CN106699810A - Nitrogen-containing heterogeneous ring compound, preparation method thereof and application of nitrogen-containing heterogeneous ring compound in inhibition of kinase activity - Google Patents

Abstract

The invention discloses a nitrogen-containing heterocyclic compound, its preparation method and its application in inhibiting kinase activity. The general formula of the nitrogen-containing heterocyclic compound is shown in formula I or formula I': in formula I or formula I', R ₁ , R ₂ , R ₃ , and R ₄ are independently selected from hydrogen, halogen, cyano, hydroxyl Any one of , amino and substituted or unsubstituted C1-C6 alkyl, and any two groups in R ₁ , R ₂ , R ₃ , R ₄ can form a 3-10-membered ring system; M ₁ , M ₂ , M ₃ are independently selected from CRa or N, and at least one of M ₁ , M ₂ and M ₃ is N; W is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2 -C6 alkenyl, unsubstituted or halogenated 4-8-membered alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 4-8-membered heterocyclic group, 5-10-membered Aryl or heteroaryl, substituted carbonyl, substituted sulfonyl, substituted or unsubstituted amino. The heterocyclic compound can inhibit EGFR mutant kinase activity or ALK kinase activity, and is a multi-target tumor treatment drug with a new action mechanism.

Description

A nitrogen-containing heterocyclic compound, its preparation method and its role in inhibiting kinase activity application

technical field

The invention relates to a nitrogen-containing heterocyclic compound, a preparation method thereof and an application in inhibiting kinase activity, belonging to the technical field of medicinal chemistry.

Background technique

Molecular targeted therapy of tumors is based on the key proteins closely related to the occurrence and development of tumors, and selectively acts on signaling proteins by chemical means to kill tumor cells. The characteristics of targeted therapy are: high specificity, strong selectivity, and lower toxicity and side effects compared with traditional chemotherapy drugs; when used in combination, it can enhance the efficacy of traditional chemotherapy; targeted inhibitors are prone to drug resistance in clinical practice and make the therapeutic drugs invalidated.

Lung cancer is the malignant tumor with the highest morbidity and mortality in the world, and the 5-year survival rate is only 16.8%. In 2010, the morbidity and mortality of lung cancer ranked first among all malignant tumors in my country. Non-small cell lung cancer (NSCLC) accounts for about 85% of all pathological types of lung cancer. The etiology of non-small cell lung cancer is complex, multi-gene, multi-target regulation, and easy to mutate to produce drug resistance. Drugs for the treatment of non-small cell lung cancer mainly include traditional chemotherapy drugs platinum, paclitaxel, antibodies, neovascularization inhibitors and targeted inhibitors. And finding anti-drug-resistant non-small cell lung cancer drugs is still a hot field in the industry.

In recent years, the US FAD has successively approved multiple ALK inhibitors, such as crizotinib, ceritinib, etc., as well as the third-generation EGFR inhibitors currently in the late clinical stage, such as AZD9219, CO1686, etc., but currently There are still problems such as poor curative effect or low selectivity of similar drugs, so it is urgent to discover and find a class of new therapeutic drugs with high mutation resistance selectivity or multi-target inhibitory activity.

Contents of the invention

The object of the present invention is to provide a nitrogen-containing heterocyclic compound and its preparation method and its application in inhibiting kinase activity. The nitrogen-containing heterocyclic compound can be used as a proliferation inhibitor of various tumor cells, and it is a new type of drug with a new mechanism of action. Multi-target tumor therapy drugs.

The nitrogen-containing heterocyclic compound provided by the present invention, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, polymorph or its prodrug, wherein , the general formula of nitrogen-containing heterocyclic compounds is shown in formula I or formula I':

In formula I or formula I':

R ₁ , R ₂ , R ₃ , R ₄ are independently selected from any one of hydrogen, halogen, cyano, hydroxyl, amino and substituted or unsubstituted C1-C6 alkyl, and R ₁ , R ₂ , R _3. Any two groups in R ₄ can form a 3-10 membered ring system;

M ₁ , M ₂ , M ₃ are independently selected from CRa or N, and at least one of M ₁ , M ₂ and M ₃ is N; Ra is hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkane One of a group and a substituted or unsubstituted C3-C8 cycloalkyl group;

W is selected from any one of the following groups: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, unsubstituted or halogenated 4-8 membered alkynyl, Substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 4-8 membered heterocyclyl, 5-10 membered aryl or heteroaryl, substituted carbonyl, substituted sulfonyl, substituted or unsubstituted amino , wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, S, P and B;

The substitution is that one or more groups in the group are substituted by at least one substituent selected from the following group: halogen, hydroxyl, amino, cyano, unsubstituted or halogenated C1-C8 alkyl, unsubstituted Substituted or halogenated C3-C8 cycloalkyl, unsubstituted or halogenated C1-C8 alkoxy, unsubstituted or halogenated C2-C6 alkenyl, unsubstituted or halogenated C2-C6 alkynyl, unsubstituted Substituted or halogenated C2-C6 acyl, unsubstituted or halogenated 5-8 membered aryl, unsubstituted or halogenated 5-8 membered heteroaryl, unsubstituted or halogenated 4-8 membered saturated heterocycle , an unsubstituted or halogenated 4-8 membered carbocyclic ring; wherein, the heteroaryl group contains 1-3 heteroatoms selected from N, O and S, and the heterocycle contains 1-3 heteroatoms selected from N , heteroatoms of O and S;

In formula I', L is selected from any one of the following groups: -CR'R"-, -O-, -NR'-, and -CR'=, wherein R' and R" are each independently hydrogen , fluorine, deuterium, C1-C6 alkyl and C1-C6 heterocycloalkyl, or wherein adjacent R' and R" form a cyclic group.

The compound represented by the above formula I or its enantiomers, diastereomers, tautomers, solvates, polymorphs, prodrugs or pharmaceutically acceptable salts; or

In the compound represented by formula I' or its enantiomers, diastereomers, tautomers, solvates, polymorphs, prodrugs or pharmaceutically acceptable salts: R ₁ , R ₂ , R ₃ and R ₄ can specifically be hydrogen.

The compound represented by the above formula I or its enantiomers, diastereomers, tautomers, solvates, polymorphs, prodrugs or pharmaceutically acceptable salts; or

Among the compounds represented by formula I' or their enantiomers, diastereomers, tautomers, solvates, polymorphs, prodrugs or pharmaceutically acceptable salts: represented by formula I The compound or the compound represented by formula I' satisfies the following 1) and/or 2):

1) In formula I or formula I', M ₁ and M ₂ are independently selected from CH or N, and at least one of M ₁ and M ₂ is N; M ₃ is selected from CF, C-CF ₃ , C-Cl Any one of , CH and N;

2) In formula I or formula I', W is selected from any of the following groups: substituted or unsubstituted C1-C6 alkyl or cycloalkyl, substituted or unsubstituted 4-10 membered heterocycle, A spiro ring or a bridged ring formed by a substituted or unsubstituted 4-10 membered cycloalkyl group and a substituted or unsubstituted 4-10 membered heterocycloalkyl group; W is specifically any of the following substituted or unsubstituted groups Species: cyclopentane, cyclohexane, tetrahydropyrrole ring, tetrahydrofuran ring, piperidine ring, tetrahydropiperidine ring, piperazine ring, morpholine ring, pyrazole ring, indazole ring, benzene ring or pyridine ring;

The substitution means that the substituent is independently selected from at least one of the following groups: halogen, hydroxyl, cyano, amino, alkyl, monoalkylamino, dialkylamino), cycloalkyl, heterocyclyl , alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, aminoalkyl, dialkylaminoalkyl, alkoxycarbonylaminoalkyl, cycloalkylalkyl, heterocyclyl Alkyl, aralkyl, alkylcycloalkyl, cycloalkylcarbonyl, alkoxycarbonyl, alkoxycarbonylheterocyclyl, (alkoxycarbonyl)(alkyl)amino, (alkoxyalkyl)( Alkyl)amino.

The compound represented by the above formula I or its enantiomers, diastereomers, tautomers, solvates, polymorphs, prodrugs or pharmaceutically acceptable salts; or

In the compound represented by formula I' or its enantiomers, diastereoisomers, tautomers, solvates, polymorphs, prodrugs or pharmaceutically acceptable salts:

The compound shown in formula I can specifically be any one of the compounds shown in the following formula I-a to the compound shown in formula I-w:

The compound shown in formula I' can specifically be any one of the following formula I'-a to formula I'-c:

The present invention further provides a method for preparing the compound represented by formula I or its enantiomers, diastereoisomers, tautomers, solvates, polymorphs, prodrugs or pharmaceutically acceptable salt; or

The method for the compound represented by formula I' or its enantiomers, diastereomers, tautomers, solvates, polymorphs, prodrugs or pharmaceutically acceptable salts, comprising the following steps :

(1) Coupling the compound shown in formula IV with the compound shown in formula V in the presence of a transition metal catalyst and/or acid/base (acid/base means acid or base) to obtain the compound shown in formula III;

In formula IV, X and LG are each independently a leaving group, and are selected from any one of halogen, sulfonate, boronic acid and boronic acid ester;

In formula III, the definition of X is the same as that of _formula IV; the definition _of M1, _M2 and M3 is the same as that of formula I or formula I';

(2) The compound shown in formula III is coupled with the compound shown in formula II or the compound shown in formula II' in the presence of transition metal catalyst and/or acid/base (acid/base means acid or base) to obtain the formula The compound shown in I or the compound shown in formula I';

In formula II, the definitions of R1, R2, R3, R4, L and W are the same as in formula I; in formula _II ', the definitions _of R1, R2, _R3 , R4, L and W are the same as in _formula I'.

In the above-mentioned preparation method, in step (1) or step (2),

The coupling reaction is carried out in a solvent, and the solvent is selected from water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, dichloromethane, At least one of 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide and dioxane;

The transition metal catalyst is selected from three (dibenzylideneacetone) dipalladium, tetrakis (triphenylphosphine) palladium, palladium acetate, palladium chloride, dichlorobis (triphenylphosphine) palladium, trifluoroacetate palladium, Triphenylphosphine palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, bis(tri-orthophenylmethylphosphine)palladium dichloride and 1,2-bis( At least one of diphenylphosphino) ethane palladium dichloride; the catalyst ligand is selected from tri-tert-butylphosphine, tri-tert-butylphosphine tetrafluoroborate, tri-n-butylphosphine, triphenylphosphine , at least one of tri-p-benzylphosphine, tricyclohexylphosphine and tri-o-benzylphosphine;

The base is an inorganic base or an organic base; the inorganic base is selected from sodium hydride, potassium hydroxide, sodium acetate, potassium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, At least one of potassium carbonate, potassium bicarbonate, sodium carbonate and sodium bicarbonate; the organic base is selected from pyridine, triethylamine, N,N-diisopropylethylamine, 1,8-diazabis At least one of cyclo[5.4.0]undec-7-ene, lithium hexamethyldisilazyl, sodium hexamethyldisilazyl and lutidine;

The acid is at least one selected from hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, formic acid and acetic acid.

The present invention also provides the compound represented by formula I or its enantiomer, diastereoisomer, tautomer, solvate, polymorph, prodrug or pharmaceutically acceptable salt; or

The compound represented by formula I' or its enantiomer, diastereoisomer, tautomer, solvate, polymorph, prodrug or pharmaceutically acceptable salt has the ability to inhibit EGFR in the preparation Use of mutants as inhibitors of kinase activity and/or function of ALK kinase activity.

The present invention further provides a kinase inhibitor, which comprises a compound represented by formula I or its enantiomers, diastereomers, tautomers, solvates, polymorphs, prodrugs or a pharmaceutically acceptable salt; or

The compound represented by formula I' or its enantiomers, diastereoisomers, tautomers, solvates, polymorphs, prodrugs or pharmaceutically acceptable salts.

The present invention also provides the compound represented by formula I or its enantiomer, diastereoisomer, tautomer, solvate, polymorph, prodrug or pharmaceutically acceptable salt; or

Compounds represented by formula I' or their enantiomers, diastereomers, tautomers, solvates, polymorphs, prodrugs or pharmaceutically acceptable salts are used in the preparation of preventive and/or Or the application in the treatment of tumor products.

In the above application, the tumor can be non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal mesenchymal tumor, leukemia, lymphoma, and nasopharyngeal carcinoma.

The present invention further provides a pharmaceutical composition, which comprises:

1) an effective amount of the compound represented by formula I or its enantiomers, diastereomers, tautomers, solvates, polymorphs, prodrugs or pharmaceutically acceptable salts; or

Compounds represented by formula I' or their enantiomers, diastereoisomers, tautomers, solvates, polymorphs, prodrugs or pharmaceutically acceptable salts;

2) A pharmaceutically acceptable carrier.

The present invention has following beneficial effects:

The compound with the general structural formula shown in formula I or the general structural formula shown in formula I' provided by the present invention can inhibit a variety of tumor cells, especially can selectively act on EGFR T790M mutation and ALK positive lung cancer cells. A multi-target lung cancer drug with a new mechanism of action.

Terms in this invention:

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited in their entirety herein are hereby incorporated by reference in their entirety unless otherwise indicated.

It is to be understood that both the foregoing brief description and the following detailed description are exemplary and explanatory only and are not restrictive of the inventive subject matter. Furthermore, the use of the term "comprises" as well as other forms, such as "comprises", "comprises" and "comprises" is not limiting.

Definitions of standard chemical terms can be found in references, including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4 THED." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectroscopy, NMR, IR and UV/VIS spectroscopy and pharmacological methods are employed. Unless specific definitions are set forth, terms employed herein in the relevant descriptions of analytical chemistry, synthetic organic chemistry, and pharmaceutical and medicinal chemistry are those that are known in the art. Standard techniques can be used in chemical syntheses, chemical analyses, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, reactions and purifications can be carried out using the manufacturer's instructions for the kit, or by methods known in the art or as described herein. The techniques and methods described above can generally be performed according to conventional methods well known in the art as described in various general and more specific documents that are cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable moieties and compounds.

When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH ₂ O- is equivalent to -OCH ₂ -.

The section headings used herein are for the purpose of organizing the article only and should not be construed as limitations on the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and treatises, are hereby incorporated by reference in their entirety.

Certain chemical groups defined herein are preceded by abbreviated symbols to indicate the total number of carbon atoms present in the group. For example, C1-6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms. The total number of carbon atoms in the abbreviated notation does not include carbons that may be present in substituents of the stated group.

In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings shown below unless otherwise specified.

In this application, the term "halogen" means fluorine, chlorine, bromine or iodine.

"Hydroxy" means an -OH group.

"Hydroxyalkyl" means an alkyl group as defined below substituted with a hydroxyl group (-OH).

"Carbonyl" means a -C(=O)- group.

"Nitro" means _-NO2 .

"Cyano" means -CN.

"Amino" refers to _-NH2 .

"Substituted amino" means an amino group substituted by one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, e.g., monoalkylamino, dialkylamino, alkyl Acylamino, aralkylamino, heteroaralkylamino, (alkoxycarbonyl)(alkyl)amino, (alkoxyalkyl)(alkyl)amino.

"Carboxy" means -COOH.

In this application, the term "alkyl", as a group or part of another group (for example, in a group such as a halogen-substituted alkyl group), means a group consisting only of carbon and hydrogen atoms, free of unsaturation Bond, straight or branched hydrocarbon chain group having eg 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms and connected to the rest of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2- ,2-Dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl and decyl, etc.

In this application, the term "alkenyl" (i.e. "alkenyl"), as a group or part of another group, means consisting only of carbon and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and connected to the rest of the molecule by a single bond, straight or branched hydrocarbon chain group, such as but not limited to vinyl, propylene group, allyl, but-1-enyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl, etc.

In this application, the term "alkynyl" (ie "alkynyl"), as a group or part of another group, means consisting only of carbon and hydrogen atoms, containing at least one triple bond and optionally one or multiple double bonds, straight or branched hydrocarbon chains having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and connected to the rest of the molecule by single bonds Groups such as, but not limited to, ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl, and the like.

In this application, the term "cycloalkyl", as a group or part of another group, means a stable non-aromatic monocyclic or polycyclic hydrocarbon group composed only of carbon and hydrogen atoms, which may include fused Ring system, bridged ring system or spiro ring system, having 3 to 15 carbon atoms, preferably having 3 to 10 carbon atoms, more preferably having 3 to 8 carbon atoms, and it is saturated or unsaturated and can be obtained via any suitable The carbon atoms are connected to the rest of the molecule by single bonds. Unless specifically stated otherwise in this specification, carbon atoms in a cycloalkyl group may be optionally oxidized. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H- Indenyl, 2,3-indenyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzene Cyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl , fluorenyl, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2] Octyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl, adamantyl, octa Hydrogen-4,7-methylene-1H-indenyl and octahydro-2,5-methylene-pentalenyl, etc.

In this application, the term "heterocyclyl", as a group or part of another group, means a group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur Stable 3- to 20-membered non-aromatic cyclic groups. Unless otherwise specified in this specification, the heterocyclic group may be a monocyclic, bicyclic, tricyclic or multicyclic ring system, which may include a fused ring system, a bridged ring system or a spiro ring system; The nitrogen, carbon, or sulfur atoms of can be optionally oxidized; the nitrogen atoms can be optionally quaternized; and the heterocyclyl can be partially or fully saturated. A heterocyclyl group can be attached to the rest of the molecule via a carbon atom or a heteroatom and by a single bond. In heterocyclyl groups comprising fused rings, one or more rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom. For the purposes of the present invention, heterocyclyl is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur group, more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclic groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, tetrahydropiperidinyl, thiomorpholinyl, 2,7-diazepine -Spiro[3.5]nonan-7-yl, 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptane- 2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxolyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl base, imidazolidinyl, imidazolidinyl, quinozinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, dihydroindolyl, octahydroindolyl, octahydroisoindolyl, pyrrolidine base, pyrazolidinyl group, phthalimido group, etc.

In this application, the term "aryl" (i.e. "aryl") as a group or part of another group means a conjugated group having 6 to 18 carbon atoms (preferably 6 to 10 carbon atoms) Hydrocarbon ring system group. For the purposes of the present invention, aryl can be a monocyclic, bicyclic, tricyclic or multicyclic ring system and can also be fused to a cycloalkyl or heterocyclyl as defined above, provided that the aryl is via The atoms on the aromatic ring are connected to the rest of the molecule by single bonds. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-Benzoxazin-3(4H)-on-7-yl and the like.

In the present application, the term "arylalkyl" refers to an alkyl group as defined above substituted with an aryl group as defined above.

In this application, the term "heteroaryl", as a group or part of another group, means having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 carbon atoms selected from the group consisting of nitrogen A 5- to 16-membered conjugated ring system group of heteroatoms of oxygen and sulfur. Unless specifically stated otherwise in this specification, heteroaryl may be a monocyclic, bicyclic, tricyclic or multicyclic ring system, and may be fused to a cycloalkyl or heterocyclyl as defined above, provided that hetero An aryl group is connected to the rest of the molecule by a single bond through an atom on the aromatic ring. A nitrogen, carbon or sulfur atom in a heteroaryl can be optionally oxidized; the nitrogen atom can be optionally quaternized. For the purposes of the present invention, heteroaryl is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably 1 to 4 heteroatoms selected from A stable 5- to 10-membered aromatic group of heteroatoms selected from nitrogen, oxygen and sulfur or a 5- to 10-membered aromatic group comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benzopyrazolyl, indolyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolyl, isoindolyl, indazolyl, isoindazolyl , Purinyl, quinolinyl, isoquinolinyl, diazinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridine Base, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxatriazolyl, cinnolinyl, quinazolinyl, phenylthio, indolizyl, o-phenanthrenyl, Isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthopyridyl, [1,2,4]triazolo[4 ,3-b]pyridazine, [1,2,4]triazolo[4,3-a]pyrazine, [1,2,4]triazolo[4,3-c]pyrimidine, [1, 2,4]triazolo[4,3-a]pyridine, imidazo[1,2-a]pyridine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyrazine Wait.

In the present application, the term "heteroarylalkyl" refers to an alkyl group as defined above substituted by a heteroaryl group as defined above.

In the present application, the term "heterocycloalkyl" refers to an alkyl group as defined above substituted by a heterocyclyl group as defined above.

In this application, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both the occurrence and non-occurrence of the event or circumstance. For example, "optionally substituted aryl" means that the aryl is substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl.

As used herein, the terms "moiety", "structural moiety", "chemical moiety", "group", "chemical group" refer to a specific segment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities embedded or attached to molecules.

"Stereoisomer" refers to compounds composed of the same atoms, bonded by the same bonds, but having different three-dimensional structures. The present invention will encompass each stereoisomer and mixtures thereof.

When olefinic double bonds are contained in the compounds of the present invention, unless otherwise stated, the compounds of the present invention are intended to include both E- and Z-geometric isomers.

"Tautomer" refers to isomers formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention are also intended to be within the scope of the invention.

The compounds of the present invention, or pharmaceutically acceptable salts thereof, may contain one or more chiral carbon atoms, and thus may give rise to enantiomers, diastereoisomers and other stereoisomeric forms. Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry. The present invention is intended to include all possible isomers, as well as their racemates and optically pure forms. The preparation of the compounds of the present invention can select racemates, diastereomers or enantiomers as starting materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

Conventional techniques for the preparation/isolation of individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high performance liquid chromatography. ), see, for example, Gerald Gübitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol.243, 2004; A.M. Stalcup, Chiral Separations, Annu.Rev.Anal.Chem.3: 341-63, 2010; Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIA OFPRACTICAL ORGANIC CHEMISTRY 5. sup. TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc. Chem. Res. 1990, 23, 128.

In this application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

"Pharmaceutically acceptable acid addition salt" refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects. Inorganic acid salts include but not limited to hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.; organic acid salts include but not limited to formate, acetate, 2,2-dichloroacetate , Trifluoroacetate, Propionate, Caproate, Caprylate, Caprate, Undecylenate, Glycolate, Gluconate, Lactate, Sebacate, Hexanoate glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, mesylate, benzenesulfonate, p-toluenesulfonate , alginate, ascorbate, salicylate, 4-amino salicylate, naphthalene disulfonate, etc. These salts can be prepared by methods known in the art.

"Pharmaceutically acceptable base addition salt" refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, those of primary, secondary, and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins , such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclic Hexylamine, Lysine, Arginine, Histidine, Caffeine, Procaine, Choline, Betaine, Ethylenediamine, Glucosamine, Methylglucamine, Theobromine, Purine, Piperazine, Piperazine Pyridine, N-ethylpiperidine, polyamine resin, etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the art.

"Polymorph" refers to the different solid crystalline phases of certain compounds of the present invention due to the existence of two or more different molecular arrangements in the solid state. Certain compounds of the present invention may exist in more than one crystalline form, and the present invention is intended to include each crystalline form and mixtures thereof.

Often, crystallization will result in solvates of the compounds of the invention. The term "solvate" as used in the present invention refers to an aggregate comprising one or more molecules of a compound of the present invention and one or more solvent molecules. The solvent may be water, in which case the solvate is a hydrate. Alternatively, the solvent may be an organic solvent. Accordingly, the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvated forms. The compounds of the invention may form true solvates, but in some cases may also retain adventitious water only or a mixture of water plus a portion of the adventitious solvent. The compounds of the present invention can be reacted in solvents or precipitated or crystallized from solvents. Solvates of the compounds of the present invention are also included within the scope of the present invention.

The present invention also includes prodrugs of the above compounds. In the present application, the term "prodrug" means a compound that can be converted to a biologically active compound of the invention under physiological conditions or by solvolysis. Accordingly, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the present invention. Prodrugs may be inactive when administered to an individual in need thereof, but are converted in vivo to the active compound of the invention. Prodrugs are generally transformed rapidly in vivo to yield the parent compound of the invention, for example, by hydrolysis in blood. Prodrug compounds typically provide solubility, tissue compatibility or sustained release advantages in mammalian organisms. Prodrugs include known amino protecting groups and carboxyl protecting groups. For specific prodrug preparation methods, please refer to Saulnier, M.G., et al., Bioorg.Med.Chem.Lett.1994, 4, 1985-1990; Greenwald, R.B., et al., J.Med.Chem.2000, 43, 475.

In this application, a "pharmaceutical composition" refers to a formulation of a compound of the present invention with a vehicle generally accepted in the art for the delivery of a biologically active compound to a mammal (eg, a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote the administration of the organism, facilitate the absorption of the active ingredient and thus exert its biological activity.

The term "pharmaceutically acceptable" as used herein refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively nontoxic, i.e., the substance can be administered to an individual without causing adverse biological effects. React or interact in an undesirable manner with any component contained in the composition.

In this application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener approved by the relevant government regulatory agency as acceptable for human or livestock use , diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent or emulsifying agent.

The "tumor" and "diseases related to abnormal cell proliferation" in the present invention include but are not limited to leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, Lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, cervical cancer, ovarian cancer, bowel cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer, etc. disease.

As used herein, the terms "prophylactic", "prevention" and "prevention" include reducing the likelihood of a disease or condition occurring or worsening in a patient.

As used herein, the term "treatment" and other similar synonyms include the following meanings:

(i) preventing the occurrence of a disease or condition in a mammal, especially when such mammal is susceptible to the disease or condition but has not been diagnosed as having the disease or condition;

(ii) inhibiting a disease or condition, i.e. arresting its development;

(iii) ameliorating a disease or condition, i.e., causing regression of the state of the disease or condition; or

(iv) Alleviating the symptoms caused by the disease or condition.

The term "effective amount", "therapeutically effective amount" or "pharmaceutically effective amount" as used herein refers to at least one agent or compound which, when administered, is sufficient to relieve to some extent one or more symptoms of the disease or condition being treated amount. The result may be a reduction and/or alleviation of a sign, symptom or cause, or any other desired change in a biological system. For example, a therapeutically "effective amount" is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant disease-modifying effect. Effective amounts suitable for any individual case can be determined using techniques such as dose escalation assays.

As used herein, the terms "administering", "administering", "administering" and the like refer to methods capable of delivering a compound or composition to the desired site of biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration and rectal administration. Administration techniques useful for the compounds and methods described herein are well known to those skilled in the art, as described, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton , those discussed in Pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

As used herein, the terms "pharmaceutical combination", "drug combination", "combination", "administration of other treatments", "administration of other therapeutic agents" and the like refer to drug treatments obtained by mixing or combining more than one active ingredient, It includes fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration to a patient of at least one compound described herein and at least one co-agent in the form of a single entity or single dosage form. The term "variable combination" refers to simultaneous, concomitant or sequential administration at variable intervals of at least one compound described herein and at least one synergistic agent as separate entities to a patient. These also apply to cocktail therapy, eg the administration of three or more active ingredients.

Those skilled in the art will also understand that in the methods described below, the functional groups of intermediate compounds may need to be protected by appropriate protecting groups. Such functional groups include hydroxyl, amino, mercapto and carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (eg tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, etc. Suitable protecting groups for amino, amidino and guanidino include tert-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable protecting groups for mercapto include -C(O)-R" (where R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like. Suitable carboxy protecting groups include alkyl, aryl or aralkyl esters.

Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, T.W. and P.G.M. Wuts, Protective Groups in OrganiSynthesis, (1999), 4th Ed., Wiley. The protecting group can also be a polymeric resin.

Description of drawings

Fig. 1 is the route diagram of compound shown in synthetic formula II or compound shown in formula II'.

Fig. 2 is a route diagram for synthesizing the compound shown in formula III.

Fig. 3 is the route diagram of compound shown in synthetic formula I or compound shown in formula I '.

detailed description

The experimental methods used in the following examples are conventional methods unless otherwise specified.

The materials and reagents used in the following examples can be obtained from commercial sources unless otherwise specified.

The intermediates in the following examples are prepared according to the following steps, wherein, the compound shown in formula II or the compound shown in formula II' is synthesized according to the route diagram in Figure 1; the compound shown in formula III is synthesized according to the route diagram in Figure 2; The compound shown in formula I or the compound shown in formula I' is synthesized according to the route diagram in Fig. 3 .

Intermediate 1:

The compound 4-bromo-2,3-dihydrobenzofuran-7-amine (2.05g, 9.58mmol) was dissolved in 1,2-dichloroethane (20mL), after stirring evenly, slowly drop into (~ 30min) into 1,2-dichloroethane (60mL) of mCPBA (7.80g, 38.2mmol) heated to reflux in advance, and continued to reflux for 2h, and the raw material disappeared. Evaporate the solvent, add EA (50mL), wash with saturated Na ₂ S ₂ O ₃ (aq) (30mL×3), 0.5M NaOH(aq) (30mL×3), column chromatography (P/E=5: 1) 1.60 g of light yellow solid was isolated with a yield of 68%. The structure verification data are as follows: ¹ H NMR(CDCl ₃ )δ(ppm): 7.84(d, J=8.8Hz, 1H), 7.11(d, J=8.8Hz, 1H), 4.92(t, J=8.8Hz, 2H),3.35(t,J＝8.8Hz,2H).

Intermediate 2:

The compound 4-bromo 7-nitro-2,3-dihydrobenzofuran (500mg, 2.05mmol) was dissolved in toluene (30mL), and Pd(OAc) ₂ (50mg, 0.21mmol), DavePhos (161mg , 0.41mmol) and K ₃ PO ₄ (1.31g, 6.15mmol, 6mL H ₂ O), after stirring evenly, add 4-dimethylaminopiperidine (789mg, 6.15mmol), under the protection of argon, reflux reaction for 20h, Raw material disappears. Cool to room temperature, evaporate the solvent, dissolve the residue in EA (30mL), wash with saturated brine (20mL×3), wash with water (20mL×2), separate and purify by column chromatography (D/M=20:1) to obtain 500mg of a yellow solid , and the yield was 84%. The structure verification data are as follows: ¹ H NMR(CDCl ₃ )δ(ppm): 7.92(d, J=8.8Hz, 1H), 6.42(d, J=8.8Hz, 1H), 4.81(t, J=8.4Hz, 2H), 3.71(d, J=12.0Hz, 2H), 3.20(t, J=8.4Hz, 2H), 3.04(m, 1H), 2.90(t, J=11.6Hz, 2H), 2.71(s, 6H), 2.25(d, J＝10.4Hz, 2H), 1.88-1.86(m, 2H).

Intermediate 3:

Using the same synthetic method as intermediate 2, replacing 4-dimethylaminopiperidine with N,N-dimethylpyrrole, 130 mg of intermediate 3 was prepared as a yellow solid with a yield of 76%. The structure verification data are as follows: ¹ H NMR (CDCl ₃ )δ (ppm): 7.87 (d, J = 9.2Hz, 1H), 6.09 (d, J = 9.6Hz, 1H), 4.77-4.67 (m, 2H), 3.77-3.40(m,6H),2.81-2.77(m,1H),2.31(s,6H),2.23-2.17(m,1H),1.92-1.87(m,1H).

Intermediate 4:

Using the same synthetic method as Intermediate 2, replacing 4-dimethylaminopiperidine with N-Boc piperazine, 163 mg of Intermediate 4 was prepared as a yellow solid with a yield of 76%. The structure verification data are as follows: ¹ H NMR(CDCl ₃ )δ(ppm): 7.93(d, J=9.2Hz, 1H), 6.42(d, J=9.2Hz, 1H), 4.81(t, J=8.4Hz, 2H), 3.57(t, J=4.8Hz, 4H), 3.24-3.17(m, 6H), 1.49(s, 6H).

Intermediate 5:

Using the same synthesis method as Intermediate 2, replacing 4-dimethylaminopiperidine with N-methylpiperazine, 84 mg of Intermediate 5 was prepared as a yellow solid with a yield of 52%. The structure verification data are as follows: ¹ H NMR(CDCl ₃ )δ(ppm): 7.92(d, J=9.2Hz, 1H), 6.43(d, J=9.2Hz, 1H), 4.80(t, J=8.8Hz, 2H), 3.27(t, J=4.8Hz, 4H), 3.21(t, J=8.8Hz, 2H), 2.55(t, J=4.8Hz, 4H), 2.36(s, 3H).

Intermediate 6:

Using the same synthetic method as Intermediate 2, 1-methyl-4-(piperidin-4-yl)piperazine was used to replace 4-dimethylaminopiperidine, and Intermediate 6 was prepared as yellow powdery solid 148 mg with a yield of 69%. The structure verification data are as follows: ¹ H NMR(CDCl ₃ )δ(ppm): 7.90(d, J=9.2Hz, 1H), 6.41(d, J=9.2Hz, 1H), 4.79(t, J=8.4Hz, 2H), 3.67(d, J=12.8Hz, 2H), 3.20(t, J=8.8Hz, 2H), 2.88(t, J=12.0Hz, 2H), 2.69(brs, 4H), 2.56(brs, 4H),2.49-2.43(m,1H),2.35(s,3H),1.98(d,J＝11.6Hz,2H),1.68-1.58(m,2H).

Intermediate 7:

Intermediate 1 (200 mg, 0.82 mmol) was dissolved in toluene (10 mL), and Pd(OAc) ₂ (20 mg, 0.08 mmol), DavePhos (65 mg, 0.16 mmol) and K ₃ PO ₄ (520 mg, 2.46 mmol, 2mL H ₂ O), after stirring evenly, add tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)- Carboxylate (760 mg, 2.46 mmol) was reacted at 95° C. for 4 h under the protection of argon, and the raw material disappeared. Cool to room temperature, evaporate the solvent, dissolve the residue with EA (30mL), wash with saturated brine (20mL×3), wash with water (20mL×2), and column chromatography (D/M=10:1) to obtain intermediate 7 yellow Powdery solid 250 mg, yield 88%. The structure verification data are as follows: ¹ H NMR (CDCl ₃ )δ (ppm): 7.91 (d, J = 8.8Hz, 1H), 6.82 (d, J = 8.8Hz, 1H), 5.91 (s, 1H), 4.83 ( t,J=8.8Hz,2H),4.09(m,2H),3.63(t,J=8.8Hz,2H),3.32(t,J=8.8Hz,2H),2.45(m,2H),1.50( s,9H).

Intermediate 8:

Intermediate 7 (190mg, 0.55mmol) was dissolved in DCM (15mL), TFA (625mg, 5.50mmol) was added, reacted at room temperature for 3h, and the starting material disappeared. After concentration, 188 mg of intermediate 8 was obtained as light yellow powdery solid with a yield of 100%. The structure verification data are as follows: ¹ H NMR (CDCl ₃ )δ (ppm): 9.07 (brs, 1H), 7.94 (d, J = 8.4Hz, 1H), 6.80 (d, J = 8.8Hz, 1H), 6.63 ( s,1H),5.89(s,1H),4.84(t,J=8.8Hz,2H),3.94(brs,2H),3.53(brs,2H),3.31(t,J=8.8Hz,2H), 2.76(brs,2H).

Intermediate 9:

Intermediate 8 (170 mg, 0.50 mmol) was dissolved in THF (10 mL) and MeOH (10 mL), and aqueous formaldehyde (120 mg, 37%, 1.50 mmol) and sodium triacetoxyborohydride (555 mg, 2.50 mmol) were added, After reacting at room temperature for 2h, the raw material disappeared. Concentrate, add EA (30 mL), wash with water (20 mL×3), and perform column chromatography (D/M=20:1) to obtain 120 mg of intermediate 9 as a pale yellow powdery solid with a yield of 92%. The structure verification data are as follows: ¹ H NMR (CDCl ₃ )δ (ppm): 7.90 (d, J = 8.8Hz, 1H), 6.83 (d, J = 8.8Hz, 1H), 5.91 (m, 1H), 4.81 ( t,J=8.8Hz,2H),3.33(t,J=8.8Hz,2H),3.16-3.15(m,2H),2.69(t,J=5.6Hz,2H),2.53(m,2H), 2.44(s,3H).

Intermediate 10:

Using the same synthesis method as Intermediate 2, 1-Boc-4-(piperidin-4-yl)piperazine was used instead of 4-dimethylaminopiperidine to prepare 156 mg of Intermediate 10 as a yellow powdery solid with a yield of 58%. The structure verification data are as follows: ¹ H NMR(CDCl ₃ )δ(ppm): 7.90(d, J=9.2Hz, 1H), 6.41(d, J=9.6Hz, 1H), 4.79(t, J=8.8Hz, 2H), 3.67(d, J=12.4Hz, 2H), 3.45(m, 4H), 3.20(t, J=8.8Hz, 2H), 2.87(t, J=12.0Hz, 2H), 2.53(m, 4H), 2.46(m, 2H), 1.94(d, J=12.0Hz, 2H), 1.66-1.59(m, 2H).

Intermediate 11:

Intermediate 2 (463mg, 1.59mmol) was dissolved in methanol (20mL), Pd/C (60mg) was added, catalytic hydrogenation was carried out for 3h, and the starting material disappeared. Pd/C was filtered off and concentrated to obtain 410 mg of intermediate 11 as a white solid with a yield of 99%. The structure verification data are as follows: ¹ H NMR (DMSO-d ₆ )δ (ppm): 6.38 (d, J = 8.0Hz, 1H), 6.24 (d, J = 8.4Hz, 1H), 4.45 (t, J = 8.4 Hz, 2H), 4.23(brs, 2H), 3.16(d, J=12.0Hz, 2H), 3.04(t, J=8.4Hz, 2H), 2.45-2.50(m, 2H), 2.31(m, 7H ),1.85(d,J＝11.6Hz,2H),1.55-1.47(m,2H).

Intermediate 12:

Using the same synthetic method as intermediate 11, intermediate 3 was used to replace intermediate 2, and intermediate 12 was obtained as off-white solid 68 mg with a yield of 96%. The structure verification data are as follows: ¹ H NMR (CDCl ₃ )δ (ppm): 6.51 (d, J = 8.4Hz, 1H), 6.06 (d, J = 8.4Hz, 1H), 4.58-4.50 (m, 2H), 3.41-3.18(m,6H),2.82(t,J=7.2Hz,1H),2.29(s,6H),2.12-2.11(m,1H),1.88-1.83(m,1H).

Intermediate 13:

Using the same synthetic method as intermediate 11, intermediate 4 was used to replace intermediate 2, and intermediate 13 was obtained as off-white solid 87 mg with a yield of 92%. The structural verification data are as follows: ¹ H NMR (DMSO-d ₆ )δ (ppm): 6.41 (d, J = 8.4Hz, 1H), 6.25 (d, J = 8.0Hz, 1H), 4.55 (brs, 2H), 4.46(t, J=8.4Hz, 2H), 3.40(m, 4H), 3.07(t, J=8.4Hz, 2H), 2.75(t, J=4.8Hz, 4H), 1.41(s, 9H).

Intermediate 14:

Using the same synthesis method as intermediate 11, intermediate 5 was used to replace intermediate 2, and intermediate 14 was obtained as a white solid (58 mg) with a yield of 100%. The structure verification data are as follows: ¹ H NMR (CDCl ₃ )δ (ppm): 6.55 (d, J = 8.4Hz, 1H), 6.43 (d, J = 8.4Hz, 1H), 4.61 (t, J = 8.4Hz, 2H), 3.32(m, 6H), 3.16(t, J=8.4Hz, 2H), 2.79(s, 3H), 1.28(m, 4H).

Intermediate 15:

Using the same synthesis method as intermediate 11, intermediate 6 was used to replace intermediate 2, and intermediate 15 was obtained as a white solid (64 mg) with a yield of 78%. The structure verification data are as follows: ¹ H NMR(CDCl ₃ )δ(ppm): 6.51(d, J=8.4Hz, 1H), 6.33(d, J=8.4Hz, 1H), 4.57(t, J=8.4Hz, 2H), 3.28(d, J=12.0Hz, 2H), 3.14(t, J=8.4Hz, 2H), 2.67-2.52(m, 10H), 2.37-2.34(m, 1H), 2.32(s, 3H ), 1.92(d, J=12.4Hz, 2H), 1.71-1.61(m, 2H).

Intermediate 16:

Using the same synthesis method as Intermediate 11, Intermediate 2 was replaced by Intermediate 7 to obtain 48 mg of Intermediate 16 as a yellowish solid with a yield of 77%. The structure verification data are as follows: ¹ H NMR (CDCl ₃ )δ (ppm): 6.85 (d, J = 8.4Hz, 1H), 6.54 (d, J = 8.0Hz, 1H), 5.71 (s, 1H), 4.55 ( t,J=8.8Hz,2H),3.55(brs,2H),3.26(t,J=8.8Hz,2H),3.09-3.07(m,2H),2.63(t,J=5.6Hz,2H), 2.51(m,2H),2.40(s,3H).

Intermediate 17:

Intermediate 16 (70mg, 0.27mmol) was dissolved in methanol (10mL), Pd/C (15mg) was added, catalytic hydrogenation was carried out for 3h, and the starting material disappeared. Pd/C was filtered off and concentrated to obtain 49 mg of light yellow solid with a yield of 79%. The structure verification data are as follows: ¹ HNMR(CDCl ₃ )δ(ppm): 6.59(d, J=8.4Hz, 1H), 6.54(d, J=8.0Hz, 1H), 5.71(s, 1H), 4.58(t ,J=8.8Hz,2H),3.46(brs,2H),3.18(t,J=8.8Hz,2H),2.98-2.95(m,2H),2.38-2.33(m,1H),2.31(s, 3H),2.05-1.98(m,2H),1.81-1.68(m,4H).

Intermediate 18:

Using the same synthetic method as intermediate 11, intermediate 9 was used to replace intermediate 2 to obtain 90 mg of light yellow solid with a yield of 90%. The structure verification data are as follows: ¹ H NMR(CDCl ₃ )δ(ppm):6.56-6.54(m,2H),4.59(t,J＝8.8Hz,2H),4.23(m,2H),3.48(ts,2H ), 3.18(t, J=8.8Hz, 2H), 2.76(m, 2H), 2.52-2.49(m, 1H), 1.74(d, J=12.4Hz, 2H), 1.64-1.55(m, 2H) .

Intermediate 19:

Using the same synthetic method as intermediate 11, intermediate 2 was replaced by intermediate 10 to obtain 55 mg of off-white solid with a yield of 74%. The structure verification data are as follows: ¹ H NMR(CDCl ₃ )δ(ppm): 6.51(d, J=8.4Hz, 1H), 6.33(d, J=8.4Hz, 1H), 4.57(t, J=8.4Hz, 2H),3.55(brs,4H),3.30(d,J=11.6Hz,2H),3.14(t,J=8.4Hz,2H),2.64-2.58(m,7H),1.90(m,2H), 1.71(m,2H),1.47(s,9H).

Intermediate 20:

Compound 4,6-dichloropyrimidine (100 mg, 0.60 mmol) and 2-(aminophenyl) dimethylphosphine oxide (51 mg, 0.30 mmol) were dissolved in n-butanol (5 mL), and DIEA (116 mg, 0.90 mmol), reflux reaction for 12h, the raw material disappeared substantially. Column chromatography (P/E=1:6) gave 50 mg of white solid with a yield of 56%. The structure verification data are as follows: ¹ H NMR (CDCl ₃ )δ (ppm): 11.02 (s, 1H), 6.62 (dd, J ₁ =8.4Hz, J ₂ =4.4Hz, 1H), 8.54 (s, 1H), 7.57-7.52(m,1H),7.29-7.23(m,1H),7.14-7.09(m,1H),6.74(s,1H),1.85(s,3H),1.82(s,3H).

Intermediate 21:

Using the same synthetic method as intermediate 20, substituting 2,4-dichloro-5-fluoropyrimidine (100 mg, 0.60 mmol) for 4,6-dichloropyrimidine, 50 mg of intermediate 21 was obtained as a white solid with a yield of 56%. The structure verification data are as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 11.84 (s, 1H), 8.80 (dd, J ₁ =8.4Hz, J ₂ =4.4Hz, 1H), 8.08 (d, J = 2.8 Hz,1H),7.62-7.58(m,1H),7.29-7.24(m,1H),7.19-7.14(m,1H),1.87(s,3H),1.84(s,3H).

Intermediate 22:

Using the same synthesis method as intermediate 20, replacing 4,6-dichloropyrimidine with 2,4-dichloropyrimidine (352mg, 2.36mmol), the intermediate 22 was obtained as a white solid 120mg with a yield of 36%. The structure verification data are as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 11.22 (s, 1H), 8.69 (dd, J ₁ =8.4Hz, J ₂ =4.4Hz, 1H), 8.14 (d, J = 5.6 Hz, 1H), 7.59-7.55(m, 1H), 7.27-7.25(m, 1H), 7.14-7.10(m, 1H), 6.58(d, J=5.6Hz, 1H), 1.85(s, 3H) ,1.82(s,3H).

Intermediates 23 and 24:

Using the same synthetic method as intermediate 20, replacing 4,6-dichloropyrimidine with 2,4-dichloro-5-trifluoromethylpyrimidine (386mg, 1.78mmol), a mixture of intermediates 23 and 24 was obtained: a white solid 210 mg, 68% yield. The structure verification data are as follows: ¹ H NMR(CDCl ₃ )δ(ppm):11.67(s,1H),11.28(s,0.5H),8.65-8.62(m,1H),8.59(s,1H),8.49- 8.46(m,1H),7.61-7.54(m,1.5H),7.34-7.22(m,2H),7.15-7.12(m,1H),1.86(s,3H),1.85(s,1.5H), 1.83(s,3H),1.81(s,1.5H).

Intermediate 25:

Using the same synthetic method as intermediate 20, substituting 4,6-dichloropyrimidine with 2,4-dichloro-1,3,5-triazine (267mg, 1.78mmol) to obtain intermediate 25: white solid 150mg, yield The rate is 60%. The structure verification data are as follows: ¹ H NMR (DMSO-d ₆ ) δ (ppm): 11.81 (brs, 1H), 8.63 (dd, J ₁ =8.4Hz, J ₂ =4.4Hz, 1H), 8.57 (s, 1H ),7.60(t,J＝8.0Hz,1H),7.33-7.27(m,1H),7.22-7.18(m,1H),1.88(s,3H),1.85(s,3H).

Intermediate 26:

Using the same synthetic method as intermediate 20, substituting 2,4,5-trichloropyrimidine (866 mg, 4.72 mmol) for 4,6-dichloropyrimidine, intermediate 26 was obtained: 483 mg of off-white solid with a yield of 65%. The structure verification data are as follows: ¹ H NMR (DMSO-d ₆ ) δ (ppm): 11.55 (brs, 1H), 8.67 (dd, J ₁ =8.4Hz, J ₂ =4.4Hz, 1H), 8.22 (s, 1H ),7.60(t,J＝8.4Hz,1H),7.32-7.28(m,1H),7.20-7.18(m,1H),1.86(s,3H),1.83(s,3H).

Example 1:

Intermediate 11 (25mg, 0.10mmol) and Intermediate 20 (35mg, 0.12mmol) were dissolved in iPrOH (1mL), concentrated hydrochloric acid (24mg, 0.25mmol) was added, microwave reaction (250w, 130°C, 120min, 300psi) . Cool to room temperature, add EA (20mL), wash with saturated sodium bicarbonate (aq) (20mL×3), wash with saturated brine (20mL×3), column chromatography (D/M/Et ₃ N=10:1:0.02 ), to obtain Example 1: off-white solid 48mg, yield rate 71%.

The structure verification data are as follows: ¹ H NMR (CDCl ₃ )δ (ppm): 10.01 (s, 1H), 8.46 (dd, J ₁ =8.4Hz, J ₂ =4.4Hz, 1H), 8.35 (s, 1H), 7.47(t, J=7.6Hz, 1H), 7.23-7.15(m, 2H), 7.02-6.98(m, 1H), 6.45(d, J=8.8Hz, 1H), 6.35(s, 1H), 5.87 (s,1H),4.60(t,J=8.8Hz,2H),3.40(d,J=12.0Hz,2H),3.20(t,J=8.8Hz,2H),2.67(t,J=12.0Hz ,2H),2.33(s,6H),2.29-2.23(m,1H),1.93(d,J=12.0Hz,2H),1.80(s,3H),1.74(s,3H),1.68-1.58( m,2H).HRMS(ESI):m/z,calcd for C ₂₇ H ₃₆ N ₆ O ₂ P[M+H ⁺ ]:507.2637,found 507.2646.

Example 2:

Using Intermediate 11 (50 mg, 0.19 mmol) and Intermediate 21 (71 mg, 0.24 mmol) as raw materials, the same method as Example 1 was used to synthesize Example 2: 84 mg of off-white solid with a yield of 84%.

The structure verification data are as follows: ¹ H NMR (DMSO-d ₆ ) δ (ppm): 11.51 (s, 1H), 8.66 (m, 1H), 8.24 (s, 1H), 8.02 (d, J = 3.2Hz, 1H ),7.54(dd,J ₁ =13.6Hz,J ₂ =7.6Hz,1H),7.32(t,J=7.6Hz,1H),7.21(d,J=8.4Hz,1H),7.08(t,J =7.2Hz, 1H), 6.44(d, J=8.8Hz, 1H), 4.49(t, J=8.4Hz, 2H), 3.41-3.39(m, 2H), 3.16(t, J=8.0Hz, 2H ),3.01(m,1H),2.64(t,J=12.0Hz,2H),2.53(s,6H),2.01(d,J=10.0Hz,2H),1.80(s,3H),1.77(s ,3H),1.80-1.65(m,2H).HRMS(ESI):m/z,calcd for C ₂₇ H ₃₅ N ₆ O ₂ PF[M+H ⁺ ]:525.2543,found 525.2557.

Example 3:

Using Intermediate 11 (40 mg, 0.15 mmol) and Intermediate 22 (54 mg, 0.19 mmol) as raw materials, the same method as in Example 1 was used to synthesize Example 3: 35 mg of an off-white solid with a yield of 45%.

The structure verification data are as follows: ¹ H NMR (DMSO-d ₆ )δ (ppm): 10.95(s, 1H), 8.51-8.50(m, 1H), 8.11(s, 1H), 7.95(d, J＝5.6Hz ,1H),7.52(d,J ₁ =12.8Hz,J ₂ =6.4Hz,1H),7.31(t,J=7.6Hz,1H),7.25(d,J=8.4Hz,1H),7.04(d ,J=7.6Hz,1H),6.43(d,J=8.8Hz,1H),5.96(d,J=5.6Hz,1H),4.49(t,J=8.4Hz,2H),3.39(m,2H ),3.17-3.13(m,3H),2.63(t,J＝12.0Hz,2H),2.43(s,6H),1.97-1.94(m,2H),1.78(s,3H),1.75(s, 3H), 1.62-1.59(m,2H). HRMS(ESI): m/z, calcd for C ₂₇ H ₃₆ N ₆ O ₂ P[M+H ⁺ ]: 507.2637, found 507.2634.

Embodiment 4 and embodiment 5:

Using Intermediate 11 (65 mg, 0.25 mmol) and Intermediates 23, 24 (108 mg, 0.31 mmol) as raw materials, the same method as in Example 1 was used to synthesize Example compounds 4 and 5: off-white solid 60 mg.

The structure verification data are as follows: ¹ H NMR(CDCl ₃ )δ(ppm):10.81(s,1H),10.36(s,0.5H),8.49-8.48(m,1H),8.35-8.32(m,2H), 7.90(d, J=7.6Hz, 1H), 7.79(d, J=7.6Hz, 0.5H), 7.46-7.34(m, 1.5H), 7.27-7.17(m, 1.5H), 7.06-7.05(m ,1.5H),6.95(s,1.5H),6.49(d,J＝8.4Hz,1H),6.37(brs,0.5H),4.65-4.61(m,3H),3.49-3.43(m,3H) ,3.21-3.17(m,3H),3.00(m,1.5H),2.77-2.72(m,12H),2.25(d,J=10.8Hz,3H),1.91-1.89(m,3H),1.84( s,4.5H),1.81(s,4.5H).HRMS(ESI):m/z,calcd for C ₂₈ H ₃₅ N ₆ O ₂ PF ₃ [M+H ⁺ ]:575.2511,found575.2527.

Embodiment 6:

Using intermediates 11 (40 mg, 0.15 mmol) and 25 (54 mg, 0.19 mmol) as raw materials, the same method as in Example 1 was used to synthesize Example compound 6: 13 mg of off-white solid, with a yield of 17%.

The structure verification data are as follows: ¹ H NMR (DMSO-d ₆ ) δ (ppm): 11.17 (s, 1H), 9.14 (brs, 1H), 8.41 (brs, 1H), 8.23 (s, 1H), 7.53 (m ,1H),7.24(m,1H),7.09-7.07(m,2H),6.46(m,1H),4.50(t,J=8.4Hz,2H),3.33(m,2H),3.17(m, 3H), 3.05(m, 1H), 2.65(t, J=11.2Hz, 2H), 2.50(s, 6H), 1.97(m, 2H), 1.78(s, 3H), 1.75(s, 3H), 1.64-1.61(m,2H).HRMS(ESI):m/z,calcd for C ₂₆ H ₃₅ N ₇ O ₂ P[M+H ⁺ ]:508.2590,found 508.2596.

Embodiment 7:

Using intermediates 11 (50mg, 0.19mmol) and 26 (75mg, 0.24mmol) as raw materials, the same method as in Example 1 was used to synthesize Example compound 7: off-white solid 74mg, yield 72%.

The structure verification data are as follows: ¹ H NMR(CDCl ₃ )δ(ppm): 10.84(s,1H),8.63(dd,J ₁ =8.4Hz,J ₂ =4.4Hz,1H),8.08(s,1H), 7.80(d, J=8.4Hz, 1H), 7.46(t, J=8.0Hz, 1H), 7.29-7.24(m, 1H), 7.11(d, J=6.8Hz, 1H), 6.81(s, 1H ), 6.43(d, J=8.4Hz, 1H), 4.60(t, J=8.8Hz, 2H), 3.38(d, J=12.0Hz, 2H), 3.21(t, J=8.4Hz, 2H), 2.66(t, J=12.0Hz, 2H), 2.33(s, 6H), 2.30-2.23(m, 1H), 1.93(d, J=11.6Hz, 2H), 1.85(s, 3H), 1.81(s ,3H),1.69-1.60(m,2H).HRMS(ESI):m/z,calcd for C ₂₇ H ₃₅ N ₆ O ₂ PCl[M+H ⁺ ]:541.2248,found 541.2257.

Embodiment 8:

Using intermediates 14 (40 mg, 0.17 mmol) and 26 (67 mg, 0.21 mmol) as raw materials, they were synthesized by the same method as in Example 1 to obtain Example 8: 40 mg of an off-white solid with a yield of 46%.

The structure verification data are as follows: ¹ H NMR(CDCl ₃ )δ(ppm): 10.86(s,1H),8.62(dd,J ₁ =8.0Hz,J ₂ =4.4Hz,1H),8.08(s,1H), 7.84(d, J=8.4Hz, 1H), 7.46(t, J=8.0Hz, 1H), 7.30-7.27(m, 1H), 7.11(d, J=6.4Hz, 1H), 6.83(s, 1H ), 6.46(d, J=8.8Hz, 1H), 4.61(t, J=8.8Hz, 2H), 3.20(d, J=8.4Hz, 2H), 3.12-3.07(m, 4H), 2.45(s ,3H),1.85(s,3H),1.82(s,3H),1.41(t,J＝7.2Hz,2H).HRMS(ESI):m/z,calcd for C ₂₅ H ₃₁ N ₆ O ₂ PCl [M+H ⁺ ]:513.1935,found513.1924.

Embodiment 9:

Using intermediates 13 (40mg, 0.12mmol) and 26 (47mg, 0.15mmol) as raw materials, they were synthesized by the same method as in Example 1 to obtain Example 9: 14mg of white solid with a yield of 22%.

The structure verification data are as follows: ¹ H NMR (DMSO-d ₆ ) δ (ppm): 11.21 (s, 1H), 8.53 (brs, 1H), 8.47 (s, 1H), 8.07 (s, 1H), 7.53 (dd , J ₁ =14.0Hz, J ₂ =8.4Hz,1H), 7.29(m,1H),7.17(d,J=8.8Hz,1H),7.10-7.08(m,1H),6.45(d,J= 8.4Hz, 1H), 5.76(s, 1H), 4.49(t, J＝8.0Hz, 2H), 3.30(m, 4H), 3.19-3.12(m, 6H), 1.78(s, 3H), 1.75( s,3H).HRMS(ESI):m/z,calcd for C ₂₄ H ₂₉ N ₆ O ₂ PCl[M+H ⁺ ]:499.1778,found 499.1779.

Example 10:

Using intermediates 12 (35mg, 0.14mmol) and 26 (55mg, 0.18mmol) as raw materials, they were synthesized by the same method as in Example 1 to prepare Example 10: 60mg of white solid with a yield of 81%.

The structure verification data are as follows: ¹ H NMR (DMSO-d ₆ ) δ (ppm): 11.19 (s, 1H), 8.56 (brs, 1H), 8.31 (s, 1H), 8.03 (s, 1H), 7.51 (dd , J ₁ =14.0Hz, J ₂ =7.2Hz, 1H), 7.28(m, 1H), 7.77(t, J=6.8Hz, 1H), 6.98(d, J=8.4Hz, 1H), 6.09(d ,J＝8.4Hz,1H),4.46-4.35(m,2H),3.52-3.24(m,6H),2.90(m,1H),2.29(s,6H),2.13-2.09(m,1H), 1.78(m,1H),1.75(s,3H),1.74(s,3H).HRMS(ESI):m/z,calcd for C ₂₆ H ₃₃ N ₆ O ₂ PCl[M+H ⁺ ]:527.2091, found 527.2104.

Example 11:

Using intermediates 15 (40 mg, 0.13 mmol) and 26 (50 mg, 0.16 mmol) as raw materials, they were synthesized by the same method as in Example 1 to obtain Example 11: 35 mg of an off-white solid with a yield of 46%.

The structure verification data are as follows: ¹ H NMR(CDCl ₃ )δ(ppm): 10.85(s,1H),8.63(dd,J ₁ =8.0Hz,J ₂ =4.0Hz,1H),8.08(s,1H), 7.81(d, J=8.8Hz, 1H), 7.46(t, J=7.2Hz, 1H), 7.30-7.25(m, 1H), 7.11(d, J=7.6Hz, 1H), 6.81(s, 1H ), 6.42(d, J=8.8Hz, 1H), 4.61(t, J=8.4Hz, 2H), 3.40(d, J=13.6Hz, 2H), 3.19(t, J=8.0Hz, 2H), 2.92-2.51(m,13H),2.01(m,2H),1.85(s,3H),1.81(s,3H),1.79-1.75(m,2H).HRMS(ESI):m/z,calcd for C ₃₀ H ₄₀ N ₇ O ₂ PCl[M+H ⁺ ]: 596.2670, found 596.2673.

Example 12:

Using intermediates 16 (30 mg, 0.13 mmol) and 26 (50 mg, 0.16 mmol) as raw materials, they were synthesized by the same method as in Example 1 to obtain Example 12: 25 mg of an off-white solid with a yield of 38%.

The structure verification data are as follows: ¹ H NMR(CDCl ₃ )δ(ppm):10.85(s,1H),8.61(m,1H),8.10(s,1H),7.97(m,1H),7.48(m,1H ),7.26(m,1H),7.13(m,1H),7.00(s,1H),6.74(m,1H),5.79(s,1H),4.59(m,2H),3.32-3.11(m, 4H),2.66-2.34(m,7H),1.85(s,3H),1.82(s,3H).HRMS(ESI):m/z,calcd for C ₂₆ H ₃₀ N ₅ O ₂ PCl[M+H ⁺ ]:510.1826,found 510.1830.

Example 13:

Using intermediates 17 (40 mg, 0.17 mmol) and 26 (67 mg, 0.21 mmol) as raw materials, they were synthesized by the same method as in Example 1 to obtain Example 13: 28 mg of an off-white solid with a yield of 38%.

The structure verification data are as follows: ¹ H NMR(CDCl ₃ )δ(ppm): 10.84(s,1H),8.61-8.60(m,1H),8.09(s,1H),7.94(d,J＝8.0Hz,1H ), 7.46(t, J=8.0Hz, 1H), 7.30-7.26(m, 1H), 7.14(t, J=6.4Hz, 1H), 6.93(s, 1H), 6.72(t, J=7.2Hz ,1H),4.62(t,J=8.4Hz,2H),3.24(t,J=8.4Hz,2H),3.02(d,J=10.0Hz,2H),2.44-2.36(m,4H),2.08 -2.05(m,2H),1.89-1.82(m,10H).HRMS(ESI):m/z,calcd for C ₂₆ H ₃₂ N ₅ O ₂ PCl[M+H ⁺ ]:512.1982,found 512.1970.

Example 14:

Intermediate 18 (30 mg, 0.09 mmol) was dissolved in toluene (4 mL), and Pd ₂ (dba) ₃ (8 mg, 0.009 mmol), DavePhos (8 mg, 0.018 mmol) and K ₃ PO ₄ (40 mg, 0.018 mmol) were added sequentially , 0.4mL H ₂ O), after stirring evenly, intermediate 26 (34mg, 0.11mmol) was added, under the protection of argon, reacted at 90°C for 1h, and the raw material disappeared. Cool to room temperature, evaporate the solvent, dissolve the residue with EA (30 mL), wash with saturated brine (20 mL×3), wash with water (20 mL×2), and perform column chromatography (D/M=10:1) to obtain Example 14: White powdery solid 36 mg, yield 64%.

The structure verification data are as follows: ¹ H NMR(CDCl ₃ )δ(ppm): 10.86(s,1H),8.61(dd,J ₁ =8.4Hz,J ₂ =4.4Hz,1H),8.10(s,1H), 7.94(d, J=8.0Hz, 1H), 7.48(t, J=8.0Hz, 1H), 7.31-7.26(m, 1H), 7.16-7.12(m, 1H), 6.93(s, 1H), 6.65 (d, J=8.8Hz, 1H), 4.63(t, J=8.4Hz, 2H), 4.27(m, 2H), 3.25(t, J=8.4Hz, 2H), 2.79(t, J=12.4Hz ,2H),2.62-2.56(m,1H),1.85(s,3H),1.82(s,3H),1.79-1.63(m,4H),1.50(s,9H).

Example 15:

Intermediate 19 (40 mg, 0.13 mmol) was dissolved in toluene (6 mL), and Pd ₂ (dba) ₃ (11 mg, 0.013 mmol), DavePhos (10 mg, 0.025 mmol) and K ₃ PO ₄ (53 mg, 0.25 mmol) were added sequentially , 1 mL H ₂ O), after stirring evenly, compound 26 (58 mg, 0.15 mmol) was added, under the protection of argon, reacted at 90° C. for 4 h, and the raw material disappeared. Cool to room temperature, evaporate the solvent, dissolve the residue with EA (30 mL), wash with saturated brine (20 mL×3), wash with water (20 mL×2), and column chromatography (D/M=20:1), to obtain Example 16: White powdery solid 70 mg, yield 81%.

The structure verification data are as follows: ¹ H NMR(CDCl ₃ )δ(ppm): 10.83(s,1H),8.62(dd,J ₁ =8.0Hz,J ₂ =4.4Hz,1H),8.08(s,1H), 7.80(d, J=8.4Hz, 1H), 7.46(t, J=7.2Hz, 1H), 7.26(m, 1H), 7.13-7.11(m, 1H), 6.82(s, 1H), 6.42(d ,J=8.8Hz,1H),4.60(t,J=8.0Hz,2H),3.53-3.38(m,6H),3.19(t,J=8.4Hz,2H),2.70-2.64(m,7H) ,1.97(brs,2H),1.85(s,3H),1.81(s,3H),1.64(m,2H),1.47(s,9H).

Example 16:

Example 14 (28 mg, 0.05 mmol) was dissolved in DCM (4 mL), TFA (0.5 mL) was added, reacted at room temperature for 3 h, and the starting material disappeared. After cooling to room temperature, the solvent was distilled off to obtain Example 16: 136 mg of white powdery solid with a yield of 57%.

The structure verification data are as follows: ¹ H NMR(CDCl ₃ )δ(ppm):10.02(s,1H),10.73(brs,1H),9.82(s,1H),9.37(s,1H),8.47(s,1H ), 7.41(d, J=7.6Hz, 1H), 7.26-7.21(m, 3H), 6.74(d, J=8.0Hz, 1H), 4.61(t, J=8.0Hz, 2H), 3.59(d ,J=9.2Hz,2H),3.24(t,J=8.0Hz,2H),3.07(m,2H),2.79(m,1H),2.19-2.15(m,2H),2.01(d,J= 12.8Hz,2H),.1.87(s,3H),1.84(s,3H).HRMS(ESI):m/z, calcd for C ₂₅ H ₃₀ N ₅ O ₂ PCl[M+H ⁺ ]:498.1826, found 498.1826.

Example 17:

Example 15 (40 mg, 0.06 mmol) was dissolved in DCM (4 mL), TFA (0.5 mL) was added, reacted at room temperature for 3 h, and the starting material disappeared. After cooling to room temperature, the solvent was distilled off to obtain Example 17: 40 mg of white powdery solid with a yield of 78%.

The structure verification data are as follows: ¹ H NMR(DMSO-d ₆ )δ(ppm):11.38(s,1H),9.16(brs,2H),8.73(s,1H),8.52(s,1H),8.10(s ,1H),7.56-7.52(m,1H),7.30(s,1H),7.16-7.11(m,2H),6.46(d,J=8.4Hz,2H),4.50(t,J=8.0Hz, 2H), 3.75(m, 4H), 3.49-3.40(m, 6H), 3.19-3.08(m, 3H), 2.70(t, J=11.6Hz, 2H), 2.12(d, J=10.0Hz, 2H ),1.79(s,3H),1.76(m,5H).HRMS(ESI):m/z,calcd for C ₂₉ H ₃₈ N ₇ O ₂ PCl[M+H ⁺ ]:582.2513,found 582.2516.

Test Example 1, Determination of ALK ^wt /ALK ^L1196M Kinase Activity by Compounds of the Present Invention

The compound of the example was centrifuged at 12,000 g for 5 min, added DMSO to prepare a 10 ^-2 M stock solution, vortexed evenly, and then sonicated for 10 min before use, and stored at -40°C (compounds with special storage requirements should be modified according to specific conditions). During the test, the compound was diluted with DMSO from the stock solution to 100 times of the tested concentration (the concentration of DMSO in the system was 1%).

Test Methods:

1. Enzyme reaction substrate Poly(Glu,Tyr) 4:1 was diluted to 20μg/mL with potassium ion-free PBS (10mM sodium phosphate buffer, 150mM NaCl, pH7.2-7.4), and 125μL/well was coated with a microtiter plate , set at 37°C for 12-16 hours. Discard the liquid in the well. Wash the plate, and wash the plate three times with T-PBS (potassium ion-free PBS containing 0.1% Tween-20, 200 μL/well), 5 minutes each time. Dry the microtiter plate in an oven at 37°C for 1-2 hours;

2. Add 49 μL of ATP solution diluted with reaction buffer (50mM HEPES pH 7.4, 50mM MgCl ₂ , 0.5mM MnCl ₂ , 0.2mMNa ₃ VO ₄ , 1mM DTT) into each well, add 1 μL of the compound to be tested in each well, and then add 50 μL of ALK ^wt /ALK ^L1196M kinase domain recombinant protein diluted in reaction buffer was used to start the reaction, and two wells without ATP control wells were required for each experiment. Put it on a shaker (100 rpm) at 37°C for 1 hour. Discard the liquid in the well, wash the plate three times with T-PBS;

3. Add antibody PY99 diluent (antibody diluted 1:500 with T-PBS containing 5 mg/mL BSA), 100 μL/well, and react on a shaker at 37°C for 0.5 hours. Discard the liquid in the well, wash the plate three times with T-PBS;

4. Add horseradish peroxidase-labeled goat anti-mouse secondary antibody dilution (the antibody is diluted with T-PBS 1:2000 containing BSA 5 mg/ml), 100 μL/well, and react on a shaker at 37°C for 0.5 hours. Discard the liquid in the well, wash the plate three times with T-PBS;

5. Add 100 μL/well of 2 mg/ml OPD chromogenic solution [dilute with 0.1M citric acid-sodium citrate buffer (pH=5.4) containing 0.03% H ₂ O ₂ ], and react in the dark at 25°C for 1-10 minute;

6. Add 2M H ₂ SO ₄ 50 μL/well to stop the reaction, and read with VERSAmax on a wavelength-tunable microplate microplate reader with a wavelength of 490 nm;

7. Result analysis, IC ₅₀ value was obtained by regression with the four-parameter method using the accompanying software of the microplate reader.

0<IC50<100nM, recorded as "+++"; 100nM<IC50<500nM, recorded as "++"; IC50>500nM, recorded as "+". The experimental results are shown in Table 1.

The formula for calculating the inhibition rate is as follows:

The inhibitory activity of table 1, embodiment 1-18 compound to ALK ^wt /ALK ^L1196M kinase

Test Example 2: Inhibitory activity of compounds against other kinases

The inhibitory activity of ALK ^L1152 , ALK ^G1202 , ALK ^F1245 , ALK ^C1156 , ALK ^G1269 , ALK ^S1206 , EGFR ^wt , EGFR ^TT90M , EGFR ^T790M/L858R , ROS and other kinases was tested using a kinase screening method similar to Test Example 1. The results show that the inhibitory activity IC50 of some examples of compounds such as Examples 7, 8, 9, 12, 13, 16, etc. to ALK ^L1152 , ALK ^G1202 , ALK ^F1245 , ALK ^C1156 , ALK ^G1269 , ALK ^S1206 , and ROS kinases are all less than 100 nM, It shows good inhibitory activity; at the same time, the IC50 of the inhibitory activity of the above compounds on EGFR ^wt , EGFR ^TT90M , EGFR ^T790M/L858R and other kinases is less than 500nM, which also shows high activity.

Test Example 3: Compounds have inhibitory activity on cell proliferation

The inhibitory activity of the compounds of the examples on cell proliferation was evaluated by Cell Titer 96 single solution cell proliferation assay. 24 hours after seeding, the cells were treated with the compounds of the examples and grown for 72 hours. Correct the cell count at time zero (treatment time), use XLfit version 4.2.2 to perform Microsoft Excel to plot the growth percentage data relative to the control group (DMSO), and determine the concentration that inhibits 50% growth (GI50 value). The results showed that compounds 7, 8, 9, 12, 13, 16, etc. of the examples had strong proliferation inhibitory activity on cell lines such as NCI-H3122 and EML4-ALK ^G1202 , with IC50 less than 100 nM; , SK-N-SH and other cell lines also have good inhibitory activity, IC50 is less than 500nM.

Claims (10)

1. compound shown in formula I, its pharmaceutically acceptable salt, enantiomter, diastereoisomer, dynamic isomer, molten Agent compound, polymorph or its prodrug；Or

Compound shown in formula I ', its pharmaceutically acceptable salt, enantiomter, diastereoisomer, dynamic isomer, solvent Compound, polymorph or its prodrug；

In formula I or formula I '：

R₁、R₂、R₃、R₄Appointing in hydrogen, halogen, cyano group, hydroxyl, amino and substituted or unsubstituted C1-C6 alkyl One kind, and R₁、R₂、R₃、R₄In any two group can be formed 3-10 unit ring system；

M₁、M₂、M₃Independently selected from CRa or N, and M₁、M₂And M₃In at least one be N；Ra be hydrogen, halogen, cyano group, substitution or One kind in unsubstituted C1-C6 alkyl and substituted or unsubstituted C3-C8 cycloalkyl；

W is selected from any one of following radicals：Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyls, Unsubstituted or halo 4~8 yuan of alkynyl group, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 4-8 units are miscellaneous Ring group, the aromatic radical or heteroaryl, substituted carbonyl, substituted sulphonyl, substituted or unsubstituted amino of 5-10 units, wherein, it is described Heterocyclic radical is comprising 1-3 selected from the hetero atom in N, O, S, P and B；

The substitution base that described one or more groups being substituted by group are selected from the following group is replaced：Halogen, hydroxyl, amino, Cyano group, unsubstituted or halo C1-C8 alkyl, unsubstituted or halo C3-C8 cycloalkyl, unsubstituted or halo C1-C8 alkane Epoxide, unsubstituted or halo C2-C6 alkenyls, unsubstituted or halo C2-C6 alkynyls, unsubstituted or halo C2-C6 acyl groups, Unsubstituted or halo 5~8 yuan of aryl, unsubstituted or halo 5~8 unit's heteroaryls, unsubstituted or halo 4~8 yuan of saturations Heterocycle, unsubstituted or halo 4~8 yuan of carbocyclic rings；Wherein, the heteroaryl includes the 1-3 hetero atom being selected from N, O and S, institute State heterocycle and include the 1-3 hetero atom selected from N, O and S；

In formula I ', L is selected from any one of following radicals：- CR ' R "-,-O- ,-NR '-and-CR '=, wherein R ' and R " each solely It is on the spot hydrogen, fluorine, deuterium, C1-C6 alkyl or Heterocyclylalkyl, or adjacent R ' and R " form cyclic group.

2. compound shown in formula according to claim 1 I or its enantiomter, diastereoisomer, dynamic isomer, Solvate, polymorph, prodrug or pharmaceutically acceptable salt；Or

It is compound shown in formula I ' or its enantiomter, diastereoisomer, dynamic isomer, solvate, polymorph, preceding Medicine or pharmaceutically acceptable salt, it is characterised in that：

Compound shown in formula I or compound shown in formula I ' meet it is following 1) and/or 2)：

1) in formula I or formula I ', M₁、M₂Independently selected from CH or N, and M₁And M₂In at least one be N；M₃Selected from C-F, C-CF₃、 Any one in C-Cl, CH and N；

2) in formula I or formula I ', W is selected from any one in following radicals：Substituted or unsubstituted C1-C6 alkyl or cycloalkyls, take Generation or unsubstituted 4-6 circle heterocycles, substituted or unsubstituted 4-10 unit's cycloalkyl and substituted or unsubstituted 4-10 circle heterocycles alkane Volution or bridged ring that base is formed；

It is described substitution refer to substitution base independently selected from：Halogen, hydroxyl, cyano group, amino, alkyl, alkyl monosubstituted amino, dialkyl amino Base, cycloalkyl, heterocyclic radical, alkoxy, hydroxy alkyl, alkoxyalkyl, hydroxy alkoxy alkyl, aminoalkyl, dialkyl amino Base alkyl, alkoxycarbonylamino, cycloalkyl-alkyl, cycloheteroalkylalkyl, aralkyl, alkyl-cycloalkyl, naphthene base carbonyl, Alkoxy carbonyl, alkoxy carbonyl heterocyclic radical, (alkoxy carbonyl group) (alkyl) amino, (alkoxyalkyl) (alkyl) amino.

3. compound shown in formula according to claim 1 and 2 I or its enantiomter, diastereoisomer, tautomerism Body, solvate, polymorph, prodrug or pharmaceutically acceptable salt；Or

It is compound shown in formula I ' or its enantiomter, diastereoisomer, dynamic isomer, solvate, polymorph, preceding Medicine or pharmaceutically acceptable salt, it is characterised in that：

Compound shown in formula I is any one in compound shown in the compound to-w of formula I shown in the-a of following formula I：

Concretely in the-a of the following formula I ' to-c of formula I ' any one of compound shown in formula I '：

4. prepare compound shown in the formula I any one of claim 1-3 or its enantiomter, diastereoisomer, Dynamic isomer, solvate, polymorph, prodrug or pharmaceutically acceptable salt；Or

It is compound shown in formula I ' or its enantiomter, diastereoisomer, dynamic isomer, solvate, polymorph, preceding The method of medicine or pharmaceutically acceptable salt, comprises the following steps：

(1) by compound shown in formula IV and compound shown in formula V, in the condition that transition-metal catalyst and/or acid/base are present Under be coupled, obtain compound shown in formula III；

In formula IV, X and LG is each independently leaving group, and selected from any in halogen, sulphonic acid ester, boric acid and borate Kind；

In formula III, the definition of X is with formula IV；M₁、M₂And M₃Definition with formula I；

(2) compound shown in formula III and compound shown in formula II or compound shown in formula II ' in transition-metal catalyst and/or Acid/base is coupled under conditions of existing, and obtains compound shown in Formulas I；

In formula II, R₁、R₂、R₃、R₄Definition with W is with formula I；In formula II ', R₁、R₂、R₃、R₄, L and W definition with formula I '.

5. method according to claim 4, it is characterised in that：In step (1) or step (2),

The coupling reaction is carried out in a solvent, and the solvent is selected from water, methyl alcohol, ethanol, isopropanol, ethylene glycol, N- methyl Pyrrolidones, dimethyl sulfoxide (DMSO), tetrahydrofuran, toluene, dichloromethane, 1,2- dichloroethanes, acetonitrile, N, N- dimethyl formyls At least one in amine, DMAC N,N' dimethyl acetamide and dioxane；

The transition-metal catalyst be selected from three (dibenzalacetone) two palladium, tetrakis triphenylphosphine palladium, palladium, palladium bichloride, Dichloro two (triphenylphosphine) palladium, trifluoracetic acid palladium, triphenylphosphine palladium acetate, [double (diphenylphosphino) ferrocene of 1,1'-] dichloro Change at least one in palladium, double (three adjacent benzyl phosphines) palladium chlorides and 1,2- bis- (diphenylphosphino) ethane palladium chloride；Institute State catalyst ligand and be selected from tri-butyl phosphine, tetrafluoro boric acid tri-butyl phosphine, tri-n-butyl phosphine, triphenylphosphine, three pairs of benzyls At least one in the adjacent benzyl phosphine of phosphine, tricyclohexyl phosphine and three；

The alkali is inorganic base or organic base；The inorganic base is selected from sodium hydride, potassium hydroxide, sodium acetate, potassium acetate, the tert-butyl alcohol In potassium, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, saleratus, sodium carbonate and sodium acid carbonate at least one Kind；The organic base is selected from pyridine, triethylamine, DIPEA, the carbon -7- of 1,8- diazabicylos [5.4.0] 11 At least one in alkene, the silicon substrate lithium of hexamethyl two, the silicon substrate sodium of hexamethyl two and lutidines；

The acid is selected from least one in hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, formic acid and acetic acid.

6. compound shown in the formula I any one of claim 1-3, its pharmaceutically acceptable salt, enantiomter, non- Enantiomter, dynamic isomer, solvate, polymorph or its prodrug；Or

Compound shown in formula I ', its pharmaceutically acceptable salt, enantiomter, diastereoisomer, dynamic isomer, solvent Compound, polymorph or its prodrug；

Preparing the application having in the inhibitor of the function of suppressing EGFR mutant kinase activities and/or ALK kinase activity.

7. a kind of kinase inhibitor, compound or its enantiomerism shown in the formula I that it includes any one of claim 1-3 Body, diastereoisomer, dynamic isomer, solvate, polymorph, prodrug or pharmaceutically acceptable salt；Or

It is compound shown in formula I ' or its enantiomter, diastereoisomer, dynamic isomer, solvate, polymorph, preceding Medicine or pharmaceutically acceptable salt.

8. compound shown in the formula I any one of claim 1-3, its pharmaceutically acceptable salt, enantiomter, non- Enantiomter, dynamic isomer, solvate, polymorph or its prodrug；Or

Compound shown in formula I ', its pharmaceutically acceptable salt, enantiomter, diastereoisomer, dynamic isomer, solvent Compound, polymorph or its prodrug；

Application in prevention and/or treatment tumour product is prepared.

9. application according to claim 8, it is characterised in that：The tumour is non-small cell lung cancer, ED-SCLC, lung Gland cancer, lung squamous cancer, cancer of pancreas, breast cancer, prostate cancer, liver cancer, cutaneum carcinoma, cell carcinoma, gastrointestinal stromal tumor, white blood Any one in disease, lymph cancer and nasopharyngeal carcinoma.

10. a kind of pharmaceutical composition, it is characterised in that：It includes：

1) compound, its pharmaceutically acceptable salt, mapping shown in the formula I any one of the claim 1-4 of effective dose Isomers, diastereoisomer, dynamic isomer, solvate, polymorph or its prodrug；With

2) pharmaceutically acceptable carrier.