, -CH2CH3, -CH(CH3)2, -OCH3, -OCF2H, -OCH2CF3 and -OCF3.

[0033] In another preferred example, in the general formula (1), X is:

[0034]

[0035]

[0036] In another preferred example, in the general formula (1), R 1 is: -H, -N(CH3)2, -CH2-(6-11 membered) heterocycloalkyl or (6-11 membered) heterocycloalkyl, where the heterocycloalkyl is: and the heterocycloalkyl may each independently be optionally substituted by one or more of the following groups: -H, -CH3, -N(CH3)2, and -CD3.

[0037] In another preferred example, in the general formula (1), R 1 is:

[0038] -H, -N(CH3)2,

[0039] In another preferred example, in the general formula (1), R 2 is:

[0040]

[0041] In various different embodiments, the compound of general formula (1) has one of the following structures:

[0042]

[0043]

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050]

[0051]

[0052]

[0053] Another object of the present invention is to provide a pharmaceutical composition which contains a pharmaceutically acceptable carrier, diluent and / or excipient, and a compound of general formula (1) of the present invention, or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates as an active ingredient.

[0054] Another object of the present invention provides the use of the compound represented by general formula (1) of the present invention, or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates or the above-mentioned pharmaceutical composition in the preparation of a medicament for treating diseases related to EGFR mutation.

[0055] Another object of the present invention further provides a method for treating, regulating and / or preventing diseases related to EGFR mutation, including administering to a subject a therapeutically effective amount of the compound represented by general formula (1) of the present invention, or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates or the above-mentioned pharmaceutical composition.

[0056] By synthesizing and carefully studying various classes of new compounds involving EGFR inhibitory effects, the inventors found that among the compounds of general formula (1), the compounds unexpectedly have strong EGFR del19 / T790M / C797S and EGFR L858R / T790M / C797S inhibitory activity and have high selectivity for wild-type EGFR WT.

[0057] It should be understood that the foregoing general description and the following detailed description of the present invention are both exemplary and illustrative and are intended to provide further explanation of the claimed invention.

[0058] Synthesis of the compound

[0059] The preparation method of the compound of general formula (1) of the present invention is specifically described below, but these specific methods do not constitute any limitation to the present invention.

[0060] The compound of general formula (1) described above can be synthesized using standard synthetic techniques or well-known techniques in combination with the methods described in the text. In addition, the solvents, temperatures and other reaction conditions mentioned herein can be changed. The starting materials for the synthesis of the compound can be obtained by synthesis or from commercial sources. The compounds described herein and other related compounds with different substituents can be synthesized using well-known techniques and raw materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 thEd., Vols. A and B (Plenum 2000, 2001), Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd The methods in Ed., (Wiley 1999). The general methods for preparing the compounds can be changed by using appropriate reagents and the conditions for introducing different groups in the molecular formulas provided herein.

[0061] On the one hand, the compounds described herein are according to methods known in the art. However, the conditions of the methods, such as reactants, solvents, bases, the amounts of the compounds used, reaction temperature, reaction time required, etc., are not limited to the following explanations. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily carried out by those skilled in the art to which the present invention pertains. On the one hand, the present invention also provides a method for preparing the compound represented by the general formula (1), wherein the compound of the general formula (1) can be prepared by the following General Reaction Scheme 1, General Reaction Scheme 2, General Reaction Scheme 3, or General Reaction Scheme 4:

[0062] General Reaction Scheme 1

[0063]

[0064] The embodiment of the compound of the general formula (1) can be prepared according to General Reaction Scheme 1, wherein R 1 、R 2 、R 4 、X, A ring and L 1 are as defined above, H represents hydrogen, and B represents boric acid, borate ester or trifluoroborate. As shown in General Reaction Scheme 1, Compound 1-1 reacts with formamide to form Compound 1-2, Compound 1-2 reacts with R 1 -X-L 1 -H under basic conditions to form Compound 1-3, Compound 1-3 reacts with R 2 -NH2 under basic conditions to form the target compound 1-4, and Compound 1-4 reacts with to carry out a coupling reaction to form Compound 1-5, and Compound 1-5 is reduced to obtain the target product 1-6.

[0065] General Reaction Scheme 2

[0066]

[0067] The embodiment of the compound of the general formula (1) can be prepared according to General Reaction Scheme 2, wherein R 1 、R 2 、X, A ring and L 1As defined above, H represents hydrogen, B represents boric acid, borate ester or trifluoroborate, and CN represents nitrile group. As shown in General Reaction Scheme 2, compound 2-1 reacts with formamide to form compound 2-2, and compound 2-2 reacts with R 1 -X-L 1 -H under basic conditions to form compound 2-3, and compound 2-3 reacts with R 2 -NH2 under basic conditions to form the target compound 2-4, and compound 2-4 reacts with to carry out a coupling reaction to form the target product compound 2-5.

[0068] General Reaction Scheme 3

[0069]

[0070] Embodiments of the compound of general formula (1) can be prepared according to General Reaction Scheme 3, wherein R 1 、R 2 、X, A ring, Y and L 1 are as defined above, H represents hydrogen, and B represents boric acid, borate ester or trifluoroborate. As shown in General Reaction Scheme 3, compound 3-1 reacts with formamide to form compound 3-2, and compound 3-2 reacts with R 1 -X-L 1 -H under basic conditions to form compound 3-3, and compound 3-3 reacts with R2-NH2 under basic conditions to form the target compound 3-4, and compound 3-4 reacts with to carry out a coupling reaction to form the target product compound 3-5.

[0071] General Reaction Scheme 4

[0072]

[0073] Embodiments of the compound of general formula (1) can be prepared according to General Reaction Scheme 4, wherein R 1 、R 2 、R 8 、R 9 、X, A ring and L 1 are as defined above, H represents hydrogen, and B represents boric acid, borate ester or trifluoroborate. As shown in General Reaction Scheme 4, compound 4-1 reacts with formamide to form compound 4-2, and compound 4-2 reacts with R 1 -X-L 1 -H under basic conditions to form compound 4-3, and compound 4-3 reacts with R 2 -NH2 under basic conditions to form the target compound 4-4, and compound 4-4 reacts with to carry out a coupling reaction and form the target product compound 4-5 under acidic conditions.

[0074] Further forms of the compound

[0075] "Pharmaceutically acceptable" as used herein refers to a substance, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., when administered to an individual, the substance does not cause undesirable biological effects or interact in a harmful manner with any of the components which it contains.

[0076] The term "pharmaceutically acceptable salt" refers to a form of a compound which does not cause significant irritation to an administered organism and does not abrogate the biological activity and properties of the compound. In certain specific aspects, pharmaceutically acceptable salts are obtained by reacting a compound of formula (1) with an acid, such as inorganic acids like hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, phosphorous acid, etc., organic acids like formic acid, acetic acid, propionic acid, oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc., and acidic amino acids like aspartic acid, glutamic acid.

[0077] It should be understood that references to pharmaceutically acceptable salts include solvated or crystalline forms, particularly solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent and are formed selectively during the crystallization process with pharmaceutically acceptable solvents such as water, ethanol, etc. A hydrate is formed when the solvent is water or an alcoholate is formed when the solvent is ethanol. Solvates of the compound of formula (1) are conveniently prepared or formed by the methods described herein. By way of example, hydrates of the compound of formula (1) are conveniently prepared by recrystallization from a mixed solvent of water / organic solvent, where the organic solvents include, but are not limited to, tetrahydrofuran, acetone, ethanol or methanol. In addition, the compounds mentioned herein can exist in non-solvated and solvated forms. In general, for the purposes of the compounds and methods provided herein, solvated forms are considered equivalent to non-solvated forms.

[0078] In other specific embodiments, the compound of formula (1) is prepared in different forms, including but not limited to, amorphous, micronized and nano-sized forms. In addition, the compound of formula (1) includes crystalline forms and can also exist as polymorphs. Polymorphs include different lattice arrangements of the same elemental composition of the compound. Polymorphs generally have different X-ray diffraction spectra, infrared spectra, melting points, densities, hardness, crystal forms, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvents, crystallization rates and storage temperatures can cause a single crystal form to predominate.

[0079] In another aspect, the compounds of formula (1) may have chiral centers and / or axial chirality and may thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers, and as cis-trans isomers. Each chiral center or axial chirality will independently give rise to two optical isomers, and all possible optical isomers and diastereomeric mixtures, as well as pure or partially pure compounds, are included within the scope of the present invention. The present invention is meant to include all such isomeric forms of these compounds.

[0080] The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, the compounds may be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C). Alternatively, hydrogen atoms may be replaced with deuterium to form deuterated compounds. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs generally have the advantages of reduced toxic and side effects, increased drug stability, enhanced efficacy, and prolonged in-vivo half-life of the drug. All isotopic compositions of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0081] The term

[0082] Unless otherwise indicated, the terms used in this application for the present invention, including the specification and the claims, are defined as follows. It should be noted that in the specification and the appended claims, the singular form "a" includes the plural meaning if not otherwise clearly indicated in the text. Unless otherwise indicated, conventional methods of mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology are used. In this application, unless otherwise indicated, the use of "or" or "and" means "and / or".

[0083] Unless otherwise specified, "alkyl" refers to saturated aliphatic hydrocarbon groups, including straight-chain and branched-chain groups having 1 to 6 carbon atoms. Lower alkyl groups having 1 to 4 carbon atoms are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, and tert-butyl. As used herein, "alkyl" includes unsubstituted and substituted alkyls, especially alkyls substituted with one or more halogens. Preferred alkyls are selected from CH3, CH3CH2, CF3, CHF2, CF3CH2, CF3(CH3)CH, i Pr, n Pr, i Bu, n Bu or t Bu.

[0084] Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, including straight-chain or branched-chain groups having 1 to 14 carbon atoms. Lower alkenyl groups having 1 to 4 carbon atoms are preferred, such as vinyl, 1-propenyl, 1-butenyl or 2-methylpropenyl.

[0085] Unless otherwise specified, "alkynyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, including straight-chain and branched-chain groups having 1 to 14 carbon atoms. Lower alkynyl groups having 1 to 4 carbon atoms are preferred, such as ethynyl, 1-propynyl or 1-butynyl.

[0086] Unless otherwise specified, "cycloalkyl" refers to a fully saturated monocyclic aliphatic hydrocarbon group having 3 to 14 carbon atoms, wherein one or more of the rings may contain one or more double bonds, but no ring has a completely conjugated π-electron system. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexane, cyclohexadiene, etc.

[0087] Unless otherwise specified, "alkoxy" refers to an alkyl group bonded to the remainder of the molecule through an ether oxygen atom. Representative alkoxy groups are alkoxy groups having 1-6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy groups, especially alkoxy groups substituted by one or more halogens. Preferred alkoxy groups are selected from OCH3, OCF3, CHF2O, CF3CH2O, i- PrO, n- PrO, i- BuO, n- BuO or t- BuO.

[0088] Unless otherwise specified, "aryl" refers to a hydrocarbon aromatic group, which is monocyclic or polycyclic, such as a monocyclic aryl ring fused to one or more carbocyclic aromatic groups. Examples of aryl groups include, but are not limited to, phenyl, naphthyl and phenanthryl.

[0089] Unless otherwise specified, "arylene" refers to a divalent aryl group as defined above. Examples of arylene groups include, but are not limited to, phenylene, naphthylene and phenanthrylene.

[0090] Unless otherwise specified, "heteroaryl" refers to an aromatic group containing one or more heteroatoms (O, S, or N), which can be monocyclic or polycyclic. For example, a monocyclic heteroaryl ring is fused with one or more carbocyclic aromatic groups or other monocyclic heterocyclic alkyl groups. Examples of heteroaryl include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzopyridyl, pyrrolopyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl,

[0091] Unless otherwise specified, "heteroarylene" refers to a divalent heteroaryl as defined above.

[0092] Unless otherwise specified, "heterocycloalkyl" refers to a non-aromatic ring or ring system that may optionally contain one or more alkenylene groups as part of the ring structure and has at least one heteroatom ring member independently selected from boron, phosphorus, nitrogen, sulfur, oxygen, and phosphorus. Heterocycloalkyl can include monocyclic, bicyclic, spirocyclic, or polycyclic (e.g., having two fused or bridged rings) ring systems. In some embodiments, heterocycloalkyl is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. The ring-forming carbon atoms and heteroatoms of heterocycloalkyl can be optionally oxidized to form oxo or sulfido groups or other oxidized bonds (e.g., C(O), S(O), C(S), or S(O)2, N-oxide, etc.), or the nitrogen atom can be quaternized. Heterocycloalkyl can be linked via a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, heterocycloalkyl contains 0 to 3 double bonds. In some embodiments, heterocycloalkyl contains 0 to 2 double bonds. The definition of heterocycloalkyl also includes moieties having one or more aromatic rings fused to the heterocycloalkyl ring (i.e., sharing bonds therewith), such as benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. Heterocycloalkyl containing a fused aromatic ring can be linked via any ring-forming atom, including the ring-forming atoms of the fused aromatic ring. Examples of heterocycloalkyl include azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa-9-azaspiro[5.5]undecanyl, 1-oxa-8-azaspiro[4.5]decanyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropanyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolidinyl, butyrolactamyl, valerolactamyl, imidazolinonyl, hydantoinyl, dioxolanyl, phthalimidyl, pyrimidine-2,4(1H,3H)-dionyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholin-S-oxide group, thiomorpholin-S,S-oxide group, piperazinyl, pyranyl, pyridone group, 3-pyrrolinyl, thiopyranyl, pyranone group, tetrahydrothienyl, 2-azaspiro[3.3]heptanyl, indolinyl,

[0093] Unless otherwise specified, "heterocycloalkylidene" refers to a divalent heterocycloalkyl as defined above.

[0094] Unless otherwise specified, "halogen" (or halo) refers to fluorine, chlorine, bromine, or iodine. The term "halo" (or "halogen-substituted") appearing in front of a group name indicates that the group is partially or fully halogenated, that is, substituted by F, Cl, Br, or I in any combination, preferably by F or Cl.

[0095] "Optional" or "optionally" means that the subsequently described event or condition may but does not necessarily occur, and this description includes both the case where the described event or condition occurs and the case where the described event or condition does not occur.

[0096] The substituent "-O-CH2-O-" means that the two oxygen atoms in the substituent are connected to two adjacent carbon atoms of a heterocycloalkyl, aryl or heteroaryl, for example:

[0097] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a single bond.

[0098] When one of the variables is selected from a chemical bond, it means that the two groups it connects are directly connected. For example, when L represents a chemical bond in X-L-Y, it means that the structure is actually X-Y.

[0099] Unless otherwise specified, the solid wedge bond and the dashed wedge bond represent the absolute configuration of a stereocenter, and the solid straight bond and the dashed straight bond represent the relative configuration of a stereocenter. The wavy line represents the solid wedge bond or the dashed wedge bond or the wavy line represents the solid straight bond or the dashed straight bond

[0100] Specific pharmaceutical and medical terms

[0101] The term "acceptable", as used herein, means that a pharmaceutical ingredient or active ingredient does not have an undue adverse effect on the health of a general therapeutic target.

[0102] The terms "treat", "treatment process" or "therapy", as used herein, include alleviating, suppressing or improving the symptoms or conditions of a disease; inhibiting the occurrence of complications; improving or preventing potential metabolic syndromes; inhibiting the occurrence of a disease or symptoms, such as controlling the development of a disease or condition; alleviating a disease or symptoms; reducing a disease or symptoms; reducing the complications caused by a disease or symptoms, or preventing or treating the signs caused by a disease or symptoms. As used herein, after administration of a certain compound or pharmaceutical composition, a certain disease, symptom or condition can be improved, especially the severity thereof can be improved, the onset can be delayed, the progression of the disease can be slowed down, or the duration of the disease can be reduced. Whether administered regularly or temporarily, continuously or intermittently, it can be attributed to or related to the situation of administration.

[0103] "Active ingredient" refers to the compound represented by the general formula (1), as well as the pharmaceutically acceptable inorganic or organic salts of the compound of general formula (1). The compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality), and may thus occur in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds, and single diastereomers. The asymmetric centers that may be present depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently give rise to two optical isomers, and all possible optical isomers and mixtures of diastereomers, as well as pure or partially pure compounds, are included within the scope of the present invention. The present invention is meant to include all such isomeric forms of these compounds.

[0104] The terms "compound", "composition", "agent", or "medicine or medicament" are used interchangeably herein and all refer to a compound or composition that, when administered to an individual (human or animal), is capable of inducing the desired pharmaceutical and / or physiological response through local and / or systemic action.

[0105] The term "administered, administering, or administration" is used herein to refer to the direct administration of the said compound or composition, or the administration of a prodrug, derivative, or analog of the active compound, etc.

[0106] Although the numerical ranges and parameters used to define the broader scope of the present invention are approximate values, the relevant values in the specific embodiments have been presented as precisely as possible herein. However, any numerical value inherently and inevitably contains standard deviations resulting from the individual test methods. Herein, "about" generally means that the actual value is within plus or minus 10%, 5%, 1%, or 0.5% of a specific value or range. Alternatively, the term "about" represents that the actual value falls within the acceptable standard error of the mean, depending on the consideration of those skilled in the art. Except for experimental examples, or unless otherwise clearly stated, it is understood that all ranges, amounts, numerical values, and percentages (such as those used to describe material amounts, time lengths, temperatures, operating conditions, quantity ratios, and others similar) used herein are modified by "about". Therefore, unless otherwise stated to the contrary, the numerical parameters disclosed in this specification and the appended claims are approximate values and may be varied as required. At a minimum, these numerical parameters should be construed as the indicated number of significant digits and the values obtained by using ordinary rounding methods.

[0107] Unless otherwise defined in this specification, the scientific and technical terms used herein have the same meanings as commonly understood by those skilled in the art. In addition, in the case of not conflicting with the context, the singular nouns used in this specification cover the plural forms of the nouns; and the plural nouns used also cover the singular forms of the nouns.

[0108] Therapeutic use

[0109] The present invention provides a method for treating diseases using the compounds of general formula (1) or pharmaceutical compositions of the present invention, including but not limited to conditions involving EGFR mutations (such as cancer).

[0110] In some embodiments, a method for cancer treatment is provided, which includes administering to an individual in need an effective amount of any of the foregoing pharmaceutical compositions comprising a compound of structural general formula (1). In some embodiments, the cancer is mediated by an EGFR mutation. In other embodiments, the cancer is a blood cancer and solid tumors, including but not limited to leukemia, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial cancer, prostate cancer, liver cancer, ovarian cancer, head and neck cancer, gastric cancer, mesothelioma or all cancer metastases.

[0111] Route of administration

[0112] The compounds of the present invention and their pharmaceutically acceptable salts can be formulated into various preparations, which contain the compounds of the present invention or their pharmaceutically acceptable salts within a safe and effective amount range and pharmacologically acceptable excipients or carriers. The "safe and effective amount" herein refers to: the amount of the compound sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound is determined according to the specific conditions such as the age, condition, and treatment course of the treatment subject.

[0113] "Pharmaceutically acceptable excipients or carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" herein means that the components in the composition can be blended with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmacologically acceptable excipients or carriers are cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween )), wetting agents (such as sodium dodecyl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0114] When the compounds of the present invention are administered, they can be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), or topically.

[0115] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier) such as sodium citrate or calcium phosphate, or with the following components: (a) fillers or bulking agents, e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, e.g., glycerol; (d) disintegrants, e.g., agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retarders, e.g., paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, e.g., cetyl alcohol and glycerol monostearate; (h) adsorbents, e.g., kaolin; and (i) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0116] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and release of the active compound or compounds in such compositions can be delayed and effected in a part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric and wax-like substances. Optionally, the active compound can also be in microcapsule form with one or more of the above excipients.

[0117] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizing agents, and emulsifying agents, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0118] In addition to these inert diluents, the compositions may also contain adjuvants such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, and perfumes.

[0119] In addition to the active compound, the suspension may contain suspending agents, e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, and agar, or mixtures of these substances.

[0120] Compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or non-aqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0121] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required, if necessary.

[0122] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds. When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal in need of treatment (such as a human), wherein the dosage during administration is a pharmaceutically effective dosage. For a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also consider factors such as the route of administration and the health status of the patient, which are within the scope of the skills of a skilled physician.

[0123] The above-mentioned features mentioned in the present invention, or the features mentioned in the embodiments, can be combined arbitrarily. All the features disclosed in the specification of this case can be used in combination with any composition form, and each feature disclosed in the specification can be replaced by any alternative feature that can provide the same, equivalent or similar purpose. Therefore, unless otherwise specified, the disclosed features are only general examples of equivalent or similar features. Detailed Description of the Invention

[0124] In the following description, the various specific aspects, characteristics and advantages of the above-mentioned compounds, methods and pharmaceutical compositions will be elaborated in detail, making the content of the present invention very clear. It should be understood here that the following detailed description and examples describe specific embodiments for reference only. After reading the description of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by this application.

[0125] In all examples, 1 1H-NMR was recorded on a Varian Mercury 400 nuclear magnetic resonance spectrometer, and the chemical shift was expressed in δ (ppm); the silica gel used for separation was 200-300 mesh unless otherwise stated, and the ratio of the eluent was in volume ratio.

[0126] The present invention uses the following abbreviations: CDCl3 represents deuterated chloroform; EtOAc represents ethyl acetate; Hexane represents n-hexane; MeCN represents acetonitrile; DCM represents dichloromethane; DIPEA represents diisopropylethylamine; Dioxane represents 1,4-dioxane; DMF represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; h represents hour; min represents minute; K2CO3 represents potassium carbonate; KF represents potassium fluoride; K3PO4 represents potassium phosphate; K2S2O8 represents potassium persulfate; min represents minute; MeOH represents methanol; MS represents mass spectrometry; (NH4)2S2O8 represents ammonium persulfate; NMR represents nuclear magnetic resonance; Pd / C represents palladium on carbon; Pd(dppf)Cl2 represents dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II); TLC represents thin layer chromatography.

[0127] Synthesis method A:

[0128] Use synthesis method A for the synthesis of Specific Example 1 (6-methylene-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(tetrahydro-2H-pyran-4-yl)-5,6-dihydropyrazino[2,3-c]isoquinoline-2-carboxamide) and Specific Example 2 (6-methyl-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(tetrahydro-2H-pyran-4-yl)-5,6-dihydropyrazino[2,3-c]isoquinoline-2-carboxamide)

[0129]

[0130] Step 1: Synthesis of compound 3,5-dichloro-6-iodopyrazine-2-carboxamide (compound int_2):

[0131] Add 3,5-dichloro-2-iodopyrazine (15 g, 54.57 mmol), formamide (300 mL) into a 500 mL single-necked flask. Stir and heat the mixture to 90 °C, then add solid (NH4)2S2O8 (25 g, 109.1 mmol) in batches. Keep the mixture at 90 °C and stir for 2 h, then add solid K2S2O8 (30 g, 109.1 mmol) in batches again. Keep the mixture at 90 °C and stir for 20 h. Monitor the reaction by LC-MS, and there are products and some remaining raw materials. Add EtOAc (150 mL) and water (300 mL) into the mixture, stir and separate the layers. Extract the aqueous phase with EtOAc (150 mL) again. Combine the organic phases, wash with saturated sodium chloride solution (150 mL) and concentrate. Purify the residue by column chromatography (EtOAc:Hexane = 0:1 to 1:5 to 1:2) to obtain the product (1.82 g, yield: 10.5%), and recover the raw material (10.3 g, yield: 68.7%).

[0132] 1 1H NMR (400 MHz, CDCl3) δ 7.28 (s, 1H), 5.78 (s, 1H); MS (ESI): 317 [M+H] + .

[0133] Step 2: Synthesis of compound 5-chloro-6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrazine-2-carboxamide (compound int_3):

[0134] Add 3,5-dichloro-6-iodopyrazine-2-carboxamide (280 mg, 0.883 mmol), 4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (267 mg, 0.971 mmol), Dioxane (20 mL) and DIPEA (228 mg, 1.766 mmol) into a 50 mL single-necked flask. After replacing the mixture with argon, stir and heat it to reflux for 2 h. After monitoring the completion of the reaction by LC-MS, concentrate the mixture, and purify the residue by column chromatography to obtain the product (368 mg, yield: 75%).

[0135] 11H NMR (400 MHz, CDCl3) δ 10.69 (s, 1H), 7.53 (d, J = 3.8 Hz, 1H), 7.51 - 7.44 (m, 2H), 6.99 - 6.88 (m, 2H), 5.67 (d, J = 3.9 Hz, 1H), 3.80 - 3.63 (m, 2H), 2.84 - 2.42 (m, 10H), 2.39 (ddt, J = 11.4, 7.3, 3.7 Hz, 1H), 1.96 (dt, J = 12.2, 3.0 Hz, 2H), 1.70 (qd, J = 12.1, 4.0 Hz, 2H); MS (ESI): 556 [M+H] + .

[0136] Step 3: Synthesis of compound 6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide (compound int_4):

[0137] Add 5-chloro-6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrazine-2-carboxamide (150 mg, 0.27 mmol), anhydrous potassium carbonate (186 mg, 1.35 mmol), anhydrous potassium fluoride (31 mg, 0.54 mmol), DMSO (5 mL), molecular sieve (200 mg, powdered) into a 50 mL single-necked flask. After purging the mixture with argon, stir at room temperature for 15 min, then add 3-tetrahydro-2H-pyran-4-amine (32 mg, 0.32 mmol). After purging the mixture with argon again, stir and heat up to 120 °C for reaction for 2 h. Monitor the completion of the reaction by LC-MS. After cooling the mixture, purify it by column chromatography to obtain the product (110 mg, yield: 65.7%).

[0138] 1 1H NMR (400 MHz, CDCl3) δ 10.64 (s, 1H), 7.62 - 7.39 (m, 2H), 7.21 (s, 1H), 6.96 - 6.76 (m, 2H), 5.41 - 5.12 (m, 2H), 4.03 (dq, J = 11.4, 3.7 Hz, 3H), 3.67 (d, J = 12.0 Hz, 2H), 3.51 (td, J = 11.6, 2.2 Hz, 2H), 2.84 - 2.50 (m, 10H), 2.44 (d, J = 11.4 Hz, 1H), 2.37 (s, 3H), 2.11 - 1.89 (m, 4H), 1.78 - 1.51 (m, 4H); MS (ESI): 621 [M+H] + .

[0139] Step 4: Synthesis of 6-Methylene-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(tetrahydro-2H-pyran-4-yl)-5,6-dihydropyrazino[2,3-c]isoquinoline-2-carboxamide (Compound 1):

[0140] 6-Iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide (700 mg, 1.22 mmol), 2-acetylphenylboronic acid (400 mg, 2.44 mmol), Pd(dppf)Cl2 (89 mg, 0.12 mmol), and K3PO4 (648 mg, 3.05 mmol) were added to Dioxane / H2O (10 mL / 2 mL), protected by argon, and reacted at 100 °C for about 0.5 h. The reaction was detected to be complete by LC / MS. The solvent was evaporated, the residue was added with water (20 mL), and TFA was added dropwise until completely dissolved and clear. It was purified by column chromatography [H2O(1‰TFA) / MeCN, 5%-5%, 100 mL, 5%-50%, 700 mL, 50%-95%, 50 mL, 95%-95%, 300 mL]. The product fractions were collected, then saturated NaHCO3 (10 mL) was added, and it was extracted three times with DCM (30 mL * 3). The organic phase was dried and evaporated to obtain a yellow solid product (606 mg, yield: 83%).

[0141] 1 H NMR (400 MHz, CDCl3) δ 10.87 (s, 1H), 8.16 - 8.10 (m, 1H), 7.67 - 7.62 (m, 2H), 7.54 (d, J = 8.9 Hz, 2H), 7.44 - 7.39 (m, 1H), 7.36 - 7.31 (m, 1H), 6.95 (d, J = 8.9 Hz, 2H), 5.34 (s, 1H), 5.10 (d, J = 2.4 Hz, 1H), 4.96 - 4.87 (m, 1H), 4.83 (d, J = 2.4 Hz, 1H), 4.12 (dd, J = 11.4, 4.7 Hz, 2H), 3.70 (d, J = 12.1 Hz, 2H), 3.53 (t, J = 11.9 Hz, 2H), 2.94 - 2.81 (m, 2H), 2.69 (dd, J = 22.0, 10.3 Hz, 6H), 2.38 (t, J = 11.4 Hz, 2H), 2.30 (s, 3H), 1.96 (d, J = 12.6 Hz, 2H), 1.77 - 1.68 (m, 4H); MS(ESI): 595 [M + H] + .

[0142] Step 5: Synthesis of 6-methyl-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(tetrahydro-2H-pyran-4-yl)-5,6-dihydropyrazino[2,3-c]isoquinoline-2-carboxamide (Compound 2):

[0143] Dissolve 6-methylene-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(tetrahydro-2H-pyran-4-yl)-5,6-dihydropyrazino[2,3-c]isoquinoline-2-carboxamide (606 mg, 1.02 mmol) in MeOH / DCM (50 mL / 20 mL), add 10% Pd / C (1.2 g), introduce H2, after changing the gas twice, react at room temperature and atmospheric pressure overnight. Detect that the reaction is complete by LC / MS, filter through a sintered funnel lined with diatomaceous earth, wash the filter cake three times with MeOH (20 mL * 3), and rotary evaporate the filtrate to obtain a yellow solid product (550 mg, yield: 90%).

[0144] 1 1H NMR (400 MHz, CDCl3) δ 10.88 (s, 1H), 8.00 (dd, J = 7.7, 1.4 Hz, 1H), 7.61 (s, 1H), 7.57 - 7.53 (m, 2H), 7.33 (td, J = 7.5, 1.3 Hz, 1H), 7.27 (td, J = 7.4, 1.4 Hz, 1H), 7.09 (dd, J = 7.7, 1.3 Hz, 1H), 6.92 - 6.86 (m, 2H), 5.31 (d, J = 13.2 Hz, 1H), 4.82 (q, J = 6.4 Hz, 1H), 4.66 (ddd, J = 12.1, 8.4, 3.7 Hz, 1H), 4.11 (d, J = 11.5 Hz, 2H), 3.66 (d, J = 12.1 Hz, 2H), 3.59 - 3.47 (m, 2H), 3.01 (s, 7H), 2.69 (t, J = 11.5 Hz, 2H), 2.60 (s, 3H), 2.20 - 2.10 (m, 2H), 1.98 (dq, J = 19.8, 7.7, 6.0 Hz, 4H), 1.69 (t, J = 14.7 Hz, 5H), 1.33 (d, J = 6.5 Hz, 3H); MS (ESI): 597 [M + H] +

[0145] By using chiral separation technology, two optically pure chiral isomers can be obtained:

[0146]

[0147] (R)-6-Methyl-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(tetrahydro-2H-pyran-4-yl)-5,6-dihydropyrazino[2,3-c]isoquinoline-2-carboxamide (Compound 2-A):

[0148] 1 H NMR (400 MHz, CDCl3) δ 10.88 (s, 1H), 8.00 (dd, J = 7.7, 1.4 Hz, 1H), 7.61 (s, 1H), 7.57 - 7.53 (m, 2H), 7.33 (td, J = 7.5, 1.3 Hz, 1H), 7.27 (td, J = 7.4, 1.4 Hz, 1H), 7.09 (dd, J = 7.7, 1.3 Hz, 1H), 6.92 - 6.86 (m, 2H), 5.31 (d, J = 13.2 Hz, 1H), 4.82 (q, J = 6.4 Hz, 1H), 4.66 (ddd, J = 12.1, 8.4, 3.7 Hz, 1H), 4.11 (d, J = 11.5 Hz, 2H), 3.66 (d, J = 12.1 Hz, 2H), 3.59 - 3.47 (m, 2H), 3.01 (s, 7H), 2.69 (t, J = 11.5 Hz, 2H), 2.60 (s, 3H), 2.20 - 2.10 (m, 2H), 1.98 (dq, J = 19.8, 7.7, 6.0 Hz, 4H), 1.69 (t, J = 14.7 Hz, 5H), 1.33 (d, J = 6.5 Hz, 3H); MS (ESI): 597 [M+H] + .

[0149] (S)-6-Methyl-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(tetrahydro-2H-pyran-4-yl)-5,6-dihydropyrazino[2,3-c]isoquinoline-2-carboxamide (Compound 2-B):

[0150] 11H NMR (400 MHz, CDCl3) δ 10.88 (s, 1H), 8.00 (dd, J = 7.7, 1.4 Hz, 1H), 7.61 (s, 1H), 7.57 - 7.53 (m, 2H), 7.33 (td, J = 7.5, 1.3 Hz, 1H), 7.27 (td, J = 7.4, 1.4 Hz, 1H), 7.09 (dd, J = 7.7, 1.3 Hz, 1H), 6.92 - 6.86 (m, 2H), 5.31 (d, J = 13.2 Hz, 1H), 4.82 (q, J = 6.4 Hz, 1H), 4.66 (ddd, J = 12.1, 8.4, 3.7 Hz, 1H), 4.11 (d, J = 11.5 Hz, 2H), 3.66 (d, J = 12.1 Hz, 2H), 3.59 - 3.47 (m, 2H), 3.01 (s, 7H), 2.69 (t, J = 11.5 Hz, 2H), 2.60 (s, 3H), 2.20 - 2.10 (m, 2H), 1.98 (dq, J = 19.8, 7.7, 6.0 Hz, 4H), 1.69 (t, J = 14.7 Hz, 5H), 1.33 (d, J = 6.5 Hz, 3H); MS (ESI): 597 [M + H] + .

[0151] Synthetic method B:

[0152] Use synthetic method B to conduct the synthesis of Example 3 (6-imino-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(tetrahydro-2H-pyran-4-yl)-5,6-dihydropyrazino[2,3-c]isoquinoline-2-carboxamide):

[0153]

[0154] Step 1: Synthesis of compound 3,5-dichloro-6-iodopyrazine-2-carboxamide (compound int_2):

[0155] Add 3,5-dichloro-2-iodopyrazine (15 g, 54.57 mmol), formamide (300 mL) into a 500 mL single-necked flask. Stir and heat the mixture to 90 °C, then add solid (NH4)2S2O8 (25 g, 109.1 mmol) in portions. Keep the mixture at 90 °C and stir for 2 h, then add solid K2S2O8 (30 g, 109.1 mmol) in portions again. Keep the mixture at 90 °C and stir for 20 h. Monitor the reaction by LC-MS, and there is product and some starting materials remaining. Add EtOAc (150 mL) and water (300 mL) into the mixture, stir and separate the layers. Extract the aqueous phase with EtOAc (150 mL) again. Combine the organic phases, wash with saturated sodium chloride solution (150 mL) and concentrate. Purify the residue by column chromatography (EtOAc:Hexane = 0:1 to 1:5 to 1:2) to obtain the product (1.82 g, yield: 10.5%), and recover the starting material (10.3 g, yield: 68.7%).

[0156] 1 1H NMR (400 MHz, CDCl3) δ 7.28 (s, 1H), 5.78 (s, 1H); MS (ESI): 317 [M+H] + .

[0157] Step 2: Synthesis of compound 5-chloro-6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrazine-2-carboxamide (compound int_3):

[0158] Add 3,5-dichloro-6-iodopyrazine-2-carboxamide (280 mg, 0.883 mmol), 4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (267 mg, 0.971 mmol), Dioxane (20 mL) and DIPEA (228 mg, 1.766 mmol) into a 50 mL single-necked flask. After purging the mixture with argon, stir and heat it to reflux for 2 h. After monitoring the completion of the reaction by LC-MS, concentrate the mixture. Purify the residue by column chromatography to obtain the product (368 mg, yield: 75%).

[0159] 11H NMR (400 MHz, CDCl3) δ 10.69 (s, 1H), 7.53 (d, J = 3.8 Hz, 1H), 7.51 - 7.44 (m, 2H), 6.99 - 6.88 (m, 2H), 5.67 (d, J = 3.9 Hz, 1H), 3.80 - 3.63 (m, 2H), 2.84 - 2.42 (m, 10H), 2.39 (ddt, J = 11.4, 7.3, 3.7 Hz, 1H), 1.96 (dt, J = 12.2, 3.0 Hz, 2H), 1.70 (qd, J = 12.1, 4.0 Hz, 2H); MS (ESI): 556 [M + H] + .

[0160] Step 3: Synthesis of 6 - iodo - 3 - ((4 - (4 - (4 - methylpiperazin - 1 - yl)piperidin - 1 - yl)phenyl)amino) - 5 - ((tetrahydro - 2H - pyran - 4 - yl)amino)pyrazine - 2 - carboxamide (Compound int_4):

[0161] Add 5 - chloro - 6 - iodo - 3 - ((4 - (4 - (4 - methylpiperazin - 1 - yl)piperidin - 1 - yl)phenyl)amino)pyrazine - 2 - carboxamide (150 mg, 0.27 mmol), anhydrous potassium carbonate (186 mg, 1.35 mmol), anhydrous potassium fluoride (31 mg, 0.54 mmol), DMSO (5 mL), molecular sieve (200 mg, powdered) into a 50 mL single - necked flask. After purging the mixture with argon and stirring at room temperature for 15 min, add 3 - (tetrahydro - 2H - pyran - 4 - yl)amine (32 mg, 0.32 mmol). After purging the mixture with argon again, stir and heat the temperature to 120 °C for 2 h. Monitor the completion of the reaction by LC - MS. After cooling the mixture, purify it by column chromatography to obtain the product (110 mg, yield: 65.7%).

[0162] 1 1H NMR (400 MHz, CDCl3) δ 10.64 (s, 1H), 7.62 - 7.39 (m, 2H), 7.21 (s, 1H), 6.96 - 6.76 (m, 2H), 5.41 - 5.12 (m, 2H), 4.03 (dq, J = 11.4, 3.7 Hz, 3H), 3.67 (d, J = 12.0 Hz, 2H), 3.51 (td, J = 11.6, 2.2 Hz, 2H), 2.84 - 2.50 (m, 10H), 2.44 (d, J = 11.4 Hz, 1H), 2.37 (s, 3H), 2.11 - 1.89 (m, 4H), 1.78 - 1.51 (m, 4H); MS (ESI): 621 [M + H] + .

[0163] Step 4: Synthesis of 6-imino-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(tetrahydro-2H-pyran-4-yl)-5,6-dihydropyrazino[2,3-c]isoquinoline-2-carboxamide (Compound 3):

[0164] Dissolve 6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide (300 mg, 0.52 mmol), 2-cyanophenylboronic acid (115 mg, 0.78 mmol), and Pd(dppf)2Cl2 (38 mg, 0.05 mmol) in NMP (9 mL), add aqueous sodium carbonate solution (2.0 M, 0.9 mL), under argon protection, heat to 120 °C and react for 1 hour. Monitor by LC-MS. After the reaction is complete, cool, and directly perform Flash reverse-phase column chromatography on the reaction solution to obtain 210 mg of a light yellow solid with a yield of 67%.

[0165] 1 H NMR (400 MHz, CDCl3) δ 10.94 (s, 1H), 8.48 (s, 1H), 8.35 (dd, J = 7.9, 1.2 Hz, 1H), 7.80 (d, J = 13.3 Hz, 1H), 7.72 (d, J = 4.4 Hz, 1H), 7.64 - 7.54 (m, 3H), 7.48 (ddd, J = 8.4, 7.2, 1.3 Hz, 1H), 7.02 - 6.94 (m, 2H), 5.76 (brs, 1H), 5.55 - 5.48 (m, 1H), 4.15 - 4.06 (m, 2H), 3.76 - 3.66 (m, 2H), 3.54 (td, J = 11.9, 2.1 Hz, 2H), 3.30 (brs, 2H), 2.75 - 2.56 (m, 6H), 2.47 (brs, 2H), 2.37 (tt, J = 11.4, 3.7 Hz, 1H), 2.28 (s, 3H), 1.99 - 1.90 (m, 2H), 1.76 - 1.63 (m, 4H), 1.58 (d, J = 12.7 Hz, 2H); MS (ESI): 596 [M + H] + .

[0166] Synthesis Method C:

[0167] Use Synthesis Method C to perform the synthesis of Specific Example 4 (3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-6-oxa-5-(tetrahydro-2H-pyran-4-yl)-5,6-dihydropyrazino[2,3-c]isoquinoline-2-carboxamide):

[0168]

[0169] Step 1: Synthesis of compound 3,5-dichloro-6-iodopyrazine-2-carboxamide (compound int_2):

[0170] Add 3,5-dichloro-2-iodopyrazine (15 g, 54.57 mmol) and formamide (300 mL) into a 500 mL single-necked flask. Stir and heat the mixture to 90 °C, then add solid (NH4)2S2O8 (25 g, 109.1 mmol) in batches. Keep the mixture at 90 °C and stir for 2 h. Then add solid K2S2O8 (30 g, 109.1 mmol) in batches again. Keep the mixture at 90 °C and stir for 20 h. Monitor the reaction by LC-MS. There is product and some remaining raw materials. Add EtOAc (150 mL) and water (300 mL) to the mixture, stir and separate the layers. Extract the aqueous phase with EtOAc (150 mL) again. Combine the organic phases, wash with saturated sodium chloride solution (150 mL) and concentrate. Purify the residue by column chromatography (EtOAc:Hexane = 0:1 to 1:5 to 1:2) to obtain the product (1.82 g, yield: 10.5%), and recover the raw material (10.3 g, yield: 68.7%).

[0171] 1 1H NMR (400 MHz, CDCl3) δ 7.28 (s, 1H), 5.78 (s, 1H); MS (ESI): 317 [M+H] + .

[0172] Step 2: Synthesis of compound 5-chloro-6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrazine-2-carboxamide (compound int_3):

[0173] Add 3,5-dichloro-6-iodopyrazine-2-carboxamide (280 mg, 0.883 mmol), 4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (267 mg, 0.971 mmol), Dioxane (20 mL) and DIPEA (228 mg, 1.766 mmol) into a 50 mL single-necked flask. After purging the mixture with argon, stir and heat it to reflux for 2 h. After monitoring the completion of the reaction by LC-MS, concentrate the mixture. Purify the residue by column chromatography to obtain the product (368 mg, yield: 75%).

[0174] 11H NMR (400 MHz, CDCl3) δ 10.69 (s, 1H), 7.53 (d, J = 3.8 Hz, 1H), 7.51 - 7.44 (m, 2H), 6.99 - 6.88 (m, 2H), 5.67 (d, J = 3.9 Hz, 1H), 3.80 - 3.63 (m, 2H), 2.84 - 2.42 (m, 10H), 2.39 (ddt, J = 11.4, 7.3, 3.7 Hz, 1H), 1.96 (dt, J = 12.2, 3.0 Hz, 2H), 1.70 (qd, J = 12.1, 4.0 Hz, 2H); MS (ESI): 556 [M + H] + .

[0175] Step 3: Synthesis of 6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide (Compound int_4):

[0176] Add 5-chloro-6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrazine-2-carboxamide (150 mg, 0.27 mmol), anhydrous potassium carbonate (186 mg, 1.35 mmol), anhydrous potassium fluoride (31 mg, 0.54 mmol), DMSO (5 mL), molecular sieve (200 mg, in powder form) into a 50 mL single-neck flask. After purging the mixture with argon and stirring at room temperature for 15 min, add 3-tetrahydro-2H-pyran-4-amine (32 mg, 0.32 mmol). After purging the mixture with argon again, stir and heat the mixture to 120 °C and react for 2 h. Monitor the completion of the reaction by LC-MS. After cooling the mixture, purify it by column chromatography to obtain the product (110 mg, yield: 65.7%).

[0177] 1 1H NMR (400 MHz, CDCl3) δ 10.64 (s, 1H), 7.62 - 7.39 (m, 2H), 7.21 (s, 1H), 6.96 - 6.76 (m, 2H), 5.41 - 5.12 (m, 2H), 4.03 (dq, J = 11.4, 3.7 Hz, 3H), 3.67 (d, J = 12.0 Hz, 2H), 3.51 (td, J = 11.6, 2.2 Hz, 2H), 2.84 - 2.50 (m, 10H), 2.44 (d, J = 11.4 Hz, 1H), 2.37 (s, 3H), 2.11 - 1.89 (m, 4H), 1.78 - 1.51 (m, 4H); MS (ESI): 621 [M + H] + .

[0178] Step 4: Synthesis of 3-((4-(4-(4-Methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-6-oxa-5-(tetrahydro-2H-pyran-4-yl)-5,6-dihydropyrazino[2,3-c]isoquinoline-2-carboxamide (Compound 4):

[0179] Dissolve 6-Iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide (200 mg, 0.35 mmol), 2-Methoxycarbonylphenylboronic acid (94 mg, 0.52 mmol), Pd(dppf)2Cl2 (26 mg, 0.04 mmol), and K3PO4 (185 mg, 0.87 mmol) in a mixed solution of dioxane and water (40 mL). Under argon protection, heat to 100 °C and react for 0.5 h. Monitor by LC-MS. After the reaction is complete, concentrate. Dissolve the residue in dichloromethane (50 mL), wash with water (30 mL × 2), concentrate the dichloromethane phase, and purify by preparative liquid chromatography to obtain a light yellow solid (60 mg, yield 29%).

[0180] 1 H NMR (400 MHz, CDCl3) δ 10.97 (s, 1H), 8.45 - 8.40 (m, 1H), 8.38 (dd, J = 8.2, 1.3 Hz, 1H), 7.81 (d, J = 4.3 Hz, 1H), 7.78 - 7.71 (m, 1H), 7.59 - 7.53 (m, 3H), 7.00 - 6.95 (m, 2H), 5.68 (ddt, J = 12.0, 7.9, 4.0 Hz, 1H), 5.59 (d, J = 4.3 Hz, 1H), 4.13 (dd, J = 11.2, 4.4 Hz, 2H), 3.72 (d, J = 12.1 Hz, 4H), 3.52 (td, J = 11.9, 2.0 Hz, 2H), 3.10 (qd, J = 12.4, 4.6 Hz, 2H), 2.79 - 2.57 (m, 6H), 2.52 - 2.40 (m, 4H), 2.37 (ddt, J = 11.4, 7.3, 3.7 Hz, 1H), 2.28 (s, 3H), 1.95 (d, J = 13.2 Hz, 2H), 1.69 (dd, J = 11.8, 3.8 Hz, 2H); MS (ESI): 597 [M+H] + .

[0181] Synthesis Method D:

[0182] Synthesis of Example 5 (6,6-dimethyl-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(tetrahydro-2H-pyran-4-yl)amino)-5,6-dihydropyrazino[2,3-c]isoquinoline-2-carboxamide) using Synthetic Method D:

[0183]

[0184] Step 1: Synthesis of compound 3,5-dichloro-6-iodopyrazine-2-carboxamide (compound int_2):

[0185] To a 500 mL single-necked flask, add 3,5-dichloro-2-iodopyrazine (15 g, 54.57 mmol) and formamide (300 mL). Stir the mixture and heat it to 90 °C. Then, add (NH4)2S2O8 (25 g, 109.1 mmol) solid in portions. Keep the mixture at 90 °C and stir for 2 h. Then, add K2S2O8 (30 g, 109.1 mmol) solid in portions again. Keep the mixture at 90 °C and stir for 20 h. Monitor the reaction by LC-MS. There is product and some remaining starting material. Add EtOAc (150 mL) and water (300 mL) to the mixture, stir, and separate the layers. Extract the aqueous phase with EtOAc (150 mL) again. Combine the organic phases, wash with saturated sodium chloride solution (150 mL), and concentrate. Purify the residue by column chromatography (EtOAc:Hexane = 0:1 to 1:5 to 1:2) to obtain the product (1.82 g, yield: 10.5%) and recover the starting material (10.3 g, yield: 68.7%).

[0186] 1 1H NMR (400 MHz, CDCl3) δ 7.28 (s, 1H), 5.78 (s, 1H); MS (ESI): 317 [M+H] + .

[0187] Step 2: Synthesis of compound 5-chloro-6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrazine-2-carboxamide (compound int_3):

[0188] To a 50 mL single-necked flask, add 3,5-dichloro-6-iodopyrazine-2-carboxamide (280 mg, 0.883 mmol), 4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (267 mg, 0.971 mmol), Dioxane (20 mL), and DIPEA (228 mg, 1.766 mmol). After purging the mixture with argon, stir and heat it to reflux for 2 h. After monitoring the reaction by LC-MS and completion, concentrate the mixture. Purify the residue by column chromatography to obtain the product (368 mg, yield: 75%).

[0189] 1 1H NMR (400 MHz, CDCl3) δ 10.69 (s, 1H), 7.53 (d, J = 3.8 Hz, 1H), 7.51 - 7.44 (m, 2H), 6.99 - 6.88 (m, 2H), 5.67 (d, J = 3.9 Hz, 1H), 3.80 - 3.63 (m, 2H), 2.84 - 2.42 (m, 10H), 2.39 (ddt, J = 11.4, 7.3, 3.7 Hz, 1H), 1.96 (dt, J = 12.2, 3.0 Hz, 2H), 1.70 (qd, J = 12.1, 4.0 Hz, 2H); MS (ESI): 556 [M+H] + .

[0190] Step 3: Synthesis of 6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide (Compound int_4):

[0191] Add 5-chloro-6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrazine-2-carboxamide (150 mg, 0.27 mmol), anhydrous potassium carbonate (186 mg, 1.35 mmol), anhydrous potassium fluoride (31 mg, 0.54 mmol), DMSO (5 mL), molecular sieve (200 mg, powdered) into a 50 mL single-necked flask. After purging the mixture with argon and stirring at room temperature for 15 min, add 3-tetrahydro-2H-pyran-4-amine (32 mg, 0.32 mmol). After purging the mixture with argon again, stir and heat the mixture to 120 °C and react for 2 h. Monitor the completion of the reaction by LC-MS. After cooling the mixture, purify it by column chromatography to obtain the product (110 mg, yield: 65.7%).

[0192] 1 1H NMR (400 MHz, CDCl3) δ 10.64 (s, 1H), 7.62 - 7.39 (m, 2H), 7.21 (s, 1H), 6.96 - 6.76 (m, 2H), 5.41 - 5.12 (m, 2H), 4.03 (dq, J = 11.4, 3.7 Hz, 3H), 3.67 (d, J = 12.0 Hz, 2H), 3.51 (td, J = 11.6, 2.2 Hz, 2H), 2.84 - 2.50 (m, 10H), 2.44 (d, J = 11.4 Hz, 1H), 2.37 (s, 3H), 2.11 - 1.89 (m, 4H), 1.78 - 1.51 (m, 4H); MS (ESI): 621 [M+H]+ .

[0193] Step 4: Synthesis of 6-(2-(2-Hydroxypropyl-2-yl)phenyl)-3-((4-(4-(4-Methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide (Compound int_5):

[0194] Dissolve 6-Iodo-3-((4-(4-(4-Methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide (200 mg, 0.35 mmol), (2-(2-Hydroxypropyl-2-yl)phenyl)boronic acid (93 mg, 0.52 mmol), Pd(dppf)2Cl2 (26 mg, 0.04 mmol), and K3PO4 (185 mg, 0.87 mmol) in a mixed solution of dioxane and water (40 mL). Under argon protection, heat the reaction mixture to 100 °C and react for 0.5 hour. Monitor the reaction by LC-MS. After completion of the reaction, concentrate the mixture. Dissolve the residue in dichloromethane (50 mL), wash with water (30 mL × 2), concentrate the dichloromethane phase, and purify by preparative liquid chromatography to obtain a light yellow solid (75 mg, yield 34%).

[0195] MS(ESI): 629[M+H] + 。

[0196] Step 5: Synthesis of 6,6-Dimethyl-3-((4-(4-(4-Methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(tetrahydro-2H-pyran-4-yl)amino)-5,6-dihydropyrazino[2,3-c]isoquinoline-2-carboxamide (Compound 5):

[0197] Dissolve 6-(2-(2-Hydroxypropyl-2-yl)phenyl)-3-((4-(4-(4-Methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide (100 mg, 0.16 mmol) in dichloromethane (10 mL). Under argon protection, at 0 °C, add boron trifluoride diethyl etherate (22.7 mg, 0.16 mmol) dropwise to the above solution. Slowly raise the temperature of the mixed solution to room temperature and react for 2 hours. Monitor the reaction by LC-MS. After completion of the reaction, concentrate the mixture and purify by preparative liquid chromatography to obtain a light yellow solid (15 mg, yield 15%).

[0198] MS(ESI): 611[M+H] + .

[0199] Synthesis of Example Compound 6-288

[0200] Using synthetic method A, synthetic method B, synthetic method C or synthetic method D and different raw materials, the target compound 6-288 in Table 1A can be obtained.

[0201] Table 1A

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237] Table 1B. NMR data of some compounds in Table 1A

[0238]

[0239]

[0240] Example 2 Detection of the inhibitory activity of the compounds of the present invention against EGFR (del19 / T790M / C797S), EGFR (L858R / T790M / C797S) or EGFR (WT) enzymes

[0241] The inhibitory effect of the compound on the enzyme activity of EGFR (del19 / T790M / C797S), EGFR (L858R / T790M / C797S) or EGFR (WT) was determined by the HTRF method. Specifically as follows:

[0242] Incubate WT or mutant EGFR protein with serially diluted compounds at 28 °C for 10 minutes, then add biotin-labeled general tyrosine kinase substrate (TK) and ATP, and react at room temperature for 40 minutes. After terminating the reaction, add Eu3+-Cryptate-labeled antibody against TK and streptavidin-XL665, and incubate at room temperature for 60 minutes. By detecting the luminescence at 615 nm and 665 nm, calculate the ratio of 665 / 615 to quantify the level of TK substrate phosphorylation. Calculate the compound inhibition percentage and IC 50 . The results are shown in Table 2 below.

[0243] Table 2. Inhibitory activities of the compounds of the present invention against EGFR (del19 / T790M / C797S), EGFR (L858R / T790M / C797S) or EGFR (WT)

[0244]

[0245]

[0246]

[0247] + indicates that the inhibition rate is less than or equal to 20%

[0248] ++ indicates that the inhibition rate is 20% to 50%

[0249] +++ indicates that the inhibition rate is greater than 50%.

[0250] N.D indicates that the activity was not measured

[0251] From the data in Table 2, it can be seen that the compounds of the present invention have good inhibitory activities against the enzymatic activities of EGFR (del19 / T790M / C797S) and EGFR (L858R / T790M / C797S), and have good selectivity for EGFR (WT).

[0252] Example 3 Anti-proliferative activities of the compounds of the present invention against Ba / F3 (EGFR del19 / T790M / C797S ) triple mutant cells and A431 (EGFR WT) cells

[0253] Seed 3000 Ba / F3 cells carrying EGFR (del19 / T790M / C797S), or 2000 A431 cells in a 384-well plate. After growing for one day, add serially diluted compounds (up to 500 nM for Ba / F3 cells and up to 10 μM for A431 cells). Three days after adding the compounds, add Cell Titer Glow to evaluate cell growth, and calculate the percentage of compound inhibition of cell growth and IC 50The values are shown in Table 3 below.

[0254] Table 3. Anti - proliferative activities of the compounds of the present invention against Ba / F3 (EGFR del19 / T790M / C797S ) triple - mutant cells and A431 wild - type (EGFRWT) cells

[0255]

[0256]

[0257] From the data in Table 3, it can be seen that the anti - proliferative activities of the vast majority of the compounds of the present invention against Ba / F3 (EGFR del19 / T790M / C797S ) triple - mutant cells are less than 100 nM. It can be seen that the compounds of the present invention all have strong anti - proliferative activities against Ba / F3 (EGFR del19 / T790M / C797S ) triple - mutant cells.

[0258] Although the specific embodiments of the present invention have been described above, those skilled in the art should understand that these are only examples. Without departing from the principle and essence of the present invention, various changes or modifications can be made to these embodiments. Therefore, the protection scope of the present invention is defined by the appended claims.

Claims

1. A compound represented by general formula (1) or an optical isomer thereof, or a pharmaceutically acceptable salt thereof: In the general formula (1): Ring A is a (5-7 membered) heteroalkylidene, phenylene or (5-10 membered) heteroarylene, wherein the heteroalkylidene, phenylene and heteroarylene are each independently optionally substituted with one or more of the following groups: -H, halogen, -NO2, -R 4 , -OR 4 , -(CH2) n OR 4 , -(CH2) n NR 4 R 5 , -NR 4 R 5 , -CN, -C(O)NR 4 R 5 , -NR 5 C(O)R 4 , -NR 5 S(O)2R 4 , -S(O) p R 4 and -S(O)2NR 4 R 5 ; Y is -O-, -N(R 4 )- or a chemical bond; Z is -C(=O)-, -C=N(R 4 )-, -C(=CH2)- or L 1 is -O- or -NH-; X is phenylene, wherein the phenylene is optionally substituted with one or more of the following groups: -H, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, and (C1-C6)haloalkoxy; R 1 is -CH2-(6-11 membered)heterocycloalkyl or (6-11 membered)heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by one or more of the following groups: -H, -R 4 、-(CH2) n NR 6 R 7 、-NR 6 R 7 、-O(CH2) m NR 6 R 7 、-N(R 5 )(CH2) m NR 6 R 7 and -R 3 ; R 2 is -H, (C1-C6) alkyl, (C3-C14) cycloalkyl, (C6-C14) aryl or (3-11 membered) heterocycloalkyl; wherein said alkyl, cycloalkyl, aryl and heterocycloalkyl are each independently optionally substituted by one or more of the following groups: halogen, -R 4 、-OH、-(CH2) n OR 4 -、-(CH2) n NR 4 R 5 -、-OR 4 、-NR 4 R 5 、-CN、-C(O)NR 4 R 5 、-NR 5 C(O)R 4 、-NR 5 S(O)2R 4 、-S(O) p R 4 、-S(O)2NR 4 R 5 ; R 3 is a (3- to 11-membered) heterocycloalkyl, wherein each of said heterocycloalkyls is independently optionally substituted with one or more of the following groups: -H, -CD3, -R 4 , -OR 4 and -NR 4 R 5 ; R 4 and R 5 each independently is -H, (C1-C6)alkyl, (C1-C6)haloalkyl or (C3-C14)cycloalkyl; R 6 and R 7 each independently is -H, (C1-C6)alkyl or (C3-C14)cycloalkyl, or R 6 and R 7 together with the N atom to which it is attached can jointly form a (3- to 11-membered) heterocycloalkyl, which heterocycloalkyl is each independently optionally substituted with one or more of the following groups: -H, -CD3, halogen, -R 4 and -OR 4 [[ID=!2]]; R 8 and R 9 are each independently -H, -D, -OR 4 , (C1-C6) alkyl or (C3-C14) cycloalkyl, or R 8 and R 9 the C atom to which it is attached can together form a (C3-C6) cycloalkyl; and p is an integer of 0, 1 or 2, n is an integer of 0, 1, 2 or 3, and m is an integer of 1, 2 or 3.

2. The compound according to claim 1 or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein in the general formula (1), ring A is a (5-7 membered)heterocycloalkylene, a phenylene or a (5-10 membered)heteroarylene, wherein the heterocycloalkylene, the phenylene and the heteroarylene are each independently optionally substituted by one or more of the following groups: -H, -NO2, -F, -Cl, -Br, -CN, -OH, -OCH3, -NH2, -N(CH3)2, -NHCOCH3, -NHSO2CH3, -SO2CH3, -CH3, -CF3, -CHF2, -CONH2 and -CH2OH.

3. The compound according to claim 2, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein in the general formula (1), Ring A is:

4. The compound according to any one of claims 1 to 3, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein in the general formula (1), Y is -CH2-, -O-, -NH-, -N(CH3)-, or a chemical bond.

5. The compound according to any one of claims 1 to 3, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein in the general formula (1), Z is -C(=O)-, -C(=NH)-, -C(=CH2)-, -CH2-, -CH(CH3)-, -CH(OH)-, -C(CH3)2-, -CD(CH3)-, -CD2-, -CH(CF3)- or -CH(CHF2)-.

6. The compound according to any one of claims 1-3, or its optical isomer, or its pharmaceutically acceptable salt, wherein in the general formula (1), X is a phenylene group, and each of the phenylene groups is independently optionally substituted by one or more of the following groups: -H, -F, -CH3, -CH2CH3, -CH(CH3)2, -OCH3, -OCF2H, -OCH2CF3, and -OCF3.

7. The compound according to claim 6, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein in the general formula (1), X is:

8. The compound or its optical isomer, or its pharmaceutically acceptable salt according to any one of claims 1-3, wherein in the general formula (1), R 1 is: -CH2-(6-11 membered) heterocycloalkyl or (6-11 membered) heterocycloalkyl, wherein the heterocycloalkyl is: and, each of the heterocycloalkyls is independently optionally substituted by one or more of the following groups: -H, -CH3, -N(CH3)2, and -CD3.

9. The compound according to claim 8, or its optical isomer, or its pharmaceutically acceptable salt, wherein in the general formula (1), R 1 is:

10. The compound according to any one of claims 1-3, or its optical isomer, or its pharmaceutically acceptable salt, wherein in the general formula (1), R 2 is:

11. The compound according to any one of claims 1 to 3, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound has one of the following structures:

12. A pharmaceutical composition, characterized in that, The invention contains a pharmaceutically acceptable excipient and the compound according to any one of claims 1 to 11, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

13. A pharmaceutical composition, characterized in that, The composition contains a pharmaceutically acceptable carrier and the compound according to any one of claims 1 to 11, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

14. A compound according to any one of claims 1 to 11, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12 or 13 for use in the preparation of a drug for treating, regulating or preventing EGFR-related diseases del19 / T790M / C797S and EGFR L858R / T790M / C797S Application of drugs in the treatment of mutation-related diseases.

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