TW202128670A - Nitrogen-containing polycyclic derivative inhibitor, preparation method therefor and application thereof - Google Patents

Abstract

The present invention relates to a nitrogen-containing polycyclic derivative inhibitor, a preparation method therefor and the application thereof. In particular, the present invention relates to a compound represented by the general formula (I), a preparation method therefor, and a pharmaceutical composition containing the compound, and the use thereof as a kinase inhibitor, especially as a receptor tyrosine kinase inhibitor (TKI). More specifically, its use as an EGFR or HER2 inhibitor in the treatment of cancer, inflammation, chronic liver disease, diabetes, cardiovascular disease and AIDS and other related diseases. Wherein, each substituent in the general formula (I) has the same definition as in the specification.

Description

Nitrogen-containing polycyclic derivative inhibitor, preparation method and application thereof

The invention belongs to the field of drug synthesis, and specifically relates to a nitrogen-containing polycyclic derivative inhibitor and a preparation method and application thereof.

There are multiple signal pathways in cells that interact with each other to control cell proliferation, growth, migration and apoptosis. Abnormal activation of signaling pathways can lead to tumors. Receptor tyrosine kinase plays an important role in the regulation of cells. Epidermal growth factor receptor (EGFR) is a member of the ErbB receptor family of transmembrane protein tyrosine kinases (including ErbB1, ErbB2, ErbB3, and ErbB4). By binding to its ligand epidermal growth factor (EGF), it can Form homodimers or form heterodimers with other receptors in the ErbB family (such as ErbB2, ErbB3, ErbB4), leading to the activation of EGFR tyrosine kinase activity. Activated EGFR can phosphorylate different substrates, thereby activating the downstream PI3K-AKT pathway and RAS-MAPK pathway, etc., and play a role in multiple processes such as cell survival, proliferation, and apoptosis.

Disorders of the EGFR signaling pathway include increased expression of ligands and receptors, EGFR gene amplification and mutations, etc., which can promote malignant transformation of cells, resulting in a variety of tumors. The occurrence of tumors. About 35% of non-small cell lung cancer (NSCLC) patients in China have EGFR mutations. The most common types of mutations are exon 19 deletion mutations (Del19) and exon 21 L858R activating mutations. Both occupy the most common EGFR mutations. About 80%. EGFR exon 20 insertion mutation is another major mutation of EGFR mutation, accounting for 4%-10% of EGFR mutations in NSCLC. There are dozens of mutation types. The common mutation types are Ex20Ins D770_N771InsSVD, Ex20Ins V769_D770InsASV, etc.

Over the years, a large number of targeted drugs have been developed for EGFR mutations in NSCLC, such as the first-generation reversible tyrosinase inhibitors (TKI) gefitinib and erlotinib for classic Del19 mutations and L858R mutations, second-generation The irreversible covalent binding inhibitor afatinib and the third-generation inhibitor osimertinib against the drug-resistant mutation EGFR T790M have very good clinical effects. However, the current EGFR inhibitors on the market have poor effect on EGFR 20 exon insertion mutations, and the patient's survival period is very short. This target requires more specific inhibitors, and there is a large clinical demand.

HER2 is another member of the ErbB family, and its amplification and mutations occur in a variety of cancers. Among them, HER2 mutations in NSCLC account for about 4%, and about 90% of HER2 mutations are exon 20 insertion mutations. The most common type of mutation is p.A775_G776insYVMA, and the currently marketed EGFR inhibitors are generally effective.

At present, many domestic and foreign pharmaceutical companies have carried out active research on EGFR&HER2 20 exon insertion mutations. Among them, Spectrum's Poziotinib (Poziotinib), Takeda's TAK-788 and Rain Therapeutics' Tasotinib (Tarloxotinib) ) Has entered clinical research, and Cullinan & Taiho's compound TAS-6417 also showed good activity in preclinical experiments.

Many EGFR inhibitors have strong inhibitory effects on EGFR wild-type, leading to clinical side effects such as skin rashes. However, for EGFR 20 exon insertion mutations and HER2 The inhibitory activity of the insertion mutation target of exon 20 also needs to be improved. Therefore, there is still a great demand for compounds that have obvious effects on EGFR and HER2 exon 20 mutations and have high selectivity for wild-type EGFR, and have a good market prospect.

The object of the present invention is to provide a compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, wherein the structure of the compound represented by general formula (I) is as follows:

in:

M is selected from CR ₁ or N;

L is selected from bond, -(CH ₂ ) _n -, -(CH ₂ ) _n NR _aa -, -(CH ₂ ) _n O-, -(CH ₂ ) _n S-, -(CH ₂ ) _n C(O )-, -(CH ₂ ) _n C(O)NR _aa -, -(CH ₂ ) _n NR _aa C(O)-, -(CH ₂ ) _n C(O)O-, -NR _aa (CH ₂ ) _n -, -O(CH ₂ ) _n -, -S(CH ₂ ) _n -, -C(O)(CH ₂ ) _n -, -C(O)NR _aa (CH ₂ ) _n -, -NR _aa C(O)(CH ₂ ) _n -, -C(O)O(CH ₂ ) _n -, -(CH ₂ ) _n P(O)R _aa -, -(CH ₂ ) _n S(O) _m -, -(CH ₂ ) _n S(O) _m NR _aa -or -(CH ₂ ) _n NR _aa S(O) _m -;

Ring A is selected from cycloalkyl, heterocyclic, aryl or heteroaryl;

Ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;

R _{1 is} selected from hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amine group, nitro group, hydroxyl group, cyano group, hydroxyalkyl group, azide Group, carboxylate group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, -(CH ₂ ) _n OR _a , -(CH ₂ ) _n NR _a R _b , -NR _a C(O)R _b , -C(O)NR _a (CH ₂ ) _n R _b , -NR _a C(O)NR _b R _c , -NR _a C(O)NR _b (CH ₂ ) _n R _c , -C≡CR _a , -NR _a C(O)CR _b =CH(CH ₂ ) _n R _c , -NR _a C(O)C≡CR _b , -C(O)NR _a R _b ,- C(O)OR _a , -NR _a S(O) _m R _b , -O(CH ₂ ) _n R _a , -(CH ₂ ) _n P(O)R _a R _b , -(CH ₂ ) _n S (O) _m NR _a R _b , -(CH ₂ ) _n C(O)R _a , -NR _a C(O)OR _b , -(CH ₂ ) _n S(O) _m R _a or -(CH ₂ ) _n NR _a S(O) _m R _b , the alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group may optionally be further substituted;

R ^a is selected from a hydrogen atom, a deuterium atom, an alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halo, amino, nitro, hydroxy, cyano, hydroxyalkyl, azide Group, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n OR _a1 , -(CH ₂ ) _n NR _a1 R _b1 , -NR _a1 (CH ₂ ) _n R _b1 , -NR _a1 (CH ₂ ) _n NR _b1 R _c1 , -NR _a1 C(O)R _b1 , -NR _a1 C(O)NR _b1 R _c1 , -NR _a1 C(O)NR _b1 (CH ₂ ) _n R _c1 , -NR _a1 C(O)C≡CR _b1 , -NR _a1 C(O)CR _b1 =CH(CH ₂ ) _n R _c1 , -NR _a1 C(O)CR _b1 =CH(CH ₂ ) _n NR _c1 R _d1 , -C(O)NR _a1 R _b1 , -C(O)OR _a1 , -NR _a1 S(O) _m R _b1 , -O(CH ₂ ) _n R _a1 , -(CH ₂ ) _n P(O)R _a1 R _b1 , -(CH ₂ ) _n S(O) _m NR _a1 R _b1 , -(CH ₂ ) _n C(O)R _a1 , -NR _a1 C(O)OR _b1 , -(CH ₂ ) _n S(O) _m R _a1 or -(CH ₂ ) _n NR _a1 S(O) _m R _b1 , the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and Heteroaryl, optionally can be further substituted;

R ^{b is} selected from hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amine group, nitro group, hydroxyl group, cyano group, hydroxyalkyl group, azide Group, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n OR _a2 , -(CH ₂ ) _n NR _a2 R _b2 , -NR _a2 (CH ₂ ) _n R _b2 , -NR _a2 (CH ₂ ) _n NR _b2 R _c2 , -NR _a2 C(O)R _b2 , -NR _a2 C(O)NR _b2 R _c2 , -NR _a2 C(O)NR _b2 (CH ₂ ) _n R _c2 , -NR _a2 C(O)C≡CR _b2 , -NR _a2 C(O)CR _b2 =CH(CH ₂ ) _n R _c2 , -NR _a2 C(O)CR _b2 =CH(CH ₂ ) _n NR _c2 R _d2 , -C(O)NR _a2 R _b2 , -C(O)OR _a2 , -NR _a2 S(O) _m R _b2 , -O(CH ₂ ) _n R _a2 , -(CH ₂ ) _n P(O)R _a2 R _b2 , -(CH ₂ ) _n S(O) _m NR _a2 R _b2 , -(CH ₂ ) _n C(O)R _a2 , -NR _a2 C(O)OR _b2 , -(CH ₂ ) _n S(O) _m R _a2 or -(CH ₂ ) _n NR _a2 S(O) _m R _b2 , the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and Heteroaryl, optionally can be further substituted;

R _aa , R _a , R _b , R _c , R _a1 , R _b1 , R _c1 , R _d1 , R _a2 , R _b2 , R _c2 or R _d2 are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, and a deuterium Alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl Or heteroaryl, the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Group, optionally can be further substituted;

x is an integer from 0 to 5;

y is an integer from 0 to 5;

m is an integer from 0 to 2; and

n is an integer from 0 to 4.

In a preferred embodiment of the present invention, L is selected from bond, -(CH ₂ ) _n -, -(CH ₂ ) _n NR _aa -, -(CH ₂ ) _n O-, -(CH ₂ ) _n S -, -(CH ₂ ) _n C(O)-, -(CH ₂ ) _n C(O)NR _aa -, -(CH ₂ ) _n NR _aa C(O)-, -(CH ₂ ) _n C( O)O-, -(CH ₂ ) _n P(O)R _aa -, -(CH ₂ ) _n S(O) _m -, -(CH ₂ ) _n S(O) _m NR _{aa -or} -(CH ₂ ) _n NR _aa S(O) _m -; preferred bond or -(CH ₂ ) _n NR _aa -; more preferred bond or -NH-.

In a preferred embodiment of the present invention, ring A is selected from C _6-14 aryl or 5-14 membered heteroaryl; preferably phenyl.

In a preferred embodiment of the present invention, ring B is selected from 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl; preferably phenyl, benzoheteroaryl or benzene And heterocyclic group; further preferred are the following groups:

、

、

、

或

。 In a further preferred embodiment of the present invention, R _{1 is} selected from a hydrogen atom, a deuterium atom, a halogen, a cyano group, an amine group, a nitro group, a hydroxyl group, an azido group, and a C _1-6 carboxylic acid C _1-6 ester group. , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl, substituted or unsubstituted 5-14 membered heteroaryl, -NR _a C(O)NR _b (CH ₂ ) _n R _c ,- C≡CR _a , -NR _a C(O)CR _b =CHR _c , -C(O)NR _a (CH ₂ ) _n R _b , -C(O)OR _a , -O(CH ₂ ) _n R _{a , - (CH 2) n S} (O) m R a , and _{- (CH 2) n P (} O) R a R b; is preferably a hydrogen atom, halo, cyano, C _1-6 alkyl, C _{1- 6} haloalkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-12 membered heterocyclic group, substituted or unsubstituted 5- 14-membered heteroaryl, -O(CH ₂ ) _n R _a or -C(O)OR _a ; further preferred are the following substituents: hydrogen atom, fluorine, chlorine, bromine, trifluoromethyl, cyano, methoxy基、-C(O)OCH(CH ₃ ) ₂ 、

,

,

,

or

.

、

、

、

或

。 In a further preferred embodiment of the present invention, R ^a is selected from a hydrogen atom, a deuterium atom, a halogen, cyano, amino, nitro, hydroxy, C _1-6 alkyl, C _2-6 alkenyl group, C _{2 -6alkynyl} , C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic group, C _6-14 aryl, 5 -14 member heteroaryl, -NR _a1 (CH ₂ ) _n R _b1 , -NR _a1 (CH ₂ ) _n NR _b1 R _c1 , -NR _a1 C(O)C≡CR _b1 , -NR _a1 C(O) CR _b1 =CH(CH ₂ ) _n R _c1 , -NR _a1 C(O)CR _b1 =CH(CH ₂ ) _n NR _c1 R _d1 , -C(O)NR _a1 (CH ₂ ) _n R _b1 , -C (O)OR _a1 , -O(CH ₂ ) _n R _a1 , -(CH ₂ ) _n P(O)R _a1 R _b1 , -NR _a1 S(O) _m R _b1 , -(CH ₂ ) _n S( O) _m NR _a1 R _b1 , -(CH ₂ ) _n C(O)R _a1 , -NR _a1 C(O)OR _b1 , -(CH ₂ ) _n S(O) _m R _a1 or -(CH ₂ ) _n NR _a1 S(O) _m R _b1 ; preferably hydrogen atom, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, substituted or unsubstituted 3-12 membered heterocyclic group, 5-14 membered heteroaryl group, -NR _a1 (CH ₂ ) _n R _b1 , -NR _a1 (CH ₂ ) _n NR _b1 R _c1 , -NR _a1 C(O)C≡CR _b1 , -NR _a1 C(O)CR _b1 =CH(CH ₂ ) _n R _c1 , -NR _a1 C(O)CR _b1 =CH(CH ₂ ) _n NR _c1 R _d1 or -O(CH ₂ ) _n R _a1 ; further preferably the following substituents: hydrogen atom, methoxy group, -NHC(O)CH=CH ₂ ,

,

,

,

or

.

In a preferred embodiment of the present invention, R ^{b is} selected from hydrogen atom, deuterium atom, halogen, cyano, amino, nitro, hydroxyl, C _1-6 alkyl, C _2-6 alkenyl, C _{2 -6alkynyl} , C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclic group, C _6-14 aryl, 5-14 membered heteroaryl Base, -NR _a2 (CH ₂ ) _n R _b2 , -NR _a2 (CH ₂ ) _n NR _b2 R _c2 , -NR _a2 C(O)C≡CR _b2 , -NR _a2 C(O)CR _b2 =CH( CH ₂ ) _n R _c2 , -NR _a2 C(O)CR _b2 =CH(CH ₂ ) _n NR _c2 R _d2 , -C(O)NR _a2 (CH ₂ ) _n R _b2 , -C(O)OR _a2 , -O(CH ₂ ) _n R _a2 , -(CH ₂ ) _n P(O)R _a2 R _b2 , -NR _a2 S(O) _m R _b2 , -(CH ₂ ) _n S(O) _m NR _a2 R _b2 , -(CH ₂ ) _n C(O)R _a2 , -NR _a2 C(O)OR _b2 , -(CH ₂ ) _n S(O) _m R _a2 or -(CH ₂ ) _n NR _a2 S( O) _m R _b2 ; preferably hydrogen atom, halogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _3-8 cycloalkyl, -(CH ₂ ) _n P(O)R _a2 R _b2 , -(CH ₂ ) _n S(O) _m R _a2 , -NR _a2 S(O) _m R _b2 , -( CH ₂ ) _n S(O) _m NR _a2 R _b2 or -C(O)NR _a2 (CH ₂ ) _n R _b2 ; further preferably the following substituents: hydrogen atom, halogen, cyclopropyl, -C(CH ₃ ) ₂ (OH), -P(O)(CH ₃ ) ₂ , -S(O) ₂ CH ₃ , -NHS(O) ₂ CH(CH ₃ ) ₂ , -S(O) ₂ NHCH ₃ or -C (O) NHCH ₃ .

In a preferred embodiment of the present invention, R ^{b is} selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, pendant oxy, thio, C _1-3 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, C _3-6 cycloalkyl, 3-10 membered heterocyclyl, C _6-12 aryl or 5-12 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, Pendant oxy, thio, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl Group, fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, bromopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, Methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl, cycloheptyl, epoxypropyl, epoxybutyl, epoxypentyl, epoxyhexyl, epoxyheptyl, azetidinyl, azetidinyl, azacyclic Pentyl, azepanyl, azepanyl, thienyl, pyrrolyl, pyridyl, pyranyl, piperazinyl, phenyl, or naphthyl.

In a further preferred embodiment of the present _{invention, R aa, R a, R} b, R c, R a1, R b1, R c1, R d1, R a2, R b2, R c2 R _d2, or each independently selected from From hydrogen atom, deuterium atom, halogen, cyano group, amino group, nitro group, hydroxyl group, C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 hydroxyalkyl group, C _1-6 cycloalkyl group , 3-12 membered heterocyclic group, C _6-14 aryl group or 5-14 membered heteroaryl group, the C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 hydroxyalkyl group, C _{3 -8} cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl are optionally further substituted by deuterium, halogen, amino, cyano, C _1-4 alkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 haloalkyl, C _2-6 alkenylcarbonyl, C _1-6 hydroxyalkyl, substituted or unsubstituted C _3-8 Cycloalkyl groups, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C _6-14 aryl groups, and substituted or unsubstituted 5-14 membered heteroaryl groups are substituted.

In a further preferred embodiment of the present invention, there is provided a compound of formula (II), its stereoisomer or pharmaceutically acceptable salt thereof, the specific structure of which is as follows:

in:

R _{2 is} selected from hydrogen atom, deuterium atom, halogen, cyano, amino, nitro, hydroxyl, azido, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1 -6} alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl, 5-14 membered heteroaryl, -NR _a1 C( O)R _b1 , -NR _a1 C(O)NR _b1 (CH ₂ ) _n R _c1 , -NR _a1 C(O)C≡CR _b1 , -NR _a1 C(O)CR _b1 =CH(CH ₂ ) _n R _c1 , -NR _a1 C(O)CR _b1 =CH(CH ₂ ) _n NR _c1 R _d1 , -C(O)NR _a1 (CH ₂ ) _n R _b1 , -C(O)OR _a1 , -O( CH ₂ ) _n R _a1 , -(CH ₂ ) _n P(O)R _a1 R _b1 , -NR _a1 S(O) _m R _b1 , -(CH ₂ ) _n S(O) _m NR _a1 R _b1 ,- (CH ₂ ) _n C(O)R _a1 , -NR _a1 C(O)OR _b1 , -(CH ₂ ) _n S(O) _m R _a1 or -(CH ₂ ) _n NR _a1 S(O) _m R _b1 ; preferably -NR _a1 C(O)R _b1 , -NR _a1 C(O)NR _b1 (CH ₂ ) _n R _c1 , -NR _a1 C(O)C≡CR _b1 , -NR _a1 C(O) CR _b1 =CH(CH ₂ ) _n R _c1 , -NR _a1 C(O)CR _b1 =CH(CH ₂ ) _n NR _c1 R _d1 ; more preferably -NHC(O)CH=CH ₂ ;

R _{3 is} selected from hydrogen atom, deuterium atom, halogen, cyano, amino, nitro, hydroxyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy Group, C _1-6 hydroxyalkyl group, C _3-8 cycloalkyl group, 3-12 membered heterocyclic group, C _6-14 aryl group, 5-14 membered heteroaryl group, --O(CH ₂ ) _n R _a1 , -NR _a1 (CH ₂ ) _n R _b1 or -NR _a1 (CH ₂ ) _n NR _b1 R _c1 , the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclic group, C _6-14 aryl and 5-14 membered heteroaryl, optionally further Halogen, cyano, hydroxyl, mercapto, C _1-4 alkyl, C _1-4 nitrile, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 hydroxyalkyl and substituted or unsubstituted One or more substituents of the substituted 3-12 membered heterocyclic group; preferably substituted 3-12 membered heterocyclic group, -NR _a1 (CH ₂ ) _n R _b1 or -NR _a1 (CH ₂ ) _n NR _b1 R _c1 ; more preferably the following groups:

R _{4 is} selected from hydrogen atom, deuterium atom, halogen, cyano, amino, nitro, hydroxyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy Group, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl; Preferred is a hydrogen atom, a methyl group, a methoxy group or an ethoxy group.

In a further preferred embodiment of the present invention, there is provided a compound of formula (III), its stereoisomer or pharmaceutically acceptable salt thereof, the specific structure of which is as follows:

in:

R _{5 is} selected from hydrogen atom, deuterium atom, halogen, cyano, amino, nitro, hydroxyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy Group, C _1-6 hydroxyalkyl group, C _3-8 cycloalkyl group, 3-12 membered heterocyclic group, C _6-14 aryl group, 5-14 membered heteroaryl group, -NR _a2 (CH ₂ ) _n R _b2 , -NR _a2 (CH ₂ ) _n NR _b2 R _c2 , -NR _a2 C(O)C≡CR _b2 , -NR _a2 C(O)CR _b2 =CH(CH ₂ ) _n R _c2 , -NR _a2 C (O)CR _b2 =CH(CH ₂ ) _n NR _c2 Rd ₂ , -C(O)NR _a2 (CH ₂ ) _n R _b2 , -C(O)OR _a2 , -O(CH ₂ ) _n R _a2 , -(CH ₂ ) _n P(O)R _a2 R _b2 , -NR _a2 S(O) _m R _b2 , -(CH ₂ ) _n S(O) _m NR _a2 R _b2 , -(CH ₂ ) _n C( O) R _a2 , -NR _a2 C(O)OR _b2 , -(CH ₂ ) _n S(O) _m R _a2 or -(CH ₂ ) _n NR _a2 S(O) _m R _b2 ; preferably a hydrogen atom, Halogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _3-8 cycloalkyl, -(CH ₂ ) _n P(O)R _a2 R _b2 , -(CH ₂ ) _n S(O) _m R _a2 , -NR _a2 S(O) _m R _b2 , -(CH ₂ ) _n S(O) _m NR _a2 R _b2 or -C(O)NR _a2 (CH ₂ ) _n R _b2 ; further preferably the following substituents: hydrogen atom, -C(CH ₃ ) ₂ (OH), -P(O)(CH ₃ ) ₂ , -S(O) ₂ CH ₃ , -NHS(O) ₂ CH(CH ₃ ) ₂ , -S(O) ₂ NHCH ₃ or -C(O)NHCH ₃ ;

R ₆ and R ₇ are each independently selected from a hydrogen atom, a deuterium atom, a halogen, a cyano group, an amino group, a nitro group, a hydroxyl group, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl; preferably hydrogen Atom or halogen;

Alternatively, R ₆ and R ₇ are linked with the carbon atom to which they are attached to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, the cycloalkyl, heterocyclyl, aryl and heteroaryl group optionally May be further substituted; preferably the following groups:

R _{8 is} selected from a hydrogen atom, a deuterium atom, a halogen, a cyano group, an amino group, a nitro group, a hydroxyl group, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, and a C _1-6 alkoxy group Group, C _1-6 hydroxyalkyl group, C _3-8 cycloalkyl group, 3-12 membered heterocyclic group, C _6-14 aryl group or 5-14 membered heteroaryl group; hydrogen atom or halogen is preferred.

In a further preferred embodiment of the present invention, there is provided a compound of formula (IV), its stereoisomer or pharmaceutically acceptable salt thereof, the specific structure of which is as follows:

In a further preferred embodiment of the present invention, there is provided a compound of formula (V), its stereoisomer or pharmaceutically acceptable salt thereof, the specific structure of which is as follows:

In a further preferred embodiment of the present invention, there is provided a compound of formula (VI), its stereoisomer or pharmaceutically acceptable salt thereof, the specific structure of which is as follows:

in:

R _{9 is} selected from hydrogen atom, deuterium atom, halogen, cyano, amino, nitro, hydroxyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy Group, C _1-6 hydroxyalkyl group, C _3-8 cycloalkyl group, 3-12 membered heterocyclic group, C _6-14 aryl group or 5-14 membered heteroaryl group; preferably hydrogen atom, C _1-6 An alkyl group or a C _3-8 cycloalkyl group; more preferably a hydrogen atom, a methyl group or a cyclopropyl group.

In a further preferred embodiment of the present invention, the general formula (VI) is further as shown in the general formula (VI-A):

R _{9 is} not a methyl group.

In a further preferred embodiment of the present invention, there is provided a compound of formula (VII), its stereoisomer or pharmaceutically acceptable salt thereof, the specific structure of which is as follows:

In a further preferred embodiment of the present invention, the compound of formula (VII), its stereoisomer or pharmaceutically acceptable salt thereof, wherein:

M is N or CR ₁ ;

、

、

、

、

、

或

； R _{1 is} selected from hydrogen, halogen, cyano, trifluoromethyl, cyano, methoxy, ethoxy, -C(O)OCH(CH ₃ ) ₂ ,

,

,

,

,

,

or

；

、

、

、

、

或

； Ring B is selected from

,

,

,

,

or

；

R ^{b is} selected from a hydrogen atom, a deuterium atom, a halogen, a cyano group, an amino group, a nitro group, a hydroxyl group, a phosphoryl group, a sulfonyl group, an aminosulfonyl group, a C _1-6 alkyl group, and a C _2-6 alkenyl group , C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclic group, C _6-14 aryl or 5-14 Member heteroaryl; preferably hydrogen atom, -P(O)(CH ₃ ) ₂ , -S(O) ₂ CH ₃ , -NHS(O) ₂ CH(CH ₃ ) ₂ , -S(O) ₂ NHCH _3. C _1-6 alkyl or C _3-8 cycloalkyl; more preferably hydrogen, methyl, -P(O)(CH ₃ ) ₂ , -S(O) ₂ CH ₃ , or cyclopropyl;

y is 1, 2 or 3, preferably 1.

In a further preferred embodiment of the present invention, a method for preparing the compound represented by general formula (VI) or its stereoisomer and pharmaceutically acceptable salt thereof is provided, which comprises the following steps:

The general formula (VI-1) reacts with the general formula (VI-2) to obtain the general formula (VI-3), and the general formula (VI-3) continues to react with the general formula (VI-4) to obtain the general formula (VI) The indicated compound or its stereoisomers and pharmaceutically acceptable salts thereof;

in:

X ₁ and X ₂ are each independently selected from halogen; preferably fluorine, chlorine, bromine or iodine; more preferably chlorine;

。 X _{3 is} selected from halogen, boric acid or boric acid ester; preferably boric acid ester; more preferably

.

The present invention also provides a preferred solution, and also relates to a pharmaceutical composition, which includes a therapeutically effective dose of the compound of general formula (I) and its stereoisomers or pharmaceutically acceptable salts thereof, and one or A variety of pharmaceutically acceptable carriers, diluents or excipients.

The present invention also provides a preferred solution, and also relates to the application of the compound of general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition in the preparation of therapeutic kinase inhibitors .

The present invention also provides a better solution, and also relates to the compound of general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition is used in the preparation of the therapeutic receptor tyrosine kinase Application of inhibitors (TKI).

The present invention also provides a better solution, and also relates to the compound of general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition is used in the preparation of therapeutic The application of HER2 inhibitors, EGFR inhibitors and EGFR monoclonal antibodies and their associated drugs in combination is more preferably inhibitors of EGFR 20 exon insertion mutations and HER2 20 exon insertion mutation targets.

The present invention also provides a better solution, and also relates to the application of the compound of general formula (I) and its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition in the preparation of drugs for the treatment of cancer-related diseases; The cancer is better to treat breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, liver cancer, solid tumor, glioma, glioblastoma, leukemia, lymphoma, myeloma and Non-small cell lung cancer.

The present invention further relates to a method for preparing the compound represented by the general formula (I), its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition for the treatment of cancer-related diseases.

The present invention also relates to a method for treating cancer-related diseases, which comprises administering to the mammal a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.

In some embodiments, the method involves the treatment of disorders such as cancer.

The treatment methods provided herein include administering to a subject a therapeutically effective amount of a compound of the invention. In one embodiment, the present invention provides methods for treating diseases including cancer-related diseases in mammals. The method includes administering to the mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof.

The third-generation EGFR inhibitors are mainly aimed at EGFR activating mutants and T790M drug-resistant mutants with high inhibition. The compounds of the present invention are better than third-generation EGFR inhibitors in terms of EGFR and/or HER2 20 exon insertion mutation targets. Shows the following advantages:

1. Improve the proliferation inhibitory activity in Ba/F3 EGFR mutant cell lines, and the preferred compound is more than 5 times higher;

2. It has good metabolic stability in rat and human liver microsomes and has certain advantages;

3. It shows a significant advantage in the in vivo pharmacodynamic tumor suppression rate on the mouse original B cell Ba/F3 EGFR-D770-N771ins_SVD transplantation tumor model.

Unless stated to the contrary, the terms used in the specification and the scope of the patent application have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbons An alkyl group having 1 to 3 carbon atoms is most preferred. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, second butyl, n-pentyl, 1,1-dimethylpropyl , 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl- 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl , 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-di Methylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl , 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4 -Ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3 -Ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. More preferably, it is a lower alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, and Dibutyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl Group, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2- Dimethylbutyl, 2,2- Dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl Butyl and so on. Alkyl groups may be substituted or unsubstituted. When substituted, the substituents may be substituted at any available attachment point. The substituents are preferably one or more of the following groups, which are independently selected from alkanes Group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, ring Alkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, pendant oxy, carboxy or carboxylate group, preferred in the present invention is methyl, ethyl, isopropyl, tertiary butyl , Haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl.

The term "alkylene" means that one hydrogen atom of an alkyl group is further substituted, for example: "methylene" refers to -CH ₂ -, "ethylene" refers to -(CH ₂ ) ₂ -, "propylene" Refers to -(CH ₂ ) ₃ -, "butylene" refers to -(CH ₂ ) ₄ -, etc. The term "alkenyl" refers to an alkyl group as defined above composed of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3 -Butenyl etc. The alkenyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and alkylthio , Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. The cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Polycyclic cycloalkyl groups include spiro, condensed and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.

The term "spirocycloalkyl" refers to a polycyclic group that shares one carbon atom (called a spiro atom) between monocyclic rings with 5 to 20 members. It may contain one or more double bonds, but none of the rings have complete Conjugated π electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of shared spiro atoms between the ring and the ring, spirocycloalkyls are classified into single spirocycloalkyls, dispirocycloalkyls or polyspirocycloalkyls, preferably monospirocycloalkyls and bispirocycloalkyls . More preferably, it is 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/5 members or 5 members/6 members monospirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

和

等；

with

Wait;

It also contains a spirocycloalkyl group in which a single spirocycloalkyl group and a heterocycloalkyl group share a spiro atom. Non-limiting examples include:

和

等。

with

Wait.

The term "fused cycloalkyl" refers to an all-carbon polycyclic group consisting of 5 to 20 members. Each ring in the system shares an adjacent pair of carbon atoms with other rings in the system. One or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl. Non-limiting examples of fused cycloalkyl groups include:

和

等。

with

Wait.

The term "bridged cycloalkyl" refers to a 5- to 20-member, all-carbon polycyclic group with any two rings sharing two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has a complete Conjugated π electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. root According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected with the parent structure is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthyl , Benzocycloheptanyl, etc. Cycloalkyl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio group, heterocycloalkylthio group, pendant oxy group, carboxyl group or carboxylate group.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) _m (where m is an integer of 0 to 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably contains 3 to 8 ring atoms; most preferably contains 3 to 8 ring atoms; further preferably contains 1-3 nitrogen atoms 3-8 membered heterocyclic group, optionally substituted by 1-2 oxygen atoms, sulfur atoms, pendant oxy groups, including nitrogen-containing monocyclic heterocyclic group, nitrogen-containing spiro heterocyclic group or nitrogen-containing fused heterocyclic group .

Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine Group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably pyrrolidinyl, piperidinyl and piperazinyl. Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; which The heterocyclic group of the spiro ring, fused ring and bridged ring involved in the ring is optionally connected to other groups by a single bond, or by any two or more atoms on the ring and other cycloalkyl groups, The heterocyclic group, the aryl group and the heteroaryl group are further connected in a ring.

The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group sharing one atom (called a spiro atom) between monocyclic rings of 5 to 20 members, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) _{Heteroatoms of m} (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of spiro atoms shared between the ring and the ring, the spiro heterocyclic group is divided into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group . More preferably, it is 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/5 members or 5 members/6 members monospiro heterocyclic groups. Non-limiting examples of spiroheterocyclic groups include:

等。

Wait.

The term "fused heterocyclic group" refers to a polycyclic heterocyclic group with 5 to 20 members. Each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more Double bond, but none of the rings have a fully conjugated π-electron system, where one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (where m is an integer from 0 to 2), and the rest of the ring The atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group . Non-limiting examples of fused heterocyclic groups include:

和

等。

with

Wait.

The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group with 5 to 14 members, and any two rings share two atoms that are not directly connected. It may contain one or more double bonds, but none of the rings has a complete common A conjugated π-electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

和

等。

with

Wait.

The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples of which include:

和

等。

with

Wait.

The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio group, heterocycloalkylthio group, pendant oxy group, carboxyl group or carboxylate group.

The term "aryl" refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group with a conjugated π-electron system, preferably 6 to 10 members, for example Phenyl and naphthyl. More preferably phenyl. The aryl ring can be fused to a heteroaryl, heterocyclic or cycloalkyl ring, including benzo 3-8 membered cycloalkyl, benzo 3-8 membered heteroalkyl, preferably benzo 3-6 Membered cycloalkyl group, benzo 3-6 membered heteroalkyl group, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, and sulfur atoms; or it also contains a three-membered nitrogen-containing fused ring containing a benzene ring .

The ring connected to the parent structure is an aryl ring, and non-limiting examples include:

和

等。

with

Wait.

The aryl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and alkylthio , Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, carboxy, or carboxylate.

The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10 members, more preferably 5 or 6 members, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyridine Azinyl and the like are preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl or thiazolyl; more preferred are pyrazolyl and oxazolyl. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

和

等。

with

Wait.

Heteroaryl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio group, heterocycloalkylthio group, carboxyl group or carboxylate group.

The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where the definition of alkyl is as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio group, heterocycloalkylthio group, carboxyl group or carboxylate group.

"Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above.

"Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.

"Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.

"Alkenyl" refers to alkenyl, also known as alkenyl, where the alkenyl may be further substituted by other related groups, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino , Halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio , Carboxyl or carboxylate.

"Alkynyl" refers to (CH≡C-), where the alkynyl group can be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen , Mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl Or carboxylate group.

The term "alkenylcarbonyl" refers to -C(O)-(alkenyl), where alkenyl is as defined above. Non-limiting examples of alkenylcarbonyl include: vinylcarbonyl, propenylcarbonyl, butenylcarbonyl. The alkenylcarbonyl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio group, heterocycloalkylthio group, carboxyl group or carboxylate group.

"Hydroxy" refers to the -OH group.

"Halogen" refers to fluorine, chlorine, bromine or iodine.

"Amino" refers to -NH ₂ .

"Cyano" refers to -CN.

"Nitro" refers to -NO ₂ .

"Carbonyl" refers to -C(O)-.

"Carboxy" refers to -C(O)OH.

"THF" means tetrahydrofuran.

"EtOAc" refers to ethyl acetate.

"MeOH" means methanol.

"DMF" refers to N,N-dimethylformamide.

"DIPEA" refers to diisopropylethylamine.

"TFA" means trifluoroacetic acid.

"MeCN" means Otoharu.

"DMA" refers to N,N-dimethylacetamide.

"Et ₂ O" means diethyl ether.

"DCE" refers to 1,2 dichloroethane.

"DIPEA" refers to N,N-diisopropylethylamine.

"NBS" refers to N-bromosuccinimide.

"NIS" refers to N-iodosuccinimide.

"Cbz-Cl" refers to benzyl chloroformate.

"Pd ₂ (dba) ₃ "refers to tris(dibenzylideneacetone) dipalladium.

"Dppf" refers to 1,1'-bisdiphenylphosphinoferrocene.

"HATU" refers to 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.

"KHMDS" refers to potassium hexamethyldisilazide.

"LiHMDS" refers to lithium bistrimethylsilylamide.

"MeLi" refers to methyl lithium.

"N-BuLi" refers to n-butyl lithium.

"NaBH(OAc) ₃ "means sodium triacetoxyborohydride.

"X is selected from A, B, or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" and other terms all express the same Meaning, which means that X can be any one or more of A, B, and C.

The hydrogen atom in the present invention can be replaced by its isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.

"Optional" or "optionally" means that the event or environment described later can but does not have to occur, and the description includes occasions where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may but does not have to be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group. .

"Substituted" refers to one or more hydrogen atoms in the group, preferably at most 5, and more preferably 1 to 3 hydrogen atoms are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amine group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.

"Pharmaceutical composition" means a mixture containing one or more of the compounds herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers and excipient. The purpose of the medicinal composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.

"Pharmaceutically acceptable salt" refers to the salt of the compound of the present invention, which is safe and effective when used in mammals, and has due biological activity.

The present invention will be further described below in conjunction with examples, but these examples do not limit the scope of the present invention.

Example

The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid-mass spectrometry (LC-MS). The NMR chemical shift (δ) is given in units of parts per million (ppm). NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvents were deuterated dimethyl sulfoxide (DMSO- d ₆ ), deuterated methanol (CD ₃ OD) and deuterated chloroform (CDCl ₃ ), and the internal standard was four Methyl Silane (TMS).

The liquid mass spectrometry LC-MS was measured with an Agilent 1200 Infinity Series mass spectrometer. HPLC determination uses Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150×4.6mm chromatographic column).

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specifications used for TLC are 0.15mm~0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm~0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as the carrier.

The starting materials in the examples of the present invention are known and can be bought on the market, or can be synthesized by using or following methods known in the art.

Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring under a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature is in degrees Celsius.

Example 1

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((5-(dimethylphosphoryl)quinoxaline-6 -Yl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

The first step: Preparation of (6-((2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

Dissolve (6-aminoquinoxalin-5-yl) dimethyl phosphine oxide (300mg, 1.36mmol) and 2,4-dichloropyrimidine (606mg, 4.07mmol) in N,N-dimethylformamide Amine (10mL), 1M potassium hexamethyldisilazide tetrahydrofuran solution (4mL, 4mmol) was added dropwise at -20°C. React for 30 minutes after the addition is complete. The temperature of the reaction system was raised to -10°C, and the reaction was continued for 2 hours. The reaction was quenched by adding aqueous ammonium chloride solution (5 mL), extracted with dichloromethane (20 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by reversed-phase column (MeCN: H ₂ O (0.1 %TFA)=40%-50%) to obtain the product (6-((2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (Intermediate 1-1 , 120mg , Yield: 27%).

MS m/z(ESI): 334.1[M+H] ⁺ .

The second step: (6-((2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl) Preparation of dimethyl phosphine oxide

Add p-toluenesulfonic acid (132mg, 0.76mmol) to 4-fluoro-2-methoxy-5-nitroaniline (114mg, 0.61mmol) and intermediate 1-1 (170mg, 0.51mmol) of 2-pentyl In an alcohol (10ml) solution, the reaction solution was heated to 100°C for 3 hours. The reaction solution was cooled and evaporated to dryness. The crude product obtained was separated by silica gel column (dichloromethane: methanol = 100: 6) to obtain the product (6-((2-((4-fluoro-2-methoxy-5-nitro) (Phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (Intermediate 1-2 , 130 mg, yield: 53%).

MS m/z(ESI): 484.1[M+H] ⁺ .

The third step: (6-((2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amine (Yl)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

Potassium carbonate (112mg, 0.81mmol) was added to the solution of N,N,N'-trimethylethylenediamine (33mg, 0.32mmol) and Intermediate 1-2 (130mg, 0.27mmol) in acetonitrile (10ml), The reaction solution was heated to 80°C for 2 hours. The reaction liquid was cooled and filtered to obtain the product (6-((2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrobenzene (Yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (Intermediate 1-3 , 120 mg, yield: 79%).

MS m/z(ESI): 566.2[M+H] ⁺ .

The fourth step: N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((5-(dimethylphosphoryl)quine Preparation of oxalin-6-yl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

Intermediate 1-3 (130 mg, 0.23 mol) was dissolved in ethanol (10 mL), ammonium chloride aqueous solution (3 mL) and iron powder (128 mg, 2.3 mmol) were added, and the reaction solution was reacted at 80° C. for 2 hours. The reaction solution was filtered, the organic phase was added with dichloromethane (30ml), washed with water (15ml*2), the solid was washed with dichloromethane (30ml), the organic phases were combined, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was dissolved in tetrahydrofuran (3mL), cooled to 0°C, triethylamine (25mg, 0.24mmol) was added, then 3-chloropropionyl chloride (28mg, 0.22mmol) was added, and the reaction was stirred at 0°C for 1 hour. 3M sodium hydroxide solution (1 mL) was added, and the reaction was stirred at room temperature for 1 hour. Water (10mL) was added, extracted with dichloromethane (10mL×2), the organic phase was dried with anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified with a silica gel preparation plate (dichloromethane/MeOH: 20/1) to obtain N- (2-((2-(Dimethylamino)ethyl)(methyl)amino)-5-((4-((5-(dimethylphosphorus)quinoxalin-6-yl)amine (Pyrimidine-2-yl)amino)-4-methoxyphenyl)acrylamide (Compound 1 , 4.1 mg, yield: 3%).

MS m/z(ESI): 590.4[M+H] ⁺ .

Example 2

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((5-(dimethylphosphoryl)quinoxaline-6 -Yl)amino)-1,3,5-triazin-2-yl)amino)-4-methoxyphenyl)acrylamide

Step 1: Preparation of (6-((4-chloro-1,3,5-triazin-2-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

Dissolve (6-aminoquinoxalin-5-yl) dimethyl phosphine oxide (200mg, 0.9mmol) in N,N-dimethylformamide (10mL), add N,N-diisopropyl Ethylamine (1.2g, 9mmol) and 2,4-dichloro-1,3,5-triazine (407mg, 2.7mmol), the reaction solution was reacted at 80°C for 3 hours. The reaction solution was poured into water (30 mL), and dichloromethane (20 mL×2) was added for extraction. The organic phase was dried with anhydrous sodium sulfate and evaporated to dryness to obtain the crude product, which was separated by silica gel column chromatography (dichloromethane:methanol=100:7) to obtain the product (6-((4-chloro-1,3,5-tri (Azin-2-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (Intermediate 2-1 , 200 mg, yield: 68%).

MS m/z(ESI): 335.1[M+H] ⁺ .

Steps two to four: N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((5-(dimethylphosphoryl) )Quinoxaline-6-yl)amino)-1,3,5-triazin-2-yl)amino)-4-methoxyphenyl)acrylamide

Steps 2-4 refer to steps 2-4 of Example 1.

MS m/z(ESI): 591.3[M+H] ⁺ .

1H NMR (400MHz, Chloroform-d) δ 12.91 (s, 1H), 10.10 (s, 1H), 9.43 (br s, 2H), 8.70 (d, J=11.5 Hz, 2H), 8.56 (s, 1H) , 8.12 (br s, 1H), 7.56 (s, 1H), 6.86-6.71 (m, 1H), 6.40 (br s, 2H), 5.77-5.63 (m, 1H), 3.86 (s, 3H), 2.93 -2.91(m, 2H), 2.72(s, 3H), 2.40-2.31(m, 8H), 2.12(s, 3H), 2.09(s, 3H).

Example 3

N-(5-((5-chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-(( 2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

For the preparation method of Example 3, refer to Example 1.

MS m/z(ESI): 624.4[M+H] ⁺ .

Example 4

N-(5-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-(( 2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

For the preparation method of Example 4, refer to Example 1.

MS m/z(ESI): 668.2[M+H] ⁺ .

Example 5

N-(5-((5-cyano-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-( (2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

The first step: Preparation of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

(6-Aminoquinoxalin-5-yl) dimethyl phosphine oxide (200mg, 0.9mmol) and 5-bromo-2,4-dichloropyrimidine (618mg, 2.7mmol) were dissolved in N, N-di Methylformamide (2 mL). At -20℃ A 1.3M lithium bistrimethylsilylamide tetrahydrofuran solution (2mL, 2.6mmol) was added dropwise to the piece, and the reaction was carried out for 30 minutes. The temperature was raised to -10°C, and the reaction was continued for 2 hours. The reaction was quenched by adding saturated aqueous ammonium chloride solution, water (10 mL) was added, and extraction was performed twice with dichloromethane (10 mL). The organic phase is dried and then spin-dried, and purified with a chromatography column (dichloromethane: methanol = 20:1) to obtain the product (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxa Lin-5-yl)dimethyl phosphine oxide (200 mg, yield: 54%).

MS m/z(ESI): 412.0[M+H] ⁺

The second step: (6-((5-bromo-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxaline- Preparation of 5-yl) dimethyl phosphine oxide

Dissolve (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (200mg, 0.48mmol) in 2-pentanol and add 4 -Fluoro-2-methoxy-5-nitroaniline (95mg, 0.51mmol) and p-toluenesulfonic acid (88mg, 051mmol), reacted at 100°C for 16 hours. After the reaction was cooled to room temperature, a solid precipitated out. After filtration, the filter cake was washed with 2-pentanol and petroleum ether to obtain the product (6-((5-bromo-2-((4-fluoro-2-methoxy-5- Nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (280 mg, yield: 100%).

MS m/z(ESI): 562.0[M+H] ⁺

The third step: (6-((5-bromo-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitro (Phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethyl phosphine oxide preparation

The third step refers to the third step of Example 1

MS m/z(ESI): 644.2[M+H] ⁺

The fourth step: (6-((5-bromo-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitro (Phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethyl phosphine oxide preparation

Add (6-((5-bromo-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl) Amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (100mg, 0.16mmol) dissolved in N,N-dimethylacetamide (2mL), and then added cyanide Zinc oxide (19mg, 0.16mmol), tris(dibenzylideneacetone) two palladium (29mg, 0.032mmol), 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl (31mg, 0.064mmol) ) And zinc powder (10mg, 0.16mmol). After replacing the nitrogen, the reaction was carried out under microwave conditions at 95°C for 1.5 hours. After filtration, water (10 mL) was added, and extraction was performed twice with dichloromethane (10 mL). The organic phase is dried and spin-dried, purified by pre-TLC (dichloromethane: methanol = 20:1) to obtain the product (6-((5-bromo-2-((4-((2-(dimethylamino)) (Ethyl) (methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide ( 70mg, yield: 76%).

MS m/z(ESI): 591.2[M+H] ⁺

The fifth step: N-(5-((5-cyano-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino) Preparation of -2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

For the fifth step, refer to the fourth step of Example 1.

MS m/z(ESI): 615.1[M+H] ⁺ .

¹ H NMR (400MHz, Chloroform-d) δ 13.30 (s, 1H), 10.26-9.90 (m, 1H) 9.22-8.99 (m, 2H), 8.71 (d, J=14.2 Hz, 2H), 8.46 (s ,1H),8.00(s,1H),7.55(s,1H),6.74(s,1H),6.23-5.94(m,2H),5.57-5.43(m,1H),3.87(s,3H), 3.39-2.79 (m, 7H), 2.74 (s, 3H), 2.49-2.29 (m, 3H), 2.14 (s, 3H), 2.11 (s, 3H).

Example 6

2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-( (5-(Dimethylphosphoryl)quinoxaline-6-yl)amino)pyrimidine-5-isopropyl carboxylate

Refer to Example 1 for the preparation method of Example 6.

MS m/z(ESI): 676.3[M+H] ⁺ .

Example 7

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((5-(dimethylphosphoryl)quinoxaline-6 -Yl)amino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

Steps one to three: (6-((5-bromo-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5 -Nitrophenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethyl phosphine oxide

Steps 1-3 refer to steps 1-3 of Example 1.

MS m/z(ESI): 644.3[M+H] ⁺ .

The fourth step: (6-((2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl) (Amino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)quinoxalin-5-yl) dimethylphosphine oxide

Under nitrogen protection, Intermediate 7-3 (200mg, 0.3mmol), 1-methyl-4-pyrazoleboronic acid pinacol ester (127mg, 0.36mmol), anhydrous potassium carbonate (124mg, 0.90mmol) and tetrakis ( Triphenylphosphine) palladium (30 mg) was dissolved in dioxane (3 mL) and reacted at 100°C overnight. The reaction solution was concentrated under reduced pressure, and the crude product was separated by column (dichloromethane: methanol: concentrated ammonia = 99:1: 0.1 to 94: 6: 0.6 gradient elution) to obtain (6-((2-((4-((2 -(Dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)-5-(1-methyl-1H-pyrazole-4 -Yl)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (Intermediate 7-4 , 103 mg, yield: 51%).

MS m/z(ESI): 646.2[M+H] ⁺ .

The fifth step: N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((5-(dimethylphosphoryl)quine (Oxaline-6-yl)amino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide preparation

Step 5 Refer to Step 4 of Example 1.

MS m/z(ESI): 670.0[M+H] ⁺ .

Example 8

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((5-(dimethylphosphoryl)quinoxaline-6 -Yl)amino)-5-(oxazol-2-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

Refer to Example 7 for the preparation method of Example 8.

MS m/z(ESI): 657.3[M+H] ⁺ .

Example 9

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((5-(dimethylphosphoryl)quinoxaline-6 -Yl)amino)-5-(pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

Refer to Example 7 for the preparation method of Example 9.

MS m/z(ESI): 667.5[M+H] ⁺ .

Example 10

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((5-(dimethylphosphoryl)quinoxaline-6 -Yl)amino)-5-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

Refer to Example 7 for the preparation method of Example 10.

MS m/z(ESI): 674.2[M+H] ⁺ .

Example 11

N-(5-((5-cyclopropyl-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2- ((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

Refer to Example 7 for the preparation method of Example 11.

MS m/z(ESI): 630.3[M+H] ⁺ .

Example 12

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((5-(dimethylphosphoryl)quinoxaline-6 -Yl)amino)-5-methoxypyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

For the preparation method of Example 12, refer to Example 1.

MS m/z(ESI): 620.1[M+H] ⁺ .

Example 13

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((5-(dimethylphosphoryl)quinoxaline-6 -Yl)amino)-5-fluoropyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

Refer to Example 1 for the preparation method of Example 13.

MS m/z(ESI): 608.2[M+H] ⁺ .

Example 14

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((5-(dimethylphosphoryl)quinoxaline-6 -Yl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

Refer to Example 1 for the preparation method of Example 14.

MS m/z(ESI): 658.4[M+H] ⁺ .

Example 15

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((5-(dimethylphosphoryl)-2,3- Dihydrobenzo[b][1,4]dioxan-6-yl)amino)-1,3,5-triazin-2-yl)amino)-4-methoxyphenyl)propene Amide

The first step: (6-((4-chloro-1,3,5-triazin-2-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxane- Preparation of 5-yl) dimethyl phosphine oxide

Add (6-((4-chloro-1,3,5-triazin-2-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl ) Dimethyl phosphine oxide (200mg, 0.88mmol) and N,N-diisopropylethylamine (1.1g, 8.8mmol) dissolved in N,N-dimethylformamide (10mL), in an ice bath 2,4-Dichloro-1,3,5-triazine (396 mg, 2.6 mmol) was added, and reacted at room temperature for 2 hours. The reaction solution was poured into water (30 mL), and dichloromethane (20 mL×2) was added for extraction. The organic phase was dried with anhydrous sodium sulfate and evaporated to dryness to obtain the crude product, which was separated by column chromatography (dichloromethane: methanol = 100:7) to obtain the product (6-((4-chloro-1,3,5-triazine) -2-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (Intermediate 15-1 , 200 mg, yield: 67%).

MS m/z(ESI): 341.1[M+H] ⁺ .

Steps two to four: N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((5-(dimethylphosphoryl) )-2,3-Dihydrobenzo[b][1,4]dioxan-6-yl)amino)-1,3,5-triazin-2-yl)amino)-4-methyl (Oxyphenyl) acrylamide preparation

Steps 2-4 refer to steps 2-4 of Example 1.

MS m/z(ESI): 597.4[M+H] ⁺ .

¹ H NMR (400MHz, Chloroform- d ) δ 11.75 (s, 1H), 10.10 (s, 1H), 9.32 (s, 1H), 8.43 (s, 1H), 8.31-8.17 (m, 1H), 7.43 ( s, 1H), 6.95 (s, 1H), 6.82-6.68 (m, 1H), 6.49-6.29 (m, 2H), 5.74-5.60 (m, 1H), 4.25 (d, J =17.7 Hz, 4H) , 3.84 (s, 3H), 2.90-2.88 (m, 2H), 2.69 (s, 3H), 2.35-2.30 (m, 8H), 1.87 (s, 3H), 1.84 (s, 3H).

Example 16

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((5-(dimethylphosphoryl)-[1,2 ,4]Triazolo[1,5-a]pyridin-6-yl)amino)-1,3,5-triazin-2-yl)amino)-4-methoxyphenyl)acrylic acid amine

Refer to Example 15 for the preparation method of Example 16.

MS m/z(ESI): 580.5[M+H]+.

Example 17

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((8-(dimethylphosphoryl)-[1,2 ,4]Triazolo[1,5-a]pyridin-7-yl)amino)-1,3,5-triazin-2-yl)amino)-4-methoxyphenyl)acrylic acid amine

Refer to Example 15 for the preparation method of Example 17.

MS m/z(ESI): 580.4[M+H] ⁺ .

Example 18

N-(2-(4-(3-(cyanomethyl)azetidin-1-yl)piperidin-1-yl)-5-((4-((5-(dimethylphosphoryl )-2,3-Dihydrobenzo[b][1,4]dioxan-6-yl)amino)-1,3,5-triazin-2-yl)amino)-4-methyl (Oxyphenyl) acrylamide

Refer to Example 15 for the preparation method of Example 18.

MS m/z(ESI): 674.1[M+H] ⁺ .

Example 19

N-(5-((4-((5-(dimethylphosphoryl)-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)amino)- 1,3,5-triazin-2-yl)amino)-4-methoxy-2-(4-(3-(methoxymethyl)azetidine-1-yl)piperidine-1 -(Yl)phenyl)acrylamide

For the preparation method of Example 19, refer to Example 15.

MS m/z(ESI): 679.3[M+H] ⁺ .

Example 20

N-(5-((4-((5-(dimethylphosphoryl)-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)amino)- 1,3,5-triazin-2-yl)amino)-4-methoxy-2-(4-(3-ethoxyazetidine-1-yl)piperidin-1-yl)benzene Base) acrylamide

For the preparation method of Example 20, refer to Example 15.

MS m/z(ESI): 679.4[M+H] ⁺ .

Example 21

N-(5-((5-chloro-4-((5-(methylsulfonyl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-((2 -(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

Refer to Example 1 for the preparation method of Example 21.

MS m/z(ESI): 626.1[M+H] ⁺ .

Example 22

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-((5-((1-methylethyl (Yl)sulfonamido)-2,3-dihydrobenzo[b][1,4]dioxan-6-yl))amino)-1,3,5-triazin-2-yl) (Amino)-phenyl)acrylamide

Refer to Example 15 for the preparation method of Example 22.

MS m/z(ESI): 642.0[M+H] ⁺ .

Example 23

N-(5-((5-cyano-4-((5-(N-methylaminosulfonyl)-2,3-dihydrobenzo[b][1,4]dioxane- 6-yl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(methyl((1-methylpyrrolidin-2-yl)methyl)amino)phenyl) Acrylamide

Refer to Example 15 for the preparation method of Example 23.

MS m/z(ESI): 664.3[M+H] ⁺ .

Example 24

2-((2-((5-propenamido-2-methoxy-4-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H )-Yl)phenyl)amino)-5-(oxazol-2-yl)pyrimidin-4-yl)amino)-N-methylbenzamide

Refer to Example 7 for the preparation method of Example 24.

MS m/z(ESI): 610.4[M+H] ⁺ .

Example 25

N-(5-((4-((4-chloro-5-fluoro-2-(2-hydroxypropan-2-yl)phenyl)amino)-5-(1-methyl-1H-pyrazole -4-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

Refer to Example 7 for the preparation method of Example 25.

MS m/z(ESI): 652.5[M+H] ⁺ .

Example 26

N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)-1,3,5-triazin-2-yl)amino)-2-((2-( (Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

method one:

The first step: Preparation of (3-(4-chloro-1,3,5-triazin-2-yl)-1-cyclopropyl-1H-indole

Dissolve 2,4-dichloropyrimidine-1,3,5-triazine (1.80g, 12mmol) in dichloroethane (20mL), cool to 0°C, add ferric chloride (3.9g, 24mmol), The reaction was stirred at room temperature for half an hour, 1-cyclopropyl-1H-indole (1.57 g, 10 mmol) was added, and the reaction was stirred at room temperature for 16 hours. Water (30mL) was added, filtered, the filtrate was extracted with dichloromethane (20mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, spin-dried, and the crude product was separated by column chromatography (petroleum ether/ethyl acetate: 100/1~3/1) purified to obtain (3-(4-chloro-1,3,5-triazin-2-yl)-1-cyclopropyl-1H-indole (Intermediate 26-1 , 1.32 g Yield: 49%), as a brown solid.

MS m/z(ESI): 271.1[M+H] ⁺ .

Steps two to four: N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)-1,3,5-triazin-2-yl)amino)-2 Preparation of -((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

Steps 2-4 refer to steps 2-4 of Example 1.

MS m/z(ESI): 527.1[M+H] ⁺ .

Method Two:

The first step: the preparation of 1-cyclopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole

Add aluminum trichloride (1.53g, 11.5mmol) to dichloromethane (27mL), add 2,6-lutidine (1mL) and 1M boron trichloride (6.7mL, 6.7mmol) in turn Methane solution. After reacting for 30 minutes, cyclopropylindole (1 g, 6.36 mmol) was added. The reaction was continued for 2 hours, and pinacol (1.65 g, 14 mmol) dissolved in triethylamine (16.8 mL) was added dropwise to the reaction system under an ice bath. After the addition is complete, react at room temperature for 2 hours. The reaction was quenched by adding ice water (40 mL), and extracted with dichloromethane (40 mL×3). The organic phase is dried and spin-dried, and purified with a chromatography column (petroleum ether) to obtain the product 1-cyclopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborole Cyclopentan-2-yl)-1H-indole (1 g, yield: 56%).

MS m/z(ESI): 284.2[M+H] ⁺

Step 2: Preparation of 4-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-1,3,5-triazine-2-amine

Dissolve 2,4-dichloro-1,3,5-triazine (600mg, 4mmol) in N,N-dimethylformamide (10mL), add N,N-diisopropyl in an ice bath Ethylamine (1 g, 8 mmol) and 4-fluoro-2-methoxy-5-nitroaniline (820 mg, 4.4 mmol) were reacted at room temperature for 3 hours. The reaction solution was poured into water (30 mL), filtered to obtain a solid, and washed with ethyl acetate to obtain the product 4-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-1,3 , 5-Triazine-2-amine (600 mg, yield: 50%).

MS m/z(ESI): 300.2[M+H] ⁺

The third step: 4-(1-cyclopropyl-1H-indol-3-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)-1,3,5- Preparation of triazine-2-amine

Dissolve 4-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-1,3,5-triazine-2-amine (150mg, 0.5mmol) in 1,4- Dioxane (12mL) and water (4mL), add 1-cyclopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Yl)-1H-indole (142 mg, 0.5 mmol), tetratriphenylphosphine (58 mg, 0.05 mmol) and sodium carbonate (106 mg, 1 mmol). After replacing the nitrogen, the reaction was carried out at 100°C for 16 hours. After filtration, dichloromethane (20mL) was added for extraction, the organic phase was dried and spin-dried, and purified with a chromatography column (dichloromethane: methanol = 10:1) to obtain the product 4-(1-cyclopropyl-1H-indole). Dol-3-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)-1,3,5-triazine-2-amine (100 mg, yield: 48%).

MS m/z(ESI): 421.2[M+H] ⁺

Steps 4 to 5: N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)-1,3,5-triazin-2-yl)amino)-2 Preparation of -((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

Steps 4-5 refer to Steps 3-4 of Example 1.

MS m/z(ESI): 527.1[M+H] ⁺ .

¹ H NMR (400MHz, Chloroform- d ) δ 12.56 (s, 1H), 10.29-10.03 (m, 1H), 9.84 (s, 1H), 9.57-9.30 (m, 1H), 9.05-8.84 (m, 1H) ), 8.72(s,1H),8.67-8.56(m,1H),7.71(s,1H),7.63-7.61(m,1H),7.31-7.28(m,1H),6.80-6.70(m,1H) ), 6.51(d, J =16.6Hz,1H), 5.74(d, J =10.5Hz,1H), 3.90(s,3H),3.51-3.44(m,1H),3.41-3.03(m,3H) , 2.95-2.60 (m, 7H), 2.43-2.18 (m, 3H), 1.25-1.10 (m, 4H).

Example 27

N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)-1,3,5-triazin-2-yl)amino)-4-methoxy-2 -(Methyl((1-methylpyrrolidin-2-yl)methyl)amino)phenyl)acrylamide

Refer to Example 26 for the preparation method of Example 27.

MS m/z(ESI): 553.3[M+H] ⁺ .

Example 28

N-(5-((4-((5-(dimethylphosphoryl)-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)amino)- 1,3,5-triazin-2-yl)amino)-4-methoxy-2-(methyl((1-methylpyrrolidin-2-yl)methyl)amino)phenyl) Acrylamide

Refer to Example 15 for the preparation method of Example 28.

MS m/z(ESI): 623.2[M+H] ⁺ .

¹ H NMR (400MHz, Chloroform-d) δ 11.76 (s, 1H), 9.70 (s, 1H), 9.56-9.23 (m, 1H), 8.44 (s, 1H), 8.34-8.18 (m, 1H), 7.36(s,1H),7.11-6.84(m,1H),6.69(s,1H),6.44(s,1H),5.78-5.61(m,1H), 4.26(d,J=14.7Hz,4H) , 3.84 (s, 3H), 3.39-3.12 (m, 1H), 3.06-2.90 (m, 1H), 2.90-2.76 (m, 1H), 2.72 (s, 3H), 2.56 (s, 3H), 2.50 -2.36 (m, 1H), 2.11-1.94 (m, 2H), 1.93-1.69 (m, 9H), 1.56-1.46 (m, 1H).

Example 29

N-(5-((5-cyano-4-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)-2- ((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

The first step: 1-cyclopropyl-1H-pyrrolo[2,3-b]pyridine

Copper acetate (6.2g, 34mmol) was added to 7-azaindole (4g, 34mmol), cyclopropylboronic acid (5.8g, 68mmol) 2,2'-bipyridine (5.3g, 34mmol) and sodium carbonate ( In a mixture of 7.2 g, 34 mmol) of 1,2-dichloroethane (100 mL), the reaction solution was heated to 85° C. under the protection of nitrogen and reacted for 12 hours. The reaction solution was cooled, water (150mL) was added, filtered, solid phase dichloromethane (60mL) washed, liquid phase separated, aqueous phase dichloromethane extraction (30mL*2), organic phases were combined, dried with anhydrous sodium sulfate, evaporated to dryness, Get crude product. The obtained crude product was separated by column (petroleum ether: dichloromethane=10:1) to obtain 1-cyclopropyl-1H-pyrrolo[2,3-b]pyridine (2.7g, yield: 50.4%).

MS m/z(ESI): 158.0[M+H] ⁺ .

The second step: 2-chloro-4-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile

Under the protection of nitrogen at 0°C, aluminum trichloride (1.07g, 8.1mmol) was added in batches to 2,4-dichloropyrimidine-5-carbonitrile (700mg, 4.0mmol) and 1-cyclopropyl-1H- In a mixture of pyrrolo[2,3-b]pyridine (637 mg, 4.0 mmol), the reactant was directly heated to 100° C. and stirred for 0.5 hour. Then cooled to 0°C, slowly added methanol (10 mL) and water (30 mL), stirred at room temperature for 30 minutes, extracted with dichloromethane (30 mL*2), combined the organic phases, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a crude product. The crude product is separated by column (petroleum ether: dichloromethane=1:1) to obtain 2-chloro-4-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine -5-carbonitrile (735 mg, yield: 62%).

MS m/z(ESI): 296.0[M+H] ⁺ .

The third step: 4-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-((4-fluoro-2-methoxy-5-nitrobenzene (Amino)pyrimidine-5-carbonitrile

Add p-toluenesulfonic acid monohydrate (643mg, 3.38mmol) to 4-fluoro-2-methoxy-5-nitroaniline (189mg, 1.01mmol) and 2-chloro-4-(1-cyclopropyl In a solution of -1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (250mg, 0.85mmol) in 2-butanol (15mL), the reaction solution was heated to 90°C for 12 hours. The reaction solution was cooled, evaporated to dryness, adjusted to pH 9 with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane (35 mL*2), the organic phase was dried with anhydrous sodium sulfate and evaporated to dryness to obtain a crude product. The crude product was separated by column (dichloromethane: ethyl acetate=5:1) to obtain the product 4-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2- ((4-Fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidine-5-carbonitrile (230 mg, yield: 61%).

MS m/z(ESI): 446.1[M+H] ⁺ .

The fourth step: 4-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-((4-((2-(dimethylamino)ethyl) (Methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine-5-carbonitrile

Potassium carbonate (214mg, 1.55mmol) was added to N,N,N'-trimethylethylenediamine (58mg, 0.57mmol) and 4-(1-cyclopropyl-1H-pyrrolo[2,3-b ]Pyridin-3-yl)-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidine-5-carbonitrile (230mg, 0.52mmol) in acetonitrile (10mL) During the reaction, the reaction solution was heated to 80°C for 2 hours. The reaction solution was cooled, evaporated to dryness, and dissolved in dichloromethane (30 mL) After hydrolysis, washed with brine (20mL*3), the organic phase was dried with anhydrous sodium sulfate and evaporated to dryness to obtain crude 4-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)- 2-((4-((2-(Dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine-5-carbonitrile( 270mg). The crude product was used directly in the next step.

MS m/z(ESI): 528.2[M+H] ⁺ .

The fifth step: 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-( 1-Cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile

Iron powder (288mg, 5.2mmol) was added to 4-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-((4-((2-(二(Methylamino) ethyl) (methyl) amino)-2-methoxy-5-nitrophenyl) amino) pyrimidine-5-carbonitrile (270 mg, 0.51 mol) in ethanol (10 mL) and saturated In the mixture of ammonium chloride aqueous solution (4 mL), the reaction solution was heated to 80° C. and reacted for 2 hours. The reaction solution was hot filtered, washed with solid dichloromethane, and evaporated to dryness in the liquid phase to obtain a crude product. Then, dichloromethane (30mL) was added to the crude product, washed with water (15mL*2), and the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to obtain a crude product 2- ((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-cyclopropyl- 1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (250mg), used directly in the next step.

MS m/z(ESI): 498.3[M+H] ⁺ .

The sixth step: 3-chloro-N-(5-((5-cyano-4-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-2- Yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)propanamide

At 0°C, 3-chloropropionyl chloride (77mg, 0.60mmol) was added to 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino )-2-Methoxyphenyl)amino)-4-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (250mg, 0.50mmol ) And triethylamine (0.21 mL, 1.51 mmol) in dichloromethane (10 mL), and the reaction solution was reacted at 0°C for 30 minutes. After evaporation to dryness, the crude product 3-chloro-N-(5-((5-cyano-4-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-2 -Yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)propanamide (250mg), used directly in the next step.

MS m/z(ESI): 588.3[M+H] ⁺ .

The seventh step: N-(5-((5-cyano-4-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino )-2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

Aqueous sodium hydroxide solution (containing sodium hydroxide (200mg, 5mmol) and water (1mL)) was added to the crude 3-chloro-N-(5-((5-cyano-4-(1-cyclopropyl-1H- Pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4- In a solution of methoxyphenyl) propionamide (290 mg, 0.50 mmol) in acetonitrile (10 mL), the reaction solution was stirred at room temperature for 16 hours. The reaction liquid is evaporated to dryness, Get crude product. The crude N,N-dimethylformamide (2mL) was dissolved, and the product N-(5-((5-cyano-4-(1-cyclopropyl-1H-pyrrolo[2,3 -b)pyridin-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)propene Amide (55 mg, yield: 20%).

¹ H NMR (400MHz, Chloroform-d) δ 10.32-9.88 (m, 1H), 9.59-9.18 (m, 1H), 8.92-8.52 (m, 3H), 8.52-8.26 (m, 1H), 7.96-7.61 (m,1H),7.24-6.99(m,1H),6.82(s,1H),6.55-6.15(m,2H),5.85-5.52(m,1H),3.89(s,3H),3.72-3.58 (m,1H),3.01-2.83(m,2H),2.74(s,3H),2.51-2.19(m,8H),1.30-1.04(m,4H).

MS m/z(ESI): 552.3[M+H] ⁺ .

Example 30

N-(5-((5-cyano-4-(3-methyl-1H-indazol-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamine (Methyl)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

Refer to Example 1 for the preparation method of Example 30.

MS m/z(ESI): 526.3[M+H] ⁺ .

¹ H NMR (400MHz, Chloroform- d ) δ 10.44-9.56 (m, 1H), 9.13 (s, 1H), 8.67 (s, 1H), 8.57-8.27 (m, 1H), 7.80-7.57 (m, 1H) ), 7.57-7.43 (m, 1H), 7.44-7.24 (m, 3H), 6.96-6.67 (m, 1H), 6.57-6.16 (m, 1H), 5.81-5.50 (m, 1H), 3.86 (s ,3H),3.45-2.08(m,16H).

Example 31

N-(5-((5-cyano-4-(1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)pyrimidin-2-yl)amino)-2-( (2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

Refer to Example 29 for the preparation method of Example 31.

MS m/z(ESI): 526.3[M+H] ⁺ .

Example 32

N-(5-((5-cyano-4-(1-methyl-1H-pyrrolo[3,2-c]pyridin-3-yl)pyrimidin-2-yl)amino)-2-( (2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

Refer to Example 29 for the preparation method of Example 32.

MS m/z(ESI): 526.2[M+H] ⁺ .

Example 33

N-(5-((5-cyano-4-(1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)pyrimidin-2-yl)amino)-2-( (2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

Refer to Example 29 for the preparation method of Example 33.

MS m/z(ESI): 526.0[M+H] ⁺ .

Example 34

N-(5-((5-cyano-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)-2-( (2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

Refer to Example 29 for the preparation method of Example 34.

MS m/z(ESI): 526.2[M+H] ⁺ .

Example 35

N-(5-((5-cyano-4-(6-methoxy-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amine Yl)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

Refer to Example 29 for the preparation method of Example 35.

MS m/z(ESI): 556.4[M+H] ⁺ .

Example 36

N-(5-((5-cyano-4-(6-methoxy-1-methyl-1H-pyrrolo[3,2-c]pyridin-3-yl)pyrimidin-2-yl)amine Yl)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

Refer to Example 29 for the preparation method of Example 36.

MS m/z(ESI): 556.1[M+H] ⁺ .

Biological test evaluation

The following further describes and explains the present invention in conjunction with test examples, but these examples are not meant to limit the scope of the present invention.

1. Test the enzyme experiment

Test Example 1. Determination of the inhibitory effect of the compound of the present invention on the kinase activity of EGFR 20 exon insertion mutation

Experimental purpose: The purpose of this test case is to measure the inhibitory ability of the compound on the kinase activity of the EGFR 20 exon insertion mutation.

Experimental equipment: centrifuge (Eppendorf 5810R), microplate reader (BioTek Synergy H1), pipette (Eppendorf & Rainin)

Experimental method: In this experiment, the TR-FRET (Time-Resolved Fluorescence Resonance Energy Transfer) method was used to study the inhibitory activity of the compound on the EGFR 20 exon insertion mutant kinase. This experiment was carried out in a 384-well plate. The experiment buffer (50mM HEPES, 1mM EGTA, 10mM MgCl ₂ , 2mM DTT, 0.01% Tween-20) was prepared, and the compound was diluted to different concentrations with the experiment buffer, 2.5 per well. Add μL to the 384-well plate, then add 2.5 μL of diluted EGFR kinase solution (0.001-0.5nM), incubate at room temperature for 10 minutes, add 5 μL of ULight-poly GT/ATP mixed solution, and incubate at room temperature for 30 minutes to 60 minutes , Add 5μL of EDTA to stop the reaction and 5μL of Eu-labeled antibody detection solution, incubate for 1 hour at room temperature, and measure the 665nm fluorescence signal value of each well with a microplate reader.

Experimental data processing method:

Use the fluorescence signal value at 665nm to calculate the inhibition rate ((positive control well value-sample well value)/(positive control well value-negative control well value))*100%, and use Graphpad Prism software to perform the concentration and inhibition rate The non-linear regression curve is fitted to obtain the IC ₅₀ value. The specific data are shown in Table 1 below:

Experimental results:

Based on the above scheme, it is concluded that the compounds of the examples of the present invention have a good inhibitory effect in the EGFR 20 exon insertion mutation kinase activity inhibition experiment.

Test Example 2. Determination of the inhibitory effect of the compound of the present invention on the activity of EGFR wild-type kinase

Experimental purpose: The purpose of this test case is to measure the inhibitory ability of the compound on the activity of EGFR wild-type kinase.

Experimental equipment: centrifuge (Eppendorf 5810R), microplate reader (BioTek Synergy H1), pipette (Eppendorf & Rainin)

Experimental method: In this experiment, the TR-FRET (Time-Resolved Fluorescence Resonance Energy Transfer) method was used to study the inhibitory activity of the compound on EGFR wild-type kinase. The experiment was carried out in a 384-well plate, and the experiment buffer (50mM HEPES, 1mM EGTA, 10mM MgCl ₂ , 2mM DTT, 0.01% Tween-20) was prepared, and the compound was diluted to different concentrations with the experiment buffer, 2μL per well Add 4μL of diluted EGFR kinase solution (0.001-0.5nM) to a 384-well plate, incubate at room temperature for 10 minutes, add 4μL of ULight-poly GT/ATP mixed solution, incubate at room temperature for 30 minutes to 60 minutes, add 5μL EDTA to stop the reaction and 5μL Eu-labeled antibody detection solution, incubate for 1 hour at room temperature, and measure the 665nm fluorescence signal value of each well with a microplate reader.

Experimental data processing method:

Use the fluorescence signal value at 665nm to calculate the inhibition rate ((positive control well value-sample well value)/(positive control well value-negative control well value))*100%, and use Graphpad Prism software to perform the concentration and inhibition rate The non-linear regression curve is fitted to obtain the IC ₅₀ value. The specific data are shown in Table 2 below:

Experimental results:

Based on the above scheme, it can be concluded that the compounds of the examples of the present invention have less inhibitory effect in the EGFR wild-type kinase inhibition test.

Test Example 3. Determination of the inhibitory effect of the compound of the present invention on the proliferation of Ba/F3 EGFR mutant cell lines

Experimental purpose: The purpose of this test case is to measure the inhibitory effect of the compound on the proliferation activity of the Ba/F3 EGFR mutant cell line.

Experimental equipment: Microplate reader (BioTek Synergy H1), pipette (Eppendorf & Rainin)

experimental method:

After culturing Ba/F3 EGFR mutant cells to a proper density, collect the cells, adjust the cells to a proper cell concentration with complete medium, spread the cell suspension on a 96-well plate, 90μL per well, and put it at 37°C, 5% CO ₂ Stick to the incubator overnight, use DMSO and culture medium to prepare compound solutions of different concentrations, set the solvent control, add the compound solution to a 96-well plate, 10μL per well, and place it in a 37°C, 5% CO ₂ incubator to continue culturing After 72h~144h, add CellTiter-Glo solution, shake and mix well, incubate in the dark for 10 minutes, and read with BioTek Synergy H1 microplate reader.

Experimental data processing method:

Use the luminescence signal value to calculate the inhibition rate, and use Graphpad Prism software to fit the concentration and inhibition rate to a nonlinear regression curve to obtain the IC ₅₀ value. The specific data are shown in Table 3 below:

Experimental results:

Based on the above scheme, it is concluded that the compounds of the examples of the present invention have a certain inhibitory effect in the inhibition test of the proliferation activity of Ba/F3 EGFR mutant cells.

Test Example 4. Metabolic stability test of liver microsomes

1. The purpose of the experiment:

The purpose of this experiment is to test the stability of the compounds of the examples in rat and human liver microsomes.

2. Experimental steps:

2.1 Preparation of compound working solution

Compound working solution preparation: add the compound stock solution to phosphate buffer, the final concentration is 20μM.

2.2 Preparation of working fluid for liver microsomes

Dilute with 100mM phosphate buffer to a final concentration of 0.625mg/mL.

2.3 Prepare NADPH and UDPGA

Weigh NADPH (reduced nicotinamide adenine dinucleotide phosphate) and UDPGA (uridine diphosphate glucuronic acid), add 100 mM phosphate buffer, and the final concentration is 20 mM.

2.4 Prepare the punch

Weigh 1 mg of Alamethicin (propamectin) and add 200 μL of DMSO to prepare a 5 mg/mL solution. Dilute with phosphate buffer to a final concentration of 50μg/mL.

2.5 Preparation of reaction stop solution

Stop solution: cold acetonitrile containing 100ng/mL labetalol hydrochloride and 400ng/mL tolbutamide as internal standards.

2.6 Incubation process

Add 400 μL of the prepared liver microsomes, 25 μL of compound working solution and 25 μL of Alamethicin to a 96-well plate in sequence, and pre-incubate at 37°C for 10 min. Then add 50μL of the prepared NADPH/UDPGA to start the reaction, and incubate at 37°C. The total volume of the reaction system is 500μL. The final content of each component is as follows:

2.7 Sample analysis

2.7.1 Chromatographic conditions:

Instrument: Shimadzu LC-30 AD;

Chromatographic column: XBridge® C18 (50*4.6mm, 5μm particle size);

Mobile phase: A: 0.1% formic acid solution, B: methanol

Extraction gradient: 0.2~1.6min 5%A to 95%A, 3.0~3.1min 95%A to 5%A

Running time: 4.0min.

2.7.2 Mass spectrometry conditions:

Instrument: API5500 Liquid Chromatography Mass Spectrometer, AB Sciex Company;

Ion source: Electrospray ionization source (ESI);

Drying gas: N ₂ , temperature 500℃;

Electrospray voltage: 5000V;

Detection method: positive ion detection;

Scanning mode: reaction monitoring (MRM) mode.

3. Experimental results:

4. Experimental conclusion:

●

The above data show that the compounds of the examples of the present invention have good metabolic stability in rat and human liver microsomes.

Test Example 5. Determination of pharmacokinetics in mice

1. Research purpose:

Balb/c mice were used as test animals to study the pharmacokinetic behavior of the compounds in mice (plasma) after oral administration.

2. Test plan:

2.1 Test drugs:

Example compounds of the present invention, self-made;

2.2 Test animals:

Balb/c mouse, male, purchased from Shanghai Jiesjie Experimental Animal Co., Ltd., animal production license number (SCXK (Shanghai) 2013-0006 N0.311620400001794).

2.3 Drug preparation:

Weigh 5 g of hydroxyethyl cellulose (HEC, CMC-Na, viscosity: 800-1200 Cps), dissolve it in 1000 mL of purified water, and add 10 g of Tween80. Mix well to form a clear solution.

The compound of the example was weighed and added to a 4-mL glass bottle respectively, and 2.4 mL of the solution was added, followed by sonication for 10 minutes to obtain a colorless and clear solution with a concentration of 1 mg/mL.

2.4 Administration:

Balb/c mice, male; PO respectively after fasting overnight, the dose was 40 mg/kg, and the dose volume was 10 mL/kg.

2.5 Sample collection:

The blood was collected before and after the administration, the blood was placed in an EDTA-2K test tube, and the plasma was separated by centrifugation at 6000 rpm at 4°C for 6 min, and stored at -80°C; food was taken 4 hours after the administration.

3. Experimental results:

The final measurement results obtained by the LCMS/MS method are shown in Table 5:

Table 5 Mouse pharmacokinetic parameters of compounds

4. Experimental conclusion:

The above data show that the compounds of the examples of the present invention have good pharmacokinetic parameters in mice.

Test Example 6. The in vivo pharmacodynamic study of the compound of the present invention on the mouse primary B cell Ba/F3 EGFR-D770-N771ins_SVD xenograft model

1. The purpose of the experiment:

To evaluate the in vivo efficacy of the compound on the mouse primary B cell Ba/F3 EGFR-D770-N771ins_SVD xenograft model.

2. Experimental equipment and reagents:

2.1 Instrument:

1. Biological safety cabinet (BSC-1300II A2, Shanghai Boxun Industrial Co., Ltd. Medical Equipment Factory)

2. Ultra-clean workbench (CJ-2F, Suzhou Feng's Laboratory Animal Equipment Co., Ltd.)

3. CO ₂ incubator (Thermo-311, Thermo)

4. Centrifuge (Centrifuge 5720R, Eppendorf)

5. Automatic cell counter (Countess II, Life Technologies)

6. Vernier calipers (CD-6"AX, Mitutoyo, Japan)

7. Cell culture flask (T75/T225, Corning)

8. Electronic balance (CPA2202S, Sartorius)

9. Electronic balance (BSA2202S-CW, Sartorius)

2.2 Reagents:

1. RPMI-1640 medium (22400-089, Gibco)

2. Fetal Bovine Serum (FBS) (10099-141C, Gibco)

3. Phosphate buffered saline (PBS) (10010-023, Gibco)

4. Tween 80 (30189828, Sinopharm reagent)

5. Sodium carboxymethyl cellulose (30036365, Sinopharm reagent)

3 Experimental operation and data processing:

3.1 Animals

BALB/c nude mice, 6-8 weeks, ♀, purchased from Shanghai Xipuer-Bikai Laboratory Animal Co., Ltd.

3.2 Cell culture and cell suspension preparation

a. Take out a Ba/F3 EGFR-D770-N771ins_SVD cell from the cell bank, resuscitate the cells with RPMI-1640 medium (RPMI-1640+10% FBS), and place the recovered cells in a cell culture flask (marked on the bottle wall) Good cell types, dates, culture names, etc.) _{are cultured in a CO 2} incubator (the temperature of the incubator is 37°C, and the CO ₂ concentration is 5%).

b. Subculture once every three days. After subculture, the cells will continue to be cultured _{in a CO 2 incubator.} Repeat this process until the number of cells meets the requirements for efficacy in the body.

c. Collect the cultured cells, count them with an automatic cell counter, and resuspend the cells in PBS according to the counting results to make a cell suspension (density 2×10 ⁷ /mL), and place in an ice box for later use.

3.3 Cell seeding

a. Label nude mice with disposable universal ear tags for rats and mice before vaccination

b. Mix the cell suspension during inoculation. Use a 1 mL syringe to draw 0.1-1 mL of the cell suspension to remove air bubbles, and then place the syringe on an ice bag for later use.

c. Set the nude mouse with the left hand, disinfect the right shoulder (vaccination site) on the right back of the nude mouse with 75% alcohol, and start the inoculation 30 seconds later.

d, inoculate test nude mice in turn (each mouse is inoculated with 0.1mL cell suspension).

3.4 Tumor-bearing mice, grouping and administration

a. According to the tumor growth, measure the tumor and calculate the tumor size from 8 to 14 days after inoculation.

Tumor volume calculation: tumor volume (mm ³ ) = length (mm) × width (mm) × width (mm)/2

b. According to the weight and tumor size of the tumor-bearing mice, the mice were randomly divided into groups, 5 mice in each group.

c. According to the grouping results, start to give the test drug (administration method: oral administration; dosing frequency: 1 time/day; dosing cycle: 14 days; vehicle: 0.5% CMC/1% Tween 80).

d. Measure and weigh the tumor twice a week after starting to give the test drug.

e. Euthanize the animal after the experiment.

f, Use Excel and other software to process data.

Calculation of compound tumor inhibition rate TGI (%):

TGI(%)=[(1-Average tumor volume at the end of treatment in a certain treatment group)/Average tumor volume at the end of treatment in the solvent control group]×100%.

60%，化合物在該模型中有效； TGI

60%, the compound is effective in this model;

TGI<60%, the compound is not effective in this model.

4. The test results are as follows in Table 6:

5. Experimental results

The above data shows that after 14 days of continuous oral administration, AZD9291 40mpk is ineffective in the Ba/F3 EGFR-D770-N771ins_SVD pharmacodynamic model, while Example 26 is effective at the same dose of 40mpk.

Claims (22)

A compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof,

in: M is selected from CR ₁ or N; L is selected from bond, -(CH ₂ ) _n -, -(CH ₂ ) _n NR _aa -, -(CH ₂ ) _n O-, -(CH ₂ ) _n S-, -(CH ₂ ) _n C(O )-, -(CH ₂ ) _n C(O)NR _aa -, -(CH ₂ ) _n NR _aa C(O)-, -(CH ₂ ) _n C(O)O-, -NR _aa (CH ₂ ) _n -, -O(CH ₂ ) _n -, -S(CH ₂ ) _n -, -C(O)(CH ₂ ) _n -, -C(O)NR _aa (CH ₂ ) _n -, -NR _aa C(O)(CH ₂ ) _n -, -C(O)O(CH ₂ ) _n -, -(CH ₂ ) _n P(O)R _aa -, -(CH ₂ ) _n S(O) _m -, -(CH ₂ ) _n S(O) _m NR _aa -or -(CH ₂ ) _n NR _aa S(O) _m -; Ring A is selected from cycloalkyl, heterocyclic, aryl or heteroaryl; Ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl; R _{1 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, hydroxyalkyl, azido, Carboxylate, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CH ₂ ) _n OR _a , -(CH ₂ ) _n NR _a R _b , -NR _a C (O)R _b , -C(O)NR _a (CH ₂ ) _n R _b , -NR _a C(O)NR _b R _c , -NR _a C(O)NR _b (CH ₂ ) _n R _c , -C≡CR _a , -NR _a C(O)CR _b =CH(CH ₂ ) _n R _c , -NR _a C(O)C≡CR _b , -C(O)NR _a R _b , -C( O)OR _a , -NR _a S(O) _m R _b , -O(CH ₂ ) _n R _a , -(CH ₂ ) _n P(O)R _a R _b , -(CH ₂ ) _n S(O ) _m NR _a R _b , -(CH ₂ ) _n C(O)R _a , -NR _a C(O)OR _b , -(CH ₂ ) _n S(O) _m R _a or -(CH ₂ ) _n NR _a S(O) _m R _b , the alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group may optionally be further substituted; R ^a is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halo, amino, nitro, hydroxy, cyano, hydroxyalkyl, azido, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n OR _a1 , -(CH ₂ ) _n NR _a1 R _b1 , -NR _a1 (CH ₂ ) _n R _b1 , -NR _a1 (CH ₂ ) _n NR _b1 R _c1 , -NR _a1 C(O)R _b1 , -NR _a1 C(O)NR _b1 R _c1 , -NR _a1 C(O)NR _b1 (CH ₂ ) _n R _c1 , -NR _a1 C(O)C≡CR _b1 , -NR _a1 C(O)CR _b1 =CH(CH ₂ ) _n R _c1 , -NR _a1 C(O)CR _b1 =CH(CH ₂ ) _n NR _c1 R _d1 , -C(O)NR _a1 R _b1 , -C(O)OR _a1 , -NR _a1 S(O) _m R _b1 , -O(CH ₂ ) _n R _a1 , -(CH ₂ ) _n P(O)R _a1 R _b1 , -(CH ₂ ) _n S(O) _m NR _a1 R _b1 , -(CH ₂ ) _n C(O)R _a1 , -NR _a1 C(O)OR _b1 ,- (CH ₂ ) _n S(O) _m R _a1 or -(CH ₂ ) _n NR _a1 S(O) _m R _b1 , the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Group, optionally can be further substituted; R ^{b is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, hydroxyalkyl, azido, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n OR _a2 , -(CH ₂ ) _n NR _a2 R _b2 , -NR _a2 (CH ₂ ) _n R _b2 , -NR _a2 (CH ₂ ) _n NR _b2 R _c2 , -NR _a2 C(O)R _b2 , -NR _a2 C(O)NR _b2 R _c2 , -NR _a2 C(O)NR _b2 (CH ₂ ) _n R _c2 , -NR _a2 C(O)C≡CR _b2 , -NR _a2 C(O)CR _b2 =CH(CH ₂ ) _n R _c2 , -NR _a2 C(O)CR _b2 =CH(CH ₂ ) _n NR _c2 R _d2 , -C(O)NR _a2 R _b2 , -C(O)OR _a2 , -NR _a2 S(O) _m R _b2 , -O(CH ₂ ) _n R _a2 , -(CH ₂ ) _n P(O)R _a2 R _b2 , -(CH ₂ ) _n S(O) _m NR _a2 R _b2 , -(CH ₂ ) _n C(O)R _a2 , -NR _a2 C(O)OR _b2 ,- (CH ₂ ) _n S(O) _m R _a2 or -(CH ₂ ) _n NR _a2 S(O) _m R _b2 , the alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl Group, optionally can be further substituted; R _aa , R _a , R _b , R _c , R _a1 , R _b1 , R _c1 , R _d1 , R _a2 , R _b2 , R _c2 or R _d2 are each independently selected from hydrogen, deuterium, alkyl, deuterated alkane Group, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or hetero Aryl groups, the alkyl groups, deuterated alkyl groups, haloalkyl groups, alkoxy groups, hydroxyalkyl groups, haloalkoxy groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups, Optional can be further substituted; x is an integer from 0 to 5; y is an integer from 0 to 5; m is an integer from 0 to 2; and n is an integer from 0 to 4. The compound according to claim 1, its stereoisomer or its pharmaceutically acceptable salt, wherein L is selected from bond, -(CH ₂ ) _n -, -(CH ₂ ) _n NR _aa -, -(CH ₂ ) _n O-, -(CH ₂ ) _n S-, -(CH ₂ ) _n C(O)-, -(CH ₂ ) _n C(O)NR _aa -, -(CH ₂ ) _n NR _aa C (O)-, -(CH ₂ ) _n C(O)O-, -(CH ₂ ) _n P(O)R _aa -, -(CH ₂ ) _n S(O) _m -, -(CH ₂ ) _n S(O) _m NR _{aa -or} -(CH ₂ ) _n NR _aa S(O) _m -; preferably selected from bond or -(CH ₂ ) _n NR _aa -; more preferably selected from bond or -NH- . The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, wherein ring A is selected from C _6-14 aryl or 5-14 membered heteroaryl; preferably phenyl. The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, wherein ring B is selected from 3-12 membered heterocyclic group, C _6-14 aryl group or 5-14 membered heteroaryl group ; Preferred phenyl, benzoheteroaryl or benzoheterocyclyl; further preferred are the following groups:

The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, wherein ring B is selected from 3-12 membered heterocyclic group, C _6-14 aryl group or 5-14 membered heteroaryl group ; Preferably benzoheteroaryl, benzoheterocyclic, pyridoheteroaryl or pyridoheterocyclyl; further preferably the following groups:

The compound according to claim 1, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R _{1 is} selected from hydrogen, deuterium, halogen, cyano, amine, nitro, hydroxyl, azido, C _1-6 carboxylic acid C _1-6 ester group, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl, substituted or unsubstituted 5-14 membered heteroaryl, -NR _a C(O) NR _b (CH ₂ ) _n R _c , -C≡CR _a , -NR _a C(O)CR _b =CHR _c , -C(O)NR _a (CH ₂ ) _n R _b , -C(O)OR _{a, -O (CH 2) n} R a, - (CH 2) n S (O) m R a , and _{- (CH 2) n P (} O) R a R b; is preferably a hydrogen atom, a halogen, a cyano group , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-12 members Heterocyclic group, substituted or unsubstituted 5-14 membered heteroaryl group, -O(CH ₂ ) _n R _a or -C(O)OR _a ; further preferred are the following substituents: hydrogen, fluorine, chlorine, bromine, Trifluoromethyl, cyano, methoxy, -C(O)OCH(CH ₃ ) ₂ ,

,

,

,

or

. The compound according to claim 1, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein ^{Ra is} selected from hydrogen, deuterium, halogen, cyano, amine, nitro, hydroxyl, C _1-6 alkane Group, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, substituted or unsubstituted 3-12 membered hetero Cyclic, C _6-14 aryl, 5-14 membered heteroaryl, -NR _a1 (CH ₂ ) _n R _b1 , -NR _a1 (CH ₂ ) _n NR _b1 R _c1 , -NR _a1 C(O)C ≡CR _b1 , -NR _a1 C(O)CR _b1 =CH(CH ₂ ) _n R _c1 , -NR _a1 C(O)CR _b1 =CH(CH ₂ ) _n NR _c1 R _d1 , -C(O)NR _a1 (CH ₂ ) _n R _b1 , -C(O)OR _a1 , -O(CH ₂ ) _n R _a1 , -(CH ₂ ) _n P(O)R _a1 R _b1 , -NR _a1 S(O) _m R _b1 , -(CH2) _n S(O) _m NR _a1 R _b1 , -(CH ₂ ) _n C(O)R _a1 , -NR _a1 C(O)OR _b1 , -(CH ₂ ) _n S(O ) _m R _a1 or -(CH ₂ ) _n NR _a1 S(O) _m R _b1 ; preferably a hydrogen atom, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1- 6} alkoxy group, a substituted or unsubstituted 3-12 membered heterocyclyl, 5-14 membered _{heteroaryl, -NR a1 (CH 2) n} R b1, -NR a1 (CH 2) n NR b1 R c1, -NR _a1 C(O)C≡CR _b1 , -NR _a1 C(O)CR _b1 =CH(CH ₂ ) _n R _c1 , -NR _a1 C(O)CR _b1 =CH(CH ₂ ) _n NR _c1 R _d1 or -O(CH ₂ ) _n R _a1 ; further preferably the following substituents: hydrogen, methoxy, -NHC(O)CH=CH ₂ ,

,

,

,

or

. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R ^{b is} selected from hydrogen, deuterium, halogen, cyano, amine, nitro, hydroxyl, C _1-6 alkane Group, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _{6 -14} aryl, 5-14 membered heteroaryl, -NR _a2 (CH ₂ ) _n R _b2 , -NR _a2 (CH ₂ ) _n NR _b2 R _c2 , -NR _a2 C(O)C≡CR _b2 ,- NR _a2 C(O)CR _b2 =CH(CH ₂ ) _n R _c2 , -NR _a2 C(O)CR _b2 =CH(CH ₂ ) _n NR _c2 R _d2 , -C(O)NR _a2 (CH ₂ ) _n R _b2 , -C(O)OR _a2 , -O(CH ₂ ) _n R _a2 , -(CH ₂ ) _n P(O)R _a2 R _b2 , -NR _a2 S(O) _m R _b2 , -( CH ₂ ) _n S(O) _m NR _a2 R _b2 , -(CH ₂ ) _n C(O)R _a2 , -NR _a2 C(O)OR _b2 , -(CH ₂ ) _n S(O) _m R _a2 Or -(CH ₂ ) _n NR _a2 S(O) _m R _b2 ; preferably hydrogen atom, halogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _2-6 alkenyl, C _2-6 Alkynyl, C _1-6 alkoxy, C _3-8 cycloalkyl, -(CH ₂ ) _n P(O)R _a2 R _b2 , -(CH ₂ ) _n S(O) _m R _a2 , -NR _a2 S(O) _m R _b2 , -(CH ₂ ) _n S(O) _m NR _a2 R _b2 or -C(O)NR _a2 (CH ₂ ) _n R _b2 ; further preferred are the following substituents: hydrogen, halogen , Cyclopropyl, -C(CH ₃ ) ₂ (OH), -P(O)(CH ₃ ) ₂ , -S(O) ₂ CH ₃ , -NHS(O) ₂ CH(CH ₃ ) ₂ ,- S(O) ₂ NHCH ₃ or -C(O)NHCH ₃ . The compound according to claim 1, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R ^{b is} selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, C _1-3 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 Haloalkoxy, C _3-6 cycloalkyl, 3-10 membered heterocyclic group, C _6-12 aryl group or 5-12 membered heteroaryl group; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino group , Hydroxy, cyano, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl , Fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, bromopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methyl Oxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, cyclopropyl, cyclobutyl, ring Pentyl, cyclohexyl, cycloheptyl, epoxypropyl, epoxybutyl, epoxypentyl, epoxyhexyl, epoxyheptyl, azetidinyl, azetidinyl, azetidine Group, azepanyl, azepanyl, thienyl, pyrrolyl, pyridyl, pyranyl, piperazinyl, phenyl, or naphthyl. The compound according to claim 1, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R _aa , R _a , R _b , R _c , R _a1 , R _b1 , R _c1 , R _d1 , R _a2 , R _b2 , R _c2 or R _d2 are each independently selected from hydrogen, deuterium, halogen, cyano, amino, nitro, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 Hydroxyalkyl group, C _1-6 cycloalkyl group, 3-12 membered heterocyclic group, C _6-14 aryl group or 5-14 membered heteroaryl group, the C _1-6 alkyl group, C _1-6 alkoxy group , C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclic group, C _6-14 aryl and 5-14 membered heteroaryl, optionally further deuterated, halogen, amine Group, cyano, C _1-4 alkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 haloalkyl, C _2-6 alkenylcarbonyl, C _1-6 hydroxy Alkyl, substituted or unsubstituted C _3-8 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted C _6-14 aryl, and substituted or unsubstituted 5-14 member Heteroaryl substitution. The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, wherein the general formula (I) is further represented by the general formula (II):

in: R _{2 is} selected from hydrogen, deuterium, halogen, cyano, amine, nitro, hydroxyl, azido, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 Alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclic group, C _6-14 aryl, 5-14 membered heteroaryl, -NR _a1 C(O) R _b1 , -NR _a1 C(O)NR _b1 (CH ₂ ) _n R _c1 , -NR _a1 C(O)C≡CR _b1 , -NR _a1 C(O)CR _b1 =CH(CH ₂ ) _n R _c1 , -NR _a1 C(O)CR _b1 =CH(CH ₂ ) _n NR _c1 R _d1 , -C(O)NR _a1 (CH ₂ ) _n R _b1 , -C(O)OR _a1 , -O(CH ₂ ) _n R _a1 ,-(CH ₂ ) _n P(O)R _a1 R _b1 , -NR _a1 S(O) _m R _b1 , -(CH ₂ ) _n S(O) _m NR _a1 R _b1 , -(CH ₂ ) _n C(O)R _a1 , -NR _a1 C(O)OR _b1 , -(CH ₂ ) _n S(O) _m R _a1 or -(CH ₂ ) _n NR _a1 S(O) _m R _b1 ; Preferred -NR _a1 C(O)R _b1 , -NR _a1 C(O)NR _b1 (CH ₂ ) _n R _c1 , -NR _a1 C(O)C≡CR _b1 , -NR _a1 C(O)CR _b1 =CH(CH ₂ ) _n R _c1 , -NR _a1 C(O)CR _b1 =CH(CH ₂ ) _n NR _c1 R _d1 ; more preferably -NHC(O)CH=CH ₂ ; R _{3 is} selected from hydrogen, deuterium, halogen, cyano, amine, nitro, hydroxyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclic group, C _6-14 aryl, 5-14 membered heteroaryl, -O(CH ₂ ) _n R _a1 ,- NR _a1 (CH ₂ ) _n R _b1 or -NR _a1 (CH ₂ ) _n NR _b1 R _c1 , the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkane Oxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclic group, C _6-14 aryl and 5-14 membered heteroaryl, optionally further substituted by halogen, cyano , Hydroxy, mercapto, C _1-4 alkyl, C _1-4 nitrile, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 hydroxyalkyl and substituted or unsubstituted 3- The 12-membered heterocyclic group is substituted by one or more substituents; preferably selected from substituted 3-12-membered heterocyclic groups, -NR _a1 (CH ₂ ) _n R _b1 or -NR _a1 (CH ₂ ) _n NR _b1 R _c1 ; more preferably the following groups:

R _{4 is} selected from hydrogen atom, deuterium atom, halogen, cyano, amino, nitro, hydroxyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy Group, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl; Preferably hydrogen, methyl, methoxy or ethoxy. The compound according to claim 9, its stereoisomer or pharmaceutically acceptable salt thereof, wherein the general formula (I) is further represented by the general formula (III):

in: R _{5 is} selected from hydrogen atom, deuterium atom, halogen, cyano, amino, nitro, hydroxyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy Group, C _1-6 hydroxyalkyl group, C _3-8 cycloalkyl group, 3-12 membered heterocyclic group, C _6-14 aryl group, 5-14 membered heteroaryl group, -NR _a2 (CH ₂ ) _n R _b2 , -NR _a2 (CH ₂ ) _n NR _b2 R _c2 , -NR _a2 C(O)C≡CR _b2 , -NR _a2 C(O)CR _b2 =CH(CH ₂ ) _n R _c2 , -NR _a2 C (O)CR _b2 =CH(CH ₂ ) _n NR _c2 R _d2 , -C(O)NR _a2 (CH ₂ ) _n R _b2 , -C(O)OR _a2 , -O(CH ₂ ) _n R _a2 , -(CH ₂ ) _n P(O)R _a2 R _b2 , -NR _a2 S(O) _m R _b2 , -(CH ₂ ) _n S(O) _m NR _a2 R _b2 , -(CH ₂ ) _n C( O) R _a2 , -NR _a2 C(O)OR _b2 , -(CH ₂ ) _n S(O) _m R _a2 or -(CH ₂ ) _n NR _a2 S(O) _m R _b2 ; preferably a hydrogen atom, Halogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _3-8 cycloalkyl, -(CH ₂ ) _n P(O)R _a2 R _b2 , -(CH ₂ ) _n S(O) _m R _a2 , -NR _a2 S(O) _m R _b2 , -(CH ₂ ) _n S(O) _m NR _a2 R _b2 or -C(O)NR _a2 (CH ₂ ) _n R _b2 ; further preferably the following substituents: hydrogen atom, -C(CH ₃ ) ₂ (OH), -P(O)(CH ₃ ) ₂ , -S(O) ₂ CH ₃ , -NHS(O) ₂ CH(CH ₃ ) ₂ , -S(O) ₂ NHCH ₃ or -C(O)NHCH ₃ ; R ₆ and R ₇ are each independently selected from a hydrogen atom, a deuterium atom, a halogen, a cyano group, an amino group, a nitro group, a hydroxyl group, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl; preferably hydrogen Atom or halogen; Alternatively, R ₆ and R ₇ are linked with the carbon atom to which they are attached to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group. The cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optional Can be further substituted; preferably the following groups:

R _{8 is} selected from hydrogen, deuterium, halogen, cyano, amine, nitro, hydroxyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, A C _1-6 hydroxyalkyl group, a C _3-8 cycloalkyl group, a 3-12 membered heterocyclic group, a C _6-14 aryl group or a 5-14 membered heteroaryl group; preferably a hydrogen atom or a halogen. The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, wherein the general formula (I) is further represented by the general formula (IV):

Or, as shown in general formula (V):

The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, wherein the general formula (I) is further represented by the general formula (VI):

in: R _{9 is} selected from hydrogen atom, deuterium atom, halogen, cyano, amino, nitro, hydroxyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy Group, C _1-6 hydroxyalkyl group, C _3-8 cycloalkyl group, 3-12 membered heterocyclic group, C _6-14 aryl group or 5-14 membered heteroaryl group; preferably hydrogen atom, C _1-6 Alkyl or C _3-8 cycloalkyl; more preferably hydrogen, methyl or cyclopropyl. The compound according to claim 14, its stereoisomer or pharmaceutically acceptable salt thereof, wherein the general formula (VI) is further represented by the general formula (VI-A):

R _{9 is} not a methyl group. The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, wherein the general formula (I) is further represented by the general formula (VII):

The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 16, wherein M is N or CR ₁ ; R _{1 is} selected from hydrogen, halogen, cyano, trifluoromethyl, cyano, methoxy, ethoxy, -C(O)OCH(CH ₃ ) ₂ ,

,

,

,

,

,

or

； Ring B is selected from

,

,

,

,

or

； R ^{b is} selected from a hydrogen atom, a deuterium atom, a halogen, a cyano group, an amino group, a nitro group, a hydroxyl group, a phosphoryl group, a sulfonyl group, an aminosulfonyl group, a C _1-6 alkyl group, and a C _2-6 alkenyl group , C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclic group, C _6-14 aryl or 5-14 Member heteroaryl; preferably hydrogen atom, -P(O)(CH ₃ ) ₂ , -S(O) ₂ CH ₃ , -NHS(O) ₂ CH(CH ₃ ) ₂ , -S(O) ₂ NHCH _3. C _1-6 alkyl or C _3-8 cycloalkyl; more preferably hydrogen, methyl, -P(O)(CH ₃ ) ₂ , -S(O) ₂ CH ₃ , or cyclopropyl; y is 1, 2 or 3, preferably 1. The compound according to any one of claims 1 to 17, its stereoisomer or a pharmaceutically acceptable salt thereof, which is selected from the following compounds:

A method for preparing the compound represented by general formula (VI) or its stereoisomers and pharmaceutically acceptable salts thereof as described in claim 15, which comprises the following steps:

The general formula (VI-1) reacts with the general formula (VI-2) to obtain the general formula (VI-3), and the general formula (VI-3) continues to react with the general formula (VI-4) to obtain the general formula (VI) The indicated compound or its stereoisomers and pharmaceutically acceptable salts thereof; in: X ₁ and X ₂ are each independently selected from halogen; preferably fluorine, chlorine, bromine or iodine; more preferably chlorine; X _{3 is} selected from halogen, boric acid or boric acid ester; preferably boric acid ester; more preferably

. A pharmaceutical composition comprising a therapeutically effective dose of the compound and its stereoisomers or pharmaceutically acceptable salts thereof according to any one of claims 1 to 18, and one or more pharmaceutically acceptable carriers or excipient. An application of the compound according to any one of claims 1 to 18, its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 20 in the preparation of kinase inhibitors, Preferably, the kinase inhibitor is a receptor tyrosine kinase inhibitor (TKI), The application of HER2 inhibitors, EGFR inhibitors and EGFR monoclonal antibodies and their associated drugs is more preferred, and the inhibitors of EGFR 20 exon insertion mutations and HER2 20 exon insertion mutation targets are further preferred. A compound as described in any one of claims 1 to 18 and its stereoisomers or pharmaceutically acceptable salts thereof or the pharmaceutical composition as described in claim 20 is used in the preparation of the treatment of cancer, inflammation, chronic liver disease, Application of drugs in diabetes, cardiovascular disease and AIDS-related diseases. Preferably, the cancer is selected from breast cancer, cervical cancer, colon cancer, lung cancer, gastric cancer, rectal cancer, pancreatic cancer, brain cancer, liver cancer, solid tumor, and glial Tumor, glioblastoma, leukemia, lymphoma, myeloma and non-small cell lung cancer.