WO2024027695A1

WO2024027695A1 - Compounds as her2 inhibitors

Info

Publication number: WO2024027695A1
Application number: PCT/CN2023/110515
Authority: WO
Inventors: 谢雨礼; 吴应鸣; 钱立晖
Original assignee: 微境生物医药科技(上海)有限公司
Priority date: 2022-08-04
Filing date: 2023-08-01
Publication date: 2024-02-08

Abstract

A class of compounds as HER2 inhibitors. Specifically, the present invention relates to compounds as shown in general formula (1), general formula (2) and general formula (3), a preparation method therefor, and the use of the compounds of general formula (1), general formula (2) and general formula (3), and isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof as HER2 inhibitors. The compounds and the isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof can be used in the preparation of drugs for treating or preventing diseases related to an HER2 protein.

Description

Compounds that act as HER2 inhibitors

Technical field

The present invention relates to the field of medicinal chemistry, and more specifically, to a class of compounds with HER2 protein inhibitory effects, preparation methods thereof, and applications of such compounds in preparing drugs for treating or preventing related diseases mediated by HER2.

Background technique

The ErbB family of epidermal growth factors consists of EGFR (ErbB-1), HER2 (ErbB-2), HER3 (ErbB-3) and HER4 (ErbB-4). The HER2 protein consists of an extracellular ligand-binding region and a single-chain transmembrane The extracellular domain of HER2 can bind to different ligands or form homo-dimers or heterodimers with ErbB family members. (hetero-dimer), and HER2 protein is often a common partner of heterodimers. When HER2 binds to its ligand, it activates tyrosine kinase by causing receptor dimerization and autophosphorylation of the intracytoplasmic tyrosine kinase region. amino acid kinase activity. The signal transduction pathway mediated by HER2 protein is mainly transduced through the MAP kinase (mitogen-activated protein kinase) and phosphatidylinositol 3-kinase (PI3K) pathways.

In tumor cells, continued activation of HER2 can lead to excessive proliferation or metastasis of tumor cells. HER2 gene amplification (HER2 amplification), HER2 protein overexpression (HER2overexpression) or continuously activating HER2 mutants (activating HER2 mutants) are common in various tumors. were detected. Approximately 1.4% of lung adenocarcinoma patients have HER2 gene amplification, while persistently activating HER2 mutants have been detected in 2.3% of lung adenocarcinomas. The mutations are mainly concentrated in the HER2 tyrosine kinase domain (kinase domain). Especially in the exon 20 region. Exon 20 insertion mutations result in the addition of amino acids between the αC-helix region (protein sequence 753-768), resulting in persistently activating HER2 mutations. Among exon 20 mutants, Y772dupYVMA (YVMA) is the most common mutated form and is detected in 34% of HER2-mutated lung cancer patients.

In terms of inhibitory activity, HER2 covalent inhibitors Poziotinib and Afatinib are more active than HER2 non-covalent inhibitors Lapatinib and Tucatinib. However, HER2 covalent inhibitors Poziotinib and Afatinib simultaneously inhibit wild-type EGFR (WT EGFR ) activity, causing greater toxicity, thus limiting its clinical application.

Therefore, there is an urgent need to research and discover highly selective HER2 inhibitors.

Contents of the invention

The invention provides a compound represented by general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

In general formula (1):

R ¹ is -H, -CH ₃ , -CCH, -OCH ₃ or halogen;

R ² is -H or halogen;

R ³ is

R ⁴ is R ^4a or R ^4b ;

R ^4a is wherein Q is a (4-6-membered) heterocycloalkylene group containing one nitrogen atom, wherein any one carbon atom in the (4-6-membered) heterocycloalkylene group may optionally be replaced by 1 or 2 of the following Group substitution: -H or -CH ₃ ;

R ^4b is wherein Z is a (4-6-membered) heterocycloalkylene group containing one nitrogen atom, wherein any one carbon atom in the (4-6-membered) heterocycloalkylene group may optionally be replaced by 1 or 2 of the following Group substitution: -H or -CH ₃ ;

R ⁵ is -H or -F;

R ^6a and R ^6b are each independently -H or (C1-C3) alkyl, wherein said (C1-C3) alkyl may be optionally substituted by 1 or 2 of the following groups: -N(R ⁸ ) ₂ or (4-6 membered) heterocycloalkyl; and at least one of R ⁵ , R ^6a and R ^6b is not -H;

R ^6c is -H or -CH ₃ ;

R ⁷ is -H or -CH ₃ ;

R ⁸ is each independently -H or (C1-C3)alkyl.

In another preferred example, in the general formula (1), R ¹ is -H, -CH ₃ , -CCH, -OCH ₃ , -F or -Cl.

In another preferred embodiment, in the general formula (1), R ² is -H, -F or -Cl.

In another preferred embodiment, in the general formula (1), R ⁷ is -CH ₃ .

In another preferred embodiment, in the general formula (1), R ⁸ is each independently -H, -CH ₃ or -CH ₂ CH ₃ .

In another preferred example, in the general formula (1), R ^6a and R ^6b are each independently -H or -CH ₃ , and the -CH ₃ may be optionally substituted by one of the following groups: - N(CH ₃ ) ₂ , -N(CH ₂ CH ₃ ) ₂ , -N(CH ₃ )(CH ₂ CH ₃ ),

In another preferred example, in the general formula (1), R ^4a is:

In another preferred example, in the general formula (1), R ^4b is:

In another specific embodiment of the invention, the compound of general formula (1) has one of the following structures:

The present invention also provides a compound represented by the general formula (2) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

In general formula (2):

R ⁹ is -H, -CH ₃ , -CCH, -OCH ₃ or halogen;

R ¹⁰ is -H or halogen;

R ¹¹ is -H or halogen; and at least one of R ⁹ , R ¹⁰ and R ¹¹ is not -H;

R ¹² is -H or -CH ₃ ;

W is

R ¹³ is -H or -F;

R ^14a and R ^14b are each independently -H or (C1-C3) alkyl, wherein the (C1-C3) alkyl may be optionally substituted by 1 or 2 of the following groups: -N(R ¹⁵ ) ₂ or (4-6 membered) heterocycloalkyl; and at least one of R ¹³ , R ^14a and R ^14b is not -H;

R ^14c is -H or -CH ₃ ;

R ¹⁵ is each independently -H or (C1-C3)alkyl.

In another preferred example, in the general formula (2), R ⁹ is -H, -CH ₃ , -CCH, -OCH ₃ , -F, -Cl or -Br.

In another preferred embodiment, in the general formula (2), R ¹⁰ is -H, -F, -Cl or -Br.

In another preferred embodiment, in the general formula (2), R ¹¹ is -H, -F or -Cl.

In another preferred example, in the general formula (2), R ¹² is -CH ₃ .

In another preferred example, in the general formula (2), R ¹⁵ is each independently -H, -CH ₃ or -CH ₂ CH ₃ .

In another preferred embodiment, in the general formula (2), R ^14a and R ^14b are each independently -H or -CH ₃ , wherein -CH ₃ may be optionally substituted by one of the following groups: -N(CH ₃ ) ₂ , -N(CH ₂ CH ₃ ) ₂ , -N(CH ₃ )(CH ₂ CH ₃ ),

In another preferred example, in the general formula (2), the structural unit W is:

In another specific embodiment of the invention, the compound of general formula (2) has one of the following structures:

The invention also provides a compound represented by the general formula (3) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

In general formula (3):

R ¹⁶ is -H, -CH ₃ , -CCH, -OCH ₃ or halogen;

R ¹⁷ is -H or halogen;

R ¹⁸ is -H or halogen; and at least one of R ¹⁶ , R ¹⁷ and R ¹⁸ is not -H;

E is

R ¹⁹ is -H or -F;

R ^20a and R ^20b are each independently -H or (C1-C3) alkyl, wherein the (C1-C3) alkyl may be optionally substituted by 1 or 2 of the following groups: -N(R ²² ) ₂ or (4-6 membered) heterocycloalkyl; and at least one of R ¹⁹ , R ^20a and R ^20b is not -H;

R ^20c is -H or -CH ₃ ;

R ²¹ is -H or -CH ₃ ;

R ²² is each independently -H or (C1-C3)alkyl.

In another preferred example, in the general formula (3), R ¹⁶ is -H, -CH ₃ , -CCH, -OCH ₃ , -F, -Cl or -Br.

In another preferred embodiment, in the general formula (3), R ¹⁷ is -H, -F, -Cl or -Br.

In another preferred example, in the general formula (3), R ¹⁸ is -H, -F or -Cl; R ¹⁸ is -H; R ¹⁸ is -F.

In another preferred embodiment, in the general formula (3), R ²² is each independently -H, -CH ₃ or -CH ₂ CH ₃ .

In another preferred embodiment, in the general formula (3), R ^20a and R ^20b are each independently -H or -CH ₃ , wherein -CH ₃ may be optionally substituted by one of the following groups: -N(CH ₃ ) ₂ , -N(CH ₂ CH ₃ ) ₂ , -N(CH ₃ )(CH ₂ CH ₃ ),

In another preferred example, in the general formula (3), the structural unit E is:

In another specific embodiment of the invention, the compound of general formula (3) has one of the following structures:

Another object of the present invention is to provide a pharmaceutical composition, which contains pharmaceutically acceptable carriers, diluents and/or excipients, as well as the general formula (1), general formula (2) and general formula of the present invention. (3) The compound, or each isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, serves as the active ingredient.

Another object of the present invention is to provide the compounds represented by the general formula (1), the general formula (2), and the general formula (3) of the present invention, or their respective isomers, crystal forms, and pharmaceutically acceptable salts. , hydrates or solvates or the above pharmaceutical compositions are used in the preparation of drugs for treating, regulating or preventing diseases related to HER2 protein.

Another object of the present invention is to provide a method for treating, regulating or preventing diseases related to HER2 protein, which includes administering to a subject a therapeutically effective amount of general formula (1), general formula (2), general formula ( 3) The compound shown, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the above pharmaceutical compositions.

By synthesizing and carefully studying a variety of new compounds with HER2 inhibitory effects, the inventor found that among the compounds of general formula (1), general formula (2), and general formula (3), the compounds unexpectedly have strong HER2 inhibitory effects active.

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

Synthesis of compounds

The preparation methods of the compounds of the present invention are described in detail below, but these specific methods do not constitute any limitation on the present invention.

The compounds described above can be synthesized using standard synthetic techniques or well-known techniques combined with the methods described herein. In addition, the solvents, temperatures and other reaction conditions mentioned herein may be varied. Starting materials for the synthesis of compounds may be synthesized or obtained from commercial sources such as, but not limited to, Aldrich Chemical Co. (Milwaukee, Wis.) or Sigma Chemical Co. (St. Louis, Mo.). The compounds described herein and other related compounds having various substituents may be synthesized using well-known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY ^4th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY ^4th Ed., Vols. A and B (Plenum 2000, 2001), Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS ^3rd Methods in Ed., (Wiley 1999). General methods of compound preparation may be modified by the use of appropriate reagents and conditions for the introduction of different groups in 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, solvents, bases, amounts of compounds used, reaction temperature, time required for reaction, etc. are not limited to the following explanations. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art. Such combinations 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 method for preparing the compound, wherein the compound of general formula (1) can be prepared by using the following general reaction scheme 1 and general reaction scheme 2, and the compound of general formula (2) can be prepared by using the following general reaction Preparation in Scheme 3: Compounds of general formula (3) can be prepared by the following general reaction scheme 4:

General reaction flow 1

Embodiments of compounds of general formula (1) may be prepared according to General Reaction Scheme 1, wherein R ¹ , R ² , R ³ , R ⁵ , R ^6a , R ^6b and R ^6c are as defined above and Y represents -H or -CH ₃ , N represents nitrogen, O represents oxygen, and ring A is a (4-6 membered) heterocycloalkyl group containing one nitrogen atom. As shown in the general reaction scheme 1, compound 1-1 and compound 1-2 undergo a substitution reaction under alkaline conditions to generate compound 1-3. Compound 1-3 undergoes an oxidation reaction to generate compound 1-4. Compound 1-4 and compound 1-5 undergoes a substitution reaction under alkaline conditions to generate compound 1-6, compound 1-6 is deprotected to generate compound 1-7, and compound 1-7 reacts with acid chloride 1-8 to generate the target product 1-9 or compound 1-7 and Acid chloride 1-10 reacts to produce target product 1-11.

General reaction process 2

Embodiments of compounds of general formula (1) may also be prepared according to General Reaction Scheme 2, wherein R ¹ , R ² , R ³ , R ⁵ , R ^6a , R ^6b and R ^6c are as defined above and Y represents -H or - CH ₃ , N represents nitrogen, O represents oxygen, and ring B is a (4-6 membered) heterocycloalkyl group containing one nitrogen atom. As shown in the general reaction scheme 2, compound 2-1 and compound 2-2 undergo a substitution reaction under alkaline conditions to generate compound 2-3. Compound 2-3 undergoes an oxidation reaction to generate compound 2-4. Compound 2-4 and compound 2-5 undergoes a substitution reaction under alkaline conditions to generate compound 2-6, compound 2-6 is deprotected to generate compound 2-7, and compound 2-7 reacts with acid chloride 2-8 to generate the target product 2-9 or compound 2-7 React with acid chloride 2-10 to produce the target product 2-11.

General reaction process 3

Embodiments of compounds of general formula (2) may be prepared according to General Reaction Scheme 3, wherein R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ^14a , R ^14b and R ^14c are as defined above and N represents nitrogen, O represents oxygen. As shown in the general reaction scheme 3, compound 3-1 and compound 3-2 undergo a substitution reaction under alkaline conditions to generate compound 3-3. Compound 3-3 undergoes an oxidation reaction to generate compound 3-4. Compound 3-4 and compound 3-5 undergoes a substitution reaction under alkaline conditions to generate compound 3-6, compound 3-6 is deprotected to generate compound 3-7, and compound 3-7 reacts with acid chloride 3-8 to generate the target product 3-9 or compound 3-7 React with acid chloride 3-10 to produce the target product 3-11.

General reaction process 4

Embodiments of compounds of general formula (3) may be prepared according to General Reaction Scheme 4, wherein R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²¹ , R ^20a , R ^20b and R ^20c are as defined above and N represents nitrogen, O represents oxygen. As shown in the general reaction scheme 4, compound 4-1 and compound 4-2 undergo a substitution reaction under alkaline conditions to generate compound 4-3. Compound 4-3 undergoes an oxidation reaction to generate compound 4-4. Compound 4-4 and compound 4-5 undergoes a substitution reaction under alkaline conditions to generate compound 4-6, compound 4-6 is deprotected to generate compound 4-7, and compound 4-7 reacts with acid chloride 4-8 to generate the target product 4-9 or compound 4-7 React with acid chloride 4-10 to produce the target product 4-11.

Further forms of compounds

"Pharmaceutically acceptable" here refers to a substance, such as a carrier or diluent, that does not obliterate the biological activity or properties of the compound and is relatively non-toxic, i.e., the substance will not cause undesirable biological effects or Interact in a harmful way with any of its components.

The term "pharmaceutically acceptable salt" refers to a form of a compound which does not cause significant irritation to the organism to which it is administered and which does not obliterate the biological activity and properties of the compound. In some specific aspects, pharmaceutically acceptable salts are obtained by reacting compounds of the general formula with acids, such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic 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.

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

In other embodiments, compounds of general formula are prepared in different forms, including, but not limited to, amorphous, comminuted, and nano-particulate forms. In addition, the compound of the general formula includes a crystalline form and may also be a polymorphic form. 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, density, hardness, crystalline form, 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.

On the other hand, compounds of the general formula may present chiral centers and/or axial chirality and thus exist as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers form, and cis-trans isomers. Each chiral center or axis of chirality 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 intended to include all such isomeric forms of these compounds.

The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, compounds can be labeled with radioactive isotopes such as tritium ( ³ H), iodine-125 ( ¹²⁵ I), and C-14 ( ¹⁴ C). For another example, hydrogen atoms can be replaced with heavy hydrogen to form deuterated compounds. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs usually have the advantages of reducing side effects and increasing the number of drugs. Stability, enhanced efficacy, extended half-life of drugs in vivo and other advantages. All variations in the isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.

the term

Unless otherwise specified, the terms used in this application, including the specification and claims, are defined as follows. It must be noted that, in the specification and the appended claims, the singular forms "a," "a" and "an" include plural referents unless the context clearly dictates otherwise. If not otherwise stated, conventional methods of mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology were used. In this application, the use of "or" or "and" means "and/or" unless stated otherwise.

Unless otherwise specified, "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 6 carbon atoms. Lower alkyl groups containing 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 by 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, "alkylene" refers to a divalent alkyl group as defined above. Examples of alkylene groups include, but are not limited to, methylene and ethylene.

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

Unless otherwise specified, "alkenylene" refers to a divalent alkenyl group as defined above.

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. Lower alkynyl groups containing 1 to 4 carbon atoms are preferred, such as ethynyl, 1-propynyl or 1-butynyl.

Unless otherwise specified, "alkynylene" refers to a divalent alkynyl group as defined above.

Unless otherwise specified, "cycloalkyl" refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic). If the carbocyclic ring contains at least one double bond, then a partially unsaturated cycloalkyl group may be referred to as a "cycloalkyl" "Alkenyl", or if the carbocyclic ring contains at least one triple bond, a partially unsaturated cycloalkyl group may be referred to as "cycloalkynyl". Cycloalkyl groups may include monocyclic or polycyclic (eg, having 2, 3, or 4 fused rings) groups and spirocycles. In some embodiments, cycloalkyl is monocyclic. In some embodiments, cycloalkyl is monocyclic or bicyclic. The ring-forming carbon atoms of the cycloalkyl group may optionally be oxidized to form oxo or sulfide radicals. Cycloalkyl also includes cycloalkylene. In some embodiments, cycloalkyl groups contain 0, 1, or 2 double bonds. In some embodiments, cycloalkyl groups contain 1 or 2 double bonds (partially unsaturated cycloalkyl groups). In some embodiments, cycloalkyl groups can be fused with aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl and cycloalkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl , norpinyl, norcarbenyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, etc.

Unless otherwise specified, "cycloalkylene" refers to a divalent cycloalkyl group as defined above.

Unless otherwise specified, "alkoxy" refers to an alkyl group bonded to the remainder of the molecule through an ether oxygen atom. Representative alkoxy groups are alkoxy groups with 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy, especially alkoxy substituted by 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, which may be monocyclic or polycyclic, for example, 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 phenanthrenyl.

Unless otherwise specified, "aryloxy" refers to an aryl group bonded to the remainder of the molecule through an ether oxygen atom. Examples of aryloxy groups include, but are not limited to, phenoxy and naphthyloxy.

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 phenylene.

Unless otherwise specified, "heteroaryl" refers to an aromatic group containing one or more heteroatoms (O, S, or N), which may be 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, quinolyl, isoquinolyl, furyl, thienyl, Isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzene Pyridyl, pyrrolopyrimidinyl, 1H-pyrrole[3,2-b]pyridyl, 1H-pyrrole[2,3-c]pyridyl, 1H-pyrrole[3,2-c]pyridyl, 1H- Pyrrole[2,3-b]pyridyl,

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

Unless otherwise specified, "heterocycloalkyl" refers to a non-aromatic ring or ring system which may optionally contain one or more alkenylene groups as ring A portion of a structure having at least one heteroatom ring member independently selected from the group consisting of boron, phosphorus, nitrogen, sulfur, oxygen and phosphorus. A partially unsaturated heterocycloalkyl group may be referred to as a "heterocycloalkenyl" if the heterocycloalkyl group contains at least one double bond, or a partially unsaturated heterocycloalkyl group if the heterocycloalkyl group contains at least one triple bond. Can be called "heterocycloalkynyl". Heterocycloalkyl groups may include monocyclic, bicyclic, spirocyclic 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 may optionally be oxidized to form oxo or sulfide radicals or other oxidative linkages (e.g., C(O), S(O), C(S), or S(O) 2. N-oxide, etc.), or the nitrogen atom can be quaternized. Heterocycloalkyl groups may be attached via ring carbon atoms or ring heteroatoms. In some embodiments, heterocycloalkyl groups contain 0 to 3 double bonds. In some embodiments, heterocycloalkyl groups contain 0 to 2 double bonds. Also included within the definition of heterocycloalkyl are moieties having one or more aromatic rings fused to (i.e., sharing a bond with) the heterocycloalkyl ring, such as piperidine, morpholine, azepine, or Benzo derivatives such as thienyl. Heterocycloalkyl groups containing fused aromatic rings may be linked via any ring-forming atom, including ring-forming atoms of fused aromatic rings. Examples of heterocycloalkyl include, but are not limited to, azetidinyl, azepanyl, dihydrobenzofuryl, dihydrofuryl, dihydropyranyl, N-morpholinyl, 3-oxa -9-azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxypiperazinyl, pyranyl, pyrrole Alkyl, quininyl, tetrahydrofuryl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolyl, scopolanoyl, 4,5,6,7-tetrahydrothiazolo[5,4 -c]pyridyl, 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolidinyl, butylidene Amide group, valerolactam group, imidazolinonyl group, hydantoin group, dioxolane group, phthalimide group, pyrimidine-2,4(1H,3H)-dione group, 1 ,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazinyl, pyranyl , Pyridonyl, 3-pyrrolinyl, thiopyranyl, pyrononyl, tetrahydrothienyl, 2-azaspiro[3.3]heptyl, indolinyl,

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

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

"Optional" or "optionally" means that the subsequently described event or condition may but need not occur, and that the description includes instances where the stated event or condition occurs and instances where the stated event or condition does not occur.

The substituent "-O-CH ₂ -O-" means that the two oxygen atoms in the substituent are connected to two adjacent carbon atoms of the heterocycloalkyl group, aryl group or heteroaryl group, 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 it is connected to are directly connected. For example, when L in X-L-Y represents a chemical bond, it means that the structure is actually X-Y.

The term "ring" includes any cyclic structure. The term "element" is intended to indicate the number of backbone atoms constituting the ring. For example, cyclohexyl, pyridyl, pyranyl, and thienyl are six-membered rings, and cyclopentyl, pyrrolyl, furyl, and thienyl are five-membered rings.

The term "fragment" refers to a specific part or functional group of a molecule. Chemical fragments are generally thought of as chemical entities contained in or attached to molecules.

Unless otherwise stated, use wedge-shaped solid line keys and wedge-shaped dotted keys To express the absolute configuration of a three-dimensional center, use the straight shape line key and straight dotted keys Represent the relative configuration of the three-dimensional center with a wavy line Represents wedge-shaped solid line key or wedge-shaped dotted key or use tilde Represents a straight solid line key or straight dotted key

Unless otherwise stated, use Represents a single or double bond.

Specific pharmaceutical and medical terms

The term "acceptable," as used herein, means that a formulation component or active ingredient does not have undue deleterious effects on the health of the general target of treatment.

The terms "treatment," "treatment," or "therapy" as used herein include alleviating, inhibiting, or ameliorating symptoms or conditions of a disease; inhibiting the development of complications; ameliorating or preventing underlying metabolic syndrome; inhibiting the development of a disease or symptoms, Such as controlling the development of a disease or condition; alleviating a disease or symptoms; making a disease or symptoms subside; alleviating complications caused by a disease or symptoms, or preventing or treating signs caused by a disease or symptoms.

As used herein, a compound or pharmaceutical composition, when administered, can ameliorate a disease, symptom or condition, especially its severity, delay its onset, slow down its progression, or reduce its duration. Circumstances that may be attributable to or related to administration, whether fixed or temporary, continuous or intermittent.

"Active ingredient" refers to the compounds of the present invention, as well as pharmaceutically acceptable inorganic or organic salts of the compounds of the present invention. The compounds of the present invention may contain one or more asymmetric centers and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers. The asymmetric centers that can exist 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 intended to include all such isomeric forms of these compounds.

The words "compound", "composition", "agent" or "medicine or medicament" are used interchangeably here, and all refer to a substance when administered to an individual (human or animal), a compound or composition that can induce a desired pharmaceutical and/or physiological response through local and/or systemic effects.

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

Notwithstanding that the numerical ranges and parameters defining the broader scope of the invention are approximations, the relevant numerical values in the specific embodiments are presented as precisely as possible. Any numerical value, however, inherently contains the standard deviation resulting from the individual testing methods used. 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 word "about" means that the actual value falls within an acceptable standard error of the mean, as would be considered by one skilled in the art. Except for experimental examples, or unless otherwise expressly stated, all ranges, quantities, numerical values and percentages used herein (such as to describe the amount of material, length of time, temperature, operating conditions, quantitative proportions and other similar ) are all modified by "about". Therefore, unless otherwise stated to the contrary, the numerical parameters disclosed in this specification and the appended claims are approximate values and may be changed as required. At a minimum, these numerical parameters should be understood to mean the number of significant digits indicated and the number resulting from ordinary rounding.

Unless otherwise defined in this specification, scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, unless there is conflict with the context, the singular noun used in this specification covers the plural form of the noun; and the plural noun used also covers the singular form of the noun.

therapeutic use

The compounds or pharmaceutical compositions of general formula (1), general formula (2), general formula (3) of the present invention can generally be used to inhibit HER2 protein, and therefore can be used to treat one or more conditions related to HER2 protein activity. Accordingly, in certain embodiments, the present invention provides methods for treating HER2 protein-mediated disorders, the methods comprising administering to a patient in need thereof the compounds of the present invention, Formula (1), Formula (2), Compounds of general formula (3), or pharmaceutically acceptable compositions thereof.

In some embodiments, methods for cancer treatment are provided, comprising administering to an individual in need thereof an effective amount of any of the foregoing compounds of formula (1), formula (2), formula (3). Pharmaceutical compositions. In some embodiments, the cancers include, but are not limited to, hematological malignancies (leukemias, lymphomas, myeloma including multiple myeloma, myelodysplastic syndromes and myelodysplastic syndromes) and solid tumors (cancers such as prostate , breast, lung, colon, pancreas, kidney, ovary, soft tissue cancer and osteosarcoma, and stromal tumor), etc.

Route of administration

The compounds of the present invention and their pharmaceutically acceptable salts can be prepared into various preparations, which contain the compounds of the present invention or their pharmaceutically acceptable salts within a safe and effective amount and pharmaceutically acceptable excipients or carriers. . The "safe and effective dose" refers to the amount of compound that is sufficient to significantly improve the condition without causing serious side effects. The safe and effective dosage of the compound is determined based on the age, condition, course of treatment and other specific conditions of the treatment subject.

"Pharmaceutically acceptable excipient or carrier" means: one or more compatible solid or liquid filler or gel substances that are suitable for human use and must be of sufficient purity and low enough toxicity . "Compatibility" here refers to the ability of the components of the composition to be blended with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable excipients or carriers include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants ( Such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

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

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed 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, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) Humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) retarder, 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 fatty acid, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills and granules may be prepared using coatings and shell materials such as enteric casings 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 waxy substances. If necessary, the active compounds can also be in microencapsulated form 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 employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, 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.

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

Suspensions may contain, in addition to the active compound, 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 contain 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 excipients include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms for topical administration of the compounds 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 that may be required.

The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds. When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, and the dosage when administered is a pharmaceutically effective dosage. For a person weighing 60 kg, the daily dose is The dosage is usually 1 to 2000 mg, preferably 50 to 100 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the skill of a skilled physician.

The above-mentioned features mentioned in the present invention or the features mentioned in the embodiments may be combined in any combination. All features disclosed in the specification of this case may be used in conjunction with any composition form. Each feature disclosed in the specification may be replaced by any alternative feature that serves the same, equivalent or similar purpose. Therefore, unless otherwise stated, the features disclosed 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 elaborated in detail, so that the content of the present invention will become clear. It should be understood that the following detailed description and examples describe specific embodiments and are for reference only. After reading the description of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent situations also fall within the scope defined by this application.

In all examples, ¹ H-NMR was recorded with a Vian Mercury 400 nuclear magnetic resonance instrument, and the chemical shift was expressed in δ (ppm); the silica gel used for separation was all 200-300 mesh (not specified), and the eluent ratios were all volume ratios.

The present invention adopts the following abbreviations: (Boc) ₂ O represents di-tert-butyl dicarbonate; CDCl ₃ represents deuterated chloroform; Cs ₂ CO ₃ represents cesium carbonate; EtOAc represents ethyl acetate; Hexane represents n-hexane; HPLC represents High performance liquid chromatography; MeCN represents acetonitrile; DCM represents dichloromethane; DIPEA represents diisopropylethylamine; Dioxane represents 1,4-dioxane; DME represents ethylene glycol dimethyl ether; DMF represents N, N -Dimethylformamide; DMAP represents 4-(dimethylamino)pyridine; DMSO represents dimethyl sulfoxide; EtOH represents ethanol; hr represents hours; IPA represents isopropyl alcohol; Represents Biotage Isolera Prime rapid preparation liquid chromatography; min represents minutes; K ₂ CO ₃ represents potassium carbonate; KOAc represents potassium acetate; KOH represents potassium hydroxide; K ₃ PO ₄ represents potassium phosphate; LiBH ₄ represents lithium borohydride; min represents minutes; MeOH represents methanol; MeONa represents sodium methoxide; MS represents mass spectrometry; NaBH(OAc) ₃ represents Sodium triacetoxyborohydride; NaH represents sodium hydrogen; NMR represents nuclear magnetic resonance; NIS represents iodosuccinimide; Pd/C represents palladium on carbon; Pd(PPh ₃ ) ₄ represents tetrakis triphenylphosphine palladium; Pd (OAc) ₂ represents palladium acetate; Pd(dppf)Cl ₂ represents [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride; PE represents petroleum ether; PPh ₃ represents triphenyl Phosphine; TEA represents triethylamine; TFA represents trifluoroacetic acid; TsOH represents p-toluenesulfonic acid; XantPhos represents 4,5-bisdiphenylphosphine-9,9-dimethylxanthene; TfOH represents trifluoromethyl Sulfonic acid; TLC stands for thin layer chromatography;

Example 1 Synthesis of Compound 1

Step 1: Synthesis of compound int_1-3:

Dissolve int_1-2 (2.00g, 13.5mmol), int_1-1 (3g, 19.4mmol) and K ₂ CO ₃ (5.1g, 37mmol) in DMF (30mL), replace with nitrogen three times, and heat the mixture to 80°C Stir for 16 hours. TLC monitoring showed that the reaction was completed. Water (300 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (300 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography to obtain a white solid (3 g, yield: 78.5%).

ESI-MS m/z:284[M+H] ⁺

Step 2: Synthesis of compound int_1-4:

Dissolve int_1-3 (1g, 3.5mmol) and 10% Pd/C (500mg) in ethanol (20mL), replace with hydrogen three times, and react at room temperature for 16 hours. LC-MS monitoring showed the reaction was complete. Pd/C was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain a white solid (760 mg, yield: 85%).

ESI-MS m/z:254[M+H] ⁺

Step 3: Synthesis of compound int_1-6:

Dissolve int_1-5 (1.00g, 4.2mmol) and int_1-4 (1.00g, 4.2mmol) in isopropanol (150mL), and heat the mixture to 50°C for 1 hour. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled and filtered, and the filter cake was washed with cold isopropanol. The filter cake was collected and dried under vacuum to obtain a crude product (1.4 g, crude product), which could be directly used in the next step of the reaction.

ESI-MS m/z:432[M+H] ⁺

Step 4: Synthesis of compound int_1-7:

Dissolve int_1-6 (1.96g, 4.55mmol) in dichloromethane (80mL), add m-chloroperoxybenzoic acid (1.5g, 6.8mmol, 77%) at 0°C, LC-MS monitoring shows that the reaction is completed . Saturated aqueous sodium bicarbonate solution (150 mL) was added to the reaction solution, the aqueous phase was extracted with dichloromethane (150 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain crude product (1.6g, crude product). The crude product can be used directly in the next reaction.

ESI-MS m/z:446[M+H] ⁺

Step 5: Synthesis of compound int_1-9:

Dissolve int_1-7 (285mg, 0.64mmol), DIPEA (145μL, 0.84mmol) and int_1-8 (152mg, 0.76mmol) in DMF (10mL). The reaction solution is raised to 70°C for 1 hour and monitored by LC-MS. , the reaction ends. After the reaction solution was cooled to room temperature, water (50 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (50 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a solid (200 mg, yield: 53.7%).

ESI-MS m/z:582[M+H] ⁺

Step 6: Synthesis of compound int_1-10:

Dissolve int_1-9 (4.6g, 7.9mmol) in dichloromethane (200mL) and methanol (50mL), cool the reaction solution to 0°C, and add HCl/dioxane solution (4N, 10mL) to the mixed solution , the reaction solution was raised to room temperature and reacted for 12 hours, and LC-MS monitored that the reaction was completed. The solvent was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a solid (3.5 g, yield: 92.1%).

ESI-MS m/z:482[M+H] ⁺

Step 7: Synthesis of Compound 1:

Dissolve int_1-10 (1g, 2.2mmol) and triethylamine (445mg, 4.4mmol) in dichloromethane (20mL), cool the mixture to 0°C, and slowly add int_1-11 (239mg) dropwise at 0°C ,2.2mmol), the reaction solution was reacted at 0°C for 2 hours, and the reaction was completed after LC-MS monitoring. Saturated sodium bicarbonate aqueous solution (150 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (150 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a solid (810 mg, yield: 66.5%).

ESI-MS m/z:554[M+H] ⁺

Example 2-145 Synthesis of Compound 2-145

Using the above synthesis method and using different raw materials, the target compound 2-145 in Table 1 can be obtained.

Table 1

Example 146 Synthesis of Compound 146

Step 1: Synthesis of compound int_146-3:

Dissolve int_146-2 (2.00g, 13.5mmol), int_146-1 (3g, 19.4mmol) and K ₂ CO ₃ (5.1g, 37mmol) in DMF (30mL), replace with nitrogen three times, and heat the mixture to 80°C Stir for 16 hours. TLC monitoring showed that the reaction was completed. Water (300 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (300 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography to obtain a white solid (3 g, yield: 78.5%).

ESI-MS m/z:284[M+H] ⁺

Step 2: Synthesis of compound int_146-4:

Dissolve int_146-3 (1g, 3.5mmol) and 10% Pd/C (500mg) in ethanol (20mL), replace with hydrogen three times, and react at room temperature for 16 hours. LC-MS monitoring showed the reaction was complete. Pd/C was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain a white solid (760 mg, yield: 85%).

ESI-MS m/z:254[M+H] ⁺

Step 3: Synthesis of compound int_146-6:

Dissolve int_146-5 (1.00g, 4.2mmol) and int_146-4 (1.00g, 4.2mmol) in isopropanol (150mL), and heat the mixture to 50°C for 1 hour. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled and filtered, and the filter cake was washed with cold isopropanol. The filter cake was collected and dried under vacuum to obtain a crude product (1.4 g, crude product), which could be directly used in the next step of the reaction.

ESI-MS m/z:432[M+H] ⁺

Step 4: Synthesis of compound int_146-7:

Dissolve int_146-6 (1.96g, 4.55mmol) in dichloromethane (80mL), add m-chloroperoxybenzoic acid (1.5g, 6.8mmol, 77%) at 0°C, LC-MS monitoring shows that the reaction is completed . Saturated aqueous sodium bicarbonate solution (150 mL) was added to the reaction solution, the aqueous phase was extracted with dichloromethane (150 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product (1.6 g, crude product), which could be directly used in the next reaction.

ESI-MS m/z:446[M+H] ⁺

Step 5: Synthesis of compound int_146-9:

Dissolve int_146-7 (285mg, 0.64mmol), DIPEA (145μL, 0.84mmol) and int_146-8 (147mg, 0.76mmol) in DMF (10mL). The reaction solution is raised to 70°C for 1 hour and monitored by LC-MS. , the reaction ends. After the reaction solution was cooled to room temperature, water (50 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (50 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a solid (120 mg, yield: 33%).

ESI-MS m/z:568[M+H] ⁺

Step 6: Synthesis of compound int_146-10:

Dissolve int_146-9 (4.5g, 7.9mmol) in dichloromethane (200mL) and methanol (50mL), cool the reaction solution to 0°C, and add HCl/dioxane solution (4N, 10mL) to the mixed solution , the reaction solution was raised to room temperature and reacted for 12 hours, and LC-MS monitored that the reaction was completed. The solvent was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a solid (3.2 g, yield: 86.7%).

ESI-MS m/z:468[M+H] ⁺

Step 7: Synthesis of Compound 146:

Dissolve int_146-10 (1g, 2.2mmol) and triethylamine (445mg, 4.4mmol) in dichloromethane (20mL), cool the mixture to 0°C, and slowly add int_146-11 (239mg) at 0°C ,2.2mmol), the reaction solution was reacted at 0°C for 2 hours, and monitored by LC-MS. Test, the reaction is over. Saturated sodium bicarbonate aqueous solution (150 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (150 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a solid (780 mg, yield: 65.7%).

ESI-MS m/z:540[M+H] ⁺

Example 147-229 Synthesis of Compounds 147-229

Using the above synthesis method and using different raw materials, the target compounds 147-229 in Table 2 can be obtained.

Table 2

Example 230 Synthesis of Compound 230

Step 1: Synthesis of compound int_230-3:

Dissolve int_230-2 (2.00g, 14.8mmol), int_230-1 (3g, 19.4mmol) and K ₂ CO ₃ (5.1g, 37mmol) in DMF (30mL), replace with nitrogen three times, and heat the mixture to 80°C. Stir for 16 hours. TLC monitoring showed that the reaction was completed. Water (300 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (300 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography to obtain a white solid (3 g, yield: 75%).

ESI-MS m/z:271[M+H] ⁺

Step 2: Synthesis of compound int_230-4:

Dissolve int_230-3 (0.9g, 3.3mmol) and 10% Pd/C (500mg) in ethanol (20mL), replace with hydrogen three times, and react at room temperature for 16 hours. LC-MS monitoring showed the reaction was complete. Pd/C was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a white solid (750 mg, yield: 95%).

ESI-MS m/z:241[M+H] ⁺

Step 3: Synthesis of compound int_230-6:

Dissolve int_230-5 (1.00g, 4.2mmol) and int_230-4 (1.00g, 4.2mmol) in isopropanol (150mL), and heat the mixture to 50°C for 1 hour. LC-MS monitoring showed the reaction was complete. The reaction solution was cooled and filtered, and the filter cake was washed with cold isopropanol. The filter cake was collected and dried under vacuum to obtain a crude product (1.3 g, crude product), which could be directly used in the next step of the reaction.

ESI-MS m/z:417[M+H] ⁺

Step 4: Synthesis of compound int_230-7:

Dissolve int_230-6 (1.9g, 4.55mmol) in dichloromethane (80mL), add m-chloroperoxybenzoic acid (1.5g, 6.8mmol, 77%) at 0°C, LC-MS monitoring shows that the reaction is completed . Saturated aqueous sodium bicarbonate solution (150 mL) was added to the reaction solution, the aqueous phase was extracted with dichloromethane (150 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product (1.5 g, crude product), which could be directly used in the next reaction.

ESI-MS m/z:433[M+H] ⁺

Step 5: Synthesis of compound int_230-9:

Dissolve int_230-7 (300mg, 0.64mmol), DIPEA (145μL, 0.84mmol) and int_230-8 (147mg, 0.76mmol) in DMF (10mL). The reaction solution is raised to 70°C for 1 hour and monitored by LC-MS. , the reaction ends. After the reaction solution was cooled to room temperature, water (50 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (50 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a solid (105 mg, yield: 29.5%).

ESI-MS m/z:555[M+H] ⁺

Step 6: Synthesis of compound int_230-10:

Dissolve int_230-9 (4.35g, 7.9mmol) in dichloromethane (200mL) and methanol (50mL), cool the reaction solution to 0°C, and add HCl/dioxane solution (4N, 10mL) to the mixed solution , the reaction solution was raised to room temperature and reacted for 12 hours, and LC-MS monitored that the reaction was completed. The solvent was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a solid (3 g, yield: 83.5%).

ESI-MS m/z:455[M+H] ⁺

Step 7: Synthesis of Compound 230:

Dissolve int_230-10 (1g, 2.2mmol) and triethylamine (445mg, 4.4mmol) in dichloromethane (20mL), cool the mixture to 0°C, and slowly add int_230-11 (239mg) dropwise at 0°C ,2.2mmol), the reaction solution was reacted at 0°C for 2 hours, and the reaction was completed after LC-MS monitoring. Saturated sodium bicarbonate aqueous solution (150 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (150 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a solid (850 mg, yield: 73.9%).

ESI-MS m/z:527[M+H] ⁺

Example 231-285 Synthesis of Compounds 231-285

Using the above synthesis method and using different raw materials, the target compounds 231-285 in Table 3 can be obtained.

table 3

Example 286 Anti-proliferative activity of compounds of the present invention on Ba/F3 (HER2 YVMA mutant) cells, Ba/F3 (HER2 WT) cells and Ba/F3 (EGFR WT) cells

3000 Ba/F3 cells carrying EGFR (WT), or 3000 Ba/F3 cells carrying HER2 (WT), or 3000 Ba/F3 cells carrying HER2 (YVMA mutant), were planted in a 384-well plate and grown One day later, serial dilutions of compound were added. Three days after adding the compound, Cell Titer Glow was added to evaluate cell growth, and the percentage of cell growth inhibited by the compound and the IC ₅₀ value were calculated. The results are shown in Table 4 below.

Table 4. Anti-proliferative activity of compounds of the present invention on Ba/F3 (HER2 YVMA mutant) cells, Ba/F3 (HER2 WT) cells and Ba/F3 (EGFR WT) cells

++++ means IC ₅₀ is less than or equal to 10nM

+++ indicates IC ₅₀ of 10nM to 50nM

++ indicates IC ₅₀ from 50nM to 100nM

+ means IC ₅₀ is greater than 500nM

It can be seen from the data in Table 4 that the anti-proliferative activity of most of the compounds of the present invention on Ba/F3 (HER2 WT) cells is less than 10 nM, and the anti-proliferative activity of Ba/F3 (HER2 YVMA mutant) mutant cells is less than 50 nM. For Ba/ The anti-proliferative activity of F3 (EGFR ^WT ) cells was greater than 500 nM. It shows that the compound of the present invention has better selectivity for WT EGFR.

Although specific embodiments 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 embodiments without departing from the principles and essence of the present invention. Revise. Accordingly, the scope of the present invention is defined by the appended claims.

Claims

A compound represented by general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

In general formula (1):

R 1 is -H, -CH 3 , -CCH, -OCH 3 or halogen;

R 2 is -H or halogen;

R 3 is

R 4 is R 4a or R 4b ;

R 4a is wherein Q is a (4-6-membered) heterocycloalkylene group containing one nitrogen atom, wherein any one carbon atom in the (4-6-membered) heterocycloalkylene group may optionally be replaced by 1 or 2 of the following Group substitution: -H or -CH 3 ;

R 4b is wherein Z is a (4-6-membered) heterocycloalkylene group containing one nitrogen atom, wherein any one carbon atom in the (4-6-membered) heterocycloalkylene group may optionally be replaced by 1 or 2 of the following Group substitution: -H or -CH 3 ;

R 5 is -H or -F;

R 6a and R 6b are each independently -H or (C1-C3) alkyl, wherein said (C1-C3) alkyl may be optionally substituted by 1 or 2 of the following groups: -N(R 8 ) 2 or (4-6 membered) heterocycloalkyl; and at least one of R 5 , R 6a and R 6b is not -H;

R 6c is -H or -CH 3 ;

R 7 is -H or -CH 3 ;

R 8 is each independently -H or (C1-C3)alkyl.
The compound of claim 1 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 1 is -H, - CH 3 , -CCH, -OCH 3 , -F or -Cl.
The compound of any one of claims 1-2 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 2 is -H, -F or -Cl.
The compound or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof according to any one of claims 1 to 3, wherein in the general formula (1), R 8 is each independently -H, -CH 3 or -CH 2 CH 3 .
The compound or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof according to any one of claims 1 to 4, wherein in the general formula (1), R 6a and R 6b are each independently -H or -CH 3 , wherein -CH 3 may be optionally substituted by one of the following groups: -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 )、
The compound or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof according to any one of claims 1 to 5, wherein in the general formula (1), R 4a is:
The compound or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof according to any one of claims 1 to 3, wherein in the general formula (1), R 4a is:
The compound or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof according to any one of claims 1 to 5, wherein in the general formula (1), R 4b is:
The compound or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof according to any one of claims 1 to 3, wherein in the general formula (1), R 4b is:
The compound or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof according to any one of claims 1 to 9, wherein in the general formula (1), wherein The compound has one of the following structures:
A compound represented by general formula (2) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

In general formula (2):

R 9 is -H, -CH 3 , -CCH, -OCH 3 or halogen;

R 10 is -H or halogen;

R 11 is -H or halogen; and at least one of R 9 , R 10 and R 11 is not -H;

R 12 is -H or -CH 3 ;

W is

R 13 is -H or -F;

R 14a and R 14b are each independently -H or (C1-C3) alkyl, wherein the (C1-C3) alkyl may be optionally substituted by 1 or 2 of the following groups: -N(R 15 ) 2 or (4-6 membered) heterocycloalkyl; and at least one of R 13 , R 14a and R 14b is not -H;

R 14c is -H or -CH 3 ;

R 15 is each independently -H or (C1-C3)alkyl.
The compound of claim 11 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (2), R 9 is -H, - CH 3 , -CCH, -OCH 3 , -F, -Cl or -Br.
The compound of any one of claims 11-12 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (2), R 10 is -H, -F, -Cl or -Br.
The compound or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof according to any one of claims 11 to 13, wherein in the general formula (2), R 11 is -H, -F or -Cl.
The compound of any one of claims 11-14 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (2), R 15 is each independently -H, -CH 3 or -CH 2 CH 3 .
The compound of any one of claims 11-15 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (2), R 14a and R 14b are each independently -H or -CH 3 , wherein -CH 3 may be optionally substituted by one of the following groups: -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 )、
The compound of any one of claims 11-16 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (2), the structure Unit W is:
The compound of any one of claims 11-14 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (2), the structure Unit W is:
The compound of any one of claims 11-18 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (2), wherein The compound has one of the following structures:
A compound represented by general formula (3) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

In general formula (3):

R 16 is -H, -CH 3 , -CCH, -OCH 3 or halogen;

R 17 is -H or halogen;

R 18 is -H or halogen; and at least one of R 16 , R 17 and R 18 is not -H;

E is

R 19 is -H or -F;

R 20a and R 20b are each independently -H or (C1-C3) alkyl, wherein the (C1-C3) alkyl can be optionally substituted by 1 or 2 of the following groups Generation: -N(R 22 ) 2 or (4-6 membered) heterocycloalkyl; and at least one of R 19 , R 20a and R 20b is not -H;

R 20c is -H or -CH 3 ;

R 21 is -H or -CH 3 ;

R 22 is each independently -H or (C1-C3)alkyl.
The compound of claim 20 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (3), R 16 is -H, - CH 3 , -CCH, -OCH 3 , -F, -Cl or -Br.
The compound of any one of claims 20-21 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (3), R 17 is -H, -F, -Cl or -Br.
The compound of any one of claims 20-22 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (3), R 18 is -H, -F or -Cl.
The compound of any one of claims 20-23 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (3), R 22 is each independently -H, -CH 3 or -CH 2 CH 3 .
The compound of any one of claims 20-24 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (3), R 20a and R 20b are each independently -H or -CH 3 , wherein -CH 3 may be optionally substituted by one of the following groups: -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 )、
The compound of any one of claims 20-25 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (3), the structure Unit E is:
The compound of any one of claims 20-23 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (3), the structure Unit E is:
The compound of any one of claims 20-27 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (3), wherein The compound has one of the following structures:
A pharmaceutical composition, characterized in that it contains pharmaceutically acceptable excipients or carriers, and the compound according to any one of claims 1 to 28, or each isomer or crystal form thereof, Pharmaceutically acceptable salts, hydrates or solvates as active ingredients.
A compound as claimed in any one of claims 1 to 28, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates or a medicament as claimed in claim 29 Use of the composition in the preparation of a medicament for the treatment or prevention of HER2-mediated related diseases.
The use of claim 30, wherein the disease is cancer, and the cancer is hematological cancer and solid tumor.