WO2018050052A1 - Compound containing pyrimidine ring, egfr inhibitor and application thereof - Google Patents

Abstract

The present invention relates to the technical field of pharmaceutical compositions and relates to a compound containing a pyrimidine ring, an epidermal growth factor receptor (EGFR) inhibitor and application thereof. The compound containing the pyrimidine ring comprises a compound represented by formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof. The EGFR inhibitor comprises the compound containing the pyrimidine ring. The compound can inhibit one or more activating or resistant mutations in EGFR and can be used to prepare drugs for controlling EGFR tyrosine kinase activity or treating EGFR related diseases, such as cancers, diabetes, immune system diseases, neurodegenerative diseases or cardiovascular diseases, and is particularly suitable for preparing drugs for treating non-small cell lung cancer caused by EGFR mutations including sensitive mutations (such as an L858R mutation or an exon 19 deletion mutation) and drug-resistance mutations (such as an EGFR T790M mutation).

Description

Pyrimidine ring-containing compound, EGFR inhibitor and application thereof Technical field

The invention belongs to the technical field of medicine, in particular to a pyrimidine ring-containing compound, and also relates to an EGFR inhibitor and its preparation for regulating EGFR tyrosine kinase activity or treating EGFR related diseases, especially non-small cell lung cancer. Drug application.

Background technique

The Epidermal Growth Factor Receptor (EGFR) is a transmembrane protein tyrosine kinase of the erbB receptor family. When bound to a growth factor ligand (eg, epidermal growth factor (EGF)), the receptor can homodimerize with an additional EGFR molecule, or with another family member (eg, erbB2 (HER2), erbB3 (HER3), Or erbB4 (HER4)) heterodimerization occurs. Homologous dimerization and/or heterodimerization of the erbB receptor results in phosphorylation of key tyrosine residues in the intracellular domain and results in stimulation of many intracellular signaling pathways involved in cell proliferation and survival. Deregulation of erbB family signaling promotes proliferation, invasion, metastasis, angiogenesis, and tumor cell survival, and has been described in many human cancers, including lung cancer, head and neck cancer, and breast cancer.

Therefore, the erbB family represented as legitimate targets for anticancer drug development, as many drugs targeting EGFR or erbB2 is now widely used in clinical applications, including Gefitinib (IRESSA ^TM), erlotinib (TARCEVA ^TM) and lapatinib (TYKERB ^TM) and the like. erbB receptor signaling and its involvement in tumorigenesis are provided in New England Journal of Medicine (2008, 358, 1160-1174) and Biochemical and Biophysical Research Communications (2004, 319, 1-11). Detailed discussion.

Lung cancer is the world's highest incidence of cancer. It ranks first among all cancers in China, and it is also the cancer with the highest morbidity and mortality in China. About 30% of lung cancer patients in China have EGFR mutations, of which L858R and exon 19 deletion mutations account for more than 90%. These patients are more sensitive to EGFR inhibitors. The existing first-generation EGFR inhibitors such as erlotinib and gefitinib have good curative effect on such patients, which can reduce tumors in more than 60% of patients and significantly prolong the progression-free survival of patients. . However, the vast majority of patients will acquire resistance within 6-12 months. This resistance pattern is a further mutation of EGFR, which reduces its sensitivity to first-generation EGFR inhibitors. The most common of these mutations is the so-called "gatekeeper" mutation T790M (Science, 2004, Vol. 304, 1497-1500; New England Journal of Medicine 2004, 350, 2129-2139), from the original L- at this site. Threonine (T) is replaced by L-methionine (M), and the mutated EGF tyrosine kinase R no longer binds to gefitinib or erlotinib, thus making the first generation of EGFR inhibitors No longer effective, resulting in such patients currently in a state of no drug availability. Clinically, 50% of patients who developed resistance to first-generation EGFR inhibitors had EGFR T790M mutations. The first generation of EGFR inhibitors, such as gefitinib and erlotinib, in the T790M mutant cell line H1975 were greater than 3 [mu]M and were essentially inactive.

The second-generation irreversible pan-EGFR inhibitor (Afatinib BIBW2992) currently on the market is significantly better than the first-generation EGFR inhibitor in patients with EGFR-mutant lung cancer. However, the second-generation inhibitor also has a strong wild-type EGFR inhibitory activity, and the inhibitory activity against wild-type EGFR is significantly higher than that of the drug-resistant T790M mutation. The toxic side effects such as rash of the patient are severe and the drug-resistant patients have poor efficacy, only small Some first-generation EGFR inhibitor-resistant patients respond to these drugs.

To improve the inhibitory activity against mutations such as resistant EGFR T790M, and at the same time reduce the inhibitory activity against wild-type EGFR, develop third-generation EGFR mutations with higher activity, better selectivity and lower toxicity. Stereoselective inhibitors are of great significance.

Summary of the invention

It is an object of the present invention to provide a pyrimidine ring-containing compound which inhibits the activation or resistance mutation of one or more EGFR.

A second object of the present invention is to provide an EGFR inhibitor comprising the above pyrimidine ring-containing compound.

A third object of the present invention is to provide a use of the above EGFR inhibitor for the preparation of a medicament for modulating EGFR tyrosine kinase activity or treating an EGFR-related disease.

In order to achieve the above object, the technical solution adopted by the present invention is:

A pyrimidine ring-containing compound comprising a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:

Wherein R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, ester, C _1-12 alkyl, C _1-12 haloalkyl, C _3-12 cycloalkyl, C _3-12 halocycloalkyl, C _1-12 alkoxy, C _1-12 haloalkoxy, C _3-12 cycloalkoxy, C _3-12 halocycloalkoxy a C _1-12 alkylthio group, a C _1-6 acyl group, a C _1-12 alkylamino group or a C _3-12 cycloalkylamino group, or a C _1-12 alkyl group having a substituent R ₁₀ , C _1-12 haloalkyl group, a C _3-12 cycloalkyl group, C _3-12 halogenated cycloalkyl, C _1-12 alkoxy, C _1-12 haloalkoxy group, a C _3-12 a cycloalkoxy group, a C _3-12 halocycloalkoxy group, a C _1-12 alkylthio group, a C _1-6 acyl group, a C _1-12 alkylamino group or a C _3-12 cycloalkylamino group, or a group formed by replacing one or more C of the above groups with one or more heteroatoms of N, O, S;

R _{3 is} selected from any one of the following structures:

R _{4 is} selected from any one of the following structures:

R ₅ is selected from C _1-12 alkyl group, with the substituent R ₁₀ is C _1-12 alkyl, C _3-12 cycloalkyl, and substituted with C _3-12 cycloalkyl group R ₁₀ group, a C _6-14 aryl group, having a substituent group R C _{10 6-14} aryl, C _5-12 heteroaryl, R C _5-12 substituent having ₁₀ heteroaryl, Or a group formed by replacing one or more C of the above groups with one or more heteroatoms of N, O, S;

X ₁ , X ₂ , X ₃ and X ₅ are each independently selected from C, N, O or S; X _{4 is} selected from C or N; X ₂ and X ₃ are each present or absent, and are bonded by X ₁ , X _{4 is} connected to each other; the dotted line represents a single bond, and the single bond exists or does not exist, but the two single bonds do not exist at the same time;

R ₆ , R ₇ , R ₈ and R ₉ are each independently selected from the group consisting of H, O, halogen, hydroxy, amino, carboxy, decyl, cyano, nitro, ester, C _1-12 alkyl, C _{1- 12} haloalkyl, C _3-12 cycloalkyl, C _3-12 halocycloalkyl, C _1-12 alkoxy, C _1-12 haloalkoxy, C _3-12 naphthenic Oxyl, C _3-12 halocycloalkoxy, C _1-12 alkylthio, C _1-6 acyl, C _1-12 alkylamino, C _3-12 cycloalkylamino, C _{6- 14} aryl, C _5-12 heteroaryl, or C _1-12 alkyl with substituent R ₁₀ , C _1-12 haloalkyl, C _3-12 cycloalkyl, C _{3 12} halocycloalkyl, C _1-12 alkoxy, C _1-12 haloalkoxy, C _3-12 cycloalkoxy, C _3-12 halocycloalkoxy, C ₁ An alkylthio group of _-12 , an acyl group of _C1-6 , an alkylamino group of _C1-12, a cycloalkylamino group of _C3-12 , an aryl group of _C6-14, a heteroaryl group of _C5-12 , or the above a group formed by replacing one or more C in the group with one or more heteroatoms of N, O, S; when R ₆ , R ₇ , R ₈ and R _{9 are} selected from O, corresponding thereto X _1, X _2, X ₃ and X ₅ is C or S, and is connected to a double bond, R ₆ R _7, R ₈ and R ₉ are the presence or absence, the number of each connected thereto by the X _1, X _2, X ₃ and X ₅ valence decisions;

_{Y 1, Y 2, Y 3} , Y 4, Y 5 are each independently selected from hydrogen, halogen, C _1-12 alkyl, C _1-12 with ₁₀ alkyl substituent R, C _3-12 cycloalkyl, substituted with a cycloalkyl group of R ₁₀ is C _3-12, C _1-12 alkylamino group or with a substituent R C ₁₀ alkylamino of _{1 to 12;}

R _{Y is} selected from an alkyl group, an alkyl group having a substituent R ₁₀ , a cycloalkyl group, a cycloalkyl group having a substituent R ₁₀ , or one or more of the above groups C is N, O, S Substituting one or more heteroatoms to form a group;

The substituent R _{10 is} selected from the group consisting of H, halogen, hydroxy, amino, carboxy, decyl, cyano, nitro, ester, alkyl of C _1-12 , cycloalkyl of C _3-12 , alkyl of C _1-12 Oxyl, C _3-12 cycloalkoxy, C _1-12 haloalkyl, C _3-12 halocycloalkyl, C _1-6 acyl, C _2-6 halo acyl, C _{1 -12} alkylamino group, a halogenated C _1-12 alkylamino, C _3-12 cycloalkylamino group, the cycloalkyl C _3-12 haloalkyl amino, C _1-12 alkylthio or C _1-12 halogenated alkylthio base;

All of the hydrogens in the above compounds are independently substituted or unsubstituted by deuterium.

In the above pyrimidine ring-containing compound, the substituted phenyl group is a halogenated phenyl group or a halogenated phenyl group having R ₁₁ ; the substituted cycloalkyl group is a halogenated cycloalkyl group or has R halocycloalkyl _11; and a substituent for the alkoxy group or a haloalkoxy group with R ₁₁ haloalkoxy; cycloalkoxy group is substituted with alkoxy or haloalkoxy ring with R a halocycloalkoxy group of ₁₁ ; the alkylamino group having a substituent is a haloalkylamino group or a haloalkylamino group having R ₁₁ ; the substituted cycloalkylamino group is a halocycloalkylamino group or a halogenated group having R ₁₁ a cycloalkylamino group; the aryl group having a substituent is a halogenated aryl group or a halogenated aryl group having R ₁₁ ; the heteroaryl group having a substituent is a halogenated heteroaryl group or a halogenated heterocyclic group having R ₁₁ Aryl.

Wherein R _{11 is} selected from the group consisting of H, hydroxy, amino, carboxy, decyl, cyano, nitro, ester, C _1-12 alkyl, C _3-12 cycloalkyl, C _1-12 alkoxy , C _3-12 cycloalkoxy, C _1-12 haloalkyl, C _3-12 halocycloalkyl, C _1-6 acyl, C _2-6 halo acyl, C _1-12 An alkylamino group, a C _1-12 haloalkylamino group, a C _3-12 cycloalkylamino group, a C _3-12 halocycloalkylamino group, a C _1-12 alkylthio group or a C _1-12 haloalkylthio group.

A pyrimidine ring-containing compound of the present invention, which comprises a compound of the formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof; the compound inhibits one or more EGFR Activation or resistance mutations, such as L858R activating mutants, Exon19 deletion EGFR activating mutants, T790M resistant mutants.

Preferably, the pyrimidine ring-containing compound comprises a compound represented by formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:

Wherein R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, ester, C _1-12 alkyl, C _1-12 haloalkyl, C _3-12 cycloalkyl, C _3-12 halocycloalkyl, C _1-12 alkoxy, C _1-12 haloalkoxy, C _3-12 cycloalkoxy, C _3-12 halocycloalkoxy a C _1-12 alkylthio group, a C _1-6 acyl group, a C _1-12 alkylamino group or a C _3-12 cycloalkylamino group, or a C _1-12 alkyl group having a substituent R ₁₀ , C _1-12 haloalkyl, C _3-12 cycloalkyl, C _3-12 halocycloalkyl, C _1-12 alkoxy, C _1-12 haloalkoxy, C _3-12 a cycloalkoxy group, a C _3-12 halocycloalkoxy group, a C _1-12 alkylthio group, a C _1-6 acyl group, a C _1-12 alkylamino group or a C _3-12 cycloalkylamino group, Or a group formed by replacing one or more C of the above groups with one or more heteroatoms of N, O, S;

R _{3 is} selected from any one of the following structures:

R _{4 is} selected from any one of the following structures:

R ₅ is selected from C _1-12 alkyl group, with the substituent R ₁₀ is C _1-12 alkyl, C _3-12 cycloalkyl, and substituted with C _3-12 cycloalkyl group R ₁₀ group, a C _6-14 aryl group, having a substituent group R C _{10 6-14} aryl, C _5-12 heteroaryl, R C _5-12 substituent having ₁₀ heteroaryl, Or a group formed by replacing one or more C of the above groups with one or more heteroatoms of N, O, S;

R ₇ and R ₈ are each independently selected from the group consisting of H, halogen, hydroxy, amino, carboxy, decyl, cyano, nitro, ester, C _1-12 alkyl, C _3-12 cycloalkyl, C ₁ Alkoxy group of _-12 , cycloalkyloxy group of C _3-12 , alkylthio group of C _1-12 , acyl group of C _1-6 , alkylamino group of C _1-12 , cycloalkylamino group of C _3-12 , An aryl group of C _{6-14 ,} a heteroaryl group of C _5-12 , or a C _1-12 alkyl group having a substituent R ₁₀ , a C _3-12 cycloalkyl group, a C _1-12 alkoxy group. , C _3-12 cycloalkoxy, C _1-12 alkylthio, C _1-6 acyl, C _1-12 alkylamino, C _3-12 cycloalkylamino, C _6-14 aryl a group, a C _5-12 heteroaryl group, or a group formed by replacing one or more C of the above groups with one or more heteroatoms of N, O, S;

_{Y 1, Y 2, Y 3} , Y 4, Y 5 are each independently selected from hydrogen, halogen, C _1-12 alkyl, C _1-12 with ₁₀ alkyl substituent R, C _3-12 cycloalkyl, substituted with a cycloalkyl group of R ₁₀ is C _3-12, C _1-12 alkylamino group or with a substituent R C ₁₀ alkylamino of _{1 to 12;}

_{The Y} R is selected from C _1-12 alkyl group, an alkyl substituent group R ₁₀ is C _1-12, C _3-12 cycloalkyl, and substituted with C _3-12 cycloalkyl group R ₁₀ a group, or a group formed by replacing one or more C of the above groups with one or more heteroatoms of N, O, S;

The substituent R _{10 is} selected from the group consisting of H, halogen, hydroxy, amino, carboxy, decyl, cyano, nitro, ester, alkyl of C _1-12 , cycloalkyl of C _3-12 , alkyl of C _1-12 Oxyl, C _3-12 cycloalkoxy, C _1-12 haloalkyl, C _3-12 halocycloalkyl, C _1-6 acyl, C _2-6 halo acyl, C _{1 -12} alkylamino group, a halogenated C _1-12 alkylamino, C _3-12 cycloalkylamino group, the cycloalkyl C _3-12 haloalkyl amino, C _1-12 alkylthio or C _1-12 halogenated alkylthio base;

All of the hydrogens in the above compounds are independently substituted or unsubstituted by deuterium.

Further preferred:

R ₁ is preferably selected from hydrogen, halogen, trifluoromethyl or cyano.

R ₂ is preferably selected from the group consisting of methoxy, monofluoromethoxy, difluoromethoxy, deuterated monofluoromethoxy, deuterated difluoromethoxy, trifluoromethoxy, C _2-6 alkoxy. a halogenated alkoxy group of C _2-6, a cycloalkoxy group of C _3-6 or a halogenated cycloalkoxy group of C _3-6 .

R ₃ is

R _{4 is} selected from any one of the following structures:

Y ₁ , Y ₂ , Y ₃ , Y ₄ , Y ₅ are each independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C ₃ a halogenated cycloalkyl group of _-6 or an alkylamino group of _1-6 .

R ₅ is preferably selected from phenyl or substituted phenyl, heteroaryl or substituted heteroaryl, and the substituent may be optionally selected from halogen, cyano, nitro, ester, C _1-4 alkyl or ring. Alkyl, C _1-4 alkoxy or cycloalkoxy, C _1-4 haloalkyl, C _1-4 acyl, C _1-6 alkylamino or cycloalkylamino, and may be monosubstituted, disubstituted or tri Replace.

The compounds of the present invention can be prepared by a variety of techniques, some of which are set forth below, and those skilled in the art will understand that these methods are representative and not limiting.

The synthesis of the above compounds is as follows:

The compound SM ₁ and the compound SM ₂ can be reacted by a method such as nucleophilic substitution or coupling to obtain a final product P (that is, a compound represented by the formula (II)).

Among them, the synthesis method of the compound SM ₁ is as follows:

The starting compound a-1 is first subjected to nucleophilic substitution reaction with R ₅ -NH ₂ to form compound a-2, and then compound a-2 is further reacted to form compound a-3 by Heck coupling reaction, and finally, ring closure is carried out to obtain compound SM ₁ .

The synthesis of compound SM ₂ is as follows:

The starting compound 1 is firstly made into a phenol sodium salt, and then reacted with methyl iodide or ethyl difluorobromoacetate to prepare a compound 3, and the compound 3 is reduced to obtain a compound 4, which is then nitrated, and the amino group is protected with di-tert-butyl dicarbonate. Compound 6 is further substituted with a precursor of the substituent R ₃ to obtain a compound 7, and the compound 7 is reduced to obtain a compound 8, which is then reacted with a precursor of the substituent R ₄ to obtain a compound SM ₂ .

A still further preferred pyrimidine ring-containing compound, the compound of formula (II) is selected from the group consisting of:

The pharmaceutically acceptable salt is a mineral acid salt or an organic acid salt selected from the group consisting of a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a sulfate salt, a hydrogen sulfate salt, a nitrate salt, and a phosphate salt. An acid phosphate; the organic acid salt is selected from the group consisting of formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, Fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, besylate, salicylate, picrate, valley Alkaloids, salicylates, ascorbates, camphorates, camphorsulfonates.

An EGFR inhibitor comprising the above pyrimidine ring-containing compound.

The EGFR inhibitor further comprises a pharmaceutically acceptable carrier.

The EGFR inhibitor of the present invention, including the composition of any one or more of the above pyrimidine ring-containing compounds, further comprises a pharmaceutically acceptable carrier.

The above pyrimidine ring-containing compounds can be administered in a suitable dosage form with one or more pharmaceutically acceptable carriers. These dosage forms are suitable for oral, rectal, topical, intraoral, and other parenteral administration (eg, For example, subcutaneous, muscle, vein, etc.).

The pharmaceutical compositions of this invention are formulated, quantified, and administered in a manner consistent with medical practice. The "effective amount" of a compound administered is determined by the particular condition being treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.

A use of the above EGFR inhibitor for the preparation of a medicament for modulating EGFR tyrosine kinase activity or treating an EGFR-related disease.

The regulation of EGFR tyrosine kinase activity or treatment of EGFR-related diseases refers to cancer, diabetes, immune system diseases, neurodegenerative diseases or cardiovascular diseases.

The EGFR inhibitor is suitable for the preparation of a medicament for regulating EGFR tyrosine kinase activity or treating EGFR-related diseases, and is particularly suitable for preparing a medicament for cancer treatment, such as non-small cell lung cancer.

A use of the above EGFR inhibitor for the preparation of a medicament for the treatment of non-small cell lung cancer.

The pyrimidine ring-containing compound of the present invention, that is, the compound of the formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, can be used for the preparation of a EGFR tyrosine kinase activity or Drugs for the treatment of EGFR-related diseases, such as cancer, diabetes, immune system diseases, neurodegenerative diseases or cardiovascular diseases, are especially suitable for the preparation of mutations by EGFR, including sensitive mutations (such as L858R mutation or deletion of exon 19) and Drug-resistant mutations (such as the EGFR T790M mutation), a therapeutic drug for non-small cell lung cancer.

The pyrimidine ring-containing compound of the present invention, that is, the compound of the formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, can be used as a single therapeutic treatment in anticancer therapy. Alternatively, or in addition to the compounds of the invention, it may be combined with conventional surgery or radiation therapy or chemotherapy or immunotherapy. These therapies can be administered in parallel, simultaneously, sequentially, or separately with the compounds of the invention, and can comprise one or more of the following: such as gefitinib, erlotinib, ect. Nipa, lapatinib, XL647, NVP-AEE-788, ARRY-334543, vandetanib, PF00299804, cetuximab, panituzumab, pertuzumab, zarumumab, Nimotuzumab, MDX-214, CDX-110, IMC-11F8, CNF2024, tandorimycin, aspironmycin, IPI-504, NVP-AUY922, and the like.

The pyrimidine ring-containing compound of the present invention is a selective inhibitor of EGFR mutations discovered by the inventors after long-term and intensive research, and in vitro experiments show that it can inhibit the proliferation of EGFRT790M/L858R double mutant enzyme at nanomolar concentration. However, the inhibition of wild-type EGFR enzyme is relatively weak. Therefore, these compounds can be used not only for the treatment of EGFR-sensitive mutant cancers, but also for the cases of secondary resistance in the current EGFR-TKI treatment; and their mutation selectivity greatly reduces the inhibition of wild-type EGFR. Toxic side effects are an ideal substitute for the first and second generation EGFR-TKI.

Unless otherwise stated, the following terms used in this application (including the specification and claims) have the definitions given below.

"Alkyl" refers to a monovalent straight or branched chain saturated hydrocarbon group containing from 1 to 12 carbon atoms consisting solely of carbon and hydrogen atoms. The "alkyl group" is preferably an alkyl group of 1 to 6 carbon atoms, that is, a C ₁ -C ₆ alkyl group, more preferably a C ₁ -C ₄ alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.

"Alkoxy" refers to a radical of the formula -OR wherein R is alkyl as defined herein. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, t-butoxy, and the like.

"Halogen (halo)" means a fluorine, chlorine, bromine or iodine substituent.

"Haloalkyl" refers to an alkyl group, as defined herein, wherein one or more hydrogens are replaced by the same or different halogens. Examples of the haloalkyl group include -CH ₂ Cl, -CH ₂ CF ₃ , -CH ₂ CCl ₃ , a perfluoroalkyl group (for example, -CF ₃ ), and the like.

"Haloalkoxy" refers to a radical of the formula -OR wherein R is haloalkyl as defined herein. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, and the like.

"Cycloalkyl" refers to a monovalent saturated carbocyclic group consisting of a mono- or bicyclic ring having from 3 to 12, preferably from 3 to 10, more preferably from 3 to 6 ring atoms. The cycloalkyl group can be optionally substituted by one or more substituents, wherein each substituent is independently hydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino or dialkylamino. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

"Cycloalkoxy" refers to a radical of the formula -OR wherein R is cycloalkyl as defined herein. Exemplary cycloalkyloxy groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.

"Acyl" refers to a radical of the formula -C(O)R wherein R is alkyl as defined herein. Exemplary acyl groups include acetyl, n-propionyl, isopropionyl, n-butyryl, isobutyryl, t-butyryl and the like.

"Ester group" refers to a radical of the formula -C(O)OR wherein R is alkyl as defined herein. Exemplary ester groups include -C(O)OMe, -C(O)OEt, and the like.

"Alkylthio" refers to _a radical of the formula -SR _a where R _a is H or alkyl as defined herein.

"Alkylamino" refers to _a radical of the formula -NR _a R _b wherein R _a is H or alkyl as defined herein and R _b is alkyl as defined herein.

"Cycloalkylamino" refers to _a radical of the formula -NR _a R _b wherein R _a is H, alkyl as defined herein or cycloalkyl as defined herein, and R _b is cycloalkane as defined herein base.

"Heteroaryl" refers to a monocyclic, bicyclic or tricyclic radical of 5 to 12 ring atoms containing at least one ring heteroatom containing one, two or three selected from N, O or S, remaining The ring atom is an aromatic ring of C, and it should be clear that the point of attachment of the heteroaryl group should be on the aromatic ring. The heteroaryl group is preferably 5-8 ring atoms, more preferably 5-6 ring atoms. Examples of heteroaryl groups include, but are not limited to, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, furanyl , pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidinyl, quinolyl, isoquinolinyl, benzofuranyl, benzofuranyl, benzothienyl, benzothiopyranyl, benzo Imidazolyl, benzoxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, fluorenyl, isodecyl, triazolyl, triazinyl , quinoxalinyl, fluorenyl, quinazolinyl, quinazinyl, naphthyridinyl, pteridinyl, oxazolyl, aza

Base, diaza

Base, acridinyl and the like.

Detailed ways

The invention will now be further described in conjunction with specific embodiments.

In a specific embodiment, the pyrimidine ring-containing compound comprises a compound of formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:

Wherein R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, ester, C _1-12 alkyl, C _1-12 haloalkyl, C _3-12 cycloalkyl, C _3-12 halocycloalkyl, C _1-12 alkoxy, C _1-12 haloalkoxy, C _3-12 cycloalkoxy, C _3-12 halocycloalkoxy a C _1-12 alkylthio group, a C _1-6 acyl group, a C _1-12 alkylamino group, a C _3-12 cycloalkylamino group, or one or more of the above groups C is N, O, S a group formed by replacing one or more heteroatoms in the group, or a group formed by substituting one or more of the above groups H by R ₁₁ ;

R _{3 is} selected from any one of the following structures:

R _{4 is} selected from any one of the following structures:

R _{5 is} selected from C _1-12 alkyl, C _1-12 haloalkyl, C _3-12 cycloalkyl, C _3-12 halocycloalkyl, aryl, haloaryl, heteroaryl Or a halogenated heteroaryl group, or a group formed by replacing one or more C of the above groups with one or more heteroatoms of N, O, S, or one or more of the above groups H a group formed by substitution of R ₁₁ ;

R ₇ and R ₈ are each independently selected from the group consisting of H, halogen, hydroxy, amino, carboxy, decyl, cyano, nitro, ester, C _1-12 alkyl, C _1-12 haloalkyl, C _{3 - 12} cycloalkyl, C _3-12 halocycloalkyl, C _1-12 alkoxy, C _1-12 haloalkoxy, C _3-12 cycloalkoxy, C _3-12 a halogenated cycloalkoxy group, a C _1-12 alkylthio group, a C _1-6 acyl group, a C _1-12 alkylamino group, a C _3-12 cycloalkylamino group or an aryl group, or one of the above groups or a group formed by replacing a plurality of C with one or more hetero atoms of N, O, S, or a group formed by substituting one or more of the above groups H by R ₁₁ ;

Y ₁ , Y ₂ , Y ₃ , Y ₄ , Y ₅ are each independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C ₃ a halogenated cycloalkyl group of _-6 or an alkylamino group of C _1-6 ;

R _{Y is} selected from C _1-12 alkyl, C _1-12 haloalkyl, C _3-12 cycloalkyl, C _3-12 halocycloalkyl, or one or more of the above groups a group formed by replacing one or more hetero atoms in N, O, S, or a group formed by substituting one or more of the above groups H by R ₁₁ ;

R _{11 is} selected from the group consisting of H, hydroxy, amino, carboxy, decyl, cyano, nitro, ester, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _1-6 haloalkyl, C _3-6 halocycloalkyl, C _1-6 acyl, C _1-6 halo acyl, C _1-6 alkane An amino group, a C _1-6 haloalkylamino group, a C _3-6 cycloalkylamino group, a C _3-6 halocycloalkylamino group, a C _1-6 alkylthio group or a C _1-6 haloalkylthio group;

All of the hydrogens in the above compounds are independently substituted or unsubstituted by deuterium.

The synthesis of the above compounds is as follows:

The compound SM ₁ and the compound SM ₂ can be reacted by a method such as nucleophilic substitution or coupling to obtain a final product P (that is, a compound represented by the formula (II)).

Among them, the synthesis method of the compound SM ₁ is as follows:

The starting compound a-1 is first subjected to nucleophilic substitution reaction with R ₅ -NH ₂ to form compound a-2, and then compound a-2 is further reacted to form compound a-3 by Heck coupling reaction, and finally, ring closure is carried out to obtain compound SM ₁ .

The synthesis of compound SM ₂ is as follows:

The starting compound 1 is firstly made into a phenol sodium salt, and then reacted with methyl iodide or ethyl difluorobromoacetate to prepare a compound 3, and the compound 3 is reduced to obtain a compound 4, which is then nitrated, and the amino group is protected with di-tert-butyl dicarbonate. Compound 6 is further substituted with a precursor of the substituent R ₃ to obtain a compound 7, and the compound 7 is reduced to obtain a compound 8, which is then reacted with a precursor of the substituent R ₄ to obtain a compound SM ₂ .

The specific implementation process is as follows:

Synthesis of Compound SM ₁ :

Among them, the synthesis of the compound A1-2: taking a 250 ml single-mouth bottle, adding 11.4 g (0.05 mol) of 2,4-dichloro-5-bromopyrimidine (compound A1-1), 6.05 g (0.06 mol) of triethyl The amine, 6.66 g (0.06 mol) of 4-fluoroaniline and 150 ml of n-butanol were heated at 75 ° C overnight with stirring and protected with argon. The next day, n-butanol was distilled off, and 100 ml of ethyl acetate and 100 ml of water were added, and the mixture was stirred for 10 minutes and then layered. The aqueous phase was extracted twice with ethyl acetate 100 mL*2. 15.7 g of product was obtained with a little 4-fluoroaniline and stirred with a little diethyl ether to give 13 g of a white solid. The analytical data for this compound are as follows: ¹ H NMR (CDCl ₃ ) δ 8.30 (s, 1H), 7.55 (m, 2H), 7.22 (broad, 1H), 7.10 (m, 2H).

Synthesis of Compound A1-SM ₁ : A 50 ml single-mouth bottle was taken, and 1.00 g (3.3 mmol) of the starting compound A1-2, 0.712 g (8.27 mmol) of crotonic acid, 4.5 g (34.8 mmol) of DIEA (4.5 g (34.8 mmol)) were sequentially added under stirring. N,N-diisopropylethylamine), 5 ml of dry tetrahydrofuran, 0.038 g (0.01 mmol) of di(cyanobenzene)palladium dichloride and 0.030 g (0.01 mmol) of tris(o-methylphenyl) phosphorus. A condensing tube is added and argon gas is protected. The reaction was carried out at 70 ° C for 16 hours while stirring. After sampling, the starting material was reacted, and 0.8 ml (8.5 mmol) of acetic anhydride was directly added at 70 °C. After 4 hours, the samples were tested and most of them were products. Cool down, add 10 ml of methanol, and pass directly through the column. There was obtained 1.1 g of an oily substance containing a large amount of acetic acid, and the mixture was stirred with ethyl acetate and petroleum ether to obtain 0.55 g of a yellow solid. The analytical data for this compound are as follows: ¹ H NMR (CDCl ₃ ) δ 8.82 (s, 1H), 7.21. (m, 4H), 6.68 (s, 1H), 2.54 (s, 3H).

A series of SM ₁ compounds (but not limited to these compounds) were synthesized using this method as follows:

Synthesis of Compound SM ₂ :

method 1:

Among them, the synthesis of the compound B1-2: 50 g of the compound B1-1 was dissolved in 250 ml of tetrahydrofuran, 12.6 g of sodium hydroxide was dissolved in 250 ml of water, and then the two were mixed and stirred overnight, the tetrahydrofuran was spun off, and the aqueous layer was It was washed twice with dichloromethane, most of the water was spun off, the remaining portion was naturally evaporated, and dried in a vacuum oven to give 55 g of an orange solid. The analytical data of the compound are as follows: 1H-NMR (400 MHz, & DMSO): δ: 7.73 (t, J = 8.22, 1H); 6.02 (dd, J = 2.97, 13.79, 1H); 5.77 (dt, J = 2.87, 7.45, 1H).

Synthesis of Compound B1-3: 7 g of Compound B1-2 and 17.5 g of potassium carbonate were added to the bottle, and then under argon atmosphere, 700 ml of DMF (dimethylformamide), 70 g of hydrophobic water and 70 g of water were added to the reaction flask. 17.5 g of ethyl bromodifluoroacetate, gradually warmed to 50 ° C, stirred overnight, TLC showed that most of the starting material disappeared, after cooling, the reaction solution was diluted with water, extracted three times with dichloromethane, combined several times, washed with water 5 The organic layer was dried and dried over a column to afford 6.2 g of pale yellow oil. The analytical data of this compound was as follows: 1H-NMR (400 MHz, CDCl ₃ ): δ: 8.01 (q, J = 5.58, 3.51, 1H); 7.07-7.15 (m, 2H).

Synthesis of Compound B1-4: 1 g of Compound 3 was dissolved in 25 ml of ethanol under a hydrogen atmosphere at room temperature under normal pressure overnight. The TLC was used to detect the disappearance of the starting material, the palladium on carbon was filtered off, washed with ethanol, and the solvent was evaporated to give a compound (yield: The analytical data of the compound are as follows: 1H-NMR (400 MHz, CDCl ₃ ): δ: 6.70-6.84 (m, 3H); 3.71 (br, 2H); MS m/z (ESI): 179 [M+H] ⁺ .

Synthesis of Compound B1-5: 0.78 g of Compound B1-4 was added portionwise to 5 ml of concentrated sulfuric acid cooled in an ice water bath at a temperature below 10 ° C to dissolve all, then 0.45 g of potassium nitrate was added and stirred at room temperature overnight. The reaction mixture was poured into ice water, then basified with aqueous ammonia. The organic layer was extracted with ethyl acetate. The organic layer was combined, washed twice with brine, dried and evaporated. The analytical data of the compound are as follows: 1H-NMR (400 MHz, CDCl ₃ ): δ: 7.46 (d, J = 6.48, 1H); 6.99 (d, J = 10.94, 1H); 4.03 (br, 1H); MS m /z(ESI): 224 [M+H] ⁺ .

Synthesis of Compound B1-6: 3.1 g of Compound B1-5 and 171 mg of DMAP (4-dimethylaminopyridine) were dissolved in 40 ml of acetonitrile, and 3.6 g of (Boc) 2 O (di-tert-butyl dicarbonate) was added thereto under ice bath. Then, it was gradually warmed to room temperature and stirred overnight, and the material disappeared by TLC, and then the reaction mixture was directly spun, and the column was passed to obtain 3 g of a yellow solid. The analytical data of the compound are as follows: 1H-NMR (400 MHz, CDCl ₃ ): δ: 8.99 (d, J = 8.10, 1H); 7.07 (d, J = 12.15, 1H); 6.85 (br, 1H); MS m /z(ESI): 324 [M+H] ⁺ .

Synthesis of compound B1-7: 1.5 g of compound B1-6, 950 mg of N,N,N'-trimethylethylenediamine and 1.8 g of diisopropyldiamine were dissolved in 20 ml of DMA (N,N-di Methyl acetamide), then warmed to 60 ° C and stirred overnight, TLC detection of the disappearance of the starting materials, the reaction solution was poured into water and EA (ethyl acetate), the aqueous layer was washed once with EA, then the EA layer was washed with water 5 The DMA was removed several times and then dried to dry the organic layer. A column of 2.2 g of a yellow solid was obtained. The crude product was used directly in the next step.

Synthesis of compound B1-8: 2.2 g of compound B1-7 was dissolved in 40 ml of EA, then 0.2 g of palladium carbon was added, and the mixture was stirred at room temperature overnight under a hydrogen atmosphere. The disappearance of the starting material by TLC, the palladium carbon was filtered off, and the mother liquor was spun off. 2 g of yellow oil. The analytical data of the compound are as follows: 1H-NMR (400 MHz, CDCl ₃ ): δ: 7.47 (s, 1H); 6.78 (s, 1H); 6.69 (br, 1H); 4.25 (br, 2H); 2.85 (t , J = 6.89, 1H); 2.62 (s, 3H); 2.36 (t, J = 6.48, 1H); 2.25 (s, 6H); MS m/z (ESI): 376 [M+H] ⁺ .

Synthesis of compound B1-SM ₂ : 2 g of compound B1-8 was dissolved in 40 ml of dichloromethane, then 0.83 g of diisopropylethylamine was added, then the nitrogen salt bath was cooled to 0 ° C and then cooled under nitrogen. 0.55 g of acryloyl chloride was added dropwise. After the dropwise addition, the temperature was gradually raised to room temperature, stirred for two hours, and the disappearance of the starting material by TLC, followed by spin-drying the reaction mixture, and then adding 5 ml of concentrated hydrochloric acid to the residue and stirring for two hours, TLC showed The raw material disappeared, and then the pH was adjusted to about 8 with a saturated aqueous solution of sodium carbonate, and the system was basified. The reaction mixture was extracted three times with EA, and the organic layer was combined, dried, and dried to give 750 mg of a yellow oil. The analytical data of the compound are as follows: 1H-NMR (400 MHz, CDCl ₃ ): δ: 8.07 (s, 1H); 6.92 (s, 1H); 6.39 (dd, J = 1.63, 17.09, 1H); 6.22 (dd, J = 10.48, 17.47, 1H); 5.68 (dd, J = 1.42, 9.91, 1H); 3.81 (br, 2H); 2.77 (t, J = 5.44, 1H); 2.63 (s, 3H); 2.23 (s) , MSH/z (ESI): 330 [M+H] ⁺ .

Method 2:

Among them, the synthesis of the compound B2-2: 50 g of the starting compound B2-1 was dissolved in 500 ml of methanol, and 10 g of Pd/C was added thereto, and hydrogenation was carried out at 35 ° C for two days. Point board monitoring, raw material reaction is completed, and processed. The Pd/C was directly filtered off, and the methanol phase was spun to obtain a crude product (yield: 39 g).

Synthesis of Compound B2-3: 39 g of the starting compound B2-2 was added to 500 ml of concentrated sulfuric acid, added under ice salt bath, and fully dissolved at T < 10 ° C; 1 liter of potassium nitrate was added thereto while maintaining the temperature, and stirred at room temperature overnight. The next day, poured into ice water, adjusted to pH > 7 with aqueous ammonia, extracted with ethyl acetate, dried, and passed through a column to give 44 g of product. The analytical data of this compound are as follows: ¹ H NMR (CDCl ₃ ) δ 7.39 (d, J = 7.2 Hz, 1H), 6.63 (d, J = 12.4 Hz, 1H), 3.94 (s, 3H), 3.90 (broad , 2H).

Synthesis of compound B2-4: 20 g of starting compound B2-3, added to 500 ml of dichloromethane, cooled to -5 ° C in an ice salt bath; 1.1 eq of di-tert-butyl dicarbonate in dichloromethane was added dropwise. After the dropwise addition, 0.2 eq of DMAP (4-dimethylaminopyridine) was added; the temperature was naturally raised to room temperature and stirred overnight; the next day, the plate was plated, the reaction was completed, and the column was passed to give 24 g of a yellow solid. The analytical data for this compound are as follows: ¹ H NMR (CDCl ₃ ) δ 8.89 (s, 1H), 6.97 (s, 1H), 6.71 (d, J = 12.4 Hz, 1H), 3.97 (s, 3H), 1.53 (s, 9H); MS: Calcd for C ₁₂ H ₁₅ FN ₂ O ₅ (MH) ^- : 286.1, Found: 285.0.

Synthesis of compound B2-5: 13.5 g of starting compound B2-4, added to 200 ml of DMA (N,N-dimethylacetamide), fully dissolved under stirring; and then added 2 eq of N, N, N'- Trimethylethylenediamine and 3 eq of DIEA (N,N-diisopropylethylamine) were heated to 110 ° C and stirred overnight; the next day, the reaction was completed; and treated, 22 g of crude oil was obtained, which was taken directly to the next step. The analytical data for this compound are as follows: ¹ H NMR (CDCl ₃ ) δ 8.54 (s, 1H), 6.85 (s, 1H), 6.60 (s, 1H), 3.90 (s, 3H), 3.22 (t, J = 6.8 Hz, 2H), 2.81 (s, 3H), 2.55 (t, J = 7.2 Hz, 2H), 2.26 (s, 6H), 1.49 (s, 9H); MS: Calcd for C ₁₇ H ₂₈ N ₄ O ₅ (M+H) ⁺ : 368.21, Found: 369.3.

Synthesis of compound B2-6: 22 g of starting compound B2-5, added to 400 ml of ethyl acetate, fully dissolved under stirring, and then added 4.07 g of Pd/C, hydrogenated at 20 ° C overnight; the next day, the raw material reaction After completion, the Pd/C was directly filtered off and concentrated to obtain a crude black oil of 17 g, which was directly taken to the next step. The analytical data of this compound are as follows: ¹ H NMR (CDCl ₃ ) δ 7.517 (s, 1H), 6.941 (s, 1H), 6.61 (s, 1H), 4.10 (m, 2H), 3.76 (s, 3H) , 2.92 (m, 2H), 2.62 (s, 3H), 2.40 (m, 2H), 2.27 (s, 6H), 1.49 (s, 9H); MS: Calcd for C ₁₇ H ₃₀ N ₄ O ₃ (M +H) ⁺ :338.23, Found: 339.4.

Synthesis of compound B2-7: 17.3 g of starting compound B2-6, 500 ml of dichloromethane and 1.2 eq of DIEA (N,N-diisopropylethylamine), cooled to -5 ° C in an ice salt bath, argon Gas protection; 1.1 eq of acryloyl chloride was added dropwise, and the temperature was naturally raised to room temperature; after 3 hours, the reaction was completed; the solvent was removed by direct distillation under low temperature to obtain a crude product of about 23 g. Go directly to the next step.

Synthesis of compound B2-SM ₂ : 23 g of starting compound B2-7, added to 50 ml of THF, cooled to -5 ° C in ice salt bath, concentrated hydrochloric acid 100 ml, temperature T < 10 ° C, stirred for 2 hours, then plate reaction Finished; treated, passed the column, and got 5.2g of product. The analytical data of this compound are as follows: ¹ H NMR (CDCl ₃ ) δ 10.10 (s, 1H), 7.97 (s, 1H), 6.68 (s, 1H), 6.41-6.21 (m, 2H), 5.65 (m, 1H), 3.81 (s, 3H), 3.76 (s, 2H), 2.82 (m, 2H), 2.65 (s, 3H), 2.20 (s, 6H); MS: Calcd for C ₁₅ H ₂₄ N ₄ O ₂ (M+H) ⁺ : 292.19, Found: 293.3.

Method 3:

Among them, the synthesis of the compound B3-2: 50 g of the starting compound B3-1 was added to 500 ml of DMF (dimethylformamide), and 1.5 eq of ethyl difluoroacetate and 2 eq of potassium carbonate were further added. Stir at room temperature for 10 min, add 3 eq of water, protect with argon; warm the oil bath to 50 ° C, after 4 hours, the reaction of the raw materials is completed, cool down to 0 ° C, quench with water; organic phase mixed with dichloromethane and petroleum ether The extract was dried, concentrated, and passed through a column to afford product 77 g. The analytical data of this compound are as follows: ¹ H NMR (CDCl ₃ ) δ 8.03 (dd, J = 9.2, 5.6 Hz, 1H), 7.149-7.081 (m, 2H), 6.645 (t, J = 72.4 Hz, 1H) .

Synthesis of compound B3-3: 77g of raw material compound B3-2, completely dissolved in 700ml of absolute ethanol, added with Pd/C 13g, hydrogenated at 20 °C overnight; spot plate monitoring, raw material reaction is completed, treatment; direct filtration of Pd /C, spin dry to get the crude product 55g, directly into the next step. The analytical data of this compound are as follows: ¹ H NMR (CDCl ₃ ) δ 6.84-6.70 (m, 3H), 6.468 (t, J = 73.6 Hz, 1H), 3.16 (broad, 2H); MS: Calcd for C ₇ H ₆ F ₃ NO (M+H) ⁺ : 178.04, Found: 178.00.

Synthesis of compound B3-4: 55g of raw material compound B3-3, added to 600ml of concentrated sulfuric acid, added under ice salt bath, fully dissolved at T<10°C, added 1ep potassium nitrate at constant temperature, and stirred at room temperature overnight; The next day, poured into ice water, adjusted to pH > 7 with aqueous ammonia, extracted with ethyl acetate, dried, and passed through a column to give 63 g of a tan product. The analytical data of this compound are as follows: ¹ H NMR (CDCl ₃ ) δ 7.46 (d, J = 7.2 Hz, 1H), 7.01 (d, J = 11.2 Hz, 1H), 6.597 (t, J = 72.4 Hz, 1H) ), 4.047 (broad, 2H).

Synthesis of compound B3-5: 11.1 g of starting compound B3-4, added to 200 ml of dichloromethane, cooled to -5 ° C in an ice salt bath, and dropwise added 1.1 eq of di-tert-butyl dicarbonate in dichloromethane After the dropwise addition, 0.2 eq of DMAP (4-dimethylaminopyridine) was added, and the temperature was naturally raised to room temperature and stirred overnight; the next day, the plate was plated, the reaction was completed, and the column was passed to obtain 9.7 g of a yellow product. The analytical data of this compound are as follows: ¹ H NMR (CDCl ₃ ) δ 9.00 (d, J = 8 Hz, 1H), 7.07 (d, J = 10.8 Hz, 1H), 6.864 (s, 1H), 6.661 (t, J = 71.2 Hz, 1H), 1.541 (s, 9H); MS: Calcd for C ₁₂ H ₁₃ F ₃ N ₂ O ₅ (MH) ^- : 323.08, Found: 321.1.

Synthesis of compound B3-6: 0.82 g of the starting compound B3-5 was weighed, dissolved in 10 mL of DMA (N,N-dimethylacetamide), 2 eq of R ₃ H and 3 eq of DIEA were added, under argon atmosphere, The reaction was carried out at 80 ° C overnight; the next day, the starting material disappeared, the DMA was removed by rotary evaporation at 80 ° C, 50 ml of saturated aqueous sodium carbonate solution and 50 ml of dichloromethane were added, and the mixture was extracted twice with dichloromethane, and the organic phases were combined, dried and concentrated. The crude product was 1.3g and was directly injected into the next step. The analytical data of this compound was as follows: MS: Calcd for C ₁₆ H ₂₁ F ₂ N ₃ O ₆ (M+H) ⁺ : 389.14, Found: 390.2.

Synthesis of compound B3-7: Weighed raw material compound B3-6 to 1.2 g, dissolved in 100 mL of ethyl acetate, and added 0.4 eq of Pd/C; hydrogenation reaction was carried out at 20 ° C overnight; the next day, the raw materials disappeared, and Pd/filtered out. C, concentrated, and passed through a column to give a product of 0.7 g. The analytical data of this compound are as follows: ¹ H NMR (CDCl ₃ ) δ 9.32 (br, 1H), 9.23 (s, 1H), 6.96 (s, 1H), 6.73 (s, 1H), 6.47 (t, J = 74.8 Hz, 1H), 5.85 (m, 1H), 5.24 (m, 1H), 3.86 (m, 4H), 2.83 (m, 4H), 1.53 (s, 9H); MS: Calcd for C ₁₆ H ₂₃ F ₂ N ₃ O ₄ (M+H) ⁺ : 359.17, Found: 360.2.

Synthesis of compound B3-8: Weigh 0.1 g of raw material acrylic acid (or substituted acrylic acid), dissolve it with 20 mL of DCM, add 0.7 eq of oxalyl chloride and one drop of DMF, and react under argon for 4 hours to form acid chloride for use. At the same time, in another reaction flask, the raw material compound B3-7 was taken out 0.2 g (0.5 eq), dissolved in 20 ml of dry dichloromethane, 0.15 g of DIEA was added, and the prepared acid chloride solution was prepared at -5 °C. It was driven into the reaction solution and allowed to react overnight. The next day, directly spin the next step. The analytical data of this compound was as follows: MS: Calcd for C ₁₉ H ₂₄ F ₃ N ₃ O ₅ (M+H) ⁺ : 431.17, Found: 432.2.

Synthesis of compound B3-SM ₂ : Weigh 0.1 g of the original compound B3-8, add 3 mL of concentrated hydrochloric acid, release bubbles when added, stir for 3 minutes; add the reaction droplets to 10 ml of saturated sodium carbonate solution, and drop , solution PH>10; dichloromethane 30ml*2 extraction, drying, concentration to obtain 0.08g product, directly into the next step. The analytical data for this compound was as follows: MS: Calcd for C ₁₄ H ₁₆ F ₃ N ₆ O ₆ (M+H) ⁺ : 331.11, Found: 332.1.

The compound SM ₂ synthesized by the above method is shown in Table 1 below.

The structure of the compound SM ₂ of Table 1 and the method used for the synthesis thereof

Using the above methods, but not limited to these methods, a series of desired compounds SM ₁ and SM _{2 are} synthesized, and then a mixture of the compound SM ₁ and the compound SM _{2 is used} to obtain a series of final products P, and the structural formula and characterization information are as follows.

Example 1

The pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-1).

The synthesis of this compound is as follows:

The compound was synthesized by taking a 100 ml single-mouth bottle, adding 60 mg of the starting amine (compound SM ₂ -1), adding 1.2 eq of p-toluenesulfonic acid monohydrate crystals, and adding 1.2 eq of the raw pyrimidine compound (SM _1-1 ). And 15 ml of 2-pentanol, and the temperature was raised to 110 ° C overnight with stirring; the next day, 2-pentanol was distilled off, 50 ml of a saturated aqueous solution of sodium carbonate and 50 ml of dichloromethane were added, and the mixture was extracted twice with dichloromethane. The organic phases were combined, dried, concentrated and purified to afford 15 mg of product. The analytical data of this compound are as follows: ¹ H NMR (CDCl ₃ ) δ 10.20 (br, 1H), 8.75 (m, 2H), 7.53 (s, 1H), 7.10 (m, 3H), 6.72 (s, 1H) , 6.36 (m, 3H), 5.74 (m, 1H), 3.82 (s, 3H), 2.84 (br, 2H), 2.67 (s, 3H), 2.46 (s, 3H), 2.30 (br, 8H); MS m/z (ESI): 564.2 [M+H] ⁺ .

Example 2

The pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-2').

The synthesis of this compound is as follows:

Among them, the synthesis method of the compound (P-2) is the same as in the first embodiment. Compound P-2' of this example (salt The acid salt is prepared by adding 200 mg of the compound P-2 to a 50 ml single-mouth bottle, adding 10 ml of acetone and 1 ml of water, and slowly adding 140 mg of a 10% by mass hydrochloric acid after the addition is completed. After the reaction was carried out for 3 h at room temperature, the reaction mixture was evaporated to dryness, and then evaporated to dryness. It is the hydrochloride salt of the compound P-2.

The analytical data for this compound are as follows: ¹ H NMR (DMSO) δ 9.65 (m, 2H), 8.78 (s, 1H), 8.34 (s, 1H), 7.38 (br, 1H), 7.35 (m, 3H), 7.15 (m, 2H), 6.83 (m, 2H), 6.27 (m, 1H), 5.77 (s, 1H), 3.76 (s, 3H), 3.18 (m, 4H), 2.69 (s, 6H), 2.49 (s, 3H), 2.42 (s, 3H); MS m/z (ESI): 528.3 [M+H] ⁺ .

Example 3

The pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-3).

The synthesis of this compound is as follows:

This compound was synthesized in the same manner as in Example 1. The analytical data of this compound are as follows: ¹ H NMR (CDCl ₃ ) δ 10.10 (br, 1H), 8.73 (m, 2H), 7.56 (s, 1H), 7.23 (m, 2H), 7.10 (m, 2H) , 6.68 (s, 1H), 6.43 (m, 3H), 5.74 (m, 1H), 3.79 (s, 3H), 2.85 (m, 2H), 2.64 (s, 3H), 2.44 (s, 3H), 2.30 (br, 8H); MS m/z (ESI): 546.2 [M+H] ⁺ .

Example 4

The pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-4).

The synthesis of this compound is as follows:

This compound was synthesized in the same manner as in Example 1. The analytical data for this compound are as follows: ¹ H NMR (CDCl ₃ ) δ 10.20 (br, 1H), 8.95 (m, 2H), 7.22 (m, 5H), 6.95 (s, 1H), 6.47 (m, 3H) , 5.76 (m, 1H), 2.81 (br, 2H), 2.66 (s, 3H), 2.47 (m, 3H), 2.30 (br, 8H); MS m/z (ESI): 583.2 [M+H] ⁺ .

Example 5

The pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-5).

The synthesis of this compound is as follows:

This compound was synthesized in the same manner as in Example 1. The analytical data for this compound are as follows: ¹ H NMR (CDCl ₃ ) δ 10.28 (br, 1H), 8.75 (m, 2H), 7.29 (m, 2H), 6.90 (m, 3H), 6.43 (m, 3H) , 5.77 (m, 1H), 2.80 (br, 2H), 2.66 (s, 3H), 2.47 (m, 3H), 2.31 (br, 8H); MS m/z (ESI): 601.2 [M+H] ⁺ .

Example 6

The pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-6).

The synthesis of this compound is as follows:

This compound was synthesized in the same manner as in Example 1. The analytical data for this compound are as follows: ¹ H NMR (CDCl ₃ ) δ 10.32 (br, 1H), 8.74 (m, 2H), 7.08 (m, 4H), 6.96 (s, 1H), 6.39 (m, 3H) , 5.75 (m, 1H), 2.80 (br, 2H), 2.67 (s, 3H), 2.47 (m, 3H), 2.31 (br, 8H); MS m/z (ESI): 601 [M+H] ⁺ .

Example 7

The pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-7).

The synthesis of this compound is as follows:

This compound was synthesized in the same manner as in Example 1. The analytical data of this compound are as follows: ¹ H NMR (CDCl ₃ ) δ 10.33 (br, 1H), 8.74 (m, 2H), 7.08 (m, 4H), 6.96 (s, 1H), 6.39 (m, 4H) , 5.75 (m, 1H), 2.80 (br, 2H), 2.67 (s, 3H), 2.47 (m, 3H), 2.31 (br, 8H); MS m/z (ESI): 600.2 [M+H] ⁺ .

Example 8

The pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-8).

The synthesis of this compound is as follows:

This compound was synthesized in the same manner as in Example 1. The analytical data of the compound are as follows: 1H-NMR (400 MHz, CDCl ₃ ): δ: 9.29 (br, 1H); 9.04 (br, 1H); 8.77 (s, 1H); 7.51 (s, 1H), 7.11 (d) , J = 9.00, 3H); 6.81 (d, J = 8.76, 2H); 6.62 (s, 1H); 6.47 (d, J = 17.28, 1H); 6.38 (s, 1H); 5.75 (d, J = 10.14,1H);3.82(s,3H);3.21(br,2H);3.01(s,6H);2.96(s,2H);2.67(br,9H);2.44(br,3H);MS m/ z (ESI): 584 [M+H] ⁺ .

Example 9

The pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-9).

The synthesis of this compound is as follows:

This compound was synthesized in the same manner as in Example 1. The analytical data of the compound are as follows: 1H-NMR (400 MHz, CDCl ₃ ): δ 10.11 (br, 1H), 8.78 (s, 1H), 7.51 (s, 1H), 6.85-6.72 (m, 4H), 6.44 - 6.36 (m, 3H), 5.71 (d, J = 12.0 Hz, 1H), 3.83 (s, 3H), 2.88 (br, 2H), 2.68 (s, 3H), 2.46 (s, 3H), 2.32 ( Br, 8H); MS m/z (ESI): 564.2 [M+H] ⁺ .

Example 10

The pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-10).

The synthesis of this compound is as follows:

This compound was synthesized in the same manner as in Example 1. The analytical data of the compound are as follows: 1H-NMR (400 MHz, CDCl ₃ ): δ: 10.15 (br, 1H), 9.46 (br, 1H), 8.68 (s, 1H), 7.71 (s, 1H), 6.80 (s) , 1H), 6.44-6.23 (m, 3H), 6.05 (t, J = 8.0 Hz, 1H), 5.67 (d, J = 8.0 Hz, 1H), 3.89 (s, 3H), 2.89 (br, 2H) , 2.71 (s, 3H), 2.37-2.27 (m, 13H), 1.97 (s, 4H), 1.62 (br, 2H); MS m/z (ESI): 520.3 [M+H] ⁺ .

Example 11

The pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-11).

The synthesis of this compound is as follows:

This compound was synthesized in the same manner as in Example 1. The analytical data of the compound are as follows: 1H NMR (CDCl3) δ 10.08 (br, 1H), 8.77 (m, 2H), 7.59 (m, 5H), 6.72 (s, 1H), 6.43 (m, 3H), 5.74 (m, 1H), 3.83 (s, 3H), 2.86 (br, 2H), 2.67 (s, 3H), 2.48 (s, 3H), 2.32 (br, 8H); MS m/z (ESI): 553.3 [M+H]+.

Example 12

The pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-12).

The synthesis of this compound is as follows:

This compound was synthesized in the same manner as in Example 1. The analytical data of the compound are as follows: 1H NMR (CDCl3) δ 10.24 (br, 1H), 8.76 (m, 2H), 7.37 (m, 3H), 7.23 (m, 3H), 6.94 (s, 1H), 6.45 (m, 4H), 5.76 (m, 1H), 2.80 (br, 2H), 2.65 (s, 3H), 2.46 (m, 3H), 2.31 (br, 8H); MS m/z (ESI): 564.0 [M+H]+.

Example 13

The pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-13).

The synthesis of this compound is as follows:

This compound was synthesized in the same manner as in Example 1. The analytical data of this compound are as follows: 1H NMR (CDCl3) δ 10.11 (br, 1H), 8.77 (m, 2H), 7.50 (m, 2H), 7.10 (m, 3H), 6.71 (s, 1H), 6.42 (m, 3H), 5.73 (m, 1H), 3.81 (s, 3H), 2.84 (br, 2H), 2.67 (s, 3H), 2.46 (m, 3H), 2.29 (br, 8H); MS m /z (ESI): 546.0 [M+H]+.

Example 14

The pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-14).

The synthesis of this compound is as follows:

This compound was synthesized in the same manner as in Example 1. The analytical data of the compound are as follows: 1H NMR (CDCl3) δ 10.05 (br, 1H), 8.78 (m, 2H), 7.50 (s, 1H), 7.36 (m, 2H), 7.20 (m, 2H), 6.70 (s, 1H), 6.40 (m, 3H), 5.74 (m, 1H), 3.80 (s, 3H), 2.85 (m, 2H), 2.66 (s, 3H), 2.46 (m, 3H), 2.29 ( Br, 8H); MS m/z (ESI): 546.0 [M+H]+.

Example 15

The pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-15).

The synthesis of this compound is as follows:

This compound was synthesized in the same manner as in Example 1. The analytical data of the compound are as follows: 1H NMR (CDCl3) δ10.05 (br, 1H), 8.75 (m, 2H), 7.49 (s, 1H), 7.33 (m, 1H), 7.20 (m, 1H), 7.01 (m, 2H), 6.69 (s, 1H), 6.47 (m, 3H), 5.74 (m, 1H), 3.79 (s, 3H), 3.75 (s, 3H), 2.85 (br, 2H), 2.66 ( s, 3H), 2.45 (m, 3H), 2.29 (br, 8H); MS m/z (ESI): 558.0 [M+H]+.

Example 16

The pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-16).

The synthesis of this compound is as follows:

This compound was synthesized in the same manner as in Example 1. The analytical data of the compound are as follows: 1H-NMR (400 MHz, CDCl3): δ: 9.92 (br, 1H); 8.7-9.2 (m, 2H); 7.68-7.70 (m, 2H); 7.41-7.46 (m, 3H) ), 6.69 (s, 1H); 6.29-6.48 (m, 3H); 5.72 (d, J = 9.4, 1H); 3.8 (s, 3H); 2.83 (t, J = 5.9, 2H); 2.65 (s) , 3H); 2.47 (s, 3H); 2.2-2.3 (m, 8H); MS m/z (ESI): 596.0 [M+H]+.

Example 17

The pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-17).

The synthesis of this compound is as follows:

This compound was synthesized in the same manner as in Example 1. The analytical data of the compound are as follows: 1H-NMR (400 MHz, CDCl3): δ: 10.0 (br, 1H); 8.5-9.2 (m, 2H); 7.95 (s, 1H); 7.77 (s, 1H), 7.3-7.6 (m, 3H); 6.69 (s, 1H); 6.2-6.5 (m, 3H); 5.7 (d, J = 9.4, 1H); 3.79 (s, 3H); 2.81 (m, 2H); 2.65 (s, 3H); 2.53 (s, 3H); 2.47 (s, 3H); 2.2-2.3 (m, 8H); MS m/z (ESI): 570.0 [M+H]+.

Example 18

The pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-18).

The synthesis of this compound is as follows:

This compound was synthesized in the same manner as in Example 1. The analytical data of the compound are as follows: 1H-NMR (400 MHz, CDCl3): δ: 9.96 (br, 1H); 9.22 (br, 1H); 8.82 (s, 1H); 7.47 (s, 1H); 6.72 (s, 1H); 6.52 (s, 1H); 6.2-6.5 (m, 5H); 5.67 (d, J = 11, 1H); 3.81 (s, 3H); 3.77 (s, 6H); 2.87 (t, J = 5.29, 2H); 2.67 (s, 3H); 2.44 (s, 3H); 2.2-2.35 (m, 8H); MS m/z (ESI): 588.0 [M+H]+.

Example 19

The pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-19).

The synthesis of this compound is as follows:

This compound was synthesized in the same manner as in Example 1. The analytical data of the compound are as follows: 1H-NMR (400 MHz, CDCl3): δ: 10.01 (br, 1H); 8.5-9.0 (m, 2H); 8.0-8.4 (m, 2H); 7.4-7.8 (m, 3H) ; 6.69 (s, 1H); 6.2-6.6 (m, 3H); 5.72 (d, J = 10.82, 1H); 3.81 (s, 3H); 2.81 (m, 2H); 2.65 (s, 3H); 2.48 (s, 3H); 2.2-2.4 (m, 8H); MS m/z (ESI): 573.2 [M+H]+.

Example 20

The pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-20).

The synthesis of this compound is as follows:

This compound was synthesized in the same manner as in Example 1. The analytical data of this compound are as follows: 1H-NMR (400 MHz, CDCl3): δ: 9.95 (br, 1H); 9.17 (br, 1H); 8.83 (s, 1H); 7.45 (s, 1H); 6.98 (s, 2H); 6.70 (s, 1H); 6.2-6.5 (m, 3H); 5.70 (d, J = 11, 1H); 3.81 (s, 3H); 2.86 (m, 2H); 2.66 (s, 3H) ; 2.46 (s, 3H); 2.34 (s, 3H); 2.3-2.34 (m, 8H); 1.95 (s, 6H); MS m/z (ESI): 570.2 [M+H]+.

Example 21

The pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-21).

The synthesis of this compound is as follows:

This compound was synthesized in the same manner as in Example 1. The analytical data of the compound are as follows: ¹ H NMR (CDCl ₃ ) δ 9.86 (br, 1H), 8.85-8.84 (m, 2H), 8.20-8.16 (m, 2H), 7.77 (d, J = 2.1 Hz, 1H), 7.62 (dd, J=2.1 Hz, 8.9 Hz, 1H), 7.42-7.38 (m, 2H), 6.64 (s, 1H), 6.42-6.68 (m, 3H), 5.71-8.69 (m, 1H) ), 3.74 (s, 3H), 2.81 (s, 2H), 2.61 (s, 3H), 2.49 (d, J = 0.68 Hz, 3H), 2.25 (m, 8H); MS m/z (ESI): 579[M+H] ⁺ .

Test: Inhibition of activity of wild-type EGFR and mutant EGFR kinase

The method was used to determine the inhibitory effect of the test substance on the activity of double mutant EGFR kinase (EGFR T790M/L858R kinase) and wild type EGFR kinase (EGFR WT).

Both wild-type EGFR and mutant EGFR (T790M/L858R) kinases used in this assay were purchased from Carna Bioscience.

experimental design:

Preparation of test compounds:

1. The test compound was formulated into a 10 mM DMSO solution, and the control compound AZD9291 was formulated into a 1 mM DMSO solution.

2. Serially dilute the test compound solution to 12 concentrations (or other desired test concentration) on a 384-well plate of TECAN EVO200 by 3-fold dilution.

3. Transfer the 20 nL test solution to a 384-well plate (Coring 3570) using Echo 550. DMSO was used as a blank control.

Perform enzyme testing:

1. Prepare a 1.3X enzyme solution containing enzyme, matrix, and cofactor as follows.

2. Incubate with 15 μL of 1.3X enzyme solution for 30 minutes at room temperature in the wells of each well.

3. Start the test by adding 5 μL of 4X ATP solution. The volume of the solution in each well should be 20 μL and the ingredients contained are shown in the table below.

Table 2 Enzyme solution parameter table in enzyme test

4. The plates were incubated for 90 minutes at room temperature and then terminated by the addition of 40 [mu]L of Stop Buffer (containing 0.5 M EDTA).

5. Analyze the experimental data of each well using EZ detection.

data analysis:

1. Using the read conversion ratio (CR), calculate the inhibition ratio according to the following formula:

2. Calculate the IC ₅₀ and K _i values using XLFit (equation 201) according to the following formula.

The test data is shown in Table 3 below.

Table 3 Activity inhibition assay results of wild-type EGFR and mutant EGFR kinase

Among them, the structure of the control compound AZD9291 (trade name: meridinib) is as follows:

Claims (10)

1. A pyrimidine ring-containing compound characterized by comprising a compound of the formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:

   

   Wherein R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, ester, C _1-12 alkyl, C _1-12 haloalkyl, C _3-12 cycloalkyl, C _3-12 halocycloalkyl, C _1-12 alkoxy, C _1-12 haloalkoxy, C _3-12 cycloalkoxy, C _3-12 halocycloalkoxy a C _1-12 alkylthio group, a C _1-6 acyl group, a C _1-12 alkylamino group or a C _3-12 cycloalkylamino group, or a C _1-12 alkyl group having a substituent R ₁₀ , C _1-12 haloalkyl group, a C _3-12 cycloalkyl group, C _3-12 halogenated cycloalkyl, C _1-12 alkoxy, C _1-12 haloalkoxy group, a C _3-12 a cycloalkoxy group, a C _3-12 halocycloalkoxy group, a C _1-12 alkylthio group, a C _1-6 acyl group, a C _1-12 alkylamino group or a C _3-12 cycloalkylamino group, or a group formed by replacing one or more C of the above groups with one or more heteroatoms of N, O, S;

   R _{3 is} selected from any one of the following structures:

   

   R _{4 is} selected from any one of the following structures:

   

   R ₅ is selected from C _1-12 alkyl group, with the substituent R ₁₀ is C _1-12 alkyl, C _3-12 cycloalkyl, and substituted with C _3-12 cycloalkyl group R ₁₀ group, a C _6-14 aryl group, having a substituent group R C _{10 6-14} aryl, C _5-12 heteroaryl, R C _5-12 substituent having ₁₀ heteroaryl, Or a group formed by replacing one or more C of the above groups with one or more heteroatoms of N, O, S;

   X ₁ , X ₂ , X ₃ and X ₅ are each independently selected from C, N, O or S; X _{4 is} selected from C or N; X ₂ and X ₃ are each present or absent, and are bonded by X ₁ , X _{4 is} connected to each other; the dotted line represents a single bond, and the single bond exists or does not exist, but the two single bonds do not exist at the same time;

   R ₆ , R ₇ , R ₈ and R ₉ are each independently selected from the group consisting of H, O, halogen, hydroxy, amino, carboxy, decyl, cyano, nitro, ester, C _1-12 alkyl, C _{1- 12} haloalkyl, C _3-12 cycloalkyl, C _3-12 halocycloalkyl, C _1-12 alkoxy, C _1-12 haloalkoxy, C _3-12 naphthenic Oxyl, C _3-12 halocycloalkoxy, C _1-12 alkylthio, C _1-6 acyl, C _1-12 alkylamino, C _3-12 cycloalkylamino, C _{6- 14} aryl, C _5-12 heteroaryl, or C _1-12 alkyl with substituent R ₁₀ , C _1-12 haloalkyl, C _3-12 cycloalkyl, C _{3 12} halocycloalkyl, C _1-12 alkoxy, C _1-12 haloalkoxy, C _3-12 cycloalkoxy, C _3-12 halocycloalkoxy, C ₁ An alkylthio group of _-12 , an acyl group of _C1-6 , an alkylamino group of _C1-12, a cycloalkylamino group of _C3-12 , an aryl group of _C6-14, a heteroaryl group of _C5-12 , or the above a group formed by replacing one or more C in the group with one or more heteroatoms of N, O, S; when R ₆ , R ₇ , R ₈ and R _{9 are} selected from O, corresponding thereto X _1, X _2, X ₃ and X ₅ is C or S, and is connected to a double bond, R ₆ R _7, R ₈ and R ₉ are the presence or absence, the number of each connected thereto by the X _1, X _2, X ₃ and X ₅ valence decisions;

   _{Y 1, Y 2, Y 3} , Y 4, Y 5 are each independently selected from hydrogen, halogen, C _1-12 alkyl, C _1-12 with ₁₀ alkyl substituent R, C _3-12 cycloalkyl, substituted with a cycloalkyl group of R ₁₀ is C _3-12, C _1-12 alkylamino group or with a substituent R C ₁₀ alkylamino of _{1 to 12;}

   _{The Y} R is selected from C _1-12 alkyl group, an alkyl substituent group R ₁₀ is C _1-12, C _3-12 cycloalkyl, and substituted with C _3-12 cycloalkyl group R ₁₀ a group, or a group formed by replacing one or more C of the above groups with one or more heteroatoms of N, O, S;

   The substituent R _{10 is} selected from the group consisting of H, halogen, hydroxy, amino, carboxy, decyl, cyano, nitro, ester, alkyl of C _1-12 , cycloalkyl of C _3-12 , alkyl of C _1-12 Oxyl, C _3-12 cycloalkoxy, C _1-12 haloalkyl, C _3-12 halocycloalkyl, C _1-6 acyl, C _2-6 halo acyl, C _{1 -12} alkylamino group, a halogenated C _1-12 alkylamino, C _3-12 cycloalkylamino group, the cycloalkyl C _3-12 haloalkyl amino, C _1-12 alkylthio or C _1-12 halogenated alkylthio base;

   All of the hydrogens in the above compounds are independently substituted or unsubstituted by deuterium.
2. The pyrimidine ring-containing compound according to claim 1, which comprises a compound represented by formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:

   

   Wherein R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, ester, C _1-12 alkyl, C _1-12 haloalkyl, C _3-12 cycloalkyl, C _3-12 halocycloalkyl, C _1-12 alkoxy, C _1-12 haloalkoxy, C _3-12 cycloalkoxy, C _3-12 halocycloalkoxy a C _1-12 alkylthio group, a C _1-6 acyl group, a C _1-12 alkylamino group or a C _3-12 cycloalkylamino group, or a C _1-12 alkyl group having a substituent R ₁₀ , C _1-12 haloalkyl, C _3-12 cycloalkyl, C _3-12 halocycloalkyl, C _1-12 alkoxy, C _1-12 haloalkoxy, C _3-12 a cycloalkoxy group, a C _3-12 halocycloalkoxy group, a C _1-12 alkylthio group, a C _1-6 acyl group, a C _1-12 alkylamino group or a C _3-12 cycloalkylamino group, Or a group formed by replacing one or more C of the above groups with one or more heteroatoms of N, O, S;

   R _{3 is} selected from any one of the following structures:

   

   R _{4 is} selected from any one of the following structures:

   

   R ₅ is selected from C _1-12 alkyl group, with the substituent R ₁₀ is C _1-12 alkyl, C _3-12 cycloalkyl, and substituted with C _3-12 cycloalkyl group R ₁₀ group, a C _6-14 aryl group, having a substituent group R C _{10 6-14} aryl, C _5-12 heteroaryl, R C _5-12 substituent having ₁₀ heteroaryl, Or a group formed by replacing one or more C of the above groups with one or more heteroatoms of N, O, S;

   R ₇ and R ₈ are each independently selected from the group consisting of H, halogen, hydroxy, amino, carboxy, decyl, cyano, nitro, ester, C _1-12 alkyl, C _3-12 cycloalkyl, C ₁ Alkoxy group of _-12 , cycloalkyloxy group of C _3-12 , alkylthio group of C _1-12 , acyl group of C _1-6 , alkylamino group of C _1-12 , cycloalkylamino group of C _3-12 , An aryl group of C _{6-14 ,} a heteroaryl group of C _5-12 , or a C _1-12 alkyl group having a substituent R ₁₀ , a C _3-12 cycloalkyl group, a C _1-12 alkoxy group. , C _3-12 cycloalkoxy, C _1-12 alkylthio, C _1-6 acyl, C _1-12 alkylamino, C _3-12 cycloalkylamino, C _6-14 aryl a group, a C _5-12 heteroaryl group, or a group formed by replacing one or more C of the above groups with one or more heteroatoms of N, O, S;

   _{Y 1, Y 2, Y 3} , Y 4, Y 5 are each independently selected from hydrogen, halogen, C _1-12 alkyl, C _1-12 with ₁₀ alkyl substituent R, C _3-12 cycloalkyl, substituted with a cycloalkyl group of R ₁₀ is C _3-12, C _1-12 alkylamino group or with a substituent R C ₁₀ alkylamino of _{1 to 12;}

   _{The Y} R is selected from C _1-12 alkyl group, an alkyl substituent group R ₁₀ is C _1-12, C _3-12 cycloalkyl, and substituted with C _3-12 cycloalkyl group R ₁₀ a group, or a group formed by replacing one or more C of the above groups with one or more heteroatoms of N, O, S;

   The substituent R _{10 is} selected from the group consisting of H, halogen, hydroxy, amino, carboxy, decyl, cyano, nitro, ester, alkyl of C _1-12 , cycloalkyl of C _3-12 , alkyl of C _1-12 Oxyl, C _3-12 cycloalkoxy, C _1-12 haloalkyl, C _3-12 halocycloalkyl, C _1-6 acyl, C _2-6 halo acyl, C _{1 -12} alkylamino group, a halogenated C _1-12 alkylamino, C _3-12 cycloalkylamino group, the cycloalkyl C _3-12 haloalkyl amino, C _1-12 alkylthio or C _1-12 halogenated alkylthio base;

   All of the hydrogens in the above compounds are independently substituted or unsubstituted by deuterium.
3. The pyrimidine ring-containing compound according to claim 1 or 2, wherein R ₃ is

   
4. The pyrimidine ring-containing compound according to claim 2, wherein the compound represented by the formula (II) is selected from the group consisting of:

   

   
5. The pyrimidine ring-containing compound according to claim 1 or 2, wherein the pharmaceutically acceptable salt is a mineral acid salt or an organic acid salt selected from the group consisting of a hydrochloride salt and a hydrobromic acid. a salt, a hydroiodide, a sulfate, a hydrogen sulfate, a nitrate, a phosphate, an acid phosphate; the organic acid salt is selected from the group consisting of formate, acetate, trifluoroacetate, propionate, Pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, B Sulfonate, besylate, salicylate, picrate, glutamate, salicylate, ascorbate, camphorate, camphorsulfonate.
6. An EGFR inhibitor comprising the pyrimidine ring-containing compound according to claim 1 or 2.
7. The EGFR inhibitor according to claim 6, further comprising a pharmaceutically acceptable carrier.
8. Use of an EGFR inhibitor according to claim 6 for the preparation of a medicament for modulating EGFR tyrosine kinase activity or treating an EGFR-related disease.
9. The use according to claim 8, wherein the regulation of EGFR tyrosine kinase activity or treatment of an EGFR-related disease refers to cancer, diabetes, an immune system disease, a neurodegenerative disease or a cardiovascular disease.
10. Use of an EGFR inhibitor according to claim 6 for the preparation of a medicament for the treatment of non-small cell lung cancer.