CN116323617A - 5,6-Dihydropyrazino[2,3-c]isoquinoline compound - Google Patents

Abstract

A compound shown in a general formula (1) and a preparation method thereof, and application of the compound shown in the general formula (1) and isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof as EGFR inhibitors in preparation of medicaments for resisting EGFR related diseases such as tumors and the like.

Description

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

This application claims the priority of Chinese application CN202010690210.3 with a filing date of July 17, 2020. This application cites the full text of the aforementioned Chinese application.

technical field

The present invention relates to the field of medicinal chemistry, and more specifically, relates to a class of 5,6-dihydropyrazino[2,3-c]isoquinoline compounds, a preparation method thereof and such compounds as EGFR inhibitors in Use in the preparation of antitumor drugs.

Background technique

Lung cancer is one of the most common malignant tumors. There are approximately 1.6 million new lung cancer cases worldwide each year, and approximately 1.4 million deaths due to lung cancer each year. 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).

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. Analysis and research on a large number of tumor cells in vitro, animal models and human tumor samples have shown that mutations in EGFR family proteins lead to the development of human tumors and are one of the important causes of the occurrence and development of various cancers. Therefore, targeting and inhibiting the activity of EGFR mutant proteins is an important means of treating related tumors.

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 types of EGFR gene mutations are exon 19 deletion (del19) and L858 missense mutation in exon 21 (L858 missense mutation). These two types of mutations lead to the continuous activation of EGFR protein independent of ligand. Although NSCLC patients with EGFR protein Del19 or L858R mutations are more sensitive to the targeted therapy of EGFR protein kinase inhibitors (EGFRTKI) such as erlotinib, gefitinib, afatinib or osimertinib, they can obtain a high clinical rate (about 60-85%) ), but this response usually does not last long, and most patients treated with first- or second-generation EGFR TKIs experience disease progression at about 11 months. Drug resistance analysis shows that in about 50-70% of drug-resistant patients, the molecular mechanism of drug resistance is the second mutation of EGFR gene, called T790M mutation (T790M+) (Cancer Discov. 2012, 2, 872-5). This secondary mutation makes the first-generation and second-generation EGFR TKIs lose their inhibitory activity against mutant tumor cells.

Osimertinib, as a third-generation covalent EGFR TKI, was developed to treat tumors with EGFR del19 and L858R mutations with or without T790M mutation. Although osimertinib has a high response rate for drug resistance caused by the T790M mutation, about 70% of patients will eventually develop drug resistance, and the disease will re-progress after about 10 months (Lung Cancer.2017, 108, 228- 231). Research on the molecular mechanism of resistance to third-generation EGFR TKIs has shown that in about 20-40% of patients who undergo osimertinib treatment and relapse, a major resistance mechanism is the acquisition of the third mutation in the EGFR gene, that is, the C797S mutation. Moreover, after treatment with third-generation EGFR TKIs, patients with the EGFR del19/L858R T790M C797S mutation could no longer respond to first-, second-, or third-generation EGFR TKIs. In 2015, Thress et al first reported the drug resistance analysis of osimertinib based on 15 patients, and found that about 40% of the drug resistance was derived from the C797S mutation (Nature Medicine, 2015, 21, 560-562). In 2017, ASCO, Piotrowska and Zhou Caicun reported drug resistance analysis of 23 and 99 patients respectively, and the analysis results of both showed that about 22% of the drug resistance was caused by the C797S mutation. Therefore, targeted inhibition of the EGFR del19/L858R T790M C797S mutation can overcome osimertinib resistance, but there is no EGFR TKI on the market that can inhibit the EGFR del19/L858R T790M C797S mutant, so research and discovery of the fourth-generation EGFR TKI to meet this requirement The unmet clinical needs are very urgent.

The EGFR del19/L858R T790M C797S mutant is a newly emerged EGFR mutant after the third-generation EGFR TKI treatment, and there are not many studies at present. Only a few fourth-generation EGFRTKIs 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 in vivo anti-tumor activity (J Med Chem. 2019, 62, 10272-10293). In the patent WO2019/015655, a class of aryl phosphine oxides was reported to have anti-EGFR del19/L858R T790M C797S mutant activity and in vivo anti-tumor activity. Its general formula A and representative compound B (Example 41 in the patent) have the following structure (please refer to the patent for the definition of each symbol in the formula):

At present, there is an urgent need to research and discover compounds with good activity and safety against EGFR del19/L858R T790M C797S mutation.

Contents of the invention

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

In general formula (1):

Ring A is (3-11 membered) heterocycloalkylene, (C6-C14) arylene or (5-10 membered) heteroarylene, wherein the heterocycloalkylene, arylene and heterocycloalkylene Each aryl group can be independently and optionally substituted by one or more of the following groups: -H, halogen, -NO ₂ , -R ⁴ , -OR ⁴ , -(CH ₂ ) _n OR ⁴ , -(CH ₂ ) _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) ₂ R ⁴ , -S(O) _p R ⁴ and -S(O) ₂ NR ⁴ R ⁵ ;

-O-、-N(R ⁴)-或化学键； Y is

-O-, -N(R ⁴ )- or a chemical bond;

Z is -C(=O)-, -C=N(R ⁴ )-, -C(=CH ₂ )- or

L ¹ is -O- or -NH-;

X is a (C6-C14) arylene group or a (5-11 membered) heteroarylene group, wherein the arylene group and the heteroarylene group may each independently be optionally substituted by 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 -H, halogen, -(CH ₂ ) _n NR ⁶ R ⁷ , -NR ⁶ R ⁷ , -O(CH ₂ ) _m NR ⁶ R ⁷ , -N(R ⁵ )(CH ₂ ) _m NR ⁶ R ⁷ , (C1-C6) alkoxy, -CH ₂ -(3-15 membered) heterocycloalkyl or (3-15 membered) heterocycloalkyl, wherein the alkoxy and heterocycloalkyl can be Each independently and optionally substituted by one or more of the following groups: -H, -R ⁴ , -(CH ₂ ) _n NR ⁶ R ⁷ , -NR ⁶ R ⁷ , -O(CH ₂ ) _m NR ⁶ R ⁷ , -N(R ⁵ )(CH ₂ ) _m NR ⁶ R ⁷ and -R ³ ;

R ² is -H, (C1-C6) alkyl, (C3-C14) cycloalkyl, (C6-C14) aryl, (3-11) heterocycloalkyl; wherein said alkyl, cycloalkane radical, aryl, and heterocycloalkyl can be independently and optionally substituted by one or more of the following groups: halogen, -R ⁴ , -OH, -(CH ₂ ) _n OR ⁴ -, -(CH ₂ ) _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) ₂ R ⁴ , -S(O) _p R ⁴ , -S(O) ₂ NR ⁴ R ⁵ ;

R ³ is a (3-11 membered) heterocycloalkyl group, wherein each of the heterocycloalkyl groups can be independently and optionally substituted by one or more of the following groups: -H, -CD ₃ , -R ⁴ , -OR ⁴ and -NR ⁴ R ⁵ ;

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

R ⁶ and R ⁷ are each independently -H, (C1-C6) alkyl or (C3-C14) cycloalkyl, or R ⁶ and R ⁷ can jointly form a (3-11 member) Heterocycloalkyl, each of which can be independently and optionally substituted by one or more of the following groups: -H, -CD ₃ , halogen, -R ⁴ and -OR ⁴ ;

R ⁸ and R ⁹ are independently -H, -D, -OR ⁴ , (C1-C6) alkyl or (C3-C14) cycloalkyl, or R ⁸ and R ⁹ can jointly 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.

In another preferred example, in the general formula (1), ring A is (5-7 membered) heterocycloalkylene, phenylene or (5-10 membered) heteroarylene, wherein Heterocycloalkylene, phenylene and heteroarylene can each independently be optionally substituted by one or more of the following groups: -H, -NO ₂ , -F, -Cl, -Br, -CN, - OH, -OCH ₃ , -NH ₂ , -N(CH ₃ ) ₂ , -NHCOCH ₃ , -NHSO ₂ CH ₃ , -SO ₂ CH ₃ , -CH ₃ , -CF ₃ , -CHF ₂ , -CONH ₂ and _-CH2OH .

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

In another preferred example, in the general formula (1), Y is -CH ₂ -, -O-, -NH-, -N(CH ₃ )- or a chemical bond.

-CH(CF ₃)-或-CH(CHF ₂)-。 In another preferred example, in the general formula (1), Z is -C(=O)-, -C(=NH)-, -C(=CH ₂ )-, -CH ₂ -, - CH(CH ₃ )-, -CH(OH)-, -C(CH ₃ ) ₂ -, -CD(CH ₃ )-, -CD ₂ -,

-CH(CF ₃ )- or -CH(CHF ₂ )-.

-OCH ₃、-OCF ₂H、-OCH ₂CF ₃和-OCF ₃。 In another preferred example, wherein in the general formula (1), X is a phenylene group or a 6-membered heteroarylene group, wherein the phenylene group and the heteroarylene group can be independently and optionally replaced by 1 or Substitution of multiples of the following groups: -H, -F, -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ ,

-OCH ₃ , -OCF ₂ H, -OCH ₂ CF ₃ and -OCF ₃ .

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

和所述杂环烷基可各自独立任选被1个或多个下列基团取代：-H、-CH ₃、

-N(CH ₃) ₂、

和-CD ₃。 In another preferred example, in the general formula (1), R ¹ is: -H, -N(CH ₃ ) ₂ , -CH ₂ -(6-11 membered) heterocycloalkyl or (6- 11 yuan) heterocycloalkyl, wherein said heterocycloalkyl is:

And the heterocycloalkyl group can be independently and optionally substituted by one or more of the following groups: -H, -CH ₃ ,

-N(CH ₃ ) ₂ ,

and - CD ₃ .

In another preference, wherein in the general formula (1), R ¹ is:

-H, -N(CH ₃ ) ₂ ,

In another preference, wherein in the general formula (1), R ² is:

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

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

Another object of the present invention provides the compound represented by the 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 It is used in the preparation of medicines for treating diseases related to EGFR mutation.

Another object of the present invention is also to provide a method for treating, regulating and/or preventing diseases related to EGFR mutation, comprising administering to the subject a therapeutically effective amount of the compound represented by the general formula (1) of the present invention, or each of them Isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the above-mentioned pharmaceutical compositions.

By synthesizing and carefully studying many types of new compounds involving EGFR inhibitory effects, the inventors found that among the compounds of general formula (1), the compound unexpectedly has strong EGFR ^{del19/T790M/C797S} and EGFR ^{L858R/T790M/C797S} inhibitory effects activity, and has high selectivity for wild-type EGFR WT.

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

compound synthesis

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.

The compounds of general formula (1) described above can be synthesized using standard synthetic techniques or known techniques combined with methods herein. In addition, solvents, temperatures and other reaction conditions mentioned herein may vary. Starting materials for the synthesis of compounds can be obtained synthetically or from commercial sources. The compounds described herein and other related compounds having various substituents can be synthesized using well known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 ^th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 ^th Ed., Vols. A and B (Plenum 2000, 2001), methods in Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS ^3rd Ed., (Wiley 1999). The general methods of compound preparation can be varied by using appropriate reagents and conditions to introduce different groups into the formulas provided herein.

In one aspect, the compounds described herein are according to methods well known in the art. However, the conditions of the method, such as reactants, solvent, base, amount of the compound used, reaction temperature, time required for the reaction, etc., are not limited to those explained below. The compound of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in the specification or known in the art. Such a combination can be easily performed by those skilled in the art to which the present invention belongs. On the one hand, the present invention also provides a preparation method of the compound represented by the general formula (1), wherein the compound of the general formula (1) can adopt the following general reaction scheme 1, general reaction scheme 2, general reaction scheme 3 or General Reaction Scheme 4 Preparation:

General reaction scheme 1

进行偶联反应生成化合物1-5，还原化合物1-5得到目标产物1-6。 The embodiment of the compound of general formula (1) can be prepared according to the general reaction scheme 1, wherein R ¹ , R ² , R ⁴ , X, ring A and L ¹ are as defined above, H represents hydrogen, B represents boronic acid, boric acid ester or trifluoroborate. As shown in general reaction scheme 1, compound 1-1 reacts with formamide to generate compound 1-2, compound 1-2 reacts with R ¹ -XL ¹ -H under basic conditions to generate compound 1-3, compound 1-3 react with R ² -NH ₂ under basic conditions to generate target compound 1-4, compound 1-4 and

A coupling reaction was performed to generate compound 1-5, and reduction of compound 1-5 gave target product 1-6.

General reaction scheme 2

进行偶联反应生成目标产物化合物2-5。 Embodiments of compounds of general formula (1) can be prepared according to general reaction scheme 2, wherein R ¹ , R ² , X, ring A and L ¹ are as defined above, H represents hydrogen, B represents boronic acid, borate or trifluoro Borate, CN represents a nitrile group. As shown in general reaction scheme 2, compound 2-1 reacts with formamide to generate compound 2-2, and compound 2-2 reacts with R ¹ -XL ¹ -H under basic conditions to generate compound 2-3, compound 2-3 and R ² -NH ₂ react under basic conditions to generate target compound 2-4, compound 2-4 and

The coupling reaction was carried out to generate the target product compound 2-5.

General reaction scheme 3

进行偶联反应生成目标产物化合物3-5。 The embodiment of the compound of general formula (1) can be prepared according to the general reaction scheme 3, wherein R ¹ , R ² , X, ring A, Y and L ¹ are as defined above, H represents hydrogen, B represents boronic acid, boronic acid ester or trifluoroborate. As shown in general reaction scheme 3, compound 3-1 reacts with formamide to generate compound 3-2, compound 3-2 reacts with R ¹ -XL ¹ -H under basic conditions to generate compound 3-3, compound 3-3 react with R ² -NH ₂ under basic conditions to generate target compound 3-4, compound 3-4 and

The coupling reaction was carried out to generate the target product compound 3-5.

General reaction scheme 4

进行偶联反应并在酸性条件下生成目标产物化合物4-5。 The embodiment 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, ring A and L ¹ are as defined above, H represents hydrogen, B represents boronic acid, borate or trifluoroborate. As shown in general reaction scheme 4, compound 4-1 reacts with formamide to generate compound 4-2, and compound 4-2 reacts with R ¹ -XL ¹ -H under basic conditions to generate compound 4-3, compound 4-3 react with R ² -NH ₂ under basic conditions to generate target compound 4-4, compound 4-4 and

The coupling reaction was carried out and the target product compound 4-5 was generated under acidic conditions.

Further forms of compounds

"Pharmaceutically acceptable" here refers to a substance, such as a carrier or diluent, that does not abolish the biological activity or properties of the compound, and that is relatively nontoxic, e.g., does not cause unwanted biological effects or Interact in a harmful manner with any of its components.

The term "pharmaceutically acceptable salt" refers to a form of a compound that does not cause significant irritation to the organism to which it is administered and that does not abolish the biological activity and properties of the compound. In some specific aspects, the pharmaceutically acceptable salt is obtained by reacting the compound of general formula (1) with an acid, such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, phosphoric acid and other inorganic acids, 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 and other organic acids and acidic amino acids such as aspartic acid and glutamic acid.

References to pharmaceutically acceptable salts are understood to include solvent added forms or crystalline forms, especially solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric solvents and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol. Solvates of compounds of general formula (1) are conveniently prepared or formed according to the methods described herein. For example, the hydrate of the compound of general formula (1) is conveniently prepared by recrystallization from a mixed solvent of water/organic solvent, and the organic solvent used includes but not limited to tetrahydrofuran, acetone, ethanol or methanol. Furthermore, the compounds mentioned herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for purposes of the compounds and methods provided herein.

In other embodiments, compounds of general formula (1) are prepared in different forms including, but not limited to, amorphous, pulverized and nano-particle sized forms. In addition, the compound of the general formula (1) includes crystalline forms and may also be regarded as polymorphic forms. Polymorphs include different lattice arrangements of the same elemental composition of a compound. Polymorphs usually 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 solvent, crystallization rate and storage temperature may cause a single crystal form to predominate.

In another aspect, the compounds of general formula (1) may have chiral centers and/or axial chirality and thus exist as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single non- Enantiomeric forms, and cis-trans isomeric forms occur. 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 invention. The present invention is meant to include all such isomeric forms of these compounds.

The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds. For example, compounds can be labeled with radioactive isotopes such as tritium ( ³ H), iodine-125 ( ¹²⁵ I), and C-14 ( ¹⁴ C). For another example, heavy hydrogen can be used to replace hydrogen atoms to form deuterated compounds. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Stability, enhanced curative effect, extended drug half-life in vivo and other advantages. All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are encompassed within the scope of the invention.

the term

Unless otherwise stated, the terms used in the present application, including the specification and claims, are defined as follows. It must be noted that in the specification and appended claims, the singular form "a" and "an" includes plural references unless the context clearly dictates otherwise. If not stated otherwise, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are used. In this application, the use of "or" or "and" means "and/or" if not stated otherwise.

Unless otherwise specified, "alkyl" means a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 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, tert-butyl. As used herein, "alkyl" includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted with one or more halogens. Preferred alkyl ^groups are selected from _CH3 , _CH3CH2 , _CF3 , _CHF2 , _{CF3CH2 , CF3} ( _CH3 )CH, _iPr , ^nPr , ^iBu , ^nBu or ^tBu .

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

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

Unless otherwise specified, "cycloalkyl" means a 3 to 14 membered all-carbon monocyclic aliphatic hydrocarbon group in which one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system . For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexane, cyclohexadiene, and the like.

Unless otherwise specified, "alkoxy" means an alkyl group bonded to the remainder of the molecule through an ether oxygen atom. Representative alkoxy groups are alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxyl. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy, especially alkoxy substituted with one or more halogens. Preferred alkoxy groups are selected from OCH ₃ , OCF ₃ , CHF ₂ O, CF ₃ CH ₂ O, ^i- PrO, ^n- PrO, ^i- BuO, ^n- BuO or ^t- BuO.

Unless otherwise specified, "aryl" refers to a hydrocarbon aromatic group, aryl is monocyclic or polycyclic, eg a monocyclic aryl ring fused with one or more carbocyclic aromatic groups. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and phenanthrenyl.

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 phenanthrenylene.

Unless otherwise specified, "heteroaryl" refers to an aromatic group containing one or more heteroatoms (O, S or N), and the heteroaryl is monocyclic or polycyclic. For example a monocyclic heteroaryl ring is fused with one or more carbocyclic aromatic groups or other monocyclic heterocycloalkyl groups. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolyl, furyl, thienyl, Isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, benzene Pyridyl, pyrrolopyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrole[2,3-c]pyridinyl, 1H-pyrrole[3,2-c]pyridinyl, 1H- Pyrrolo[2,3-b]pyridyl,

Unless otherwise specified, "heteroarylene" refers to a divalent heteroaryl group as defined above.

Unless otherwise specified, "heterocycloalkyl" means a non-aromatic ring or ring system which may optionally contain as part of the ring structure one or more alkenylene groups having at least one group independently selected from boron, phosphorus, , nitrogen, sulfur, oxygen, and phosphorus heteroatom ring members. Heterocycloalkyl groups can include monocyclic, bicyclic, spiro, or polycyclic (eg, 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 the heterocycloalkyl group can be optionally oxidized to form oxo or sulfide groups or other oxidized linkages (e.g., C(O), S(O), C(S), or S(O) 2, N-oxide, etc.), or the nitrogen atom can be quaternized. A heterocycloalkyl group can be attached via a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, heterocycloalkyl groups contain 0 to 3 double bonds. In some embodiments, heterocycloalkyl groups contain 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties having one or more aromatic rings fused to (ie, sharing a bond with) the heterocycloalkyl ring, such as piperidine, morpholine, azepine, etc. benzo or thienyl derivatives. A heterocycloalkyl group containing a fused aromatic ring may be attached via any ring-forming atom, including ring-forming atoms of a fused aromatic ring. Examples of heterocycloalkyl groups include azetidinyl, azepanyl, dihydrobenzofuryl, dihydrofuryl, dihydropyranyl, N-morpholinyl, 3-oxa-9- Azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, Quinyl, Tetrahydrofuranyl, Tetrahydropyranyl, 1,2,3,4-Tetrahydroquinolyl, Tropanyl, 4,5,6,7-Tetrahydrothiazolo[5,4-c] Pyridyl, 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolidinyl, butyrolactam, Valerolactam group, imidazolinone group, hydantoin group, dioxolanyl group, phthalimide group, pyrimidine-2,4(1H,3H)-dione group, 1,4- Dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholine-S-oxide, thiomorpholine-S, S-oxide, piperazinyl, pyranyl, pyridone Base, 3-pyrrolinyl, thiopyranyl, pyronenyl, tetrahydrothiophenyl, 2-azaspiro[3.3]heptanyl, indolinyl,

Unless otherwise specified, "heterocycloalkylene" refers to a divalent heterocycloalkyl group as defined above.

Unless otherwise specified, "halogen" (or halo) refers to fluorine, chlorine, bromine or iodine. The term "halo" (or "halogen substitution") appearing before the group name means that the group is partially or fully halogenated, that is, substituted by F, Cl, Br or I in any combination, preferably Substituted by F or Cl.

"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

The substituent "-O-CH ₂ -O-" means that two oxygen atoms in the substituent are connected to two adjacent carbon atoms of heterocycloalkyl, aryl or heteroaryl, such as:

When the number of a linking group is 0, such as -(CH ₂ ) ₀ -, it means that the linking group is a single bond.

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

和楔形虚线键

表示一个立体中心的绝对构型，用直形实线键

和直形虚线键

表示立体中心的相对构型，用波浪线

表示楔形实线键

或楔形虚线键

或用波浪线

表示直形实线键

或直形虚线键

Unless otherwise noted, keys with wedge-shaped solid lines

and dotted wedge keys

Indicates the absolute configuration of a stereocenter, with a straight solid-line bond

and straight dashed keys

Indicates the relative configuration of the stereocenter, with a wavy line

Indicates wedge-shaped solid-line bond

or dotted wedge key

or with tilde

Indicates a straight solid line key

or straight dotted key

Certain pharmaceutical and medical terms

The term "acceptable", as used herein, means that a formulation ingredient or active ingredient does not have an undue adverse effect on health for the general purpose of treatment.

The term "treatment", "course of treatment" or "therapy" as used herein includes alleviating, suppressing or ameliorating the symptoms or conditions of a disease; inhibiting the development of complications; ameliorating or preventing the underlying metabolic syndrome; inhibiting the development of diseases or symptoms, Such as controlling the development of a disease or condition; alleviating a disease or a symptom; causing a disease or a symptom to regress; alleviating a complication caused by a disease or a symptom, or preventing or treating a symptom caused by a disease or a symptom. As used herein, a certain compound or pharmaceutical composition, after administration, can improve a certain disease, symptom or situation, especially improve its severity, delay the onset, slow down the progression of the disease, or reduce the duration of the disease. Circumstances that may be attributable to or related to the administration, whether fixed or episodic, continuous or intermittent.

"Active ingredient" refers to the compound represented by the general formula (1), and the pharmaceutically acceptable inorganic or organic salts of the compound of the general formula (1). The compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality) and thus exist as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single non- Enantiomers occur in the form of enantiomers. The asymmetric centers that can exist 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 diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the invention. The present invention is meant to include all such isomeric forms of these compounds.

The terms "compound", "composition", "agent" or "medicine or medicament" are used interchangeably herein and refer to a In animals), a compound or composition capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.

The term "administered, administering, or administration" as used herein means direct administration of the compound or composition, or administration of a prodrug, derivative, or analog of the active compound wait.

Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the relative numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently inherently contain standard deviations resulting from their individual testing methodology. As used herein, "about" generally means that the actual value is within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range. Alternatively, the term "about" means that the actual value falls within an acceptable standard error of the mean, as considered by those skilled in the art. Except for the experimental examples, or unless otherwise expressly stated, all ranges, quantities, numerical values and percentages used herein should be understood (for example, to describe the amount of material used, the length of time, temperature, operating conditions, quantitative ratios and other similar Those) are modified by "about". Therefore, unless otherwise stated to the contrary, the numerical parameters disclosed in the specification and the appended claims are approximate values and may be changed as required. At a minimum, these numerical parameters should be understood as the number of significant digits indicated plus the usual rounding method.

Unless otherwise defined in this specification, the meanings of scientific and technical terms used herein are the same as the usual meanings understood by those skilled in the art. In addition, the singular nouns used in this specification include the plural forms of the nouns, and the plural nouns used also include the singular forms of the nouns, unless the context conflicts with the context.

therapeutic use

The present invention provides a method of using the compound of general formula (1) or the pharmaceutical composition of the present invention to treat diseases, including but not limited to conditions involving EGFR mutations (such as cancer).

In some embodiments, there is provided a method for treating cancer, the method comprising administering an effective amount of any of the aforementioned pharmaceutical compositions comprising the compound of general structural formula (1) to an individual in need thereof. In some embodiments, the cancer is mediated by EGFR mutations. In other embodiments, the cancer is 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, stomach cancer, mesothelioma or all cancer metastases.

Route of administration

The compounds of the present invention and their pharmaceutically acceptable salts can be made into various preparations, which contain the compounds of the present invention or their pharmaceutically acceptable salts and pharmaceutically acceptable excipients or carriers within the range of safe and effective amounts . Wherein "safe and effective amount" refers to: the amount of the compound is sufficient to obviously improve the condition without producing serious side effects. The safe and effective dose of the compound is determined according to the specific conditions such as the age, condition, and course of treatment of the subject to be treated.

)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。 "Pharmaceutically acceptable excipient or carrier" means: one or more compatible solid or liquid filler or gel substances, which are suitable for human use and must be of sufficient purity and low enough toxicity . "Compatibility" herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound. Examples of pharmaceutically acceptable excipients or carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants ( Such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween

), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.

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

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 dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, hard Calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also contain buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner. Examples of usable embedding components are polymeric substances and waxy substances. The active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.

Besides such inert diluents, the compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.

Dosage forms for topical administration of a compound of this invention 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 which may be required, if necessary.

The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds. When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily The dosage is usually 1-2000 mg, preferably 50-1000 mg. Of course, factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.

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 combination, 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 ways

In the following description, various specific aspects, characteristics and advantages of the above-mentioned compounds, methods and pharmaceutical compositions will be described in detail, so that the content of the present invention becomes very clear. It is to be understood that the following detailed description and examples describe specific embodiments and are given by 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 situations also fall within the scope defined in the present application.

In all the examples, ¹ H-NMR was recorded by a Varian Mercury 400 nuclear magnetic resonance apparatus, and the chemical shifts were expressed in δ (ppm); the silica gel used for separation was 200-300 mesh, and the ratio of the eluent was volume ratio.

The present invention adopts the following abbreviations: _CDCl 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 stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; h stands for hour; min stands for minute; K ₂ CO ₃ stands for potassium carbonate; KF stands for potassium fluoride; K ₃ PO ₄ stands for potassium phosphate; K ₂ S ₂ O ₈ stands for potassium persulfate; min stands for minute; MeOH stands for methanol; MS stands for mass spectrum; (NH ₄ ) ₂ S ₂ O ₈ stands for ammonium persulfate; NMR stands for nuclear magnetic resonance; Pd /C stands for palladium on carbon; Pd(dppf) _Cl2 stands for 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; TLC stands for thin layer chromatography.

Synthetic method A:

Specific Example 1 (6-methylene-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino) was carried out using synthetic method A -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 -Synthesis of -5,6-dihydropyrazino[2,3-c]isoquinoline-2-carboxamide)

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

Add 3,5-dichloro-2-iodopyrazine (15g, 54.57mmol), formamide (300mL) into a 500mL single-necked bottle, stir the mixture and heat up to 90°C, then add (NH ₄ ) ₂ S ₂ O in batches ₈ (25g, 109.1mmol) solid, the mixture was kept at 90°C and stirred for 2h, then K ₂ S ₂ O ₈ (30g, 109.1mmol) solid was added in batches, and the mixture was kept at 90°C and stirred for 20h. LC-MS monitored the reaction to have products, and the remaining part was raw materials. EtOAc (150mL) and water (300mL) were added to the mixture, stirred and separated, the aqueous phase was extracted with EtOAc (150mL), the combined organic phase was washed with saturated sodium chloride solution (150mL), concentrated, and the residue was subjected to column chromatography Purification (EtOAc:Hexane=0:1 to 1:5 to 1:2) gave the product (1.82 g, yield: 10.5%), and recovered the starting material (10.3 g, yield: 68.7%).

¹ H NMR (400MHz, CDCl ₃ ) δ7.28(s, 1H), 5.78(s, 1H); MS(ESI): 317[M+H] ⁺ .

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

3,5-dichloro-6-iodopyrazine-2-carboxamide (280mg, 0.883mmol), 4-(4-(4-methylpiperazin-1-yl)piperidine-1 -yl)aniline (267mg, 0.971mmol), Dioxane (20mL) and DIPEA (228mg, 1.766mmol), the mixture was replaced with argon, stirred and heated to reflux for 2h. After the completion of the reaction was monitored by LC-MS, the mixture was concentrated, and the residue was purified by column chromatography to obtain the product (368 mg, yield: 75%).

¹ H NMR (400MHz, CDCl ₃ ) δ10.69(s, 1H), 7.53(d, J=3.8Hz, 1H), 7.51-7.44(m, 2H), 6.99-6.88(m, 2H), 5.67( d, J=3.9Hz, 1H), 3.80-3.63(m, 2H), 2.84-2.42(m, 10H), 2.39(ddt, J=11.4, 7.3, 3.7Hz, 1H), 1.96(dt, J= 12.2, 3.0Hz, 2H), 1.70 (qd, J=12.1, 4.0Hz, 2H); MS(ESI): 556[M+H] ⁺ .

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

分子筛(200mg，粉末状)，混合液氩气置换后室温搅拌15min，后加入3-四氢-2H-吡喃-4-胺(32mg，0.32mmol)，混合液氩气置换后搅拌升温至120℃反应2h。LC-MS监测反应完成，混合液降温后柱层析纯化得产物(110mg，收率：65.7％)。 Add 5-chloro-6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrazine-2 - carboxamide (150mg, 0.27mmol), anhydrous potassium carbonate (186mg, 1.35mmol), anhydrous potassium fluoride (31mg, 0.54mmol), DMSO (5mL),

Molecular sieves (200 mg, powder), the mixture was replaced by argon and stirred at room temperature for 15 min, then 3-tetrahydro-2H-pyran-4-amine (32 mg, 0.32 mmol) was added, the mixture was replaced by argon and the temperature was raised to 120 ℃ reaction 2h. The completion of the reaction was monitored by LC-MS, and the product (110 mg, yield: 65.7%) was purified by column chromatography after the mixture was cooled down.

¹ H NMR (400MHz, CDCl ₃ ) δ10.64(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, 3.7Hz, 3H), 3.67(d, J=12.0Hz, 2H), 3.51(td, J=11.6, 2.2Hz, 2H), 2.84-2.50(m, 10H) , 2.44(d, J=11.4Hz, 1H), 2.37(s, 3H), 2.11-1.89(m, 4H), 1.78-1.51(m, 4H); MS(ESI): 621[M+H] ⁺ .

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

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)Cl ₂ (89 mg, 0.12 mmol), K ₃ PO ₄ (648mg, 3.05mmol) was added to Dioxane/H ₂ O (10mL/2mL), protected by argon, and reacted at 100°C for about 0.5h. LC/MS detected that the reaction was complete. Spin dry, add water (20mL) to the residue, add TFA dropwise until completely dissolved, and purify by column chromatography [H ₂ O(1‰TFA)/MeCN, 5%-5%, 100mL, 5%-50%, 700mL, 50%-95%, 50mL, 95%-95%, 300mL] to collect product fractions, add saturated NaHCO ₃ (10mL), extract three times with DCM (30mL*3), and dry the organic phase to obtain a yellow solid product ( 606 mg, yield: 83%).

¹ H NMR (400MHz, CDCl ₃ ) δ10.87(s, 1H), 8.16-8.10(m, 1H), 7.67-7.62(m, 2H), 7.54(d, J=8.9Hz, 2H), 7.44- 7.39(m, 1H), 7.36-7.31(m, 1H), 6.95(d, J=8.9Hz, 2H), 5.34(s, 1H), 5.10(d, J=2.4Hz, 1H), 4.96-4.87 (m, 1H), 4.83(d, J=2.4Hz, 1H), 4.12(dd, J=11.4, 4.7Hz, 2H), 3.70(d, J=12.1Hz, 2H), 3.53(t, J= 11.9Hz, 2H), 2.94-2.81(m, 2H), 2.69(dd, J=22.0, 10.3Hz, 6H), 2.38(t, J=11.4Hz, 2H), 2.30(s, 3H), 1.96( d, J=12.6Hz, 2H), 1.77-1.68(m, 4H); MS(ESI): 595[M+H] ⁺ .

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

6-methylene-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(tetrahydro-2H-pyridine Pyran-4-yl)-5,6-dihydropyrazino[2,3-c]isoquinoline-2-carboxamide (606mg, 1.02mmol) was dissolved in MeOH/DCM (50mL/20mL) and added 10% Pd/C (1.2g), feed H ₂ , ventilate twice, and react overnight at room temperature and normal pressure. LC/MS detected that the reaction was complete. The sand core funnel was covered with diatomaceous earth for filtration, the filter cake was washed three times with MeOH (20 mL*3), and the filtrate was spin-dried to obtain a yellow solid product (550 mg, yield: 90%).

¹ H NMR (400MHz, CDCl ₃ ) δ10.88(s, 1H), 8.00(dd, J=7.7, 1.4Hz, 1H), 7.61(s, 1H), 7.57-7.53(m, 2H), 7.33( td, J=7.5, 1.3Hz, 1H), 7.27(td, J=7.4, 1.4Hz, 1H), 7.09(dd, J=7.7, 1.3Hz, 1H), 6.92-6.86(m, 2H), 5.31 (d, J=13.2Hz, 1H), 4.82(q, J=6.4Hz, 1H), 4.66(ddd, J=12.1, 8.4, 3.7Hz, 1H), 4.11(d, J=11.5Hz, 2H) , 3.66(d, J=12.1Hz, 2H), 3.59-3.47(m, 2H), 3.01(s, 7H), 2.69(t, J=11.5Hz, 2H), 2.60(s, 3H), 2.20- 2.10(m, 2H), 1.98(dq, J=19.8, 7.7, 6.0Hz, 4H), 1.69(t, J=14.7Hz, 5H), 1.33(d, J=6.5Hz, 3H); MS(ESI ): 597[M+H] ⁺ .

Using chiral separation technology, two optically pure chiral isomers can be obtained:

(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):

¹ H NMR (400MHz, CDCl ₃ ) δ10.88(s, 1H), 8.00(dd, J=7.7, 1.4Hz, 1H), 7.61(s, 1H), 7.57-7.53(m, 2H), 7.33( td, J=7.5, 1.3Hz, 1H), 7.27(td, J=7.4, 1.4Hz, 1H), 7.09(dd, J=7.7, 1.3Hz, 1H), 6.92-6.86(m, 2H), 5.31 (d, J=13.2Hz, 1H), 4.82(q, J=6.4Hz, 1H), 4.66(ddd, J=12.1, 8.4, 3.7Hz, 1H), 4.11(d, J=11.5Hz, 2H) , 3.66(d, J=12.1Hz, 2H), 3.59-3.47(m, 2H), 3.01(s, 7H), 2.69(t, J=11.5Hz, 2H), 2.60(s, 3H), 2.20- 2.10(m, 2H), 1.98(dq, J=19.8, 7.7, 6.0Hz, 4H), 1.69(t, J=14.7Hz, 5H), 1.33(d, J=6.5Hz, 3H); MS(ESI ): 597[M+H] ⁺ .

(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):

¹ H NMR (400MHz, CDCl ₃ ) δ10.88(s, 1H), 8.00(dd, J=7.7, 1.4Hz, 1H), 7.61(s, 1H), 7.57-7.53(m, 2H), 7.33( td, J=7.5, 1.3Hz, 1H), 7.27(td, J=7.4, 1.4Hz, 1H), 7.09(dd, J=7.7, 1.3Hz, 1H), 6.92-6.86(m, 2H), 5.31 (d, J=13.2Hz, 1H), 4.82(q, J=6.4Hz, 1H), 4.66(ddd, J=12.1, 8.4, 3.7Hz, 1H), 4.11(d, J=11.5Hz, 2H) , 3.66(d, J=12.1Hz, 2H), 3.59-3.47(m, 2H), 3.01(s, 7H), 2.69(t, J=11.5Hz, 2H), 2.60(s, 3H), 2.20- 2.10(m, 2H), 1.98(dq, J=19.8, 7.7, 6.0Hz, 4H), 1.69(t, J=14.7Hz, 5H), 1.33(d, J=6.5Hz, 3H); MS(ESI ): 597[M+H] ⁺ .

Synthetic method B:

Specific Example 3 (6-imino-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5 was carried out using Synthetic Method B -Synthesis of (tetrahydro-2H-pyran-4-yl)-5,6-dihydropyrazino[2,3-c]isoquinoline-2-carboxamide):

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

Add 3,5-dichloro-2-iodopyrazine (15g, 54.57mmol), formamide (300mL) into a 500mL single-necked bottle, stir the mixture and heat up to 90°C, then add (NH ₄ ) ₂ S ₂ O in batches ₈ (25g, 109.1mmol) solid, the mixture was kept at 90°C and stirred for 2h, then K ₂ S ₂ O ₈ (30g, 109.1mmol) solid was added in batches, and the mixture was kept at 90°C and stirred for 20h. LC-MS monitored the reaction to have products, and the remaining part was raw materials. EtOAc (150mL) and water (300mL) were added to the mixture, stirred and separated, the aqueous phase was extracted with EtOAc (150mL), the combined organic phase was washed with saturated sodium chloride solution (150mL), concentrated, and the residue was subjected to column chromatography Purification (EtOAc:Hexane=0:1 to 1:5 to 1:2) gave the product (1.82 g, yield: 10.5%), and recovered the starting material (10.3 g, yield: 68.7%).

¹ H NMR (400MHz, CDCl ₃ ) δ7.28(s, 1H), 5.78(s, 1H); MS(ESI): 317[M+H] ⁺ .

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

3,5-dichloro-6-iodopyrazine-2-carboxamide (280mg, 0.883mmol), 4-(4-(4-methylpiperazin-1-yl)piperidine-1 -yl)aniline (267mg, 0.971mmol), Dioxane (20mL) and DIPEA (228mg, 1.766mmol), the mixture was replaced with argon, stirred and heated to reflux for 2h. After the completion of the reaction was monitored by LC-MS, the mixture was concentrated, and the residue was purified by column chromatography to obtain the product (368 mg, yield: 75%).

¹ H NMR (400MHz, CDCl ₃ ) δ10.69(s, 1H), 7.53(d, J=3.8Hz, 1H), 7.51-7.44(m, 2H), 6.99-6.88(m, 2H), 5.67( d, J=3.9Hz, 1H), 3.80-3.63(m, 2H), 2.84-2.42(m, 10H), 2.39(ddt, J=11.4, 7.3, 3.7Hz, 1H), 1.96(dt, J= 12.2, 3.0Hz, 2H), 1.70 (qd, J=12.1, 4.0Hz, 2H); MS(ESI): 556[M+H] ⁺ .

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

分子筛(200mg，粉末状)，混合液氩气置换后室温搅拌15min，后加入3-四氢-2H-吡喃-4-胺(32mg，0.32mmol)，混合液氩气置换后搅拌升温至120℃反应2h。LC-MS监测反应完成，混合液降温后柱层析纯化得产物(110mg，收率：65.7％)。 Add 5-chloro-6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrazine-2 - carboxamide (150mg, 0.27mmol), anhydrous potassium carbonate (186mg, 1.35mmol), anhydrous potassium fluoride (31mg, 0.54mmol), DMSO (5mL),

Molecular sieves (200 mg, powder), the mixture was replaced by argon and stirred at room temperature for 15 min, then 3-tetrahydro-2H-pyran-4-amine (32 mg, 0.32 mmol) was added, the mixture was replaced by argon and the temperature was raised to 120 ℃ reaction 2h. The completion of the reaction was monitored by LC-MS, and the product (110 mg, yield: 65.7%) was purified by column chromatography after the mixture was cooled down.

¹ H NMR (400MHz, CDCl ₃ ) δ10.64(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, 3.7Hz, 3H), 3.67(d, J=12.0Hz, 2H), 3.51(td, J=11.6, 2.2Hz, 2H), 2.84-2.50(m, 10H) , 2.44(d, J=11.4Hz, 1H), 2.37(s, 3H), 2.11-1.89(m, 4H), 1.78-1.51(m, 4H); MS(ESI): 621[M+H] ⁺ .

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

6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H-pyran -4-yl)amino)pyrazine-2-carboxamide (300mg, 0.52mmol), 2-cyanophenylboronic acid (115mg, 0.78mmol), Pd(dppf) _2Cl2 ( _38mg , 0.05mmol) in NMP (9mL), add sodium carbonate aqueous solution (2.0M, 0.9mL), under the protection of argon, heat up to 120 ° C for 1 hour, LC-MS monitoring, the reaction is completed, cooled, and the reaction solution is directly flash reversed-phase column chromatography to obtain Light yellow solid 210mg, yield 67%.

¹ H NMR (400MHz, CDCl ₃ ) δ10.94(s, 1H), 8.48(s, 1H), 8.35(dd, J=7.9, 1.2Hz, 1H), 7.80(d, J=13.3Hz, 1H) , 7.72(d, J=4.4Hz, 1H), 7.64-7.54(m, 3H), 7.48(ddd, J=8.4, 7.2, 1.3Hz, 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, 2.1Hz, 2H), 3.30(brs, 2H ), 2.75-2.56(m, 6H), 2.47(brs, 2H), 2.37(tt, J=11.4, 3.7Hz, 1H), 2.28(s, 3H), 1.99-1.90(m, 2H), 1.76- 1.63(m, 4H), 1.58(d, J=12.7Hz, 2H); MS(ESI): 596[M+H] ⁺ .

Synthetic method C:

Specific Example 4 (3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-6-oxa-5 was carried out using Synthetic Method C -Synthesis of (tetrahydro-2H-pyran-4-yl)-5,6-dihydropyrazino[2,3-c]isoquinoline-2-carboxamide):

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

Add 3,5-dichloro-2-iodopyrazine (15g, 54.57mmol), formamide (300mL) into a 500mL single-necked bottle, stir the mixture and heat up to 90°C, then add (NH ₄ ) ₂ S ₂ O in batches ₈ (25g, 109.1mmol) solid, the mixture was kept at 90°C and stirred for 2h, then K ₂ S ₂ O ₈ (30g, 109.1mmol) solid was added in batches, and the mixture was kept at 90°C and stirred for 20h. LC-MS monitored the reaction to have products, and the remaining part was raw materials. EtOAc (150mL) and water (300mL) were added to the mixture, stirred and separated, the aqueous phase was extracted with EtOAc (150mL), the combined organic phase was washed with saturated sodium chloride solution (150mL), concentrated, and the residue was subjected to column chromatography Purification (EtOAc:Hexane=0:1 to 1:5 to 1:2) gave the product (1.82 g, yield: 10.5%), and recovered the starting material (10.3 g, yield: 68.7%).

¹ H NMR (400MHz, CDCl ₃ ) δ7.28(s, 1H), 5.78(s, 1H); MS(ESI): 317[M+H] ⁺ .

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

3,5-dichloro-6-iodopyrazine-2-carboxamide (280mg, 0.883mmol), 4-(4-(4-methylpiperazin-1-yl)piperidine-1 -yl)aniline (267mg, 0.971mmol), Dioxane (20mL) and DIPEA (228mg, 1.766mmol), the mixture was replaced with argon, stirred and heated to reflux for 2h. After the completion of the reaction was monitored by LC-MS, the mixture was concentrated, and the residue was purified by column chromatography to obtain the product (368 mg, yield: 75%).

¹ H NMR (400MHz, CDCl ₃ ) δ10.69(s, 1H), 7.53(d, J=3.8Hz, 1H), 7.51-7.44(m, 2H), 6.99-6.88(m, 2H), 5.67( d, J=3.9Hz, 1H), 3.80-3.63(m, 2H), 2.84-2.42(m, 10H), 2.39(ddt, J=11.4, 7.3, 3.7Hz, 1H), 1.96(dt, J= 12.2, 3.0Hz, 2H), 1.70 (qd, J=12.1, 4.0Hz, 2H); MS(ESI): 556[M+H] ⁺ .

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

分子筛(200mg，粉末状)，混合液氩气置换后室温搅拌15min，后加入3-四氢-2H-吡喃-4-胺(32mg，0.32mmol)，混合液氩气置换后搅拌升温至120℃反应2h。LC-MS监测反应完成，混合液降温后柱层析纯化得产物(110mg，收率：65.7％)。 Add 5-chloro-6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrazine-2 - carboxamide (150mg, 0.27mmol), anhydrous potassium carbonate (186mg, 1.35mmol), anhydrous potassium fluoride (31mg, 0.54mmol), DMSO (5mL),

Molecular sieves (200 mg, powder), the mixture was replaced by argon and stirred at room temperature for 15 min, then 3-tetrahydro-2H-pyran-4-amine (32 mg, 0.32 mmol) was added, the mixture was replaced by argon and the temperature was raised to 120 ℃ reaction 2h. The completion of the reaction was monitored by LC-MS, and the product (110 mg, yield: 65.7%) was purified by column chromatography after the mixture was cooled down.

¹ H NMR (400MHz, CDCl ₃ ) δ10.64(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, 3.7Hz, 3H), 3.67(d, J=12.0Hz, 2H), 3.51(td, J=11.6, 2.2Hz, 2H), 2.84-2.50(m, 10H) , 2.44(d, J=11.4Hz, 1H), 2.37(s, 3H), 2.11-1.89(m, 4H), 1.78-1.51(m, 4H); MS(ESI): 621[M+H] ⁺ .

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

6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H-pyran -4-yl)amino)pyrazine-2-carboxamide (200mg, 0.35mmol), 2-methoxycarbonylphenylboronic acid (94mg, 0.52mmol), Pd(dppf) ₂ Cl ₂ (26mg, 0.04mmol), K ₃ PO ₄ (185mg, 0.87mmol), dissolved in a mixed solution of dioxane and water (40mL), under the protection of argon, the temperature was raised to 100°C for 0.5 hours, monitored by LC-MS, the reaction was completed, concentrated, the residue It was dissolved in dichloromethane (50 mL), washed with water (30 mL*2), the dichloromethane phase was concentrated, and the preparative liquid phase was purified to obtain a light yellow solid (60 mg, yield 29%).

¹ H NMR (400MHz, CDCl ₃ ) δ10.97(s, 1H), 8.45-8.40(m, 1H), 8.38(dd, J=8.2, 1.3Hz, 1H), 7.81(d, J=4.3Hz, 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, 4.0Hz, 1H), 5.59(d, J=4.3Hz, 1H), 4.13(dd, J=11.2, 4.4Hz, 2H), 3.72(d, J=12.1Hz, 4H), 3.52(td, J=11.9, 2.0Hz, 2H), 3.10( qd, J=12.4, 4.6Hz, 2H), 2.79-2.57(m, 6H), 2.52-2.40(m, 4H), 2.37(ddt, J=11.4, 7.3, 3.7Hz, 1H), 2.28(s, 3H), 1.95(d, J=13.2Hz, 2H), 1.69(dd, J=11.8, 3.8Hz, 2H); MS(ESI): 597[M+H] ⁺ .

Synthetic method D:

Using synthetic method D to carry out specific 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) Synthesis:

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

Add 3,5-dichloro-2-iodopyrazine (15g, 54.57mmol), formamide (300mL) into a 500mL single-necked bottle, stir the mixture and heat up to 90°C, then add (NH ₄ ) ₂ S ₂ O in batches ₈ (25g, 109.1mmol) solid, the mixture was kept at 90°C and stirred for 2h, then K ₂ S ₂ O ₈ (30g, 109.1mmol) solid was added in batches, and the mixture was kept at 90°C and stirred for 20h. LC-MS monitored the reaction to have products, and the remaining part was raw materials. EtOAc (150mL) and water (300mL) were added to the mixture, stirred and separated, the aqueous phase was extracted with EtOAc (150mL), the combined organic phase was washed with saturated sodium chloride solution (150mL), concentrated, and the residue was subjected to column chromatography Purification (EtOAc:Hexane=0:1 to 1:5 to 1+2) gave the product (1.82 g, yield: 10.5%), and recovered the starting material (10.3 g, yield: 68.7%).

¹ H NMR (400MHz, CDCl ₃ ) δ7.28(s, 1H), 5.78(s, 1H); MS(ESI): 317[M+H] ⁺ .

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

3,5-dichloro-6-iodopyrazine-2-carboxamide (280mg, 0.883mmol), 4-(4-(4-methylpiperazin-1-yl)piperidine-1 -yl)aniline (267mg, 0.971mmol), Dioxane (20mL) and DIPEA (228mg, 1.766mmol), the mixture was replaced with argon, stirred and heated to reflux for 2h. After the completion of the reaction was monitored by LC-MS, the mixture was concentrated, and the residue was purified by column chromatography to obtain the product (368 mg, yield: 75%).

¹ H NMR (400MHz, CDCl ₃ ) δ10.69(s, 1H), 7.53(d, J=3.8Hz, 1H), 7.51-7.44(m, 2H), 6.99-6.88(m, 2H), 5.67( d, J=3.9Hz, 1H), 3.80-3.63(m, 2H), 2.84-2.42(m, 10H), 2.39(ddt, J=11.4, 7.3, 3.7Hz, 1H), 1.96(dt, J= 12.2, 3.0Hz, 2H), 1.70 (qd, J=12.1, 4.0Hz, 2H); MS(ESI): 556[M+H] ⁺ .

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

分子筛(200mg，粉末状)，混合液氩气置换后室温搅拌15min，后加入3-四氢-2H-吡喃-4-胺(32mg，0.32mmol)，混合液氩气置换后搅拌升温至120℃反应2h。LC-MS监测反应完成，混合液降温后柱层析纯化得产物(110mg，收率：65.7％)。 Add 5-chloro-6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrazine-2 - carboxamide (150mg, 0.27mmol), anhydrous potassium carbonate (186mg, 1.35mmol), anhydrous potassium fluoride (31mg, 0.54mmol), DMSO (5mL),

Molecular sieves (200 mg, powder), the mixture was replaced with argon and stirred at room temperature for 15 min, then 3-tetrahydro-2H-pyran-4-amine (32 mg, 0.32 mmol) was added, the mixture was replaced with argon and the temperature was raised to 120 ℃ reaction 2h. The completion of the reaction was monitored by LC-MS, and the product (110 mg, yield: 65.7%) was purified by column chromatography after the mixture was cooled down.

¹ H NMR (400MHz, CDCl ₃ ) δ10.64(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, 3.7Hz, 3H), 3.67(d, J=12.0Hz, 2H), 3.51(td, J=11.6, 2.2Hz, 2H), 2.84-2.50(m, 10H) , 2.44(d, J=11.4Hz, 1H), 2.37(s, 3H), 2.11-1.89(m, 4H), 1.78-1.51(m, 4H); MS(ESI): 621[M+H] ⁺ .

Step 4: Compound 6-(2-(2-hydroxypropyl-2-yl)phenyl)-3-((4-(4-(4-methylpiperazin-1-yl)piperidine-1- Base) phenyl) amino)-5-((tetrahydro-2H-pyran-4-yl) amino) pyrazine-2-carboxamide (compound int-5) synthesis:

6-iodo-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H-pyran -4-yl)amino)pyrazine-2-carboxamide (200mg, 0.35mmol), (2-(2-hydroxypropyl-2-yl)phenyl)boronic acid (93mg, 0.52mmol), Pd(dppf) ₂ Cl ₂ (26mg, 0.04mmol), K ₃ PO ₄ (185mg, 0.87mmol), dissolved in a mixed solution of dioxane and water (40mL), under argon protection, heated to 100°C for 0.5 hours, LC -MS monitoring, the reaction was completed, concentrated, the residue was dissolved in dichloromethane (50mL), washed with water (30mL*2), the dichloromethane phase was concentrated, and the preparative liquid phase was purified to obtain a light yellow solid (75mg, yield 34%) .

MS(ESI): 629[M+H] ⁺ .

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

6-(2-(2-hydroxypropyl-2-yl)phenyl)-3-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)benzene Base)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide (100mg, 0.16mmol) was dissolved in dichloromethane (10mL) under argon protection , at 0°C, boron trifluoride diethyl ether (22.7 mg, 0.16 mmol) was added dropwise to the above solution, the mixed solution was slowly raised to room temperature for 2 hours, monitored by LC-MS, the reaction was completed, concentrated, and purified by preparative liquid phase , to obtain a light yellow solid (15 mg, yield 15%).

MS(ESI): 611[M+H] ⁺ .

The synthesis of embodiment compound 6-288

Using Synthesis Method A, Synthesis Method B, Synthesis Method C or Synthesis Method D, using different raw materials, the target compound 6-288 in Table 1A can be obtained.

Table 1A

Table 1B. NMR data of some compounds in Table 1A

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

The inhibitory effect of compounds on EGFR (del19/T790M/C797S), EGFR (L858R/T790M/C797S) or EGFR (WT) enzyme activity was determined by HTRF method. details as follows:

WT or mutant EGFR protein was incubated with serially diluted compounds at 28°C for 10 minutes, then biotin-labeled universal tyrosine kinase substrate (TK) and ATP were added, and reacted at room temperature for 40 minutes. After terminating the reaction, Eu3+-Cryptate labeled antibody against TK and streptavidin-XL665 were added and incubated at room temperature for 60 minutes. The level of TK substrate phosphorylation was quantified by detecting the luminescence at 615 nm and 665 nm and calculating the ratio 665/615. The percent inhibition and _IC50 of the compounds were calculated compared to the control group. The results are shown in Table 2 below.

Table 2. Compounds of the present invention have inhibitory activity against EGFR (del19/T790M/C797S), EGFR (L858R/T790M/C797S) or EGFR (WT)

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

++ means 20% to 50% inhibition

+++ indicates an inhibition rate greater than 50%.

N.D means activity not determined

From the data in Table 2, it can be seen that the compounds of the present invention have better inhibitory activity on the enzyme activities of EGFR (del19/T790M/C797S) and EGFR (L858R/T790M/C797S), and have better selectivity to EGFR (WT).

Example 3 Anti-proliferation activity of compounds of the present invention on Ba/F3 (EGFR ^{del19/T790M/C797S} ) triple mutant cells and A431 (EGFR WT) cells

3000 Ba/F3 cells carrying EGFR (del19/T790M/C797S), or 2000 A431 cells were planted in a 384-well plate, and after one day of growth, a serially diluted compound was added (Ba/F3 cells up to 500nM, A431 cells up to 10uM ). Three days after the compound was added, Cell Titer Glow was added to evaluate the cell growth, and the percentage of inhibition of cell growth and the _IC50 value of the compound were calculated. The results are shown in Table 3 below.

Table 3. Antiproliferative activity of compounds of the present invention on Ba/F3 (EGFR ^{del19/T790M/C797S} ) triple mutant cells, A431 wild-type (EGFR WT) cells

As can be seen from the data in Table 3, the antiproliferative activity of most compounds of the present invention to Ba/F3 (EGFR ^{del19/T790M/C797S} ) triple mutant cells is all less than 100nM, as seen that the compounds of the present invention all have very strong Ba/F3 (EGFR ^{del19 /T790M/C797S} ) triple mutant cell antiproliferative activity.

Although the specific implementations of the present invention have been described above, those skilled in the art should understand that these are only examples, and various changes or changes can be made to these implementations without departing from the principle and essence of the present invention. Revise. Accordingly, the protection scope of the present invention is defined by the appended claims.

Claims (13)

1. A compound represented by general formula (1) or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:

   

   in the general formula (1):

   ring a is (3-11 membered) heterocycloalkylene, (C6-C14) arylene or (5-10 membered) heteroarylene, wherein the heterocycloalkylene, arylene and heteroarylene may each independently be optionally substituted with 1 or more of the following groups: -H, halogen, -NO ₂ 、-R ⁴ 、-OR ⁴ 、-(CH ₂ ) _n OR ⁴ 、-(CH ₂ ) _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) ₂ R ⁴ 、-S(O) _p R ⁴ and-S (O) ₂ NR ⁴ R ⁵ ；

   Y is

   

   -O-、-N(R ⁴ ) -or a chemical bond;

   z is-C (=O) -, -C=N (R) ⁴ )-、-C(＝CH ₂ ) -or

   

   L ¹ is-O-or-NH-;

   x is (C6-C14) arylene or (5-11 membered) heteroarylene, wherein the arylene and heteroarylene may each independently be optionally substituted with 1 or more of the following groups: -H, halogen, (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy and (C1-C6) haloalkoxy;

   R ¹ is-H, halogen, - (CH) ₂ ) _n NR ⁶ R ⁷ 、-NR ⁶ R ⁷ 、-O(CH ₂ ) _m NR ⁶ R ⁷ 、-N(R ⁵ )(CH ₂ ) _m NR ⁶ R ⁷ (C1-C6) alkoxy, -CH ₂ - (3-15 membered) heterocycloalkyl or (3-15 membered) heterocycloalkyl, wherein said alkoxy and heterocycloalkyl may each independently be optionally substituted with 1 or more of the following groups: -H, -R ⁴ 、-(CH ₂ ) _n NR ⁶ R ⁷ 、-NR ⁶ R ⁷ 、-O(CH ₂ ) _m NR ⁶ R ⁷ 、-N(R ⁵ )(CH ₂ ) _m NR ⁶ R ⁷ and-R ³ ；

   R ² is-H, (C1-C6) alkyl, (C3-C14) cycloalkyl, (C6-C14) aryl, (3-11 membered) heterocycloalkyl; wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl groups may each independently be optionally substituted with 1 or more of halogen, -R ⁴ 、-OH、-(CH ₂ ) _n OR ⁴ -、-(CH ₂ ) _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) ₂ R ⁴ 、-S(O) _p R ⁴ 、-S(O) ₂ NR ⁴ R ⁵ ；

   R ³ Is a (3-11 membered) heterocycloalkyl, wherein each of said heterocycloalkyl groups may be independently optionally substituted with 1 or more of the following groups: -H, -CD ₃ 、-R ⁴ 、-OR ⁴ and-NR ⁴ R ⁵ ；

   R ⁴ And R is ⁵ Each independently is-H, (C1-C6) alkyl, (C1-C6) haloalkyl or (C3-C14) cycloalkyl;

   R ⁶ and R is ⁷ Each independently is-H, (C1-C6) alkyl or (C3-C14) cycloalkyl, or R ⁶ And R is ⁷ The N atoms to which they are attached can together form a (3-11 membered) heterocycloalkyl which can each independently be optionally substituted with 1 or more of the following groups: -H, -CD ₃ Halogen, -R ⁴ and-OR ⁴ ；

   R ⁸ And R is ⁹ Is respectively independent-H, -D, -OR ⁴ (C1-C6) alkyl or (C3-C14) cycloalkyl, or R ⁸ And R is ⁹ The C atoms to which they are attached can together form a (C3-C6) cycloalkyl group; 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 of claim 1, or each isomer, each crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), the a ring is (5-7 membered) heterocycloalkylene, phenylene or (5-10 membered) heteroarylene, wherein the heterocycloalkylene, phenylene and heteroarylene may each independently be optionally substituted with 1 or more of the following groups: -H, -NO ₂ 、-F、-Cl、-Br、-CN、-OH、-OCH ₃ 、-NH ₂ 、-N(CH ₃ ) ₂ 、-NHCOCH ₃ 、-NHSO ₂ CH ₃ 、-SO ₂ CH ₃ 、-CH ₃ 、-CF ₃ 、-CHF ₂ 、-CONH ₂ and-CH ₂ OH。
3. The compound of claim 2, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), ring a is:

   

   

   
4. a compound according to any one of claims 1 to 3, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), Y is-CH ₂ -、-O-、-NH-、-N(CH ₃ ) -or a chemical bond.
5. The compound according to any one of claims 1 to 4, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), Z is-C (=o) -, -C (=nh) -, -C (=ch) ₂ )-、-CH ₂ -、 -CH(CH ₃ )-、-CH(OH)-、-C(CH ₃ ) ₂ -、-CD(CH ₃ )-、-CD ₂ -、

   

   -CH(CF ₃ ) -or-CH (CHF) ₂ )-。
6. The compound of any one of claims 1-5, or each isomer, each crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein in the general formula (1), X is phenylene or 6 membered heteroarylene, wherein the phenylene and heteroarylene may each independently be optionally substituted with 1 or more of the following groups: -H, -F, -CH ₃ 、-CH ₂ CH ₃ 、-CH(CH ₃ ) ₂ 、

   

   -OCH ₃ 、-OCF ₂ H、-OCH ₂ CF ₃ and-OCF ₃ 。
7. The compound of claim 6, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), X is:

   
8. the compound according to any one of claims 1 to 7, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), R ¹ The method comprises the following steps: -H, -N (CH) ₃ ) ₂ 、-CH ₂ -(6-11-membered) heterocycloalkyl or (6-11-membered) heterocycloalkyl, wherein said heterocycloalkyl is:

   

   

   and the heterocycloalkyl groups may each independently be optionally substituted with 1 or more of the following groups: -H, -CH ₃ 、

   

   -N(CH ₃ ) ₂ 、

   

   

   and-CD ₃ 。
9. The compound according to claim 8, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), R ¹ The method comprises the following steps: -H, -N (CH) ₃ ) ₂ 、

   

   
10. A compound according to any one of claims 1 to 9, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate thereof An solvate or solvate, wherein in the general formula (1), R ² The method comprises the following steps:

    

    
11. the compound of any one of claims 1-10, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the compound has one of the following structures:

    

    

    

    

    

    

    

    

    

    

    
12. a pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and, as active ingredient, a compound according to any one of claims 1 to 11, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof.
13. Use of a compound according to any one of claims 1-11, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to claim 12, for the manufacture of a medicament for the treatment, modulation or prevention of a disease associated with EGFR mutation.