CN117500813A - Arylphosphine compounds - Google Patents

Abstract

An aryl phosphine oxide compound. In particular to 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 and pharmaceutically acceptable salts thereof as EGFR inhibitors in preparation of medicaments for resisting EGFR related diseases such as tumors and the like.

Description

Arylphosphine compounds

The present application claims priority from chinese application CN202110672233.6, with application date 2021, 6, 17. The present application refers to the entirety of the above-mentioned chinese application.

Technical Field

The invention relates to the field of pharmaceutical chemistry, in particular to novel aryl phosphine oxide compounds, a preparation method thereof and application of the compounds as EGFR inhibitors in preparation of antitumor drugs.

Background

Lung cancer is one of the common malignant tumors, and the number of new lung cancer cases worldwide is about 160 ten thousand per year, and the number of death patients caused by lung cancer is about 140 ten thousand per year. And wherein non-small cell lung cancer (NSCLC) accounts for about 80% -85% of the total lung cancer (Nature, 2018,553,446-454).

The EGFR protein family is a class of protein kinases responsible for the conduction of mitogenic signals and plays an important role in growth and development. Analysis and research of a large number of in vitro tumor cells, animal models and human tumor samples indicate that mutation of EGFR family proteins leads to human tumor development, and is one of the important causes of various cancers. Targeting and inhibiting the activity of EGFR muteins is therefore an important means for the treatment of related tumors.

Studies have shown that EGFR gene mutations can be found in about 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 the exon 19 deletion (del 19) and the L858R transliteration (L858 missense mutation) mutation in exon 21. Both types of mutations result in sustained activation of the EGFR protein independent of ligand. Although NSCLC patients with mutations in EGFR protein Del19 or L858R are more sensitive to targeted treatment with EGFR protein kinase inhibitors (EGFR TKIs) such as erlotinib, gefitinib, afatinib or osiertinib, a higher (around 60-85%) objective remission rate (objective response rate, ORR) can be achieved clinically, but this response does not generally last too long, and most patients with first or second generation EGFR TKIs develop disease progression at about 11 months. Drug resistance analysis showed that in approximately 50-70% of drug resistant patients, the mechanism of the drug resistance molecule was that the EGFR gene acquired the second mutation, termed the T790M mutation (T790 m+) (Cancer discovery.2012, 2,872-5). This secondary mutation deprives the first and second generation EGFR TKIs of inhibitory activity against mutant tumor cells.

Osimertinib was developed as a third generation covalent EGFR TKI to treat tumors with EGFR del19 and L858R mutations with or without the T790M mutation. Although osimertinib has a higher response rate to resistance caused by the T790M mutation, about 70% of patients eventually develop resistance as well, and the disease progresses again after about 10 months (Lung cancer.2017,108, 228-231). Molecular mechanism studies on the resistance of the third generation EGFR TKI have shown that in about 20-40% of patients undergoing OSimertinib treatment and relapse, one of the main resistance mechanisms is the EGFR gene to acquire the third triple mutation, the C797S mutation. Moreover, patients with EGFR del19/L858R T790M C797S mutants were no longer able to respond to the first, second or third generation EGFR TKIs after treatment with the third generation EGFR TKI. In 2015, thread et al reported for the first time that about 40% of the resistance was mutated from C797S based on an analysis of the resistance of 15 patients to osiert inib (Nature Medicine,2015,21,560-562). In 2017 ASCO, piotrowska and Zhou Caicun reported drug resistance analyses for 23 and 99 patients, respectively, both of which showed about 22% of drug resistance caused by the C797S mutation. So targeted inhibition of EGFR del19/L858R T790M C797S mutation can overcome the osiert inib resistance, but no EGFR TKI on the market can inhibit EGFR del19/L858R T790M C797S mutant yet, so research and discovery of fourth generation EGFR TKI to meet this unmet clinical need is urgent.

The EGFR del19/L858R T790M C797S mutant was not much studied at present as a newly emerging EGFR mutant after treatment with a third generation EGFR TKI. Only a few fourth generation EGFR TKIs currently reported to inhibit EGFR del19/L858R T790M C797S mutants. For example Boehringer Ingelheim reports that a class of macrocyclic compounds BI-4020 has anti-EGFR del19/L858R T790M C797S mutant activity and in vivo antitumor activity (J Med chem.2019,62, 10272-10293). In patent WO2019/015655, however, a class of aryl phosphorus oxygen compounds is reported to have anti-EGFR del19/L858R T790M C797S mutant activity as well as in vivo anti-tumor activity. The structure of compound 41 is represented by the general formula Y and the examples in the patent (the definition of each symbol in the formula refers to the patent):

at present, there is an urgent need to study and find compounds with good activity against EGFR del19/L858R T790M C797S mutation.

Disclosure of Invention

The invention provides a compound shown in a general formula (1) or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:

in the general formula (1):

R ¹ is-Cl or-Br;

R ² and R is ³ Each independently is-H, halogen, -CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C14) cycloalkyl;

R ⁴ And R is ⁵ Each independently is-H, halogen, -CN, -S (O) ₂ R ⁸ (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C14) cycloalkyl, (C6-C14) aryl, (3-11 membered) heterocycloalkyl or (5-11 membered) heteroaryl, wherein said (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C14) cycloalkyl, (C6-C14) aryl, (3-11 membered) heterocycloalkyl or (5-11 membered) heteroaryl may be substituted by a substituent selected from the group consisting ofEach independently optionally substituted with 1 or more of the following groups: -H, halogen, -R ⁸ 、-OH、-(CH ₂ ) _n OR ⁸ 、-(CH ₂ ) _n NR ⁸ R ⁹ 、-OR ⁸ 、-NR ⁸ R ⁹ 、-CN、-C(O)NR ⁸ R ⁹ 、-NR ⁹ C(O)R ⁸ 、-NR ⁹ S(O) ₂ R ⁸ 、-S(O) _p R ⁸ and-S (O) ₂ NR ⁸ R ⁹ The method comprises the steps of carrying out a first treatment on the surface of the Or R is ⁴ And R is ⁵ The atoms to which they are attached can together form a 6-membered aryl or (5-6 membered) heteroaryl, wherein the 6-membered aryl or (5-6 membered) heteroaryl can each independently be optionally substituted with 1 or more of the following groups: -H, -CD ₃ Halogen, -R ⁸ and-OR ⁸ ；

R ⁶ is-H, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C14) cycloalkyl, (C6-C14) aryl, (3-11 membered) heterocycloalkyl or (5-11 membered) heteroaryl, wherein said (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C14) cycloalkyl, (C6-C14) aryl, (3-11 membered) heterocycloalkyl or (5-11 membered) heteroaryl may each independently be optionally substituted with 1 or more of the following groups: -H, halogen, -R ⁸ 、-OH、-(CH ₂ ) _n OR ⁸ 、-(CH ₂ ) _n NR ⁸ R ⁹ 、-OR ⁸ 、-NR ⁸ R ⁹ 、-CN、-C(O)NR ⁸ R ⁹ 、-NR ⁹ C(O)R ⁸ 、-NR ⁹ S(O) ₂ R ⁸ 、-S(O) _p R ⁸ and-S (O) ₂ NR ⁸ R ⁹ ；

R ⁷ Is (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C14) cycloalkyl, (C6-C14) aryl, (3-11 membered) heterocycloalkyl or (5-11 membered) heteroaryl, wherein said (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C14) cycloalkyl (C6-C14) aryl, (3-11 membered) heterocycloalkyl or (5-11 membered) heteroaryl, each independently optionally substituted with 1 or more of the following groups: -H, halogen, -R ⁸ 、-OH、-(CH ₂ ) _n OR ⁸ 、-(CH ₂ ) _n NR ⁸ R ⁹ 、-OR ⁸ 、-NR ⁸ R ⁹ 、-CN、-C(O)NR ⁸ R ⁹ 、 -NR ⁹ C(O)R ⁸ 、-NR ⁹ S(O) ₂ R ⁸ 、-S(O) _p R ⁸ and-S (O) ₂ NR ⁸ R ⁹ ；

R ⁸ And R is ⁹ Each independently is-H, (C1-C6) alkyl, (C1-C6) haloalkyl or (C3-C14) 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 0, 1, 2 or 3.

In another preferred embodiment, wherein R in the general formula (1) ² And R is ³ Each independently is-H, -F, -Cl, -CN, (C1-C3) alkyl, (C1-C3) haloalkyl, (C3-C6) cycloalkyl.

In another preferred embodiment, wherein R in the general formula (1) ² And R is ³ Each independently is: -H, -F, -Cl, -CN, -CH ₃ 、-CF ₃ Or (b)R ² And R is ³ Each independently is preferably-H, -F or-CH ₃ 。

In another preferred embodiment, wherein R in the general formula (1) ⁴ And R is ⁵ Each independently is-H, -F, -Cl, -CN, -S (O) ₂ CH ₃ (C1-C3) alkyl, (C1-C3) haloalkyl, (C3-C6) cycloalkyl, phenyl, (3-6 membered) heterocycloalkyl or (5-6 membered) heteroaryl, wherein said (C1-C3) alkyl, (C1-C3) haloalkyl, (C3-C6 Cycloalkyl, (3-6 membered) heterocycloalkyl or (5-6 membered) heteroaryl, each independently optionally substituted with 1 or more of the following groups: -H, -F, -Cl, -CH ₃ 、-OH、-OCH ₃ -CN; or R is ⁴ And R is ⁵ The atoms to which they are attached can together form a 6-membered aryl or (5-6 membered) heteroaryl, wherein the 6-membered aryl or (5-6 membered) heteroaryl can each independently be optionally substituted with 1 or more of the following groups: -H, -F, -Cl, -CH ₃ and-OCH ₃ 。

In another preferred embodiment, wherein in the general formula (1), the structural unitThe method comprises the following steps:

preferably is

In another preferred embodiment, wherein R in the general formula (1) ⁶ is-H, (C1-C3) alkyl, (C1-C3) haloalkyl, (C3-C6) cycloalkyl, (C6-C10) aryl, (3-6 membered) heterocycloalkyl or (5-6 membered) heteroaryl; wherein the (C1-C3) alkyl, (C1-C3) haloalkyl, (C3-C6) cycloalkyl, (C6-C10) aryl, (3-6 membered) heterocycloalkyl or (5-6 membered) heteroaryl may each independently be optionally substituted with 1 or more of the following groups: -H, -F, -Cl, -CH ₃ 、-OH、-OCH ₃ 、-CN。

In another preferred embodiment, wherein R in the general formula (1) ⁶ The method comprises the following steps: -H, -CH ₃ 、-CH ₂ CH ₃ Or (b)R ⁶ preferably-CH ₂ CH ₃ Or (b)R ⁶ More preferably-CH ₂ CH ₃ 。

In another preferred embodiment, wherein R in the general formula (1) ⁷ Is (C1-C3) alkyl, (C1-C3) haloalkyl, (C3-C5) cycloalkyl, aryl, (3-6 membered) heterocycloalkyl or (5-6 membered) heteroaryl; wherein the (C1-C3) alkyl, (C1-C3) haloalkyl, (C3-C5) cycloalkyl, aryl, (3-6 membered) heterocycloalkyl or (5-6 membered) heteroaryl may each independently be optionally substituted with 1 or more of the following groups: -H, -F, -Cl, -CH ₃ 、-OH、-OCH ₃ 、-CN。

In another preferred embodiment, wherein R in the general formula (1) ⁷ The method comprises the following steps: -CH ₃ 、-CH ₂ CH ₃ 、-CF ₃ Or (b)R ⁷ preferably-CH ₃ The method comprises the steps of carrying out a first treatment on the surface of the m is preferably 2 or 3.

In various embodiments, representative compounds of the present invention have one of the following structures:

it is another object of the present invention to provide a pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent and/or excipient, and the compound of the general formula (1) of the present invention, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, as an active ingredient.

Still another object of the present invention is to provide the use of the compound represented by the general formula (1) of the present invention, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof or the above pharmaceutical composition for the preparation of a medicament for treating, modulating or preventing diseases associated with EGFR mutation.

Still another object of the present invention is to provide a method for treating EGFR mutation related diseases, comprising administering to a subject a therapeutically effective amount of the compound of formula (1) of the present invention or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof or a pharmaceutical composition thereof.

By synthesizing and carefully studying a number of classes of novel compounds involved in EGFR inhibition, the inventors have found that among the compounds of general formula (1), the compounds unexpectedly have a stronger EGFR (del 19/T790M/C797S), EGFR (L858R/T790M/C797S), EGFR (del 19/T790M) and EGFR (L858R/T790M) inhibitory activity, and that the compounds of the invention unexpectedly have a higher Cmax in vivo pharmacokinetic experiments in mice, compared to representative compound 41 in WO2019015655A 1.

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.

Synthesis of Compounds

The process for preparing the compound of the general formula (1) of the present invention is specifically described below, but these specific processes do not constitute any limitation on the present invention.

The compounds of formula (1) described above may be synthesized using standard synthetic techniques or well known techniques in combination with the methods described herein. In addition, the solvents, temperatures and other reaction conditions mentioned herein may vary. The starting materials for the synthesis of the compounds may 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), green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 ^rd Ed., (Wiley 1999). The general method of preparation of the compounds may be varied by the use of appropriate reagents and conditions for introducing different groups into the formulae 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 the reactants, solvents, bases, amounts of the compounds used, reaction temperature, time required for the reaction, etc., are not limited to the explanation below. The compounds of the present invention may also optionally be conveniently prepared by combining the various synthetic methods described in this specification or known in the art, such combination being readily apparent to those skilled in the art to which the present invention pertains. In one aspect, the present invention also provides a method for preparing the compound represented by the general formula (1), wherein the compound represented by the general formula (1) can be prepared by the following general reaction scheme 1:

general reaction scheme 1

The compounds of formula (1) may be prepared according to general scheme 1, wherein R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ M and p are as defined above, H represents hydrogen and Cl represents chlorine. As shown in general scheme 1, compounds 1-1 andreacting under alkaline condition to generate compound 1-2, and reacting compound 1-2 with compound 1-3 under acidic condition to generate target compound 1-4.

Further forms of the compounds

By "pharmaceutically acceptable" is meant herein a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and which is relatively non-toxic, e.g., administration of a material to an individual does not cause an undesired biological effect or interact in a deleterious manner with any of the components thereof in which it is contained.

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 does not abrogate the biological activity and properties of the compound. In certain specific aspects, the pharmaceutically acceptable salts are obtained by reacting a compound of formula (1) with an acid, such as an inorganic acid, e.g., hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, 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 an acidic amino acid, e.g., aspartic acid, glutamic acid.

References to pharmaceutically acceptable salts are understood to include solvent-added forms or crystalline forms, particularly solvates or polymorphs. Solvates contain a stoichiometric or non-stoichiometric amount of solvent 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 the compounds of formula (1) are conveniently prepared or formed in accordance with the methods described herein. For example, the hydrate of the compound of formula (1) is conveniently prepared by recrystallisation from a mixed solvent of water/organic solvents including, but not limited to, tetrahydrofuran, acetone, ethanol or methanol. Furthermore, the compounds mentioned herein can exist in unsolvated and solvated forms. In summary, for the purposes of the compounds and methods provided herein, solvated forms are considered to correspond to unsolvated forms.

In other specific embodiments, the compounds of formula (1) are prepared in different forms including, but not limited to, amorphous, crushed and nano-sized forms. In addition, the compound of formula (1) includes crystalline forms and may also be polymorphic forms. Polymorphs include different lattice arrangements of the same elemental composition of the compound. Polymorphs typically 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 crystalline form to dominate.

In another aspect, the compounds of formula (1) may have chiral centers and/or axial chiralities and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomeric forms, and cis-trans isomeric forms. Each chiral center or axial chiral will independently produce 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 non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds can be labeled with radioisotopes, such as tritium @, for example ³ H) Iodine-125% ¹²⁵ I) And C-14% ¹⁴ C) A. The invention relates to a method for producing a fibre-reinforced plastic composite For another example, deuterium can be substituted for a hydrogen atom to form a deuterated compound, and the bond between deuterium and carbon is stronger than the bond between normal hydrogen and carbon, and generally deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, prolonging in vivo half-life of drugs, and the like, compared to non-deuterated drugs. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

Terminology

The terms used in the present application, including the specification and claims, are defined as follows, unless otherwise indicated. It must be noted that, in the specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Conventional methods of mass spectrometry, nuclear magnetism, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are used, if not otherwise indicated. In this application, the use of "or" and "means" and/or "unless otherwise indicated.

Unless otherwise specified, "alkyl" refers to saturated aliphatic hydrocarbon groups, 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, particularly alkyl groups substituted with one or more halogens. Preferred alkyl groups are selected from CH ₃ 、CH ₃ CH ₂ 、CF ₃ 、CHF ₂ 、CF ₃ CH ₂ 、CF ₃ (CH ₃ )CH、 ⁱ Pr、 ⁿ Pr、 ⁱ Bu、 ⁿ Bu or ^t Bu。

Unless otherwise specified, "cycloalkyl" refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic), a partially unsaturated cycloalkyl may be referred to as "cycloalkenyl" if the carbocycle contains at least one double bond, or "cycloalkynyl" if the carbocycle contains at least one triple bond. Cycloalkyl groups may include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spiro rings. In some embodiments, cycloalkyl is monocyclic. In some embodiments, cycloalkyl is monocyclic or bicyclic. The ring-forming carbon atoms of cycloalkyl groups may optionally be oxidized to form oxo or thioionic groups. Cycloalkyl groups also include cycloalkylene groups. In some embodiments, cycloalkyl contains 0, 1, or 2 double bonds. In some embodiments, cycloalkyl contains 1 or 2 double bonds (partially unsaturated cycloalkyl). In some embodiments, cycloalkyl groups may be fused with aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups may be fused with aryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups may be fused with aryl and heterocycloalkyl groups. In some embodiments, cycloalkyl groups may be fused to aryl and cycloalkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, pinyl, carenyl, bicyclo [1.1.1] pentyl, bicyclo [2.1.1] hexane, and the like.

Unless otherwise specified, "aryl" refers to a hydrocarbon aromatic group, an aryl group being monocyclic or polycyclic, e.g., 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.

Unless otherwise specified, "heteroaryl" refers to an aromatic group containing one or more heteroatoms (O, S or N), heteroaryl being monocyclic or polycyclic. For example, a monocyclic heteroaryl ring is fused to one or more carbocyclic aromatic groups or other monocyclic heteroaryl groups. Examples of heteroaryl groups 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 ] pyridyl, 1H-pyrrolo [2,3-c ] pyridyl, 1H-pyrrolo [3,2-c ] pyridyl, and 1H-pyrrolo [2,3-b ] pyridyl.

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 having at least one heteroatom ring member independently selected from boron, phosphorus, nitrogen, sulfur, oxygen, and phosphorus. If the heterocycloalkyl group contains at least one double bond, then the partially unsaturated heterocycloalkyl group may be referred to as "heterocycloalkenyl", or if the heterocycloalkyl group contains at least one triple bond, then the partially unsaturated heterocycloalkyl group may be referred to as "heterocycloalkynyl". Heterocycloalkyl groups can include monocyclic, bicyclic, spiro, or polycyclic (e.g., having two fused or bridged rings) ring systems. In some embodiments, the heterocycloalkyl group 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 thioxo groups or other oxidized bonds (e.g., C (O), S (O), C (S) or S (O) 2, N-oxides, etc.), or nitrogen The atoms may be quaternized. Heterocycloalkyl groups may be attached via a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains from 0 to 3 double bonds. In some embodiments, heterocycloalkyl contains from 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are benzo derivatives having one or more aromatic rings fused to (i.e., sharing a bond with) the heterocycloalkyl ring, such as piperidine, morpholine, azepine, thienyl, or the like. The heterocycloalkyl group containing the fused aromatic ring may be attached via any ring-forming atom, including ring-forming atoms of the fused aromatic ring. Examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa-9-azaspiro [5.5 ]]Undecyl, 1-oxa-8-azaspiro [4.5 ]]Decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quininyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3, 4-tetrahydroquinolinyl, 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, butyllactam, valerolactam, imidazolone, hydantoin, dioxolanyl, phthalimido, pyrimidine-2, 4 (1H, 3H) -dione, 1, 4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholin-S-oxide, thiomorpholin-S, S-oxide, piperazinyl, pyranyl, pyridonyl, 3-pyrrolinyl, thiopyranyl, pyronyl, tetrahydrothienyl, 2-azaspiro [3.3 ] ]Heptyl, indolinyl, and,

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

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

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

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

When one of the variables is selected from a bond, the two groups to which it is attached are indicated as being directly linked, e.g., when L in X-L-Y represents a bond, it is indicated that the structure is in fact X-Y.

The term "membered ring" includes any cyclic structure. The term "meta" is meant to indicate the number of backbone atoms that make up the ring. For example, cyclohexyl, pyridyl, pyranyl, thiopyranyl are six-membered rings and cyclopentyl, pyrrolyl, furanyl and thiophenyl are five-membered rings.

The term "fragment" refers to a specific portion or functional group of a molecule. Chemical fragments are generally considered to be chemical entities contained in or attached to a molecule.

Unless otherwise indicated, with solid wedge bondsAnd a wedge-shaped dotted bondRepresenting the absolute configuration of a solid centre by straight solid keysAnd straight dotted line keyRepresenting the relative configuration of the three-dimensional center by wavy linesSolid key representing wedge shapeOr wedge-shaped dotted bondOr by wave linesRepresenting straight solid keysOr straight dotted line key

Unless otherwise indicated, use ofRepresents a single bond or a double bond.

Specific pharmaceutical and medical terminology

The term "acceptable" as used herein, means that a prescription component or active ingredient does not unduly adversely affect the health of the general therapeutic objective.

The terms "treat," "course of treatment," or "therapy" as used herein include alleviation, inhibition, or amelioration of symptoms or conditions of a disease; inhibit the occurrence of complications; improving or preventing underlying metabolic syndrome; inhibiting the occurrence of a disease or condition, such as controlling the progression of a disease or condition; alleviating a disease or symptom; causing the disease or symptom to subside; alleviating complications caused by diseases or symptoms, or preventing or treating signs caused by diseases or symptoms. As used herein, a compound or pharmaceutical composition, upon administration, may result in an improvement in a disease, symptom, or condition, particularly an improvement in severity, delay of onset, slow progression, or decrease in duration. Whether stationary or temporary, continuous or intermittent, may be due to or associated with administration.

"active ingredient" refers to a compound of formula (1), as well as pharmaceutically acceptable inorganic or organic salts of the compound of formula (1). The compounds of the invention may contain one or more asymmetric centers (chiral centers or axial chiralities) and thus appear as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers. Asymmetric centers that may be present depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce 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 "pharmaceutical (medicine or medicament)" are used interchangeably herein and refer to a compound or composition capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic effects when administered to an individual (human or animal).

The term "administration (administered, administering or administeration)" as used herein refers to the administration of the compound or composition directly, or the administration of a prodrug (pro), derivative (derivative), or analog (analog) of the active compound, and the like.

Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. However, any numerical value inherently contains certain standard deviations found in their respective testing measurements. 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 average value, as determined by one of ordinary skill in the art. Except in the experimental examples, or where otherwise explicitly indicated, all ranges, amounts, values, and percentages used herein (e.g., to describe amounts of materials, lengths of time, temperatures, operating conditions, ratios of amounts, and the like) are to be understood to be modified by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the present specification and attached claims are approximations that may vary depending upon the desired properties. At least these numerical parameters should be construed as indicating the number of significant digits and by applying ordinary rounding techniques.

Unless defined otherwise herein, the meanings of scientific and technical terms used herein are the same as commonly understood by one of ordinary skill in the art. Furthermore, as used in this specification, the singular noun encompasses the plural version of the noun without conflict with the context; plural nouns as used also encompasses singular versions of the noun.

Therapeutic use

The present invention provides methods of treating diseases, including but not limited to conditions involving EGFR mutations (e.g., cancer), using compounds of formula (1) or pharmaceutical compositions of the present invention.

In some embodiments, there is provided a method for treating cancer, the method comprising administering to an individual in need thereof an effective amount of any of the foregoing pharmaceutical compositions comprising a compound of formula (1). In some embodiments, the cancer is mediated by EGFR mutations. In other embodiments, the cancer is lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, breast cancer, urothelial cancer, prostate cancer, ovarian cancer, head and neck cancer, gastric cancer, mesothelioma, or all cancer metastasis.

Route of administration

The compounds of the present invention and pharmaceutically acceptable salts thereof can be formulated into a variety of formulations comprising a safe and effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable excipient or carrier. Wherein "safe, effective amount" means: the amount of the compound is 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 age, illness and treatment course of the subject.

"pharmaceutically acceptable excipient or carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable excipients or carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyalcohol (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), and emulsifying agent (such as) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like.

The compounds of the present invention may 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 the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.

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 the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.

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 commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.

In addition to these inert diluents, the compositions can also include 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 as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-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 nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

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 which may be required if necessary.

The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds. When a pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective dose, and the daily dose is usually 1 to 2000mg, preferably 50 to 1000mg, for a human having a body weight of 60 kg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.

The above-mentioned features of the invention, or of the embodiments, may be combined in any desired manner. All of the features disclosed in this specification may be combined with any combination of the features disclosed in this specification, and the various features disclosed in this specification may be substituted for any alternative feature serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, the disclosed features are merely general examples of equivalent or similar features.

Detailed Description

The details of the various specific aspects, features and advantages of the above-described compounds, methods, pharmaceutical compositions will be set forth in the following description in order to provide a thorough understanding of the present invention. It is to be understood that the detailed description and examples, which follow, describe specific embodiments for reference only. Various changes and modifications to the present invention will become apparent to those skilled in the art upon reading the present description, and such equivalents fall within the scope of the present application.

In all of the embodiments described herein, the present invention, ¹ H-NMR was recorded on a Varian Mercury 400 Nuclear magnetic resonance apparatus, chemical shifts being expressed as delta (ppm); the silica gel for separation is not illustrated as 200-300 meshes, and the ratio of the eluents is volume ratio.

The invention adopts the following abbreviations: CDCl ₃ Represents deuterated chloroform; DMSO-d ₆ Represents deuterated dimethyl sulfoxide; CD (compact disc) ₃ OD represents deuterated methanol; t-BuOH represents tert-butanol; etOAc represents ethyl acetate; hexane represents n-Hexane; DCM represents dichloromethane; meOH represents methanol; ACN represents acetonitrile; 1,4-Dioxane represents 1, 4-Dioxane; DMF represents N, N-dimethylformamide; acOH represents acetic acid; THF represents tetrahydrofuran; DMSO represents dimethylsulfoxide; hr represents hours; min represents minutes; ICl represents iodine chloride; KOAc represents potassium acetate; k (K) ₃ PO ₄ Represents potassium phosphate; cs (cells) ₂ CO ₃ Represents cesium carbonate; k (K) ₂ CO ₃ Represents potassium carbonate; liHMDS represents lithium bis (trimethylsilyl) amide; MS stands for mass spectrum; msOH represents methanesulfonic acid; CSA represents camphorsulfonic acid; NMR represents nuclear magnetic resonance; pd/C represents palladium on carbon; pd (OAc) ₂ Represents palladium acetate; pd (dppf) ₂ Cl ₂ Represents [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride; pd (dtbpf) Cl ₂ Represents dichloro [1,1' -bis (di-tert-butylphosphine) ferrocene palladium (II); naBH (OAc) ₃ Represents sodium triacetoxyborohydride; TFA represents trifluoroacetic acid; FA represents formic acid; TEA represents triethylamine; TLC stands for thin layer chromatography; prep-HPLC represents preparative high performance liquid chromatography; XPhos represents 2-dicyclohexylphosphorus-2 ',4',6' -triisopropylbiphenyl; xantphos represents 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene.

EXAMPLE 1 Synthesis of Compound 1

Step 1: synthesis of Compound int_1-2

To a 100mL single-necked flask was added int_1-1 (5 g,13.4 mmol), potassium vinylfluoroborate (2.154 g,16.08 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (490 mg,0.67 mmol), potassium phosphate (7.1 g,33.49 mmol), DMF (50 mL) and water (10 mL), and the mixed solution was reacted at 95℃for about 3 hours under argon. LC-MS monitoring was complete, the mixture was concentrated, and the residue was purified by 100-200 mesh silica gel column (Hexane: etOAc=3:0 to 3:1 to 2:1) to give the product as a yellow solid (4.3 g, yield: 100%).

ESI-MS m/z:321[M+H] ⁺

Step 2: synthesis of Compound int_1-3

To a 500mL single flask was added int_1-2 (4.3 g,13.4 mmol), meOH (50 mL), DCM (5 mL), 10% Pd/C (500 mg, wt=55%) and the mixture was replaced 3 times with hydrogen, followed by stirring at room temperature and pressure for hydrogenation for 20 hours. After completion of the LC-MS detection reaction, the mixture was filtered through celite, the cake was rinsed with methanol, and the filtrate was concentrated to dryness to give the product as a brown oil (3.73 g, yield: 95%).

ESI-MS m/z:293[M+H] ⁺

Step 3: synthesis of Compound int_1-4

To a 100mL single-necked flask was added int_1-3 (1 g,3.42 mmol), 1, 4-dioxane (10 mL), dilute hydrochloric acid (20 mL,0.5M aqueous solution), and the mixture was heated to reflux under argon for about 1.5 hours. After the completion of the reaction by LC-MS, the mixture was cooled, the pH was adjusted to 8 to 9 with saturated sodium carbonate solution, extracted twice with ethyl acetate (30 mL x 2), and the combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the organic phases were concentrated to dryness to give a pale yellow solid product (660 mg, yield: 78%).

ESI-MS m/z:249[M+H] ⁺

Step 4: synthesis of Compound int_1-5

To a 100mL single flask was added int_1-4 (440 mg,1.77 mmol), piperazine-1-carboxylic acid tert-butyl ester (330 mg,1.77 mmol), DCM (20 mL) and glacial acetic acid (160 mg,2.66 mmol), and after stirring the mixture at room temperature under argon for about 1 hour, naBH (OAc) was added ₃ (564 mg,2.66 mmol) and the mixture was stirred at room temperature overnight. After completion of LC-MS detection, the mixture was added with saturated sodium bicarbonate solution (50 mL), stirred, separated, the aqueous phase was extracted twice with DCM (30 mL x 2), the combined organic phases were washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to dryness to give a brown oil (740 mg).

ESI-MS m/z:319[M-Boc+H] ⁺

Step 5: synthesis of Compound int_1-6

To a 100mL single-necked flask was added int_1-5 (740 mg,1.77 mmol), DCM (10 mL), TFA (3 mL), and the reaction was stirred at room temperature under argon for about 2 hours. After completion of the LC-MS detection reaction, the mixture was concentrated, and the residue was purified by column chromatography to give the product (562 mg, yield: 99.7%).

ESI-MS m/z:319[M+H] ⁺

Step 6: synthesis of Compound int_1-7

To a 100mL single flask was added int_1-6 (292 mg,1.76 mmol), meOH (10 mL), (methylsulfonyl) ethylene (188 mg,1.77 mmol), and the reaction was stirred at room temperature under argon for 48 hours. LC-MS detected the product, and the mixture was concentrated to give a crude product, which was purified by column chromatography to give the product as a brown oil (40 mg, yield: 5.3%).

ESI-MS m/z:425[M+H] ⁺

Step 7: synthesis of Compound int_1-9

Int_1-8 (100 mg,0.69 mmol) was dissolved in acetic acid (2 mL) and a solution of iodine monochloride (144.4 mg,0.90 mmol) in acetic acid (1 mL) was added dropwise at 10 ℃. Naturally heating to room temperature and stirring for 2 hours. TLC detection showed the reaction was complete. The reaction solution was poured into 30 g of crushed ice and stirred for 10 minutes. Saturated aqueous sodium thiosulfate (1 ml) was added thereto, and the mixture was stirred at room temperature for 5 minutes. Ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was subjected to column chromatography to give a pale yellow solid (80 mg, yield: 42.9%).

MS(ESI):272[M+H] ⁺ .

Step 8: synthesis of Compound int_10

int_1-9 (11 g,40.58 mmol), dimethylphosphine oxide (6.33 g,81.16 mmol), cs ₂ CO ₃ (26.4 g,81.2 mmol), palladium acetate (1.82 g,8.12 mmol), XPhos (2.35 g,4.06 mmol) was suspended in DMF (200 mL). Stirring for 3 hours at 105 ℃ under the protection of argon. LCMS monitored the reaction was complete. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution gradient: DCM/meoh=50:1). The desired product was obtained as a yellow solid (6.3 g, yield: 70.2%). ¹ H NMR:(400MHz,CHLOROFORM-d)δ＝8.57(d,J＝1.9Hz,1H),8.51(d,J＝1.9Hz,1H),7.88(d,J＝9.1Hz,1H),7.04(dd,J＝4.1,9.2Hz,1H),2.05(s,3H),2.01(s,3H)；MS(ESI):222[M+H] ⁺ .

Step 9: synthesis of Compound int_12

Int_1-10 (6.3 g,28.5 mmol) was dissolved in anhydrous tetrahydrofuran (200 mL) and LiHMDS tetrahydrofuran solution (34.18 mL,34.18mmol, 1M) was added dropwise at 0deg.C under argon. After stirring at 0℃for 10 minutes, 5-bromo-2, 4-dichloropyrimidine (7.14 g,31.3 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was subjected to column chromatography to give the desired product as a yellow solid (5.06 g, yield: 43.1%).

¹ H NMR:(400MHz,CDCl ₃ )δ＝13.10(s,1H),9.05(dd,J＝4.1,9.4Hz,1H),8.84(d,J＝1.8Hz,1H),8.77(d,J＝1.8Hz,1H),8.44(s,1H),8.29(d,J＝9.5Hz,1H),2.17(s,3H),2.14(s,3H)；MS(ESI):412[M+H] ⁺ .

Step 10: synthesis of Compound 1

Int_1-7 (40 mg,0.094 mmol) and int_1-12 (39 mg,0.094 mmol) were added to t-butanol (5 mL), methanesulfonic acid (36 mg,0.38 mmol) was added dropwise and the reaction mixture was allowed to react overnight at 80℃with LCMS monitoring the reaction completion, concentrated under reduced pressure, and the crude product was isolated and purified by Prep-HPLC (0.1% TFA) to afford the desired product as a yellow solid (13 mg, yield: 17.3%).

¹ H NMR(400MHz,CDCl ₃ )δ12.49(s,1H),8.97(dd,J＝9.5,4.1Hz,1H),8.74(dd,J＝16.4,1.9Hz,2H),8.27(d,J＝0.9Hz,1H),8.08(d,J＝9.5Hz,1H),8.00(s,1H),7.38(s,1H),6.64(s,1H),3.85(d,J＝0.9Hz,3H),3.17(t,J＝6.5Hz,2H),3.10(d,J＝11.5Hz,2H),3.03(s,3H),2.94(t,J＝6.5Hz,2H),2.68(t,J＝11.4Hz,10H),2.51(q,J＝7.5Hz,3H),2.12(dd,J＝14.3,0.9Hz,6H),1.99(s,2H),0.88(t,J＝7.6Hz,3H).

ESI-MS m/z:800[M+H] ⁺

EXAMPLE 2 Synthesis of Compound 16

Step 1: synthesis of Compound int_16-2

Int_16-1 (2.0 g,7.14 mmol), dimethylphosphine oxide (480 mg,10.1 mmol), potassium acetate (1.32 g,13.5 mmol), palladium acetate (120 mg, 532. Mu. Mol), xantphos (312 mg, 539. Mu. Mol) were dissolved in 25mL dioxane. Reflux stirring is carried out for 4 hours under the protection of argon. LC-MS monitored the reaction was complete and no starting material had remained. After the reaction solution was concentrated under reduced pressure to remove a part of the solvent, water and DCM were added to dilute, extraction was performed 3 times with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO ₂ MeOH/dcm=0-2%) purification. The desired product was obtained as a pale yellow solid (1.07 g, yield 64.3%).

ESI-MS m/z:248[M+H] ⁺

Step 2: synthesis of Compound int_16-3

Int_16-2 (970 mg,3.91 mmol), cyclopropylboronic acid (404 mg,4.70 mmol), pd (dtbpf) Cl ₂ (250 mg, 390. Mu. Mol) potassium phosphate (1.66 g,7.82 mmol) was dissolved in a mixed solution of 15mL dioxane and 3mL water. Reflux stirring is carried out for 7 hours under the protection of argon. LC-MS monitored the reaction was complete and no starting material had remained. After the reaction solution was concentrated under reduced pressure to remove a part of the solvent, water and DCM were added to dilute, extraction was performed 3 times with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO ₂ MeOH/dcm=0-3.3%) was purified. The product was obtained as a white solid (400 mg, yield 46.7%).

ESI-MS m/z:210[M+H] ⁺

Step 3: synthesis of Compound int_16-4

Int_16-3 (400 mg,1.91 mmol) was dissolved in 10mL of ultra-dry THF and lithium bis (trimethylsilyl) amide solution (1M in THF,2.9 mL) was slowly added dropwise under argon at-10deg.C. After stirring at-10℃for 10 minutes, 5-bromo-2, 4-dichloropyrimidine (523 mg,2.29 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction was quenched by addition of saturated aqueous ammonium chloride, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by beating to give the product as a yellow solid (340 mg, yield 44.4%).

ESI-MS m/z:400[M+H] ⁺

Step 4: synthesis of Compound 16

Int_16-4 (100 mg, 250. Mu. Mol), int1_1-12 (106 mg, 250. Mu. Mol) and methanesulfonic acid (292 mg, 2000. Mu. Mol) were dissolved in 10mL of t-butanol. The reaction was carried out overnight at 80℃under an argon atmosphere. The LC-MS monitored the reaction was essentially complete with little starting material remaining. The reaction was adjusted to pH 2 by the addition of dilute hydrochloric acid, the organic phase was washed 2 times with EA, the aqueous phase was adjusted to pH 10 with sodium hydroxide, and extracted with DCM. The solvent was removed by concentration under reduced pressure and the residue was purified by Prep-HPLC (0.1% fa). Further purification by TLC preparation (DCM/meoh=20/1) afforded the desired product as a yellow solid (40 mg, 36.1% yield).

¹ H NMR(400MHz,DMSO-d ₆ )δ9.20(s,1H),8.43(s,1H),7.61–7.47(m,3H),7.40(d,J＝8.4Hz,1H),6.81(s,1H),3.82(s,3H),3.29–3.24(m,2H),3.01(s,5H),2.67(d,J＝13.8Hz,5H),2.59(q,J＝7.5Hz,10H),2.13–2.03(m,1H),2.02–1.80(m,2H),1.69(dd,J＝18.6,13.6Hz,6H),1.38(s,2H),1.17(t,J＝7.5Hz,3H),1.12–1.03(m,2H),0.84–0.80(m,2H).

ESI-MS m/z:788[M+H] ⁺

EXAMPLE 3 Synthesis of Compound 17

Step 1: synthesis of Compound int_17-2

Int_1-1 (3.55 g,9.51 mmol), int_17-1 (2.07 g,9.94 mmol), pd (dppf) ₂ Cl ₂ (665 mg,0.95 mmol) and potassium carbonate (2.57 g,18.6 mmol) were added to a mixed solution of 60mL dioxane and 15mL water. Reflux under argon blanket. LC-MS monitored the reaction was complete and no starting material had remained. After the reaction solution was concentrated under reduced pressure to remove a part of the solvent, water and DCM were added to dilute, extraction was performed 3 times with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO ₂ MeOH/dcm=0-2%) purification. The intermediate was obtained as a white solid (2.91 g, yield 82.0%).

ESI-MS m/z:375[M+H] ⁺

Step 2: synthesis of Compound int_17-3

Int_17-2 (2.91 g,7.72 mmol), ammonium chloride (871 mg,15.5 mmol) and iron powder (1.30 g,23.2 mmol) were dissolved in a mixed solution of 35mL ethanol and 7mL water. The reaction was heated at reflux overnight. TLC monitored the reaction was complete, no starting material had remained, and a new spot was formed. After filtration and partial solvent removal by concentration of the filtrate under reduced pressure, water and DCM were added for dilution and extraction 3 times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product as a black solid (2.54 g, yield 95.5%).

ESI-MS m/z:345[M+H] ⁺

Step 3: synthesis of Compound int_17-4

To a mixture of 10mL of dilute hydrochloric acid (2M in water) and 50mL of dioxane was added int_17-3 (1.56 g,4.53 mmol), and the mixture was heated at reflux overnight. LC-MS monitored the reaction was complete and no starting material had remained. The reaction was quenched with saturated sodium bicarbonate solution, extracted three times with EA, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the product as a black viscous liquid (676 mg, yield 49.7%).

ESI-MS m/z:301[M+H] ⁺

Step 4: synthesis of Compound int_17-5

Int_17-5 (100 mg, 330. Mu. Mol), N-Boc piperazine (74 mg, 400. Mu. Mol), HOAc (24 mg, 400. Mu. Mol) and TEA (40 mg, 400. Mu. Mol) were dissolved in DCM and stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (212 mg,1.00 mmol) was then added thereto, and the mixture was stirred at room temperature for 1 hour. LC-MS monitored the reaction was complete and no starting material had remained. After the reaction solution was concentrated under reduced pressure to remove the solvent, water and acetonitrile were added to dilute the mixture, and the mixture was purified by flash chromatography (ACN/1% TFA aqueous solution=5% -20%). The trifluoroacetate salt of the desired product was obtained as a black solid after lyophilization (120 mg, yield 62.2%).

ESI-MS m/z:371[M+H-Boc] ⁺

Step 5: synthesis of Compound int_17-6

Int_17-5 (120 mg, 205. Mu. Mol) was dissolved in a mixed solution of 2mL of hydrogen chloride/dioxane (4M) and 2mL of methanol, and stirred at room temperature for 1 hour. LC-MS monitored the reaction was complete and no starting material had remained. The reaction was purified by flash preparative liquid chromatography (ACN/1%o TFA aqueous solution=5% -10%). The trifluoroacetate salt of the product was obtained as a black solid after lyophilization (80 mg, yield 79.8%).

ESI-MS m/z:371[M+H] ⁺

Step 6: synthesis of Compound int_17-7

Int_17-6 (80 mg, 165. Mu. Mol), TEA (50. Mu.L) and (methylsulfonyl) ethylene (40 mg, 380. Mu. Mol) were dissolved in 3mL of methanol. The reaction was carried out at room temperature for 2 hours. LC-MS monitored the reaction was complete and no starting material had remained. The reaction was purified by flash preparative liquid chromatography (ACN/1%o TFA aqueous solution=5% -25%). The product was obtained as a black solid after extraction (32 mg, 40.7% yield).

ESI-MS m/z:477[M+H] ⁺

Step 7: synthesis of Compound int_17-8

To a mixture of 12mL of water and 60mL of ethanol, int_17-8 (4.5 g,16.2 mmol), iron powder (2.8 g,48.6 mmol) and ammonium chloride (1.9 g,32.4 mmol) were added and heated at reflux for 5 hours. LC-MS monitored the reaction was complete and no starting material had remained. The filter cake was washed with ethanol, the filtrate was concentrated under reduced pressure to remove most of the solvent, then water was added for dilution, and extraction was performed 3 times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product as a pale yellow solid (3.4 g, yield 84.8%).

ESI-MS m/z:248[M+H] ⁺

Step 8: synthesis of Compound int_17-10

Int_17-9 (355 mg,1.44 mmol), dimethylphosphine oxide (168 mg,2.16 mmol), potassium phosphate (630 mg,2.88 mmol), palladium acetate (32 mg, 144. Mu. Mol), xantphos (166 mg, 288. Mu. Mol) were dissolved in 10mL dioxane. Reflux reaction overnight under argon. LC-MS monitored the reaction was complete and no starting material had remained. After the reaction solution was concentrated under reduced pressure to remove most of the solvent, water and methanol were added for dilution, and the above mixture was purified by flash chromatography (ACN/1%o TFA aqueous solution=5% -35%). The trifluoroacetate salt of the key product was obtained as a white solid (381 mg, yield 85.2%).

ESI-MS m/z:198[M+H] ⁺

Step 9: synthesis of Compound int_17-11

Int_17-10 (trifluoroacetate salt, 3831 mg,1.22 mmol) was dissolved in 10mL of ultra-dry THF, and lithium bis (trimethylsilyl) amide solution (1M in THF,3.1 mL) was slowly added dropwise at-10deg.C under argon, and stirred for 5 min at-10deg.C after the addition. The reaction mixture was added to a solution of 5-bromo-2, 4-dichloropyrimidine (333 mg,1.46 mmol) in ultra-dry THF at-10℃and after the addition was completed, the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. LC-MS monitored the reaction was complete and no starting material had remained. Quenching with saturated ammonium chloride, extracting with DCM for 3 times, mixing the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying with column chromatography (SiO ₂ MeOH/dcm=0-4%) purification. The solid was concentrated under reduced pressure to give the desired product as a white solid (335 mg, yield 70.6%).

ESI-MS m/z:388[M+H] ⁺

Step 9: synthesis of Compound 17

Int_17-10 (21 mg, 54. Mu. Mol), int_17-7 (22 mg, 54. Mu. Mol), 4A molecular sieve (50 mg) and camphorsulfonic acid (63 mg, 270. Mu. Mol) were dissolved in 3mL of 2, 4-dimethyl-3-pentanol. The reaction was carried out overnight at 80℃under an argon atmosphere. The LC-MS monitored the reaction was essentially complete with little starting material remaining. The reaction was adjusted to pH 2 by the addition of dilute hydrochloric acid, the organic phase was washed 2 times with EA, the aqueous phase was adjusted to pH 10 with sodium hydroxide, and extracted with DCM. The solvent was removed by concentration under reduced pressure and the residue was purified by flash chromatography (ACN/1%o aqueous fa=10% -60%). Formate salt of the desired product was obtained as a black solid (10 mg, 22.3% yield) after lyophilization.

¹ H NMR(400MHz,CD ₃ OD)δ8.29(s,1H),8.27(s,1H),8.08(d,J＝3.4Hz,1H),7.89(s,1H),7.65(d,J＝8.0Hz,1H),7.33(dd,J＝7.9,3.4Hz,1H),6.90(s,1H),3.96(s,14H),3.05(s,3H), 2.76(t,J＝11.8Hz,2H),2.46(s,3H),2.43(s,3H),2.28(d,J＝11.6Hz,2H),1.96(dd,J＝13.3,9.4Hz,8H),1.20(d,J＝4.1Hz,2H),1.13(d,J＝7.2Hz,2H).

ESI-MS m/z:828[M+H] ⁺

EXAMPLE 4 Synthesis of Compound 20

Step 1: synthesis of Compound int_20-1

The hydrochloride salt of int_1-5 (100 mg, 314. Mu. Mol), potassium carbonate (109 mg, 785. Mu. Mol) and 2-chloroethyl methyl sulfide (38 mg, 377. Mu. Mol) were dissolved in 5mL of ACN. The reaction was carried out at 75℃for 2 hours under argon atmosphere. LC-MS monitored the reaction was complete and no starting material had remained. The reaction was purified by flash preparative liquid chromatography (ACN/1%o TFA aqueous solution=5% -30%). The desired product was obtained as a white solid (76 mg, yield 61.8%).

ESI-MS m/z:393[M+H] ⁺

Step 2: synthesis of Compound 20

Int_1-12 (41 mg, 99. Mu. Mol), int_20-1 (30 mg, 76. Mu. Mol) and camphorsulfonic acid (113 mg, 486. Mu. Mol) were dissolved in 5mL of t-butanol. The reaction was carried out overnight at 80℃under an argon atmosphere. The LC-MS monitored the reaction was essentially complete with little starting material remaining. The reaction was adjusted to pH 2 by the addition of dilute hydrochloric acid, the organic phase was washed 2 times with EA, the aqueous phase was adjusted to pH 10 with sodium hydroxide, and extracted with DCM. The solvent was removed by concentration under reduced pressure and the residue was purified by Prep-HPLC. The formate salt of the product was obtained as a yellow solid (10 mg, 36.1% yield) after lyophilization.

¹ H NMR(400MHz,CD ₃ OD)δ8.86(dd,J＝9.7,3.2Hz,2H),8.80(d,J＝2.0Hz,1H),8.54(s,1H),8.23(s,1H),7.97(d,J＝9.5Hz,1H),7.63(s,1H),6.79(s,1H),3.84(s,3H),3.11(d,J＝11.6Hz,2H),2.92–2.59(m,15H),2.48(q,J＝7.5Hz,4H),2.16–2.11(m,9H),1.73(tt,J＝12.7,6.3Hz,2H),0.83(t,J＝7.5Hz,3H).

ESI-MS m/z:768[M+H] ⁺

Examples 5-23 Synthesis of specific Compounds 2-15, 18, 19, 21-23

Using the synthetic methods of examples 1-4, the target compounds 2-15, 18, 19, 21-23 of Table 1 were obtained using different starting materials.

TABLE 1

Comparative Compound A

Comparative compound a was prepared as described in WO2019/015655, example 41.

EXAMPLE 24 detection of inhibitory Activity of the Compounds of the invention against EGFR (del 19/T790M/C797S), EGFR (L858R/T790M/C797S) or EGFR (WT) enzymes

Inhibition of EGFR (del 19/T790M/C797S), EGFR (L858R/T790M/C797S) or EGFR (WT) enzyme activity by compounds was assayed using the HTRF method. The method comprises the following steps:

after incubation of WT or mutant EGFR proteins with gradient diluted compounds for 10 min at 28℃biotin-labeled universal tyrosine kinase substrate (TK) and ATP were added and reacted at room temperature for 40 min. After termination of the reaction, eu3+ -Cryptate labeled antibody against TK and streptavidine-XL 665 were added and incubated at room temperature for 60 minutes. The level of TK substrate phosphorylation was quantified by detecting luminescence at 615nm and 665nm, calculating the ratio 665/615. Calculating percent inhibition of compound and IC compared to control group ₅₀ . The results are shown in Table 2 below.

TABLE 2 inhibitory Activity of the compounds of the invention against EGFR (del 19/T790M/C797S), EGFR (L858R/T790M/C797S) or EGFR (WT)

+ represents an inhibition rate of 20% or less

++ means an inhibition of 20% to 50%

++ indicates an inhibition of greater than 50%

N.D represents activity unmeasured

As can be seen from the data in Table 2, the compounds of the present invention have better inhibitory activity against EGFR (del 19/T790M/C797S) and EGFR (L858R/T790M/C797S) enzyme activities and better selectivity against EGFR (WT).

Example 25 comparison of inhibitory Activity of Compounds of the invention and comparative Compound A against EGFR (del 19/T790M/C797S), EGFR (L858R/T790M/C797S), EGFR (del 19/T790M), EGFR (L858R/T790M), EGFR (del 19), EGFR (L858R) or EGFR (WT)

Inhibition of EGFR (del 19/T790M/C797S), EGFR (L858R/T790M/C797S), EGFR (del 19/T790M), EGFR (L858R/T790M), EGFR (del 19), EGFR (L858R) or EGFR (WT) enzyme activity by compounds was assayed using the HTRF method. The method comprises the following steps:

after incubation of WT or mutant EGFR proteins with gradient diluted compounds for 10 min at 28℃biotin-labeled universal tyrosine kinase substrate (TK) and ATP were added and reacted at room temperature for 40 min. After termination of the reaction, eu3+ -Cryptate labeled antibody against TK and streptavidine-XL 665 were added and incubated at room temperature for 60 minutes. The level of TK substrate phosphorylation was quantified by detecting luminescence at 615nm and 665nm, calculating the ratio 665/615. Calculating percent inhibition of compound and IC compared to control group ₅₀ . The results are shown in Table 3 below.

TABLE 3 inhibitory Activity of inventive and comparative Compound A against EGFR (del 19/T790M/C797S), EGFR (L858R/T790M/C797S), EGFR (del 19/T790M), EGFR (L858R/T790M), EGFR (del 19), EGFR (L858R) or EGFR (WT) (IC ₅₀ ,nM)

	1	Comparative Compound A
EGFR(del19/T790M/C797S)	0.173	0.338
EGFR(L858R/T790M/C797S)	0.187	0.251
EGFR(del19/T790M)	0.109	0.238
EGFR(L858R/T790M)	0.209	0.328
EGFR(del19)	0.930	0.882
EGFR(L858R)	3.082	2.698
EGFR(WT)	12.39	10.07

As can be seen from the data in Table 3, compared with comparative compound A, compound 1 of the present invention has better inhibitory activity on EGFR (del 19/T790M/C797S), EGFR (L858R/T790M) and EGFR (del 19/T790M) enzyme activities, indicating that the introduction of sulfone group into the structure unexpectedly increases the inhibitory activities of EGFR (del 19/T790M/C797S), EGFR (L858R/T790M) and EGFR (L858R/T790M) enzyme activities.

EXAMPLE 26 the Compounds of the invention against Ba/F3 (EGFR ^{del19/T790M/C797S} ) Antiproliferative activity of triple mutant cells

3000 EGFR-carrying (del 19/T790M/C797S) Ba/F3 cells were seeded in 384-well plates and after one day of growth, a gradient of diluted compound (Ba/F3 cells up to 500 nM) was added. Three days after the addition of the compound, cell Titer Glow was added to evaluate Cell growth, and the percentage of the compound inhibiting Cell growth and IC were calculated ₅₀ Values, results are shown in Table 4 below.

TABLE 4 Compounds of the invention against Ba/F3 (EGFR ^{del19/T790M/C797S} ) Antiproliferative activity of triple mutant cells

Compounds of formula (I)	IC 50 (nM)
1	11
Comparative Compound A	15

As can be seen from the data in Table 4, compound 1 of the present invention has a strong Ba/F3 (EGFR ^{del19/T790M/C797S} ) Antiproliferative activity of the triple mutant cells.

EXAMPLE 27 in vivo pharmacokinetic experiments of Compounds of the invention

CD-1 female mice 7 to 10 weeks old were selected and dosed intravenously and orally at 2mg/Kg and 10mg/Kg, respectively. Mice were fasted for at least 12 hours prior to dosing and fed was resumed 4 hours after dosing, with free water throughout the experiment. The day of the experiment, i.e. the animals of the intravenous group were given the corresponding compounds by single injection via the tail vein in a volume of 10ml/Kg. Animals in the oral group were given the corresponding compounds by a single injection by gavage, the administration volume being 10ml/Kg. Animals were weighed prior to dosing and dosing volumes were calculated from body weight. The sample collection time is as follows: 0.083 (injection group), 0.25,0.5,1,2,4,8, 24h. About 200uL of whole blood was collected through the submaxillary venous plexus at each time point for preparing plasma high performance liquid chromatography-tandem mass spectrometryLC-MS/MS). All animals were CO-processed after collection of PK samples at the last time point ₂ The anesthesia is euthanized. Using Phoenix WinNonlin ^TM Non-compartmental model of version8.3 (Certara) pharmacokinetic software plasma concentrations were processed and pharmacokinetic parameters were calculated using a linear log trapezoidal method. The in vivo pharmacokinetic results are shown in table 5 below.

TABLE 5 results of in vivo pharmacokinetic evaluation of the Compounds of the invention

As can be seen from the data in Table 5, the peak time (T _max ) Decreasing and Cmax increasing. Compared with the comparative compound A, the sulfonyl compound 1 of the invention has unexpectedly higher Cmax, so that higher blood concentration can be achieved. And sulfone compound 1 has unexpectedly lower T _max The peak of the blood concentration can be reached in a shorter time.

While particular embodiments of the present invention have been described above, it will be appreciated by those skilled in the art that these are merely illustrative, and that many changes and modifications may be made to these embodiments without departing from the principles and spirit of the invention. Accordingly, the scope of the invention is defined by the appended claims.

Claims (11)

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):

   R ¹ is-Cl or-Br;

   R ² and R is ³ Each independently is-H, halogen, -CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C14) cycloalkyl;

   R ⁴ And R is ⁵ Each independently is-H, halogen, -CN, -S (O) ₂ R ⁸ (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C14) cycloalkyl, (C6-C14) aryl, (3-11 membered) heterocycloalkyl, or (5-11 membered) heteroaryl, wherein said (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C14) cycloalkyl, (C6-C14) aryl, (3-11 membered) heterocycloalkyl, or (5-11 membered) heteroaryl may each independently be optionally substituted with 1 or more of the following groups: -H, halogen, -R ⁸ 、-OH、-(CH ₂ ) _n OR ⁸ 、-(CH ₂ ) _n NR ⁸ R ⁹ 、-OR ⁸ 、-NR ⁸ R ⁹ 、-CN、-C(O)NR ⁸ R ⁹ 、-NR ⁹ C(O)R ⁸ 、-NR ⁹ S(O) ₂ R ⁸ 、-S(O) _p R ⁸ and-S (O) ₂ NR ⁸ R ⁹ The method comprises the steps of carrying out a first treatment on the surface of the Or R is ⁴ And R is ⁵ The atoms to which they are attached can together form a 6-membered aryl or (5-6 membered) heteroaryl, wherein the 6-membered aryl or (5-6 membered) heteroaryl can each independently be optionally substituted with 1 or more of the following groups: -H, -CD ₃ Halogen, -R ⁸ and-OR ⁸ ；

   R ⁶ is-H, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C14) cycloalkyl, (C6-C14) aryl, (3-11 membered) heterocycloalkyl or (5-11 membered) heteroaryl, wherein said (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C14) cycloalkyl,(C6-C14) aryl, (3-11 membered) heterocycloalkyl or (5-11 membered) heteroaryl may each independently be optionally substituted with 1 or more of the following groups: -H, halogen, -R ⁸ 、-OH、-(CH ₂ ) _n OR ⁸ 、-(CH ₂ ) _n NR ⁸ R ⁹ 、-OR ⁸ 、-NR ⁸ R ⁹ 、-CN、-C(O)NR ⁸ R ⁹ 、-NR ⁹ C(O)R ⁸ 、-NR ⁹ S(O) ₂ R ⁸ 、-S(O) _p R ⁸ and-S (O) ₂ NR ⁸ R ⁹ ；

   R ⁷ Is (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C14) cycloalkyl, (C6-C14) aryl, (3-11 membered) heterocycloalkyl or (5-11 membered) heteroaryl, wherein said (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C14) cycloalkyl, (C6-C14) aryl, (3-11 membered) heterocycloalkyl or (5-11 membered) heteroaryl may each independently be optionally substituted with 1 or more of the following groups: -H, halogen, -R ⁸ 、-OH、-(CH ₂ ) _n OR ⁸ 、-(CH ₂ ) _n NR ⁸ R ⁹ 、-OR ⁸ 、-NR ⁸ R ⁹ 、-CN、-C(O)NR ⁸ R ⁹ 、-NR ⁹ C(O)R ⁸ 、-NR ⁹ S(O) ₂ R ⁸ 、-S(O) _p R ⁸ and-S (O) ₂ NR ⁸ R ⁹ ；

   R ⁸ And R is ⁹ Each independently is-H, (C1-C6) alkyl, (C1-C6) haloalkyl or (C3-C14) 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 0, 1, 2 or 3.
2. The process of claim 1A compound or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R in the general formula (1) ² And R is ³ Each independently is-H, -F, -Cl, -CN, (C1-C3) alkyl, (C1-C3) haloalkyl, (C3-C6) cycloalkyl.
3. The compound according to claim 2, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), R ² And R is ³ Each independently is: -H, -F, -Cl, -CN, -CH ₃ 、-CF ₃ Or (b)
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), R ⁴ And R is ⁵ Each independently is-H, -F, -Cl, -CN, -S (O) ₂ CH ₃ (C1-C3) alkyl, (C1-C3) haloalkyl, (C3-C6) cycloalkyl, phenyl, (3-6 membered) heterocycloalkyl, or (5-6 membered) heteroaryl, wherein said (C1-C3) alkyl, (C1-C3) haloalkyl, (C3-C6) cycloalkyl, phenyl, (3-6 membered) heterocycloalkyl, or (5-6 membered) heteroaryl may each independently be optionally substituted with 1 or more of the following groups: -H, -F, -Cl, -CH ₃ 、-OH、-OCH ₃ -CN; or R is ⁴ And R is ⁵ The atoms to which they are attached can together form a 6-membered aryl or (5-6 membered) heteroaryl, wherein the 6-membered aryl or (5-6 membered) heteroaryl can each independently be optionally substituted with 1 or more of the following groups: -H, -F, -Cl, -CH ₃ and-OCH ₃ 。
5. The compound according to claim 4, or each isomer, each crystal form, pharmaceutically acceptable thereofA salt, hydrate or solvate, wherein in the general formula (1), the structural unitThe method comprises the following steps:
6. the compound according to any one of claims 1 to 5, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), R ⁶ is-H, (C1-C3) alkyl, (C1-C3) haloalkyl, (C3-C6) cycloalkyl, (C6-C10) aryl, (3-6 membered) heterocycloalkyl or (5-6 membered) heteroaryl, wherein said (C1-C3) alkyl, (C1-C3) haloalkyl, (C3-C6) cycloalkyl, (C6-C10) aryl, (3-6 membered) heterocycloalkyl or (5-6 membered) heteroaryl may each independently be optionally substituted with 1 or more of the following groups: -H, -F, -Cl, -CH ₃ 、-OH、-OCH ₃ 、-CN。
7. The compound according to claim 6, wherein R in the general formula (1), or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof ⁶ The method comprises the following steps: -H, -CH ₃ 、-CH ₂ CH ₃ Or (b)
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 ⁷ Is (C1-C3) alkyl, (C1-C3) haloalkyl, (C3-C5) cycloalkyl, aryl, (3-6 membered) heterocycloalkyl or(5-6 membered) heteroaryl, wherein the (C1-C3) alkyl, (C1-C3) haloalkyl, (C3-C5) cycloalkyl, aryl, (3-6 membered) heterocycloalkyl or (5-6 membered) heteroaryl may each independently be optionally substituted with 1 or more of the following groups: -H, -F, -Cl, -CH ₃ 、-OH、-OCH ₃ 、-CN。
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 ⁷ The method comprises the following steps: -CH ₃ 、-CH ₂ CH ₃ 、-CF ₃ Or (b)
10. The compound of any one of claims 1-9, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the compound has one of the following structures:
11. a pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and, as active ingredient, a compound according to any one of claims 1 to 10, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof.