CN111484484A - 2,4-Diarylaminopyrimidine Derivatives Containing Aromatic Heterocycles and Their Preparation and Application - Google Patents

Abstract

The invention relates to 2, 4-diarylaminopyrimidine derivatives containing aromatic heterocyclic rings shown in a general formula I, optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, a preparation method thereof and a pharmaceutical composition taking the compounds shown in the general formula I as active ingredients, wherein a substituent R is₁、R₂、R₃、R₄、R₅、R₆X, Y, Z have the meaning given in the description. The invention also relates to the conversion of the general formula IThe compound has strong A L K and ROS1 kinase inhibition effect, and also relates to the application of the compound, optical isomers and pharmaceutically acceptable salts thereof in preparing medicaments for treating and/or preventing diseases caused by abnormal expression of A L K and ROS1, in particular to the application in preparing medicaments for treating and/or preventing cancers.

Description

2,4-Diarylaminopyrimidine Derivatives Containing Aromatic Heterocycles and Their Preparation and Application

technical field

The invention belongs to the technical field of medicine, and relates to 2,4-diarylaminopyrimidine derivatives containing aromatic heterocycles, optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, their preparation methods and the compounds containing the 2,4-diarylaminopyrimidine derivatives. pharmaceutical composition of the compound. The present invention also relates to the strong ALK and ROS1 kinase inhibitory effect of the compound and its application in the preparation of medicines for the treatment and/or prevention of diseases caused by abnormal expression of ALK and ROS1, especially in the preparation of therapeutic and/or Use in medicines for the prevention of cancer.

Background technique

The research of kinase-targeted drugs has become an important direction in the research and development of anti-tumor drugs, among which protein kinases are the most studied class. Impaired or abnormal signaling processes due to mutation or rearrangement of protein kinases can lead to abnormal cell growth, differentiation, metabolism, and biological behavior, which in turn can induce a variety of tumors.

Protein kinases (PKs) are enzymes that catalyze the phosphorylation of hydroxyl groups on tyrosine, serine and threonine residues of proteins through the transfer of terminal phosphates of ATP, mainly including protein tyrosine kinases (PKs). kinase, PTK) and serine-threonine kinase (Serine-threonine kinase, STK). These enzymes regulate cell growth, differentiation and proliferation, etc. through signal transduction pathways.

Anaplastic lymphoma kinase (ALK), a member of the insulin receptor tyrosine kinase family, was first discovered in anaplastic large cell lymphoma AMS3 cells in 1994. single-chain transmembrane protein. ALK was expressed at a high level during embryonic development, and then gradually decreased, with a small amount expressed in adulthood. The protein consists of an extramembrane part, a transmembrane region and an intramembrane catalytic region. The downstream signaling pathways are Ras-ERK, JAK3-STAT3, and PI3-K/Akt, etc. These pathways are closely related to cell proliferation, survival, and migration.

In 1994, Morri et al. found that the ALK gene on chromosome 2 and the nucleophosmin (nucleophosmin) gene on chromosome 5 were misplaced and fused, and the rearranged mutant gene NPM-ALK was carcinogenic. In 2007, Japanese scientists Soda et al. first discovered ALK gene mutation in lung adenocarcinoma tissue: an inversion mutation occurred in the short arm of chromosome 2, making exons 1 to 13 of the echinoderms microtubule-associated protein 4 (EML4) gene and NIH-3T3 fibroblasts transfected with the EML4-ALK fusion gene exons 20-29 of the ALK gene have the ability of malignant transformation. About 3% to 7% of NSCLC patients have EML4-ALK fusion gene. In addition, studies have shown that ALK gene mutations are involved in the pathogenesis of various tumors, including anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, and neuroblastoma. Therefore, targeting ALK inhibitors can achieve anti-tumor goals by inhibiting ALK downstream-related signals.

The c-ros sarcoma oncogene receptor tyrosine kinase ROS1 (ROS proto-oncogene 1) is also a haplotype receptor tyrosine kinase. Fusion, overexpression, and mutation of the ROS1 gene all lead to dysregulation of the ROS1 protein. Abnormal ROS1 protein kinase will activate multiple downstream oncogenic signaling pathways that control cell proliferation, survival and cell cycle. ROS1 is highly expressed in various tumor cells, and its amino acid sequence homology with ALK is 49%, and the homology of ATP binding region is as high as 77%. Various ALK inhibitors can inhibit the activity of ROS1 in vitro.

The present invention designs and synthesizes a series of 2,4-diarylaminopyrimidine derivatives containing aromatic heterocycles. The in vitro activity screening showed that these compounds have obvious antitumor activity.

SUMMARY OF THE INVENTION

The present invention relates to aromatic heterocycle-containing 2,4-diarylaminopyrimidine derivatives represented by general formula I and optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,

in,

n=1 or 2

X is independently C, N, O or S, and may be substituted by R _;

Y is independently C, N, O or S, and may be substituted by R _;

Z is independently C, N, O or S, and may be substituted by R _;

R ₁ is hydroxy, halogen, nitro, amino, cyano, (C ₁ -C ₆ ) alkylsulfinyl, (C ₁ -C ₆ ) alkylsulfonyl, (C ₁ -C ₆ )alkoxy , (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl acyl, (C ₁ -C ₆ ) alkyl amido, (C ₁ -C ₆ ) alkylsulfonamido, by 1- 2 (C ₁ -C ₆ ) alkyl substituted aminomethyl (acetyl) acyl, 1-2 hydroxy (C ₁ -C ₆ ) alkyl substituted aminomethyl (acetyl) acyl, (C ₁ -C _{3 )} ) alkylenedioxy;

R ₂ is halogen, halogenated or unhalogenated (C ₁ -C ₆ )alkyl, hydroxy, cyano, amino, nitro;

R ₃ is H, halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkylthio, halogen or/and hydroxy or/and amino substituted (C ₁ -C ₆ )alkyl, halogen or/and hydroxy or/and amino substituted (C ₁ -C ₆ )alkoxy, halogen or/and hydroxy or/and amino substituted (C ₁ -C ₆ ) alkylthio;

R ₄ is H, (C ₁ -C ₆ ) alkyl, 3-6 membered saturated or partially saturated carbocyclic ring, (C ₁ -C ₆ ) alkyl acyl or (C ₁ -C ₆ ) alkylsulfonyl;

R ₅ is H, (C ₁ -C ₆ ) alkyl, 3-6 membered saturated or partially saturated carbocycle, (C ₁ -C ₆ ) alkyl acyl or alkylsulfonyl; or NR ₇ R ₈ , NH _m COR ₇ R ₈ , NH _m CONH _m R ₇ R ₈ , SO ₂ (CH ₂ ) _m NR ₇ R ₈ , SO ₂ (CH ₂ ) _m CONR ₇ R ₈ , CONH _m R ₇ R ₈ , (CH ₂ ) _p R ₇ R ₈ , (CH ₂ ) _p N _m R ₇ R ₈ , CO(CH ₂ ) _p R ₇ R ₈ , NH _m CO(CH ₂ ) _p R ₇ R ₈ , NH _m (CH ₂ ) _p COR ₇ R ₈ , NH _m CO(CH ₂ ) _p NH _m R ₇ R ₈ , COR ₇ ;

R ₆ is H, (C ₁ -C ₆ )alkyl, 3-6 membered saturated or partially saturated carbocycle, (C ₁ -C ₆ )alkylacyl or (C ₁ -C ₆ )alkylsulfonyl; or NR ₇ R ₈ , NH _m COR ₇ R ₈ , NH _m CONH _m R ₇ R ₈ , SO ₂ (CH ₂ ) _m NR ₇ R ₈ , SO ₂ (CH ₂ ) _m CONR ₇ R ₈ , CONH _m R ₇ R ₈ , (CH ₂ ) _p R ₇ R ₈ , (CH ₂ ) _p N _m R ₇ R ₈ , CO(CH ₂ ) _p R ₇ R ₈ , NH _m CO(CH ₂ ) _p R ₇ R ₈ , NH _m (CH ₂ ) _p COR ₇ R ₈ , NH _m CO(CH ₂ ) _p NH _m R ₇ R ₈ ;

R ₇ and R ₈ are the same or different and are independently selected from H, (C ₁ -C ₁₀ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, (C ₁ -C ₁₀ ) alkoxy, (C 1 -C 10 ) ₂ -C ₁₀ ) alkenyl, (C ₂ -C ₁₀ ) alkynyl, cyano, carboxyl, hydroxy, amino, hydroxy and/or amino substituted (C ₁ -C ₁₀ ) alkyl, hydroxy and/or amino substituted (C ₁ -C ₁₀ )alkoxy;

or R ₇ and R ₈ together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group other than the one attached to R ₇ and R ₈ In addition to the nitrogen atom, optionally containing 0-4 heteroatoms selected from N, O and/or S, the heterocyclic group or heteroaryl group is optionally substituted by 0-3 identical or different R ₉ ;

R ₉ is (C ₁ -C ₁₀ )alkyl, (C ₃ -C ₇ )cycloalkyl, (C ₁ -C ₁₀ )alkoxy, hydroxy, carboxy, amino, hydroxy and/or amino substituted (C ₁ -C ₁₀ )alkyl, hydroxy and/or amino-substituted (C ₁ -C ₁₀ )alkoxy, halogen, halo(C ₁ -C ₁₀ )alkyl, halo(C ₁ -C ₁₀ )alkane Oxygen, nitro;

m independent is 0-2, p independent is 0-6.

The present invention relates to aromatic heterocycle-containing 2,4-diarylaminopyrimidine derivatives represented by general formula I and optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,

in,

n=1 or 2

X is independently C, N, O or S, and may be substituted by R _;

Y is independently C, N, O or S, and may be substituted by R _;

Z is independently C, N, O or S, and may be substituted by R _;

R ₁ is hydroxy, halogen, nitro, amino, cyano, (C ₁ -C ₃ ) alkylsulfinyl, (C ₁ -C ₃ ) alkylsulfonyl, (C ₁ -C ₃ )alkoxy , (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkyl acyl, (C ₁ -C ₃ ) alkyl amido, (C ₁ -C ₃ ) alkylsulfonamido, by 1- 2 (C ₁ -C ₃ ) alkyl substituted aminomethyl (acetyl) acyl, 1-2 hydroxy (C ₁ -C ₃ ) alkyl substituted aminomethyl (acetyl) acyl, alkylenedioxy ;

R ₂ is halogen, halogenated or unhalogenated (C ₁ -C ₃ )alkyl, hydroxy, cyano, amino, nitro;

R ₃ is H, halogen, (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkoxy, (C ₁ -C ₃ )alkylthio, halogen or/and hydroxy or/and amino substituted (C ₁ -C ₃ ) alkyl, halogen or/and hydroxy or/and amino substituted (C ₁ -C ₃ )alkoxy, halogen or/and hydroxy or/and amino substituted (C ₁ -C ₃ ) alkylthio;

R ₄ is H, (C ₁ -C ₃ ) alkyl, 3-6 membered saturated or partially saturated carbocyclic ring, (C ₁ -C ₃ ) alkyl acyl or (C ₁ -C ₃ ) alkylsulfonyl;

R ₅ is H, (C ₁ -C ₃ )alkyl, 3-6 membered saturated or partially saturated carbocycle, (C ₁ -C ₃ )alkyl acyl or (C ₁ -C ₃ )alkylsulfonyl; or NR ₇ R ₈ , NH _m COR ₇ R ₈ , NH _m CONH _m R ₇ R ₈ , SO ₂ (CH ₂ ) _m NR ₇ R ₈ , SO ₂ (CH ₂ ) _m CONR ₇ R ₈ , CONH _m R ₇ R ₈ , (CH ₂ ) _p R ₇ R ₈ , (CH ₂ ) _p N _m R ₇ R ₈ , CO(CH ₂ ) _p R ₇ R ₈ , NH _m CO(CH ₂ ) _p R ₇ R ₈ , NH _m (CH ₂ ) _p COR ₇ R ₈ , NH _m CO(CH ₂ ) _p NH _m R ₇ R ₈ , COR ₇ ;

R ₆ is H, (C ₁ -C ₃ )alkyl, 3-6 membered saturated or partially saturated carbocycle, (C ₁ -C ₃ ) alkyl acyl or (C ₁ -C ₃ ) alkylsulfonyl; or NR ₇ R ₈ , NH _m COR ₇ R ₈ , NH _m CONH _m R ₇ R ₈ , SO ₂ (CH ₂ ) _m NR ₇ R ₈ , SO ₂ (CH ₂ ) _m CONR ₇ R ₈ , CONH _m R ₇ R ₈ , (CH ₂ ) _p R ₇ R ₈ , (CH ₂ ) _p N _m R ₇ R ₈ , CO(CH ₂ ) _p R ₇ R ₈ , NH _m CO(CH ₂ ) _p R ₇ R ₈ , NH _m (CH ₂ ) _p COR ₇ R ₈ , NH _m CO(CH ₂ ) _p NH _m R ₇ R ₈ ;

R ₇ and R ₈ are the same or different and are independently selected from H, (C ₁ -C ₃ )alkyl, (C ₃ -C ₆ )cycloalkyl, (C ₁ -C ₃ )alkoxy, (C 1 -C 3 )alkoxy ₂ - _C4 )alkenyl, (C2 _{- C4} )alkynyl, cyano, carboxyl, hydroxyl, amino, hydroxyl and/or amino-substituted ( _{C1 -} C3)alkyl, hydroxyl and/or amino-substituted (C ₁ -C ₃ )alkoxy;

or R ₇ and R ₈ together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group other than the one attached to R ₇ and R ₈ In addition to the nitrogen atom, optionally containing 0-4 heteroatoms selected from N, O and/or S, the heterocyclic group or heteroaryl group is optionally substituted by 0-3 identical or different R ₉ ;

R ₉ is (C ₁ -C ₃ )alkyl, (C ₃ -C ₆ )cycloalkyl, (C ₁ -C ₃ )alkoxy, hydroxy, carboxy, amino, hydroxy and/or amino substituted (C _{1 -} C3)alkyl, hydroxy and/or amino-substituted ( _{C1 -} C3)alkoxy, halogen, halo( _{C1 -} C3)alkyl, halo( _{C1 -} C3)alkane Oxygen, nitro;

m independent is 0-2, p independent is 0-6.

The present invention relates to aromatic heterocycle-containing 2,4-diarylaminopyrimidine derivatives represented by general formula I and optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,

in,

n=1

X is independently C, N, O or S, and may be substituted by R _;

Y is independently C, N, O or S, and may be substituted by R _;

Z is independently C, N, O or S, and may be substituted by R _;

R ₁ is (C ₁ -C ₃ ) alkylsulfinyl, (C ₁ -C ₃ ) alkylsulfonyl, (C ₁ -C ₃ ) alkoxy, (C ₁ -C ₃ ) alkyl, ( C ₁ -C ₃ ) alkyl acyl, (C ₁ -C ₃ ) alkyl amido, (C ₁ -C ₃ ) alkylsulfonamido, substituted with 1-2 (C ₁ -C ₃ ) alkyl The aminomethyl (acetyl) acyl group, the amino methyl (acetyl) acyl group substituted by 1-2 hydroxy (C ₁ -C ₃ ) alkyl groups, and alkylenedioxy;

R ₂ is halogen, hydroxyl, cyano, amino, nitro;

R ₃ is H, halogen, (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkoxy, halogen or/and hydroxy or/and amino-substituted (C ₁ -C ₃ )alkyl, halogen or/and hydroxy or/and amino substituted (C ₁ -C ₃ )alkoxy;

R ₄ is H, (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkylacyl or (C ₁ -C ₃ )alkylsulfonyl;

R ₅ is H, (C ₁ -C ₃ )alkyl; or NH _m CONH _m R ₇ R ₈ , CONH _m R ₇ R ₈ , (CH ₂ ) _p R ₇ R ₈ , (CH ₂ ) _p N _m R ₇ R ₈ , CO(CH ₂ ) _p R ₇ R ₈ , NH _m CO(CH ₂ ) _p R ₇ R ₈ , NH _m (CH ₂ ) _p COR ₇ R ₈ , NH _m CO(CH ₂ ) _p NH _m R ₇ R ₈ , COR ₇ ;

R ₆ is H, (C ₁ -C ₃ )alkyl; or NH _m CONH _m R ₇ R ₈ , CONH _m R ₇ R ₈ , (CH ₂ ) _p R ₇ R ₈ , (CH ₂ ) _p N _m R ₇ R ₈ , CO(CH ₂ ) _p R ₇ R ₈ , NH _m CO(CH ₂ ) _p R ₇ R ₈ , NH _m (CH ₂ ) _p COR ₇ R ₈ , NH _m CO(CH ₂ ) _p NH _m R ₇ R ₈ ;

R ₇ and R ₈ are the same or different and are independently selected from H, (C ₁ -C ₃ )alkyl, (C ₃ -C ₆ )cycloalkyl, (C ₁ -C ₃ )alkoxy, (C 1 -C 3 )alkoxy ₂ - _C4 )alkenyl, (C2 _{- C4} )alkynyl, cyano, carboxyl, hydroxyl, amino, hydroxyl and/or amino-substituted ( _{C1 -} C3)alkyl;

or R ₇ and R ₈ together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl or 4-6 membered heteroaryl group other than the one attached to R ₇ and R ₈ In addition to the nitrogen atom, optionally containing 0-4 heteroatoms selected from N, O and/or S, the heterocyclic group or heteroaryl group is optionally substituted by 0-2 identical or different R ₉ ;

R ₉ is (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkoxy, hydroxy, carboxy, amino, hydroxy and/or amino-substituted (C ₁ -C ₃ )alkyl;

m independent is 0-2, p independent is 0-6.

The present invention relates to aromatic heterocycle-containing 2,4-diarylaminopyrimidine derivatives represented by general formula I and optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,

in,

n=1

X is independently C, N, O or S, and may be substituted by R _;

Y is independently C, N, O or S, and may be substituted by R _;

Z is independently C, N, O or S, and may be substituted by R _;

R ₁ is (C ₁ -C ₃ ) alkylamido, (C ₁ -C ₃ ) alkylsulfonamido, carbamoyl substituted by 1-2 (C ₁ -C ₃ ) alkyl groups;

R ₂ is halogen, hydroxyl, cyano;

R ₃ is H, halogen, (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkoxy;

R ₄ is H, (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkylacyl or (C ₁ -C ₃ )alkylsulfonyl;

R ₅ is H, NH _m CONH _m R ₇ R ₈ , CONH _m R ₇ R ₈ , (CH ₂ ) _p N _m R ₇ R ₈ , NH _m CO(CH ₂ ) _p NH _m R ₇ R ₈ , COR ₇ ;

R ₆ is H, (C ₁ -C ₃ )alkyl; or NH _m CONH _m R ₇ R ₈ , CONH _m R ₇ R ₈ , (CH ₂ ) _p N _m R ₇ R ₈ , NH _m CO(CH _{2 )} ) _p NH _m R ₇ R ₈ ;

R ₇ and R ₈ are the same or different, and are independently selected from H, (C ₁ -C ₃ )alkyl, (C ₃ -C ₆ )cycloalkyl, (C ₁ -C ₃ )alkoxy, and hydroxy-substituted (C ₁ -C ₃ ) alkyl, hydroxyl;

Or R ₇ and R ₈ together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group, and the heterocyclic group optionally contains 0-2 alternatives in addition to the nitrogen atom to which R ₇ and R ₈ are attached. A heteroatom from N, O and/or S, the heterocyclyl group is optionally substituted with 0-1 identical or different R ₉ ;

R ₉ is (C ₁ -C ₃ )alkyl, hydroxy, hydroxy-substituted (C ₁ -C ₃ )alkyl;

m independent is 0-1, p independent is 0-3.

The present invention relates to aromatic heterocycle-containing 2,4-diarylaminopyrimidine derivatives represented by general formula I and optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,

in,

n=1

X is independently C or N, and may be substituted by R _;

Y is N, and can be substituted by R ₄ ;

Z is independently C or N, and may be substituted by R _;

R ₁ is (C ₁ -C ₃ ) alkylamido, (C ₁ -C ₃ ) alkylsulfonamido, carbamoyl substituted by 1-2 (C ₁ -C ₃ ) alkyl groups;

R ₂ is halogen;

R ₃ is H;

R ₄ is H;

R ₅ is NH _m CONH _m R ₇ R ₈ , CONH _m R ₇ R ₈ , (CH ₂ ) _p N _m R ₇ R ₈ , COR ₇ ;

R ₆ is (C ₁ -C ₃ )alkyl; or (CH ₂ ) _p N _m R ₇ R ₈ ;

R ₇ and R ₈ are the same or different, and are independently selected from H, (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkoxy, hydroxy-substituted (C ₁ -C ₃ )alkyl, hydroxyl;

Or R ₇ and R ₈ together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group, the heterocyclic group optionally contains 0-1 optional 0-1 in addition to the nitrogen atom to which R ₇ and R ₈ are attached. A heteroatom from N, O and/or S, the heterocyclyl group is optionally substituted with 0-1 identical or different R ₉ ;

R ₉ is (C ₁ -C ₃ )alkyl, hydroxy, hydroxy-substituted (C ₁ -C ₃ )alkyl;

m independent is 0-1, p independent is 0-3.

The present invention relates to aromatic heterocycle-containing 2,4-diarylaminopyrimidine derivatives represented by general formula I and optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,

in,

n=1

X is independently C or N, and may be substituted by R _;

Y is N, and can be substituted by R ₄ ;

Z is independently C or N, and may be substituted by R _;

R ₁ is acetylamino, methanesulfonylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl;

R ₂ is Cl;

R ₃ is H;

R ₄ is H;

R ₅ is CONH _m R ₇ R ₈ , COR ₇ ;

R ₆ is methyl; or (CH ₂ ) _p N _m R ₇ R ₈ ;

R ₇ and R ₈ are the same or different, and are independently selected from H, (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkoxy, hydroxy-substituted (C ₁ -C ₃ )alkyl, hydroxyl;

Or R ₇ and R ₈ together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group, the heterocyclic group optionally contains 0-1 optional 0-1 in addition to the nitrogen atom to which R ₇ and R ₈ are attached. A heteroatom from N, O and/or S, the heterocyclyl group is optionally substituted with 0-1 identical or different R ₉ ;

R ₉ is (C ₁ -C ₃ )alkyl, hydroxy, hydroxy-substituted (C ₁ -C ₃ )alkyl;

m independent is 0-1, p independent is 0-3.

The present invention relates to aromatic heterocycle-containing 2,4-diarylaminopyrimidine derivatives represented by general formula I and optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,

in,

n=1

X is N;

Y is N, and can be substituted by R ₄ ;

Z is C, and can be replaced by R ₆ ;

R ₁ is acetylamino, methanesulfonylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl;

R ₂ is Cl;

R ₃ is H;

R ₄ is H;

R ₆ is (CH ₂ ) _p N _m R ₇ R ₈ ;

R ₇ and R ₈ are the same or different, and are independently selected from H, (C ₁ -C ₃ )alkyl, and hydroxy-substituted (C ₁ -C ₃ )alkyl;

Or R ₇ and R ₈ together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group, the heterocyclic group optionally contains 0-1 optional 0-1 in addition to the nitrogen atom to which R ₇ and R ₈ are attached. A heteroatom from N, O and/or S, the heterocyclyl group is optionally substituted with 0-1 identical or different R ₉ ;

R ₉ is (C ₁ -C ₃ )alkyl, hydroxy, hydroxy-substituted (C ₁ -C ₃ )alkyl;

m independent is 1, p independent is 1.

The present invention relates to aromatic heterocycle-containing 2,4-diarylaminopyrimidine derivatives represented by general formula I and optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,

in,

n=1

X is N;

Y is N, and can be substituted by R ₄ ;

Z is C, and can be replaced by R ₆ ;

R ₁ is acetylamino, methanesulfonylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl;

R ₂ is Cl;

R ₃ is H;

R ₄ is H;

_R6 is

The present invention relates to aromatic heterocycle-containing 2,4-diarylaminopyrimidine derivatives represented by general formula I and optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,

in,

n=1

X is C, and may be substituted by R _;

Y is N, and can be substituted by R ₄ ;

Z is C, and can be replaced by R ₆ ;

R ₁ is methanesulfonylamino, N-methylcarbamoyl;

R ₂ is Cl;

R ₃ is H;

R ₄ is H;

R ₅ is CONH _m R ₇ R ₈ , COR ₇ ;

R ₆ is methyl;

R ₇ and R ₈ are the same or different, and are independently selected from H, (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkoxy, hydroxy-substituted (C ₁ -C ₃ )alkyl, hydroxyl;

Or R ₇ and R ₈ together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group, the heterocyclic group optionally contains 0-1 optional 0-1 in addition to the nitrogen atom to which R ₇ and R ₈ are attached. A heteroatom from N, O and/or S, the heterocyclyl group is optionally substituted with 0-1 identical or different R ₉ ;

R ₉ is (C ₁ -C ₃ )alkyl, hydroxy, hydroxy-substituted (C ₁ -C ₃ )alkyl;

m independent is 1.

The present invention relates to aromatic heterocycle-containing 2,4-diarylaminopyrimidine derivatives represented by general formula I and optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,

in,

n=1

X is C, and may be substituted by R _;

Y is N, and can be substituted by R ₄ ;

Z is C, and can be replaced by R ₆ ;

R ₁ is methanesulfonylamino, N-methylcarbamoyl;

R ₂ is Cl;

R ₃ is H;

R ₄ is H;

_R5 is

R ₆ is methyl.

The compounds of the present invention and their optical isomers, pharmaceutically acceptable salts, solvates or prodrugs are preferably the following compounds, but these compounds do not imply any limitation to the present invention:

N-(2-((5-Chloro-2-((2-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidine -4-yl)amino)phenyl)methanesulfonamide

2-(5-Chloro-2-((2-(((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidine-4- yl)amino)-N,N-dimethylbenzamide

N-(2-((5-Chloro-2-((2-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidine -4-yl)amino)phenyl)acetamide

2-((5-Chloro-2-((2-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazol-6-yl)amino )pyrimidin-4-yl)amino)-N-methylphenylcarboxamide

N-(2-((5-Chloro-2-((2-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazole-6- yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide

2-((5-Chloro-2-((2-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazol-6-yl)amino )pyrimidin-4-yl)amino)-N,N-dimethylbenzamide

N-(2-((5-Chloro-2-((2-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazole-6- yl)amino)pyrimidin-4-yl)amino)phenyl)acetamide

2-((5-Chloro-2-((2-((dimethylamino)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)amino)-N -methylbenzamide

N-(2-((5-Chloro-2-((2-((dimethylamino)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)amino )phenyl)methanesulfonamide

2-((5-Chloro-2-((2-((dimethylamino)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)amino)-N ,N-Dimethylbenzamide

N-(2-((5-Chloro-2-((2-((dimethylamino)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)amino )phenyl)acetamide

N-(2-((5-Chloro-2-((2-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)amino )phenyl)methanesulfonamide

N-(2-((5-Chloro-2-((2-((4-ethylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidine -4-yl)amino)phenyl)methanesulfonamide

N-(2-((5-Chloro-2-((2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)amino )phenyl)methanesulfonamide

2-((5-Chloro-2-((2-((4-methylpiperidin-1-yl)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidine-4- base)amino)-N-methylbenzamide

N-(2-((5-Chloro-2-((2-((4-methylpiperidin-1-yl)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidine -4-yl)amino)phenyl)methanesulfonamide

N-(2-((5-Chloro-2-((2-((4-methylpiperidin-1-yl)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidine -4-yl)amino)phenyl)acetamide

N-(2-((5-Chloro-2-((2-((4-hydroxypiperidin-1-yl)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidine- 4-yl)amino)phenyl)methanesulfonamide

N-(2-((5-Chloro-2-(((2-((diisopropylamino)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl )amino)phenyl)methanesulfonamide

N-(2-((5-Chloro-2-((2-(morpholinomethyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)amino)phenyl ) methanesulfonamide

N-(2-((5-Chloro-2-((2-((diethylamino)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)amino) phenyl)methanesulfonamide

N-(2-((5-Chloro-2-((2-(thiomorpholinomethyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)amino) phenyl)methanesulfonamide

2-((5-Chloro-2-((2-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)amino)-N ,N-Dimethylbenzamide

2-((5-Chloro-2-((2-((4-ethylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidine-4- yl)amino)-N,N-dimethylbenzamide

2-((5-Chloro-2-((2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)amino)-N ,N-Dimethylbenzamide

2-((5-Chloro-2-((2-(morpholinomethyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)amino)-N,N- dimethylbenzamide

2-((5-Chloro-2-((2-((diethylamino)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)amino)-N, N-Dimethylbenzamide

2-((5-Chloro-2-((2-(thiomorpholinomethyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)amino)-N, N-Dimethylbenzamide

Ethyl 6-((5-chloro-4-((2-(methylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-2-methyl-1H-indole-3-carboxylate ester

6-((5-Chloro-4-((2-(methylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-2-methyl-1H-indole-3-carboxylate methyl ester

N-(2-((5-Chloro-2-((2-methyl-3-(4-methylpiperazine-1-carbonyl)-1H-indol-6-yl)amino)pyrimidine-4- yl)amino)phenyl)methanesulfonamide

N-(2-((5-Chloro-2-((3-(4-(2-hydroxyethyl)piperazine-1-carbonyl)-2-methyl-1H-indol-6-yl)amino )pyrimidin-4-yl)amino)phenyl)methanesulfonamide

6-((5-Chloro-4-((2-(methylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-N-(2-hydroxyethyl)-2-methyl- 1H-Indole-3-carboxamide

N-(2-((5-Chloro-2-((3-(4-ethylpiperazine-1-carbonyl)-2-methyl-1H-indol-6-yl)amino)pyrimidine-4- yl)amino)phenyl)methanesulfonamide

N-(2-((5-Chloro-2-((2-methyl-3-(4-methylpiperidine-1-carbonyl)-1H-indol-6-yl)amino)pyrimidine-4- yl)amino)phenyl)methanesulfonamide

N-(2-((5-Chloro-2-((3-(4-hydroxypiperidine-1-carbonyl)-2-methyl-1H-indol-6-yl)amino)pyrimidin-4-yl )amino)phenyl)methanesulfonamide

N-(2-((5-Chloro-2-((2-methyl-3-(piperidine-1-carbonyl)-1H-indol-6-yl)amino)pyrimidin-4-yl)amino) phenyl)methanesulfonamide

N-(2-((5-Chloro-2-((2-methyl-3-(morpholine-4-carbonyl)-1H-indol-6-yl)amino)pyrimidin-4-yl)amino) phenyl)methanesulfonamide

N-(2-((5-Chloro-2-((2-methyl-3-(thiomorpholine-4-carbonyl)-1H-indol-6-yl)amino)pyrimidin-4-yl) Amino)phenyl)methanesulfonamide

N-(2-((5-Chloro-2-((2-methyl-3-(pyrrolidine-1-carbonyl)-1H-indol-6-yl)amino)pyrimidin-4-yl)amino) phenyl)methanesulfonamide

(R)-N-(2-((5-Chloro-2-((3-(2-(hydroxymethyl)pyrrolidine-1-carbonyl)-2-methyl-1H-indol-6-yl )amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide

N-(2-((5-Chloro-2-((3-(3-hydroxyazetidine-1-carbonyl)-2-methyl-1H-indol-6-yl)amino)pyrimidine- 4-yl)amino)phenyl)methanesulfonamide

6-((5-Chloro-4-((2-(methylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-N,N,2-trimethyl-1H-indole- 3-Carboxamide

2-((5-Chloro-2-((2-methyl-3-(4-methylpiperazine-1-carbonyl)-1H-indol-6-yl)amino)pyrimidin-4-yl)amino )-N-methylbenzamide

6-((5-Chloro-4-((2-(methylcarbamoyl)phenyl)amino)pyrimidin-2-yl)amino)-N,N,2-trimethyl-1H-indole- 3-Carboxamide

2-((5-Chloro-2-((2-methyl-3-(morpholine-4-carbonyl)-1H-indol-6-yl)amino)pyrimidin-4-yl)amino)-N- methylbenzamide

2-((5-Chloro-2-((2-methyl-3-(4-methylpiperidine-1-carbonyl)-1H-indol-6-yl)amino)pyrimidin-4-yl)amino )-N-methylbenzamide

2-((5-Chloro-2-((3-(4-hydroxypiperidine-1-carbonyl)-2-methyl-1H-indol-6-yl)amino)pyrimidin-4-yl)amino) -N-methylbenzamide

6-((5-Chloro-4-((2-(methylcarbamoyl)phenyl)amino)pyrimidin-2-yl)amino)-N,N-diethyl-2-methyl-1H- indole-3-carboxamide

6-((5-Chloro-4-((2-(methylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-2-methyl-1H-indole-3-carboxylic acid

Moreover, the aromatic heterocycle-containing 2,4-diarylaminopyrimidine derivatives of the general formula I of the present invention can be formed into pharmaceutically acceptable salts with acids according to some common methods in the art to which the present invention pertains. Pharmaceutically acceptable addition salts include inorganic and organic acid addition salts, with addition salts with the following acids being particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid , benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, etc.

Furthermore, the present invention also includes prodrugs of the derivatives of the present invention. The prodrugs of the derivatives of the present invention are pyrimidine derivatives of the general formula I, which are obtained by forming an ester of a hydroxyl-containing R ₅ or R ₆ group with a carboxyl compound (ester prodrugs). They may themselves be less active or even inactive, but after administration are converted into the corresponding biologically active form under physiological conditions (eg by metabolism, solvolysis or otherwise).

In the present invention, "halogen" refers to fluorine, chlorine, bromine or iodo; "alkyl" refers to straight-chain, branched alkyl or cycloalkyl; "alkylene" refers to straight-chain or branched alkylene alkyl.

We have found that the compound of the present invention has tumor cell growth inhibitory activity in vitro, therefore, it can be used for the preparation of a medicament for the treatment and/or prevention of cancer, such as breast, lung, liver, kidney, colon, rectum, stomach, prostate, bladder, uterus , pancreas, bone marrow, testis, ovary, lymph, soft tissue, head and neck, thyroid, esophagus, cancer and leukemia, neuroblastoma, etc.

Through the in vitro activity test of inhibiting human anaplastic large cell lymphoma cells Karpas299 highly expressing NPM-ALK protein and human lung adenocarcinoma cells NCI-H2228 highly expressing EML4-ALK protein, the compounds of the present invention have significant effects on lung cancer cells and lymphoma cells. Inhibitory effect, especially for the preparation of medicaments for the treatment and/or prevention of lung cancer and lymphoma.

The active compounds of the present invention or their pharmaceutically acceptable salts and their solvates can be used alone as the only anti-tumor drugs, or can be used together with existing anti-tumor drugs (such as platinum drug cisplatin, camptothecin drug iritinib) Kang, vinblastine drugs Noviben, etc.) are used in combination. Combination therapy is accomplished by administering the individual therapeutic components simultaneously, sequentially or separately.

The examples and preparations provided hereinafter further illustrate and illustrate the compounds of the present invention and methods for their preparation. It should be understood that the scope of the following examples and preparations is not sufficient to limit the scope of the invention in any way.

The following synthetic schemes summarize and describe the preparation of the derivatives of formula I of the present invention, all starting materials were prepared in the manner described in these schemes, by methods well known to those of ordinary skill in the art of organic chemistry, or are commercially available. All final derivatives of the present invention are prepared by methods described in these schemes, or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All variables applied in these routes are as defined below or as defined in the claims.

According to the formula I derivatives of the present invention, the nucleophilic substitution reaction of intermediates M-1 and M-2 in corresponding solvents or intermediates M-3 and corresponding HNR ₇ R can be carried out according to the methods of route 1 and route 2. ₈ was prepared by N-acylation in the corresponding solvent. wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₆ , R ₇ and R ₈ in the compound are as defined in the claims.

Intermediates M _-- 1 can be obtained by the condensation of intermediates XII with substituted dichloropyrimidines according to scheme 3. wherein R ₁ and R ₂ in the compound are as defined in the claims.

Intermediate M-2 can be obtained by cyclization of intermediate XIII and chloroacetic acid according to route 4 to obtain intermediate XIV, and then N-alkylation reaction with the corresponding small molecular amine to obtain intermediate XV, which is finally obtained by nitro reduction. Wherein, R ₃ , R ₄ , R ₇ and R ₈ in the compound are as defined in the claims, and the reduction method includes hydrogen/Pd-C/alcohol system, hydrazine hydrate/ferric chloride hexahydrate/activated carbon/alcohol system , metal/acid or ammonium chloride system, stannous chloride dihydrate/alcohol system.

Intermediate M-3 can be substituted by intermediate XVI and R ₆ substituted acetoacetate methyl/ethyl ester according to route 5 to obtain intermediate XVII, and then obtain intermediate XVIII by reduction method, and then undergo affinity with intermediate M-1. The nuclear substitution reaction yields intermediate XIX, which is finally obtained by hydrolysis. Wherein, R ₁ , R ₂ , R ₃ and R ₆ in the compound are as defined in the claims, and the reduction method includes hydrogen/Pd-C/alcohol system, hydrazine hydrate/ferric chloride hexahydrate/activated carbon/alcohol system , metal/acid or ammonium chloride system, stannous chloride dihydrate/alcohol system. Hydrolysis methods include solvent systems consisting of inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, and alcohol/water or tetrahydrofuran.

When R ₁ is methanesulfonylamino or acetamido, and R ₂ is Cl, the preparation methods of intermediates M ₁ -1 and M ₂ -1 are shown in Scheme 6.

When R ₁ is N-methylcarbamoyl or N,N-dimethylcarbamoyl, and R ₂ is Cl, the preparation methods of intermediates M ₃ -1 and M ₄ -1 are shown in Scheme 7.

The preparation of intermediate M- ₂ when _R3 is H and R4 is H is shown in Scheme 8.

When R ₁ is methanesulfonylamino or N-methylcarbamoyl, R ₃ is H, and R ₆ is methyl, the preparation methods of intermediates M ₁ -3 and M ₂ -3 are shown in Scheme 9.

Detailed ways:

The examples are intended to illustrate rather than limit the scope of the invention. The hydrogen nuclear magnetic resonance spectrum of the compound was determined by BrukerARX-400, and the mass spectrum was determined by Agilent 1100LC/MSD; all reagents used were of analytical or chemical purity.

wherein R ₂ is Cl, R ₃ is H, R ₄ is H, Z is C, and n=1.

Table I

Example 1:

Step A N-(2,5-Dichloropyrimidin-4yl)-1,2-diphenylamine (III)

Add 30.00g (0.16mol) o-phenylenediamine (II) and 17.70g (0.16mol) 2,4,5-trichloropyrimidine to 300mL of dry isopropanol (i-PrOH), slowly add 42.30g ( 0.33mol) N,N-diisopropylethylamine, and the temperature was raised to 80°C for 1.5h. Suction filtration while hot to obtain 37.35 g of white powder solid with a yield of 89.7%.

Step B N-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)methanesulfonamide (M ₁ -1)

Under ice bath conditions, 10 g (0.04 mol) of intermediate III and 9.3 g (0.12 mol) of pyridine (Py) were added to 50 mL of dry tetrahydrofuran, and 5.4 g (0.05 mol) of methanesulfonyl chloride was slowly added dropwise. After the dropping was completed, the reaction was carried out at room temperature for 2.5 hours, filtered with suction, and washed with tetrahydrofuran (10 mL×3) to obtain 11.7 g of a white powder solid with a yield of 89.3%.

Step C 2-(Chloromethyl)-6-nitro-1H-benzo[d]imidazole (VI)

At room temperature, 10.0 g (0.07 mol) of 4-nitro-o-phenylenediamine (V), 12.3 g (0.13 mol) of chloroacetic acid and 50 mL of water were added to 133 mL of concentrated hydrochloric acid, and the reaction was refluxed for 4 h. The reaction solution was placed at room temperature, adjusted to pH=9 with ammonia water, and suction filtered to obtain an orange-red solid. The obtained solid was recrystallized from methanol to obtain 8.9 g of a pale yellow solid with a yield of 64.5%.

Step D 2-((4-Methylpiperazin-1-yl)methyl)-6-nitro-1H-benzo[d]imidazole (VII-1)

At room temperature, 9.0 g (0.04 mol) VI was dissolved in 100 mL tetrahydrofuran (THF), 8.5 g (0.09 mol) N-methylpiperazine and 11.8 g (0.09 mol) anhydrous potassium carbonate were added, and the reaction was carried out at 50 °C for 2 hours. . The reaction solution was cooled to room temperature, poured into 20 mL of water, stirred for 30 minutes, and filtered with suction to obtain 8.0 g of a light brown solid with a yield of 68.3%.

Step E 2-((4-Methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-6-amine (M ₁ -2)

At room temperature, 5.0 g (0.02 mol) of VII-1 was dissolved in 50 mL of 90% ethanol solution, and 0.74 g (2.7 mmol) of ferric chloride hexahydrate and 0.07 g (5.5 mmol) of activated carbon powder were added. After the temperature was raised to 40°C, 50 mL of 80% hydrazine hydrate was added dropwise, and the temperature was raised to reflux for 1 hour after dropping. Suction filtration while hot, and the filtrate was evaporated to dryness to obtain 4.3 g of off-white solid, yield 97.0%

Step F N-(2-((5-Chloro-2-((2-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-6-yl)amino ) pyrimidin-4-yl)amino)phenyl)methanesulfonamide (Example I)

At room temperature, 0.7 g (2.9 mmol) of M ₁ -2 was dissolved in 10 mL of isopropanol, 0.85 g (2.9 mmol) of M ₁ -1 and 0.50 g (2.9 mmol) of p-toluenesulfonic acid were added, and the reaction was carried out at 80 ° C for 6 hours . The reaction solution was placed at room temperature, added 20 mL of water, adjusted to pH=8 with saturated sodium bicarbonate solution, extracted three times with 60 mL of ethyl acetate, and the combined organic phases were evaporated to dryness to obtain 0.46 g of a light brown solid with a yield of 31.9%, which was obtained by column chromatography. Pale yellow solid.

mp: 232.5-233.4°C; ESI-MS [M+H] ⁺ (m/z): 542.38; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.27 (s, 1H), 8.74 (s, 1H) ,8.21(d,J＝7.6Hz,1H),8.15(s,1H),7.78(s,1H),7.35(d,J＝5.8Hz,2H),7.33(s,2H),7.13(d, J=7.0Hz, 1H), 7.09(dd, J=7.5, 1.7Hz, 2H), 3.67(s, 2H), 2.89(s, 3H), 2.50–2.42(m, 3H), 2.38(s, 4H) ),2.18(s,4H).

Example 2N-(2-((5-Chloro-2-((2-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazole- 6-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide

According to the method of step D in Example 1, using VI as raw material, N-alkylation reaction with N-hydroxyethylpiperazine was carried out to prepare 2-(4-((6-nitro-1H-benzo[d] Imidazol-2-yl)methyl)piperazin-1-yl)ethyl-1-ol (VII-2). The yield was 83.0%.

According to the method of Step E in Example 1, using VII-2 as raw material, 2-(4-((6-amino-1H-benzo[d]imidazol-2-yl)methyl)piperazine was obtained by reduction reaction -1-yl)ethyl-1-ol (M ₂ -2), yield 97.8%.

According to the method of Step F in Example 1, using M ₁ -1 and M ₂ -2 as raw materials, Example 2 was prepared, and the yield was 80.5%.

mp: 237.6-240.2°C; ESI-MS [M+H] ⁺ (m/z): 572.46; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.05 (s, 1H), 9.27 (s, 1H) ,8.63(s,1H),8.18(d,J=7.8Hz,1H),8.15(s,1H),7.76(s,1H),7.35(d,J=7.9Hz,2H),7.32(s, 2H), 7.19(t, J＝7.4Hz, 1H), 7.12(t, J＝7.0Hz, 1H), 4.38(s, 1H), 3.66(s, 2H), 3.50(d, J＝4.0Hz, 2H), 3.47(d, J=6.1Hz, 2H), 2.92(s, 3H), 2.47(s, 4H), 2.39(t, J=6.2Hz, 4H).

Example 3 N-(2-((5-Chloro-2-((2-((dimethylamino)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidine-4- yl)amino)phenyl)methanesulfonamide

According to the method of step D in Example 1, using VI as raw material, N,N-dimethyl-1-(6-nitro-1H- Benzo[d]imidazol-2-yl)methanamine (VII-3). The yield was 96.2%.

According to the method of step E in Example 1, using VII-3 as raw material, 2-((dimethylamino)methyl)-1H-benzo[d]imidazol-6-amine (M ₃ -2 ) with a yield of 92.6%.

According to the method of Step F in Example 1, using M ₁ -1 and M ₃ -2 as raw materials, Example 3 was prepared, and the yield was 95.9%.

mp: 212.3-215.1°C; ESI-MS [M+H] ⁺ (m/z): 487.28; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.14 (s, 1H), 9.27 (s, 1H) ,8.57(s,1H),8.16(s,1H),8.15(s,1H),7.74(s,1H),7.36(d,J=7.8Hz,2H),7.33(s,1H),7.29( d, J＝9.7Hz, 1H), 7.25(d, J＝7.7Hz, 1H), 7.16(t, J＝7.1Hz, 1H), 3.63(s, 3H), 2.94(s, 2H), 2.24( s, 6H).

Example 4 N-(2-((5-Chloro-2-((2-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidine-4- yl)amino)phenyl)methanesulfonamide

According to the method of step D in Example 1, using VI as raw material, N-alkylation reaction with hexahydropyridine (piperidine) was carried out to prepare 6-nitro-2-(piperidin-1-ylmethyl)-1H - Benzo[d]imidazole (VII-4). The yield was 85.7%.

According to the method of step E in Example 1, using VII-4 as raw material, 2-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-6-amine (M ₄ - 2), the yield was 90.5%.

According to the method of Step F in Example 1, using M ₁ -1 and M ₄ -2 as raw materials, Example 4 was prepared, and the yield was 91.7%.

mp: 228.5-230.7°C; ESI-MS [M+H] ⁺ (m/z): 527.35; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.04 (s, 1H), 9.26 (s, 1H) ,8.63(s,1H),8.18(d,J=8.0Hz,1H),8.15(s,1H),7.75(s,1H),7.35(dd,J=7.8,1.2Hz,2H),7.32( s, 2H), 7.19(t, J=7.4Hz, 1H), 7.11(t, J=7.1Hz, 1H), 3.63(s, 2H), 2.92(s, 3H), 2.41(s, 4H), 1.55–1.52(m, 4H), 1.40(d, J=4.4Hz, 2H).

Example 5 N-(2-((5-Chloro-2-((2-((4-ethylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-6-yl) Amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide

According to the method of step D in Example 1, using VI as raw material, N-alkylation reaction with N-ethylpiperazine was carried out to prepare 2-((4-ethylpiperazin-1-yl)methyl)-6 -Nitro-1H-benzo[d]imidazole (VII-5). The yield was 83.0%.

According to the method of step E in Example 1, using VII-5 as raw material, 2-((4-ethylpiperazin-1-yl)methyl)-1H-benzo[d]imidazole-6 is obtained by reduction reaction - Amine (M ₅ -2) in 92.2% yield.

According to the method of Step F in Example 1, using M ₁ -1 and M ₅ -2 as raw materials, Example 5 was prepared, and the yield was 81.9%.

mp: 232.9-234.2°C; ESI-MS [M+H] ⁺ (m/z): 556.48; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.03 (s, 1H), 9.28 (s, 1H) ,8.64(s,1H),8.18(d,J=7.9Hz,1H),8.16(s,1H),7.77(s,1H),7.35(d,J=7.7Hz,2H),7.32(s, 1H), 7.19(dd, J=15.2, 7.3Hz, 2H), 7.15–7.09(m, 1H), 3.57(s, 2H), 2.93(s, 3H), 2.85(dd, J=14.3, 7.1Hz ,2H),2.44(s,4H),2.40–2.27(m,4H),0.99–0.97(m,3H).

Example 6 N-(2-((5-Chloro-2-((2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidine-4- yl)amino)phenyl)methanesulfonamide

According to the method of step D in Example 1, using VI as raw material, N-alkylation reaction with tetrahydropyrrole was carried out to prepare 6-nitro-2-(pyrrolidin-1-ylmethyl)-1H-benzo[ d] Imidazole (VII-6). The yield was 85.9%.

According to the method of Step E in Example 1, using VII-6 as a raw material, 2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-6-amine (M ₆ - 2), the yield was 95.0%.

According to the method of Step F in Example 1, using M ₁ -1 and M ₆ -2 as raw materials, Example 6 was prepared, and the yield was 85.5%.

mp: 215.9-219.0°C; ESI-MS [M+H] ⁺ (m/z): 513.40; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 12.08 (s, 1H), 9.26 (s, 1H) ,8.65(s,1H),8.19(d,J=7.5Hz,1H),8.15(s,1H),7.75(s,0H),7.34(d,J=7.5Hz,2H),7.33(s, 2H), 7.18(t, J=7.1Hz, 1H), 7.11(t, J=7.5Hz, 1H), 3.79(s, 2H), 2.92(s, 3H), 2.54(s, 4H), 1.73( s,4H).

Example 7 N-(2-((5-Chloro-2-((2-((4-methylpiperidin-1-yl)methyl)-1H-benzo[d]imidazol-6-yl) Amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide

According to the method of step D in Example 1, using VI as raw material, N-alkylation reaction with 4-methylpiperidine was carried out to prepare 2-((4-methylpiperidin-1-yl)methyl)-6 -Nitro-1H-benzo[d]imidazole (VII-7). The yield was 76.9%.

According to the method of step E in Example 1, using VII-7 as raw material, 2-((4-methylpiperidin-1-yl)methyl)-1H-benzo[d]imidazole-6 was obtained by reduction reaction - Amine (M ₇ -2) in 93.9% yield.

According to the method of Step F in Example 1, using M ₁ -1 and M ₇ -2 as raw materials, Example 7 was prepared, and the yield was 89.6%.

mp: 219.6-221.2°C; ESI-MS [M+H] ⁺ (m/z): 541.48; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 12.07 (s, 1H), 9.24 (s, 1H) ,8.98(s,1H),8.30(s,1H),8.12(s,1H),7.80(s,1H),7.34(s,2H),7.27(d,J＝7.8Hz,2H),6.95( t, J＝7.3Hz, 1H), 6.89(s, 1H), 3.65(s, 2H), 2.83(s, 3H), 2.80(s, 4H), 2.04(t, J＝11.1Hz, 2H), 1.59(d,J＝11.9Hz,2H),1.19(dd,J＝10.6,1.4Hz,1H),0.90(d,J＝6.5Hz,3H).

Example 8 N-(2-((5-Chloro-2-((2-((4-hydroxypiperidin-1-yl)methyl)-1H-benzo[d]imidazol-6-yl)amino )pyrimidin-4-yl)amino)phenyl)methanesulfonamide

According to the method of step D in Example 1, using VI as raw material, N-alkylation reaction with 4-hydroxypiperidine was carried out to prepare 1-((6-nitro-1H-benzo[d]imidazol-2-yl ) methyl)piperidin-4-ol (VII-8). The yield was 97.0%.

According to the method of step E in Example 1, using VII-8 as raw material, 1-((6-amino-1H-benzo[d]imidazol-2-yl)methyl)piperidine-4- Alcohol (M ₈ -2), yield 95.0%.

According to the method of Step F in Example 1, using M ₁ -1 and M ₈ -2 as raw materials, Example 8 was prepared, and the yield was 83.2%.

mp: 240.2-243.7°C; ESI-MS [M+H] ⁺ (m/z): 543.57; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.09 (s, 1H), 9.29 (s, 1H) ,8.50(s,1H),8.18(s,1H),8.13(d,J=7.8Hz,1H),7.77(s,1H),7.39(d,J=7.8Hz,2H),7.33(s, 2H), 7.30(d, J=8.5Hz, 1H), 7.19(t, J=7.1Hz, 1H), 4.66(s, 1H), 3.77(s, 1H), 2.97(s, 3H), 2.81( s, 2H), 2.30(s, 2H), 1.76(d, J=11.2Hz, 2H), 1.48(d, J=9.2Hz, 2H).

Example 9 N-(2-((5-Chloro-2-((2-((diisopropylamino)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidine-4- yl)amino)phenyl)methanesulfonamide

According to the method of step D in Example 1, using VI as raw material, N-alkylation reaction with diisopropylamine was carried out to prepare N-isopropyl-N-((6-nitro-1H-benzo[d]imidazole) -2-yl)methyl)propan-2-amine (VII-9). The yield was 70.2%.

According to the method of Step E in Example 1, using VII-9 as raw material, 2-((diisopropylamino)methyl)-1H-benzo[d]imidazol-6-amine (M ₉ -2), the yield was 89.0%.

According to the method of Step F in Example 1, using M ₁ -1 and M ₉ -2 as raw materials, Example 9 was prepared, and the yield was 75.2%.

mp: 240.2-243.7°C; ESI-MS [M+H] ⁺ (m/z): 543.60; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.56 (s, 1H), 9.26 (s, 1H) ,8.69(s,1H),8.21(d,J=6.1Hz,1H),8.14(s,1H),7.78(s,1H),7.34(d,J=6.6Hz,2H),7.30(s, 2H), 7.12(dd, J＝11.6, 8.1Hz, 2H), 3.79(s, 2H), 3.04(d, J＝6.1Hz, 2H), 2.91(s, 3H), 1.03(d, J＝5.8 Hz, 12H).

Example 10 N-(2-((5-Chloro-2-((2-(morpholinomethyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)amino )phenyl)methanesulfonamide

According to the method of step D in Example 1, using VI as raw material, N-alkylation reaction with morpholine was carried out to prepare 4-((6-nitro-1H-benzo[d]imidazol-2-yl)methyl ) morpholine (VII-10). The yield was 91.5%.

According to the method of Step E in Example 1, using VII-10 as a raw material, 2-(morpholinomethyl)-1H-benzo[d]imidazol-6-amine (M _10-2 ) was obtained by reduction reaction, The yield was 93.7%.

According to the method of Step F in Example 1, using M ₁ -1 and M ₁₀ -2 as raw materials, Example 10 was prepared, and the yield was 85.3%.

mp: 222.8-223.9°C; ESI-MS [M+H] ⁺ (m/z): 529.39; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.08 (s, 1H), 9.27 (s, 1H) ,8.71(s,1H),8.21(d,J=7.3Hz,1H),8.15(s,1H),7.79(s,1H),7.33(s,2H),7.33(s,22H),7.17– 7.05(m, 2H), 3.68(s, 2H), 3.62–3.60(m, 4H), 2.90(s, 3H), 2.46(s, 4H).

Example 11 N-(2-((5-Chloro-2-((2-((diethylamino)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidine-4- yl)amino)phenyl)methanesulfonamide

According to the method of step D in Example 1, using VI as raw material, N-alkylation reaction with diethylamine was carried out to prepare N-ethyl-N-((6-nitro-1H-benzo[d]imidazole- 2-yl)methyl)ethylamine (VII-11). The yield was 85.2%.

According to the method of Step E in Example 1, using VII-11 as a raw material, 2-((diethylamino)methyl)-1H-benzo[d]imidazol-6-amine (M ₁₁ -2 ) with a yield of 90.1%.

According to the method of Step F in Example 1, using M ₁ -1 and M ₁₁ -2 as raw materials, Example 11 was prepared, and the yield was 65.2%.

mp: 202.1-205.4°C; ESI-MS [M+H] ⁺ (m/z): 515.51; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.96 (s, 1H), 9.68 (s, 1H) ,9.23(s,1H),9.05(s,1H),8.33(d,J=7.7Hz,1H),8.11(s,1H),7.82(s,1H),7.34(s,2H),7.26( d, J=7.8Hz, 2H), 6.93(t, J=7.1Hz, 1H), 3.75(s, 2H), 2.78(s, 3H), 2.58–2.52(m, 4H), 1.03(t, J =7.1Hz,6H).

Example 12 N-(2-((5-Chloro-2-((2-(thiomorpholinomethyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl )amino)phenyl)methanesulfonamide

According to the method of Step D in Example 1, using VI as raw material, N-alkylation reaction with thiomorpholine was carried out to prepare 4-((6-nitro-1H-benzo[d]imidazol-2-yl) Methyl)thiomorpholine (VII-12). The yield was 81.9%.

According to the method of Step E in Example 1, using VII-12 as a raw material, 2-(thiomorpholinomethyl)-1H-benzo[d]imidazol-6-amine (M ₁₂ -2 ) with a yield of 92.2%.

According to the method of Step F in Example 1, using M ₁ -1 and M ₁₂ -2 as raw materials, Example 12 was prepared, and the yield was 81.9%.

mp: 222.9-224.2°C; ESI-MS [M+H] ⁺ (m/z): 545.58; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.44 (s, 1H), 9.37 (s, 1H) ,8.98(s,1H),8.84–8.56(m,1H),8.43(s,1H),8.23(s,1H),8.08(d,J=12.0Hz,1H),7.53(d,J=6.9 Hz, 1H), 7.34(d, J＝47.6Hz, 2H), 7.12(d, J＝51.4Hz, 2H), 3.51(s, 2H), 3.02(d, J＝3.5Hz, 4H), 2.92( s,34H),2.51(s,4H).

Example 13 N-(2-((5-Chloro-2-((2-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-6-yl) Amino)pyrimidin-4-yl)amino)phenyl)acetamide

N-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl) was prepared according to the method of step B in Example 1, using III as raw material, and N-acylation reaction with acetyl chloride. Acetamide (M ₂ -1).

According to the method of Step F in Example 1, using M ₂ -1 and M ₁ -2 as raw materials, Example 13 was prepared, and the yield was 78.6%.

mp: 230.2-235.5°C; ESI-MS [M+H] ⁺ (m/z): 506.39; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.28 (s, 1H), 8.63 (s, 1H) ,8.18(d,J＝8.3Hz,1H),8.16(s,1H),7.77(s,1H),7.36

(d, J=7.8Hz, 1H), 7.32 (s, 1H), 7.23–7.17 (m, 1H), 7.13 (dd, J=13.7, 7.8Hz, 2H), 6.61 (s, 1H), 6.46 ( d, J＝8.4Hz, 1H), 3.57(s, 2H), 2.93(s, 3H), 2.85(dd, J＝14.4, 7.2Hz, 3H), 2.44(s, 4H), 2.34(dt, J =13.8,7.0Hz,4H).

Example 14 N-(2-((-Chloro-2-((2-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazole- 6-yl)amino)pyrimidin-4-yl)amino)phenyl)acetamide

According to the method of Step F in Example 1, using M ₂ -1 and M ₂ -2 as raw materials, Example 14 was prepared, and the yield was 92.0%.

mp: 270.9-273.0°C; ESI-MS [M+H] ⁺ (m/z): 536.58; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.00 (s, 1H), 10.09 (s, 1H) ,9.18(s,1H),8.42(s,1H),8.11(s,1H),7.84(d,J=7.2Hz,1H),7.69(s,1H),7.31(s,2H),7.28( d, J=7.9Hz, 2H), 7.17(t, J=7.5Hz, 1H), 4.44(s, 1H), 3.66(s, 2H), 3.51(s, 2H), 3.48(d, J=6.0 Hz, 2H), 2.49–2.45 (m, 4H), 2.45–2.39 (m, 4H), 2.10 (s, 3H).

Example 15 N-(2-((5-Chloro-2-((2-((dimethylamino)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidine-4- yl)amino)phenyl)acetamide

According to the method of Step F in Example 1, using M ₂ -1 and M ₃ -2 as raw materials, Example 15 was prepared, and the yield was 85.5%.

mp: 212.7.9-213.2°C; ESI-MS [M+H] ⁺ (m/z): 451.39; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.08 (s, 1H), 10.13 (s, 1H), 9.18(s, 1H), 8.43(s, 1H), 8.12(s, 1H), 7.85(d, J=7.7Hz, 1H), 7.70(d, J=36.2Hz, 1H), 7.38– 7.30(m, 2H), 7.28(d, J=7.6Hz, 2H), 7.17(t, J=7.5Hz, 1H), 3.61(s, 2H), 2.23(s, 6H), 2.11(s, 3H ).

Example 16 N-(2-((5-Chloro-2-((2-((4-methylpiperidin-1-yl)methyl)-1H-benzo[d]imidazol-6-yl) Amino)pyrimidin-4-yl)amino)phenyl)acetamide

According to the method of Step F in Example 1, using M ₂ -1 and M ₇ -2 as raw materials, Example 16 was prepared, and the yield was 92.8%.

mp: 215.7.9-218.0°C; ESI-MS [M+H] ⁺ (m/z): 505.58; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.04 (s, 1H), 10.15 (s, 1H), 9.16(s, 1H), 8.43(s, 1H), 8.11(s, 1H), 7.84(d, J=7.9Hz, 1H), 7.69(s, 1H), 7.30(d, J=7.1 Hz, 2H), 7.27(d, J＝7.6Hz, 2H), 7.15(t, J＝7.5Hz, 1H), 3.63(s, 2H), 2.81(d, J＝11.2Hz, 2H), 2.10( s, 3H), 1.56(t, J=20.4Hz, 2H), 1.23(s, 4H), 1.17(s, 1H), 0.89(d, J=6.3Hz, 3H).

Example 17 2-((5-Chloro-2-((2-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazole-6- yl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide

Step A: 2-Amino-N-methylbenzamide (XII-1)

At room temperature, 20.0 g (0.12 mol) of isatoic anhydride (IV) was dissolved in 100.0 mL of ethanol, stirring was started, and 14.45 mL (0.15 mol) of 40% methylamine aqueous solution was slowly added dropwise to complete the reaction. 50 mL of saturated brine was added to the reaction solution, followed by stirring for 20 minutes. It was extracted three times with 750 mL of ethyl acetate, the organic phases were combined, and the solvent was evaporated to dryness to obtain 15.8 g of a pale yellow solid. Yield 85.7%.

According to the method of step A in Example 1, using XII-1 and 2,4,5,-trichloropyrimidine as raw materials, 2-((2,5-dichloropyrimidin-4-yl was prepared by N-acylation reaction ) amino)-N-methylbenzamide (M ₃ -1), yield 79.5%.

According to the method of Step F in Example 1, using M ₃ -1 and M ₂ -2 as raw materials, Example 17 was prepared, and the yield was 31.9%.

mp: 282.9-285.0°C; ESI-MS [M+H] ⁺ (m/z): 536.56; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.16 (s, 1H), 11.69 (s, 1H) ,9.38(s,1H),8.83(s,1H),8.78(s,1H),8.20(s,1H),7.83(s,1H),7.75(d,J＝7.6Hz,1H),7.39( s, 2H), 7.33(d, J=8.7Hz, 1H), 7.09(t, J=7.4Hz, 1H), 5.70(d, J=7.7Hz, 1H), 3.68(s, 2H), 3.50( d, J＝4.7Hz, 2H), 3.47(d, J＝6.1Hz, 2H), 2.81(d, J＝4.1Hz, 3H), 2.47(s, 4H), 2.38(t, J＝6.1Hz, 4H).

Example 18 2-((5-Chloro-2-((2-((dimethylamino)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)amino )-N-methylbenzamide

According to the method of Step F in Example 1, using M ₃ -1 and M ₃ -2 as raw materials, Example 18 was prepared, and the yield was 50.0%.

mp: 216.7-218.0°C; ESI-MS [M+H] ⁺ (m/z): 451.49; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.22 (s, 1H), 11.69 (s, 1H) ,9.38(s,1H),8.85(d,J=6.2Hz,1H),8.78(d,J=4.0

Hz, 1H), 8.20(s, 1H), 7.82(s, 1H), 7.76(d, J=7.7Hz, 1H), 7.39(d, J=12.0Hz, 2H), 7.35(s, 1H), 7.10(t, J=7.4Hz, 1H), 3.65(s, 2H), 2.82(d, J=4.2Hz, 3H), 2.25(s, 6H).

Example 19 2-((5-Chloro-2-((2-((4-methylpiperidin-1-yl)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidine -4-yl)amino)-N-methylbenzamide

According to the method of Step F in Example 1, using M ₃ -1 and M ₇ -2 as raw materials, Example 19 was prepared, and the yield was 72.5%.

mp: 225.3-226.9°C; ESI-MS [M+H] ⁺ (m/z): 505.68; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 12.17 (s, 1H), 11.68 (s, 1H) ,9.37(s,1H),8.84(s,1H),8.79(s,1H),8.19(s,1H),7.82(s,1H),7.75(d,J＝7.7Hz,1H),7.39( s, 2H), 7.33(d, J=8.3Hz, 1H), 7.08(t, J=7.4Hz, 1H), 3.66(s, 2H), 2.83(s, 3H), 2.81(d, J=4.1 Hz,4H),2.04(t,J＝11.1Hz,2H),1.59(d,J＝12.5Hz,2H),1.19(dd,J＝11.7,2.0Hz,1H),0.90(d,J＝6.4 Hz, 3H).

Example 20 2-((5-Chloro-2-((2-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidine -4-yl)amino)-N,N-dimethylbenzamide

According to the method of step A in Example 17, using IV and dimethylamine as raw materials, 2-amino-N,N-dimethylbenzamide (XII-2) was prepared by N-acylation reaction, and the yield was 99.4%. .

According to the method of step A in Example 1, using XII-2 and 2,4,5,-trichloropyrimidine as raw materials, 2-((2,5-dichloropyrimidin-4-yl was prepared by N-acylation reaction )amino)-N,N-dimethylbenzamide (M ₄ -1), yield 71.8%.

According to the method of Step F in Example 1, using M ₄ -1 and M ₁ -2 as raw materials, Example 20 was prepared, and the yield was 74.5%.

mp: 227.3-229.2°C; ESI-MS [M+H] ⁺ (m/z): 520.45; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.29 (s, 1H), 9.16 (s, 1H) ,8.37(d,J＝7.8Hz,1H),8.17(s,1H),7.80(s,1H),7.41(d,J＝7.4Hz,2H),7.34(d,J＝8.7Hz,1H) ,7.14(t,J＝7.5Hz,1H),6.07(s,1H),5.64(s,1H),3.67(s,2H),3.51(s,4H),2.98(s,4H),2.36( s,6H),2.16(s,3H).

Example 21 2-((5-Chloro-2-((2-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazole-6- base)amino)pyrimidine-4-amino)-N,N-dimethylbenzamide

According to the method of Step F in Example 1, using M ₄ -1 and M ₂ -2 as raw materials, Example 21 was prepared, and the yield was 65.0%.

mp: 275.6-278.6°C; ESI-MS [M+H] ⁺ (m/z): 550.56; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.14 (s, 1H), 9.30 (s, 1H) ,9.18(s,1H),8.38(d,J=8.0Hz,1H),8.17(s,1H),7.80(s,1H),7.42(d,J=7.6Hz,2H),7.37(d, J=12.9Hz, 1H), 7.33(s, 1H), 7.15(t, J=7.2Hz, 1H), 4.66(s, 1H), 3.67(s, 2H), 3.50(d, J=5.8Hz, 2H), 3.47(d, J=6.0Hz, 2H), 2.99(s, 6H), 2.46(s, 4H), 2.40–2.35(m, 4H).

Example 22 2-((5-Chloro-2-((2-((dimethylamino)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)amino )-N,N-Dimethylbenzamide

According to the method of Step F in Example 1, using M ₄ -1 and M ₃ -2 as raw materials, Example 22 was prepared, and the yield was 69.3%.

mp: 212.9-214.5°C; ESI-MS [M+H] ⁺ (m/z): 465.32; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.20 (s, 1H), 9.29 (s, 1H) ,9.17(s,1H),8.38(d,J=8.6Hz,1H),8.17(s,1H),7.79(s,1H),7.44–7.39(m,2H),7.34(s,2H), 7.15(t, J=7.4Hz, 1H), 3.62(s, 2H), 2.99(s, 6H), 2.23(s, 6H).

Example 23 2-((5-Chloro-2-((2-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)amino )-N,N-Dimethylbenzamide

According to the method of Step F in Example 1, using M ₄ -1 and M ₄ -2 as raw materials, Example 23 was prepared, and the yield was 80.0%.

mp: 222.7-223.6°C; ESI-MS [M+H] ⁺ (m/z): 505.32; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.09 (s, 1H), 9.29 (s, 1H) ,9.16(s,1H),8.38(d,J=8.2Hz,1H),8.17(s,1H),8.09(d,J=15.0Hz,1H),7.80(s,1H),7.41(d, J=7.6Hz, 2H), 7.39(s, 1H), 7.32(s, 1H), 3.66(s, 2H), 2.99(s, 6H), 2.44(s, 4H), 1.54(d, J=5.1 Hz,4H),1.40(s,2H).

Example 24 2-((5-Chloro-2-((2-((4-ethylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidine -4-yl)amino)-N,N-dimethylbenzamide

According to the method of step F in Example 1, using M ₄ -1 and M ₅ -2 as raw materials, Example 24 was prepared, and the yield was 70.2%.

mp: 225.6.9-226.9°C; ESI-MS [M+H] ⁺ (m/z): 534.42; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.40 (s, 1H), 9.21 (s, 1H), 8.36(d, J=7.9Hz, 1H), 8.19(s, 1H), 8.01(d, J=49.2Hz, 1H), 7.50(d, J=7.7Hz, 2H), 7.43(d, J=8.6Hz, 2H), 7.12(d, J=7.7Hz, 2H), 3.89(s, 2H), 3.10(s, 2H), 2.99(s, 6H), 2.52(s, 4H), 2.29( s,4H),1.17(t,J＝7.1Hz,3H).

Example 25 2-((5-Chloro-2-((2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)amino )-N,N-Dimethylbenzamide

According to the method of Step F in Example 1, using M ₄ -1 and M ₆ -2 as raw materials, Example 25 was prepared, and the yield was 76.9%.

mp: 221.2.9-223.2°C; ESI-MS [M+H] ⁺ (m/z): 491.50; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.20 (s, 1H), 9.32 (s, 1H), 9.17(s, 1H), 8.37(d, J=8.4Hz, 1H), 8.18(s, 1H), 7.85(s, 1H), 7.47–7.41(m, 2H), 7.37(s, 2H) ), 7.16(t, J=7.3Hz, 1H), 4.05(s, 2H), 2.99(s, 6H), 2.81(s, 4H), 1.81(s, 4H).

Example 26 2-((5-Chloro-2-((2-(morpholinomethyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)amino)-N ,N-Dimethylbenzamide

According to the method of step F in Example 1, using M ₄ -1 and M ₁₀ -2 as raw materials, Example 26 was prepared, and the yield was 71.6%.

mp: 234.6.9-237.8°C; ESI-MS [M+H] ⁺ (m/z): 507.49; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 12.17(s, 1H), 9.31(s, 1H), 9.18(s, 1H), 8.38(d, J=8.4Hz, 1H), 8.17(s, 1H), 7.82(s, 1H), 7.42(d, J=7.6Hz, 2H), 7.34( t, J=7.4Hz, 2H), 7.15 (t, J=7.4Hz, 1H), 3.69 (s, 2H), 3.63–3.60 (m, 4H), 2.98 (d, J=8.1Hz, 6H), 2.46(s,4H).

Example 27 2-((5-Chloro-2-((2-((diethylamino)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)amino) -N,N-Dimethylbenzamide

According to the method of Step F in Example 1, using M ₄ -1 and M ₁₁ -2 as raw materials, Example 27 was prepared, and the yield was 71.6%.

mp: 214.6.9-217.5°C; ESI-MS [M+H] ⁺ (m/z): 493.66; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.02 (s, 1H), 9.31 (s, 1H), 9.18(s, 1H), 8.38(d, J=8.5Hz, 1H), 8.18(s, 1H), 7.84(s, 1H), 7.42(dd, J=7.6, 1.5Hz, 2H), 7.33(dd,J=8.6,1.7Hz,2H),7.15(t,J=7.5Hz,1H),3.87(s,2H),2.99(s,6H),2.64(d,J=6.9Hz,4H ),1.06(t,J=7.1Hz,6H).

Example 28 2-((5-Chloro-2-((2-(thiomorpholinomethyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)amino) –N,N-Dimethylbenzamide

According to the method of Step F in Example 1, using M ₄ -1 and M ₁₂ -2 as raw materials, Example 28 was prepared, and the yield was 59.8%.

mp: 227.0-230.2°C; ESI-MS [M+H] ⁺ (m/z): 523.51; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.11 (s, 1H), 9.34 (s, 1H) ,9.18(s,1H),8.37(d,J=8.5Hz,1H),8.18(s,1H),7.86(s,1H),7.42(d,J=6.4Hz,2H),7.37(t, J=7.7Hz, 2H), 7.16(t, J=7.4Hz, 1H), 3.80(s, 2H), 2.99(s, 6H), 2.78(d, J=3.0Hz, 4H), 2.68(d, J=3.9Hz, 4H).

Example 29 6-((5-Chloro-4-((2-(methylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-2-methyl-1H-indole-3- Ethyl carboxylate

Step A 2-(2,4-Dinitrophenyl)-3-oxobutyric acid ethyl ester (IX-1)

At room temperature, 1.31 g (11.3 mmol) of ethyl acetoacetate and 1.26 g (11.3 mmol) of potassium tert-butoxide were added to 10 mL of tetrahydrofuran, stirred at room temperature for 2 hours, and then 1.0 g (5.4 mmol) of 2,4-dinitrogen was added. Fluorobenzene (VIII), reacted for 1 hour. After adding 1.2M hydrochloric acid to adjust pH=2, the mixture was left to stand for layers, the upper organic phase was collected, the organic solvent was evaporated to dryness, and dried to obtain 1.4 g of a yellow solid with a yield of 91.19%.

Step B 6-Amino-2-methyl-1H-indole-3-carboxylic acid ethyl ester (X-1)

At room temperature, 0.5 g (1.7 mmol) of IX was dissolved in 15 mL of ethanol, 2.29 g (10.1 mmol) of stannous chloride dihydrate and 1.2 mL of concentrated hydrochloric acid were added, and the reaction was refluxed for 4 hours. The reaction solution was poured into 30% sodium hydroxide solution, stirred for 30 minutes, extracted with ethyl acetate, and the organic phases were combined and evaporated to dryness. Dry brown solid 0.2 g, yield 54.1%.

According to the method of Step F in Example 1, using M ₁ -1 and X-1 as raw materials, Example 29 was prepared, and the yield was 58.3%.

mp: 172.9-173.7°C; ESI-MS [M+H] ⁺ (m/z): 515.36; ¹ H NMR (400 MHz, DMSO-d ₆ ) 11.66 (s, 1H), 9.29 (s, 1H), 8.93 (s, 1H), 8.30(d, J=7.2Hz, 1H), 8.14(s, 1H), 7.78(s, 1H), 7.73(d, J=8.8Hz, 1H), 7.35(d, J= 8.5Hz, 1H), 7.30 (d, J=7.4Hz, 1H), 7.07–6.93 (m, 2H), 4.26 (dd, J=13.9, 6.8Hz, 2H), 2.83 (s, 3H), 2.62 ( s,3H),1.34(dd,J=18.6,11.7Hz,3H).

Example 30 6-((5-Chloro-4-((2-(methylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-2-methyl-1H-indole-3- Methyl Carboxylate

According to the method of Step A in Example 29, using VIII as a raw material, C-alkylation reaction with methyl acetoacetate was carried out to prepare methyl 2-(2,4-dinitrophenyl)-3-oxobutyrate (IX-2). The yield was 98.9%.

According to the method of step B in Example 29, using IX-2 as raw material, 6-amino-2-methyl-1H-indole-3-carboxylic acid methyl ester (X-2) was obtained by reduction reaction, and the yield was 90.5%.

According to the method of Step F in Example 1, using M ₁ -1 and X-2 as raw materials, Example 30 was prepared, and the yield was 90.98%.

mp: 174.7-176.2°C; ESI-MS [M+H] ⁺ (m/z): 501.30; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.64 (s, 1H), 9.38 (s, 1H) ,9.30(s,1H),8.53(s,1H),8.19(s,1H),8.17(s,1H),7.79(d,J＝8.4Hz,1H),7.69(d,J＝8.6Hz, 1H), 7.39(d, J＝7.7Hz, 1H), 7.33(d, J＝8.6Hz, 1H), 7.30(t, J＝7.6Hz, 1H), 7.21(t, J＝7.5Hz, 1H) ,3.80(s,3H),2.97(s,3H),2.62(s,3H).

Example 31 6-((5-Chloro-4-((2-(methylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-2-methyl-1H-indole-3- carboxylic acid

At room temperature, 0.5 g (1.0 mmol) of Example 30 was put into 10 mL of methanol, 0.32 g (8.0 mmol) of sodium hydroxide was dissolved in 1 mL of water, the prepared sodium hydroxide solution was dropped into methanol, and the reaction was refluxed for 6 hours. . After leaving the reaction solution at room temperature, 1M hydrochloric acid was added dropwise to adjust pH=1, suction filtration, and drying to obtain 0.46 g of a dark purple solid with a yield of 94.9%. The crude product was purified by column chromatography to give an off-white solid.

mp: 207.2-210.3°C; ESI-MS [M+H] ⁺ (m/z): 487.39; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.96 (s, 1H), 11.64 (s, 1H) ,9.38(s,1H),9.30(s,1H),8.53(s,1H),8.19(s,1H),8.17(s,1H),7.79(d,J＝8.4Hz,1H),7.69( d, J＝8.6Hz, 1H), 7.39(d, J＝7.7Hz, 1H), 7.33(d, J＝8.6Hz, 1H), 7.30(t, J＝7.6Hz, 1H), 7.21(t, J=7.5Hz, 1H), 2.97(s, 3H), 2.62(s, 3H).

Example 32 N-(2-((5-Chloro-2-((2-methyl-3-(4-methylpiperazine-1-carbonyl)-1H-indol-6-yl)amino)pyrimidine- 4-yl)amino)phenylmethanesulfonamide

0.5 g (1.02 mmol) of Example 31, 0.20 g (2.05 mmol) of N-methylpiperazine, 0.78 g (2.05 mmol) of HATU, 0.012 g (0.10 mmol) of 4-dimethylaminopyridine (DMAP) and 0.53 g of (4.12 mmol) N,N-diisopropylethylamine (DIPEA) was dissolved in 10 mL of N,N-dimethylformamide (DMF) and reacted at room temperature for 1 hour. 20 mL of water was added to the reaction solution and stirred, and 60 mL of ethyl acetate was extracted three times, and the organic phases were combined. After washing once with 5% lithium chloride solution and once with saturated brine, 0.12 g of the brown solid of the solvent was evaporated to dryness, and the yield was 34.3%. The crude product was purified by column chromatography to give a pale yellow solid.

mp: 223.2-225.7°C; ESI-MS [M+H] ⁺ (m/z): 569.39; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.22 (s, 1H), 9.25 (s, 1H) ,8.81(s,1H),8.32-8.09(m,2H),7.67(s,1H),7.33(s,2H),7.20(s,1H),7.07(s,1H),6.61(s,1H) ), 3.49(s, 4H), 2.96(s, 3H), 2.87(s, 3H), 2.36(d, J=19.2Hz, 4H), 2.22(s, 3H).

Example 33 N-(2-((5-Chloro-2-((3-(4-(2-hydroxyethyl)piperazine-1-carbonyl)-2-methyl-1H-indol-6-yl )amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide

According to the method of Example 32, using Example 31 and N-hydroxyethylpiperazine as raw materials, Example 33 was prepared, and the yield was 94.6%.

mp: 239.6.2-242.7°C; ESI-MS [M+H] ⁺ (m/z): 599.69; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.21 (s, 1H), 9.39 (s, 1H), 9.27(s, 1H), 8.52(s, 1H), 8.17(s, 1H), 8.14(d, J=8.0Hz, 1H), 7.62(s, 1H), 7.40(dd, J=7.9 ,1.3Hz,1H),7.32(d,J＝1.8Hz,1H),7.31–7.28(m,1H),7.22(dd,J＝7.6,1.2Hz,1H),7.17(d,J＝8.7Hz ,1H),4.49(s,1H),3.53(dd,J=11.6,5.6Hz,4H),3.49(s,4H),3.38(dd,J=14.0,7.0Hz,2H),2.96(d, J=5.2Hz, 3H), 2.47(s, 2H), 2.38(s, 3H).

Example 34 6-((5-Chloro-4-((2-(methylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-N-(2-hydroxyethyl)-2- Methyl-1H-indole-3-carboxamide

According to the method of Example 32, using Example 31 and ethanolamine as raw materials, Example 34 was prepared, and the yield was 92.5%.

mp: 232.3.2-234.9°C; ESI-MS [M+H] ⁺ (m/z): 530.37; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.25 (s, 1H), 9.61 (s, 1H), 9.27(s, 1H), 8.62(s, 1H), 8.22(d, J=7.9Hz, 1H), 8.17(s, 1H), 7.72(s, 1H), 7.57(d, J=8.7 Hz,1H),7.37(d,J=7.1Hz,1H),7.29(d,J=8.7Hz,1H),7.24(d,J=7.6Hz,1H),7.21–7.17(m,1H), 7.16(d,J＝7.4Hz,1H),4.79(s,1H),3.55(t,J＝5.9Hz,2H),3.37(dd,J＝11.5,5.7Hz,2H),2.95(s,3H) ),2.55(s,3H).

Example 35 N-(2-((5-Chloro-2-((2-methyl-3-(4-ethylpiperazine-1-carbonyl)-1H-indol-6-yl)amino)pyrimidine- 4-yl)amino)phenyl)methanesulfonamide

According to the method of Example 32, using Example 31 and N-ethylpiperazine as raw materials, Example 35 was prepared, and the yield was 78.9%.

mp: 221.6.2-224.0°C; ESI-MS [M+H] ⁺ (m/z): 583.47; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.21 (s, 1H), 9.28 (s, 1H), 8.51(s, 1H), 8.18(s, 1H), 8.14(d, J=7.8Hz, 1H), 7.62(s, 1H), 7.40(d, J=7.6Hz, 1H), 7.31( d, J=7.9Hz, 2H), 7.22 (d, J=7.4Hz, 1H), 7.18 (d, J=8.8Hz, 1H), 3.51 (s, 6H), 2.97 (s, 3H), 2.49– 2.44(m, 4H), 2.39(s, 3H), 1.05(t, J=6.7Hz, 3H).

Example 36 N-(2-((5-Chloro-2-((2-methyl-3-(4-methylpiperidine-1-carbonyl)-1H-indol-6-yl)amino)pyrimidine- 4-yl)amino)phenyl)methanesulfonamide

According to the method of Example 32, using Example 31 and 4-methylpiperidine as raw materials, Example 36 was prepared, and the yield was 75.3%.

mp: 217.6.2-219.6°C; ESI-MS [M+H] ⁺ (m/z): 568.40; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.21 (s, 1H), 9.30 (s, 1H), 9.21(s, 1H), 8.09(s, 1H), 7.75(s, 1H), 7.31(d, J=8.4Hz, 1H), 7.25–7.15(m, 2H), 6.83(t, J =7.7Hz,1H),6.65(t,J=7.5Hz,1H),6.09-6.04(m,2H),2.89(s,3H),2.70(s,4H),2.37(s,3H),1.63 (d, J=10.9Hz, 4H), 0.94 (d, J=5.6Hz, 3H), 0.86 (dd, J=9.5, 6.1Hz, 1H).

Example 37 N-(2-((5-Chloro-2-((2-methyl-3-(4-hydroxypiperidine-1-carbonyl)-1H-indol-6-yl)amino)pyrimidine-4 -yl)amino)phenyl)methanesulfonamide

According to the method of Example 32, using Example 31 and 4-hydroxypiperidine as raw materials, Example 37 was prepared, and the yield was 85.2%.

mp: 230.2.2-232.9°C; ESI-MS [M+H] ⁺ (m/z): 570.56; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.14 (s, 1H), 9.30 (s, 1H), 9.25(s, 1H), 8.49(s, 1H), 8.17(s, 1H), 8.13(d, J=7.5Hz, 1H), 7.61(s, 1H), 7.39(d, J=7.9 Hz, 1H), 7.30(dd, J＝18.9, 8.7Hz, 2H), 7.21(t, J＝7.6Hz, 1H), 7.15(d, J＝8.4Hz, 1H), 4.75(s, 1H), 3.77(d, J=47.9Hz, 4H), 3.51(s, 1H), 3.13(dd, J=21.1, 10.5Hz, 4H), 2.97(s, 3H), 2.37(s, 3H).

Example 38 N-(2-((5-Chloro-2-((2-methyl-3-(piperidin-1-carbonyl)-1H-indol-6-yl)amino)pyrimidin-4-yl) Amino)phenyl)methanesulfonamide

According to the method of Example 32, using Example 31 and hexahydropyridine (piperidine) as raw materials, Example 38 was prepared, and the yield was 95.6%.

mp: 216.9.2.2-219.2°C; ESI-MS [M+H] ⁺ (m/z): 554.57; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.14 (s, 1H), 9.40 (s, 1H), 9.24(s, 1H), 8.58(s, 1H), 8.17(s, 1H), 8.16(s, 1H), 7.63(s, 1H), 7.37(d, J=7.9Hz, 1H), 7.27(dd,J=8.6,1.5Hz,1H),7.25–7.22(m,1H),7.17(d,J=4.3Hz,1H),7.16(s,1H),3.46(s,4H),2.94 (s,3H),2.37(s,3H),1.61(s,2H),1.50(s,4H).

Example 39 N-(2-((5-Chloro-2-((2-methyl-3-(morpholin-4-carbonyl)-1H-indol-6-yl)amino)pyrimidin-4-yl) Amino)phenyl)methanesulfonamide

According to the method of Example 32, using Example 31 and morpholine as raw materials, Example 39 was prepared, and the yield was 56.5%.

mp: 222.2-225.9°C; ESI-MS [M+H] ⁺ (m/z): 556.49; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.23 (s, 1H), 9.30 (s, 1H) ,9.27(s,1H),8.52(s,1H),8.17(s,1H),8.15(d,J=8.0Hz,1H),7.65(s,1H),7.39(d,J=7.8Hz, 1H), 7.30(d, J=8.3Hz, 2H), 7.21(t, J=7.6Hz, 2H), 3.62(s, 4H), 3.49(s, 4H), 2.97(s, 3H), 2.39( s, 3H).

Example 40 N-(2-((5-Chloro-2-((2-methyl-3-(thiomorpholine-4-carbonyl)-1H-indol-6-yl)amino)pyrimidine-4- yl)amino)phenyl)methanesulfonamide

According to the method of Example 32, using Example 31 and thiomorpholine as raw materials, Example 40 was prepared, and the yield was 47.8%.

mp: 221.3-223.5°C; ESI-MS [M+H] ⁺ (m/z): 572.38; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.20 (s, 1H), 9.31 (s, 1H) ,9.26(s,1H),8.50(s,1H),8.18(s,1H),8.15(d,J=8.0Hz,1H),7.65(s,1H),7.39(d,J=7.8Hz, 1H), 7.33(t, J＝7.7Hz, 1H), 7.28(dd, J＝8.7, 1.5Hz, 1H), 7.22(d, J＝7.7Hz, 1H), 7.18(d, J＝8.8Hz, 1H), 3.76(s, 4H), 2.98(s, 3H), 2.60(s, 4H), 2.38(s, 3H).

Example 41 N-(2-((5-Chloro-2-((2-methyl-3-(pyrrolidine-1-carbonyl)-1H-indol-6-yl)amino)pyrimidin-4-yl) Amino)phenyl)methanesulfonamide

According to the method of Example 32, using Example 31 and tetrahydropyrrole as raw materials, Example 41 was prepared, and the yield was 98.0%.

mp: 213.9-216.5°C; ESI-MS [M+H] ⁺ (m/z): 540.50; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.16 (s, 1H), 9.22 (s, 1H) ,9.12(s,1H),8.38(s,1H),8.11(s,1H),7.73(s,1H),7.27(d,J＝8.7Hz,1H),7.22(dd,J＝14.8,9.2 Hz,1H),6.92(s,1H),6.79(s,1H),6.21–5.98(m,2H),2.76(s,3H),2.38(s,3H),1.84(s,4H),0.86 (s,4H).

Example 42 (R)-N-(2-((5-Chloro-2-((3-(2-(hydroxymethyl)pyrrolidine-1-carbonyl)-2-methyl-1H-indole- 6-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide

According to the method of Example 32, using Example 31 and L-prolinol as raw materials, Example 42 was prepared, and the yield was 95.7%.

mp: 233.6-235.3°C; ESI-MS [M+H] ⁺ (m/z): 570.42; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.10 (s, 1H), 9.28 (s, 1H) ,9.24(s,1H),8.53(s,1H),8.17(d,J=2.9Hz,1H),8.16(s,1H),7.62(s,1H),7.38(d,J=7.7Hz, 1H), 7.25(d, J＝8.9Hz, 2H), 7.17(dd, J＝12.8, 6.5Hz, 2H), 4.83(s, 1H), 3.42(d, J＝5.2Hz, 2H), 2.96( s, 3H), 2.72 (s, 1H), 2.37 (s, 3H), 2.07–1.94 (m, 2H), 1.94–1.81 (m, 2H), 0.95–0.75 (m, 2H).

Example 43 N-(2-((5-Chloro-2-((3-(3-hydroxyazetidine-1-carbonyl)-2-methyl-1H-indol-6-yl)amino) Pyrimidine-4-yl)amino)phenyl)methanesulfonamide

According to the method of Example 32, using Example 31 and N-tetracyclobutan-3-ol as raw materials, Example 43 was prepared, and the yield was 32.1%.

mp: 228.6-231.7°C; ESI-MS [M+H] ⁺ (m/z): 542.39; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.27 (s, 1H), 9.30 (d, J= 20.4Hz, 1H), 9.27(s, 1H), 8.50(s, 1H), 8.18(s, 1H), 8.15(d, J=8.1Hz, 1H), 7.63(s, 1H), 7.40(d, J=7.7Hz, 1H), 7.36–7.30 (m, 1H), 7.29 (s, 1H), 7.23 (dd, J=17.1, 9.5Hz, 2H), 5.69 (d, J=6.2Hz, 1H), 4.16(t, J=7.7Hz, 2H), 3.75(dd, J=9.5, 4.4Hz, 2H), 3.48(d, J=17.9Hz, 1H), 2.98(s, 3H), 2.45(s, 3H) ).

Example 44 6-((5-Chloro-4-((2-(methylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-N,N,2-trimethyl-1H- indole-3-carboxamide

According to the method of Example 32, using Example 31 and dimethylamine (40% aqueous solution) as raw materials, Example 44 was prepared, and the yield was 32.1%.

mp: 212.3-216.0°C; ESI-MS [M+H] ⁺ (m/z): 514.59; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.14 (s, 1H), 9.90 (s, 1H) ,9.25(s,1H),8.50(s,1H),8.18(s,1H),8.15(s,1H),7.64(s,1H),7.39(d,J＝7.6Hz,1H),7.31( t, J=7.5Hz, 1H), 7.28–7.22 (m, 1H), 7.17 (dd, J=18.5, 7.9Hz, 2H), 2.98 (s, 9H), 2.36 (s, 3H).

Example 45 2-((5-Chloro-2-((2-methyl-3-(4-methylpiperazine-1-carbonyl)-1H-indol-6-yl)amino)pyrimidine-4- base)amino)-N-methylbenzamide

According to the method of step F in Example 1, using M ₃ -1 and X-2 as starting materials, 6-((5-chloro-4-((2-(methylcarbamoyl)phenyl)amino)pyrimidine was prepared -2-yl)amino)-2-methyl-1H-indole-3-carboxylic acid methyl ester (XI-2), yield 73.75%.

According to the method of Example 31, 6-((5-chloro-4-((2-(methylcarbamoyl)phenyl)amino)pyrimidin-2-yl)amino was obtained by hydrolysis reaction using XI-2 as raw material )-2-methyl-1H-indole-3-carboxylic acid (M ₂ -3), yield: 92.30%.

According to the method of Example 32, using M ₂ -3 and N-methylpiperazine as raw materials, Example 45 was prepared, and the yield was 91.9%.

mp: 208.9-210.4°C; ESI-MS [M+H] ⁺ (m/z): 533.62; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.70 (s, 1H), 11.29 (s, 1H) ,9.36(s,1H),8.87(d,J＝8.1Hz,1H),8.77(d,J＝4.4Hz,1H),8.20(s,1H),7.76(d,J＝7.9Hz,1H) ,7.71(s,1H),7.40(d,J＝7.4Hz,1H),7.32(dd,J＝8.6,1.5Hz,1H),7.27(d,J＝8.5Hz,1H),7.11(t, J=7.5Hz, 1H), 3.51(s, 3H), 2.81(d, J=4.5Hz, 3H), 2.39(s, 3H), 2.33(s, 4H), 2.21(s, 4H).

Example 46 6-((5-Chloro-4-((2-(methylcarbamoyl)phenyl)amino)pyrimidin-2-yl)amino)-N,N,2-trimethyl-1H- indole-3-carboxamide

According to the method of Example 32, using M ₂ -3 and dimethylamine (40% aqueous solution) as raw materials, Example 46 was prepared, and the yield was 80.92%.

mp: 206.3-208.9°C; ESI-MS [M+H] ⁺ (m/z): 478.63; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.71 (s, 1H), 11.22 (s, 1H) ,9.34(s,1H),8.89(d,J=8.0Hz,1H),8.76(d,J=4.6Hz,1H),8.20(s,1H),7.76(s,1H),7.74(s, 1H), 7.40(t, J＝8.1Hz, 1H), 7.28(dd, J＝8.6, 1.3Hz, 1H), 7.24(d, J＝8.5Hz, 1H), 7.11(t, J＝7.5Hz, 1H), 2.99(s, 6H), 2.81(d, J=4.4Hz, 3H), 2.38(s, 3H).

Example 47 2-((5-Chloro-2-((2-methyl-3-(morpholine-4-carbonyl)-1H-indol-6-yl)amino)pyrimidin-4-yl)amino) -N-methylbenzamide

According to the method of Example 32, using M ₂ -3 and morpholine as raw materials, Example 47 was prepared, and the yield was 50.39%. mp: 216.9-219.3°C; ESI-MS [M+H] ⁺ (m/z): 520.38; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.72 (s, 1H), 11.35 (s, 1H) ,9.38(s,1H),8.89(d,J=7.6Hz,1H),8.80(d,J=4.5Hz,1H),8.21(s,1H),8.15(s,1H),7.77(d, J=7.9Hz, 1H), 7.42(t, J=7.3Hz, 1H), 7.31(s, 1H), 7.12(t, J=7.5Hz, 1H), 6.77(d, J=6.2Hz, 1H) ,3.51(s,4H),3.05(s,4H),2.82(d,J＝4.5Hz,3H),2.42(s,3H).

Example 48 2-((5-Chloro-2-((2-methyl-3-(4-methylpiperidine-1-carbonyl)-1H-indol-6-yl)amino)pyrimidine-4- base)amino)-N-methylbenzamide

According to the method of Example 32, using M ₂ -3 and morpholine as raw materials, Example 48 was prepared, and the yield was 91.23%. mp: 212.9-215.8°C; ESI-MS [M+H] ⁺ (m/z): 532.67; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.69 (s, 1H), 11.23 (s, 1H) ,9.35(s,1H),8.86(s,1H),8.77(s,1H),8.20(s,1H),7.75(d,J＝7.5Hz,1H),7.70(s,1H),7.40( s, 1H), 7.27(dd, J=19.0, 8.6Hz, 2H), 7.10(t, J=7.5Hz, 1H), 2.89(s, 4H), 2.81(d, J=4.3Hz, 3H), 2.38(s, 3H), 1.63(d, J=10.2Hz, 4H), 1.07(s, 1H), 0.94(d, J=5.4Hz, 3H).

Example 49 2-((5-Chloro-2-((2-methyl-3-(4-hydroxypiperidin-1-carbonyl)-1H-indol-6-yl)amino)pyrimidin-4-yl )amino)-N-methylbenzamide

According to the method of Example 32, using M ₂ -3 and morpholine as raw materials, Example 49 was prepared, and the yield was 83.65%. mp: 231.8-234.2°C; ESI-MS [M+H] ⁺ (m/z): 534.61; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.69 (s, 1H), 11.24 (s, 1H) ,9.35(s,1H),8.87(d,J=7.5Hz,1H),8.76(d,J=4.3Hz,1H),8.20(s,1H),8.07(s,1H),7.75(d, J=7.8Hz, 1H), 7.40(s, 1H), 7.26(q, J=8.4Hz, 2H), 7.11(t, J=7.3Hz, 1H), 4.76(s, 1H), 3.51(s, 1H), 3.20–3.07(m, 4H), 2.81(d, J=4.0Hz, 3H), 2.38(s, 3H), 1.30(d, J=37.7Hz, 4H).

Study on the antitumor activity of the product of the present invention

In vitro antitumor cell activity

In vitro inhibition of human anaplastic large cell lymphoma cells Karpas299 with high expression of NPM-ALK protein and human lung adenocarcinoma cells NCI-H2228 with high expression of EML4-ALK protein and EGFR were carried out on the pyrimidine derivatives of the above formula I according to the present invention Activity screening of highly expressed human lung adenocarcinoma cell A549.

(1) After the cells were recovered and passaged 2-3 times to stabilize, they were digested from the bottom of the culture flask with trypsin solution (0.25%). The cell digestion solution was poured into a centrifuge tube, and then the culture solution was added to stop the digestion. Centrifuge the centrifuge tube at 800 r/min for 10 min, discard the supernatant, add 5 mL of culture medium, mix the cells by pipetting, pipette 10 μL of the cell suspension and add it to a cell counting plate for counting, and adjust the cell concentration to 10 ⁴ cells/well. In the 96-well plate, 100 μL of cell suspension was added to the rest of the 96-well plates, except that A1 was a blank well without cells. The 96-well plate was placed in an incubator for 24 h.

(2) Dissolve the test sample with 50 μL of dimethyl sulfoxide, then add an appropriate amount of culture medium to dissolve the sample into 2 mg/mL liquid, and then dilute the sample in a 24-well plate to 20, 4, 0.8, 0.16, 0.032 μg/mL.

Each concentration was added to 3 wells, in which the growth of cells in the surrounding two rows and two columns was greatly affected by the environment, and was only used for blank cell wells. The 96-well plate was placed in an incubator for 72 h.

(3) Discard the medicated culture medium in the 96-well plate, wash the cells twice with phosphate buffered solution (PBS), add 100 μL of MTT (0.5 mg/mL) to each well and put it in the incubator for 4 hours, then discard To the MTT solution, add 100 μL of dimethyl sulfoxide. Shake on a magnetic shaker to fully dissolve the surviving cells and the MTT reaction product formazan, and put it into a microplate reader to measure the results. The drug IC ₅₀ value can be obtained by the Bliss method.

Table 1 shows the inhibitory activity of the compounds in lymphoma Karpas299 and lung adenocarcinoma cells A549.

Table 1

L1196M ALK and ROS1 enzyme activity assay

The assay used to measure L1196M ALK enzymatic activity was based on an enzyme-linked immunosorbent assay. The specific operations are:

Example compounds, 50 pM L1196M ALK and 5 uM ATP in assay buffer (25 mM MOPS, Ph 7.4, 1 mM DTT, 5 mM MgCl ₂ , 1 mM MnCl ₂ , 0.1 %) on 0.25 mg/mL PGT-coated plates at room temperature NaN ₃ ) was incubated for 20 min. The reaction mixture was removed by washing and the phosphopolymer substrate was detected with a 0.2 ug/mL horseradish peroxidase-conjugated phosphotyrosine specific clone antibody. The developed substrate color was quantified spectrophotometrically at 450 nm after the color development was terminated by the addition of 1 M phosphoric acid.

The test operation of ROS1 enzyme activity is the same as that of L1196M ALK enzyme activity test method.

The inhibitory data of example compounds on L1196M ALK and ROS1 are shown in Table 2.

Table 2

The compounds of general formula I in the present invention can be administered alone, but are usually administered in admixture with a pharmaceutically acceptable carrier. The choice of the pharmaceutically acceptable carrier depends on the desired route of administration and standard pharmaceutical practice. Various drugs of this type of compound are used below. The preparation methods of dosage forms, such as tablets, capsules, injections, aerosols, suppositories, films, drop pills, external liniments and ointments, illustrate their new applications in the pharmaceutical field.

Claims (10)

1. The aromatic heterocycle-containing 2,4-diarylaminopyrimidine derivatives represented by general formula I and their optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,

in, n=1 or 2 X is independently C, N, O or S, and may be substituted by R _; Y is independently C, N, O or S, and may be substituted by R _; Z is independently C, N, O or S, and may be substituted by R _; R ₁ is hydroxy, halogen, nitro, amino, cyano, (C ₁ -C ₆ ) alkylsulfinyl, (C ₁ -C ₆ ) alkylsulfonyl, (C ₁ -C ₆ )alkoxy , (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl acyl, (C ₁ -C ₆ ) alkyl amido, (C ₁ -C ₆ ) alkylsulfonamido, by 1- 2 (C ₁ -C ₆ ) alkyl substituted aminomethyl (acetyl) acyl, 1-2 hydroxy (C ₁ -C ₄ ) alkyl substituted aminomethyl (acetyl) acyl, (C ₁ -C _{3 )} ) alkylenedioxy; R ₂ is halogen, halogenated or unhalogenated (C ₁ -C ₆ )alkyl, hydroxy, cyano, amino, nitro; R ₃ is H, halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkylthio, halogen or/and hydroxy or/and amino substituted (C ₁ -C ₆ )alkyl, halogen or/and hydroxy or/and amino substituted (C ₁ -C ₆ )alkoxy, halogen or/and hydroxy or/and amino substituted (C ₁ -C ₆ ) alkylthio; R ₄ is H, (C ₁ -C ₆ ) alkyl, 3-6 membered saturated or partially saturated carbocyclic ring, (C ₁ -C ₆ ) alkyl acyl or (C ₁ -C ₆ ) alkylsulfonyl; R ₅ is H, (C ₁ -C ₆ )alkyl, 3-6 membered saturated or partially saturated carbocycle, (C ₁ -C ₆ )alkylacyl or (C ₁ -C ₆ )alkylsulfonyl; or NR ₇ R ₈ , NH _m COR ₇ R ₈ , NH _m CONH _m R ₇ R ₈ , SO ₂ (CH ₂ ) _m NR ₇ R ₈ , SO ₂ (CH ₂ ) _m CONR ₇ R ₈ , CONH _m R ₇ R ₈ , (CH ₂ ) _p R ₇ R ₈ , (CH ₂ ) _p N _m R ₇ R ₈ , CO(CH ₂ ) _p R ₇ R ₈ , NH _m CO(CH ₂ ) _p R ₇ R ₈ , NH _m (CH ₂ ) _p COR ₇ R ₈ , NH _m CO(CH ₂ ) _p NH _m R ₇ R ₈ , COR ₇ ; R ₆ is H, (C ₁ -C ₆ )alkyl, 3-6 membered saturated or partially saturated carbocycle, (C ₁ -C ₆ )alkylacyl or (C ₁ -C ₆ )alkylsulfonyl; or NR ₇ R ₈ , NH _m COR ₇ R ₈ , NH _m CONH _m R ₇ R ₈ , SO ₂ (CH ₂ ) _m NR ₇ R ₈ , SO ₂ (CH ₂ ) _m CONR ₇ R ₈ , CONH _m R ₇ R ₈ , (CH ₂ ) _p R ₇ R ₈ , (CH ₂ ) _p N _m R ₇ R ₈ , CO(CH ₂ ) _p R ₇ R ₈ , NH _m CO(CH ₂ ) _p R ₇ R ₈ , NH _m (CH ₂ ) _p COR ₇ R ₈ , NH _m CO(CH ₂ ) _p NH _m R ₇ R ₈ ; R ₇ and R ₈ are the same or different and are independently selected from H, (C ₁ -C ₁₀ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, (C ₁ -C ₁₀ ) alkoxy, (C 1 -C 10 ) ₂ -C ₁₀ ) alkenyl, (C ₂ -C ₁₀ ) alkynyl, cyano, carboxyl, hydroxy, amino, hydroxy and/or amino substituted (C ₁ -C ₁₀ ) alkyl, hydroxy and/or amino substituted (C ₁ -C ₁₀ )alkoxy; or R ₇ and R ₈ together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group other than the one attached to R ₇ and R ₈ In addition to the nitrogen atom, optionally containing 0-4 heteroatoms selected from N, O and/or S, the heterocyclic group or heteroaryl group is optionally substituted by 0-3 identical or different R ₉ ; R ₉ is (C ₁ -C ₁₀ )alkyl, (C ₃ -C ₇ )cycloalkyl, (C ₁ -C ₁₀ )alkoxy, hydroxy, carboxy, amino, hydroxy and/or amino substituted (C ₁ -C ₁₀ )alkyl, hydroxy and/or amino-substituted (C ₁ -C ₁₀ )alkoxy, halogen, halo(C ₁ -C ₁₀ )alkyl, halo(C ₁ -C ₁₀ )alkane Oxygen, nitro; m is independently 0-2, p is independently 0-6, preferably 0-4, more preferably 0-2. 2. The aromatic heterocycle-containing 2,4-diarylaminopyrimidine derivatives represented by the general formula I of claim 1 and optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, in, n=1 or 2; X is independently C, N, O or S, and may be substituted by R _; Y is independently C, N, O or S, and may be substituted by R _; Z is independently C, N, O or S, and may be substituted by R _; Preferably, n=1; X is independently C or N, and may be substituted by R _; Y is independently C or N, and may be substituted by R _; Z is independently C or N, and may be substituted by R _; More preferably, n=1; X is independently C or N, and may be substituted by R _; Y is N, and can be replaced by R ₄ ; Z is C and may be substituted by R ₆ . 3. The aromatic heterocyclic ring-containing 2,4-diarylaminopyrimidine derivatives represented by the general formula I of claim 1 or 2 and optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, R ₁ is (C ₁ -C ₆ ) alkylamido, (C ₁ -C ₆ ) alkylsulfonamido, carbamoyl substituted with 1-2 (C ₁ -C ₆ ) alkyl groups. 4. The aromatic heterocyclic ring-containing 2,4-diarylaminopyrimidine derivatives of general formula I according to any one of claims 1-3 and optical isomers, pharmaceutically acceptable salts, solvates or pro- medicine, R ₂ is halogen, hydroxyl, cyano, amino, nitro; R ₃ is H, halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy; R ₄ is H, (C ₁ -C ₆ )alkyl; Preferably, R ₂ is halogen; R ₃ is H, (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkoxy; R ₄ is H, (C ₁ -C ₃ )alkyl; More preferably, R ₂ is Cl; R ₃ is H; _R4 is H. 5. The aromatic heterocycle-containing 2,4-diarylaminopyrimidine derivatives of formula I according to any one of claims 1-4 and optical isomers, pharmaceutically acceptable salts, solvates or pro- medicine, R ₅ is H, (C ₁ -C ₆ )alkyl, 3-6 membered saturated or partially saturated carbocycle, (C ₁ -C ₆ )alkylacyl or (C ₁ -C ₆ )alkylsulfonyl; or NR ₇ R ₈ , NH _m COR ₇ R ₈ , NH _m CONH _m R ₇ R ₈ , SO ₂ (CH ₂ ) _m NR ₇ R ₈ , SO ₂ (CH ₂ ) _m CONR ₇ R ₈ , CONH _m R ₇ R ₈ , (CH ₂ ) _p R ₇ R ₈ , (CH ₂ ) _p N _m R ₇ R ₈ , CO(CH ₂ ) _p R ₇ R ₈ , NH _m CO(CH ₂ ) _p R ₇ R ₈ , NH _m (CH ₂ ) _p COR ₇ R ₈ , NH _m CO(CH ₂ ) _p NH _m R ₇ R ₈ , COR ₇ ; R ₆ is H, (C ₁ -C ₆ )alkyl, 3-6 membered saturated or partially saturated carbocycle, (C ₁ -C ₆ )alkylacyl or (C ₁ -C ₆ )alkylsulfonyl; or NR ₇ R ₈ , NH _m COR ₇ R ₈ , NH _m CONH _m R ₇ R ₈ , SO ₂ (CH ₂ ) _m NR ₇ R ₈ , SO ₂ (CH ₂ ) _m CONR ₇ R ₈ , CONH _m R ₇ R ₈ , (CH ₂ ) _p R ₇ R ₈ , (CH ₂ ) _p N _m R ₇ R ₈ , CO(CH ₂ ) _p R ₇ R ₈ , NH _m CO(CH ₂ ) _p R ₇ R ₈ , NH _m CO(CH ₂ ) _p NH _m R ₇ R ₈ , NH _m (CH ₂ ) _p COR ₇ R ₈ ; R ₇ and R ₈ are the same or different and are independently selected from H, (C ₁ -C ₁₀ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, (C ₁ -C ₁₀ ) alkoxy, (C 1 -C 10 ) ₂ -C ₁₀ ) alkenyl, (C ₂ -C ₁₀ ) alkynyl, cyano, carboxyl, hydroxy, amino, hydroxy and/or amino substituted (C ₁ -C ₁₀ ) alkyl, hydroxy and/or amino substituted (C ₁ -C ₁₀ )alkoxy; or R ₇ and R ₈ together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group other than the one attached to R ₇ and R ₈ In addition to the nitrogen atom, optionally containing 0-4 heteroatoms selected from N, O and/or S, the heterocyclic group or heteroaryl group is optionally substituted by 0-3 identical or different R ₉ ; R ₉ is (C ₁ -C ₁₀ )alkyl, (C ₃ -C ₇ )cycloalkyl, (C ₁ -C ₁₀ )alkoxy, hydroxy, carboxy, amino, hydroxy and/or amino substituted (C ₁ -C ₁₀ )alkyl, hydroxy and/or amino-substituted (C ₁ -C ₁₀ )alkoxy, halogen, halo(C ₁ -C ₁₀ )alkyl, halo(C ₁ -C ₁₀ )alkane Oxygen, nitro; Preferably, R ₅ is CONH _m R ₇ R ₈ , (CH ₂ ) _p N _m R ₇ R ₈ , NH _m CONH _m R ₇ R ₈ , COR ₇ ; R ₆ is (C ₁ -C ₃ ) alkyl, (CH ₂ ) _p N _m R ₇ R ₈ ; NH _m CO(CH ₂ ) _p N _m R ₇ R ₈ ; R ₇ and R ₈ are the same or different, and are independently selected from H, (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkoxy, hydroxy-substituted (C ₁ -C ₃ )alkyl, hydroxyl; Or R ₇ and R ₈ together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group, the heterocyclic group optionally contains 0-1 optional 0-1 in addition to the nitrogen atom to which R ₇ and R ₈ are attached. From a heteroatom of N, O and/or S, the heterocyclyl or heteroaryl is optionally substituted with 0-1 identical or different R ₉ ; R ₉ is (C ₁ -C ₃ )alkyl, hydroxy-substituted (C ₁ -C ₃ )alkyl More preferably, _R5 is:

R ₆ is: methyl,

6. The aromatic heterocycle-containing 2,4-diarylaminopyrimidine derivatives represented by general formula I and their optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, N-(2-((5-Chloro-2-((2-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidine -4-yl)amino)phenyl)methanesulfonamide 2-(5-Chloro-2-((2-(((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidine-4- yl)amino)-N,N-dimethylbenzamide N-(2-((5-Chloro-2-((2-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidine -4-yl)amino)phenyl)acetamide 2-((5-Chloro-2-((2-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazol-6-yl)amino )pyrimidin-4-yl)amino)-N-methylphenylcarboxamide N-(2-((5-Chloro-2-((2-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazole-6- yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide 2-((5-Chloro-2-((2-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazol-6-yl)amino )pyrimidin-4-yl)amino)-N,N-dimethylbenzamide N-(2-((5-Chloro-2-((2-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazole-6- yl)amino)pyrimidin-4-yl)amino)phenyl)acetamide 2-((5-Chloro-2-((2-((dimethylamino)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)amino)-N -methylbenzamide N-(2-((5-Chloro-2-((2-((dimethylamino)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)amino )phenyl)methanesulfonamide 2-((5-Chloro-2-((2-((dimethylamino)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)amino)-N ,N-Dimethylbenzamide N-(2-((5-Chloro-2-((2-((dimethylamino)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)amino )phenyl)acetamide N-(2-((5-Chloro-2-((2-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)amino )phenyl)methanesulfonamide N-(2-((5-Chloro-2-((2-((4-ethylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidine -4-yl)amino)phenyl)methanesulfonamide N-(2-((5-Chloro-2-((2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)amino )phenyl)methanesulfonamide 2-((5-Chloro-2-((2-((4-methylpiperidin-1-yl)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidine-4- base)amino)-N-methylbenzamide N-(2-((5-Chloro-2-((2-((4-methylpiperidin-1-yl)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidine -4-yl)amino)phenyl)methanesulfonamide N-(2-((5-Chloro-2-((2-((4-methylpiperidin-1-yl)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidine -4-yl)amino)phenyl)acetamide N-(2-((5-Chloro-2-((2-((4-hydroxypiperidin-1-yl)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidine- 4-yl)amino)phenyl)methanesulfonamide N-(2-((5-Chloro-2-(((2-((diisopropylamino)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl )amino)phenyl)methanesulfonamide N-(2-((5-Chloro-2-((2-(morpholinomethyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)amino)phenyl ) methanesulfonamide N-(2-((5-Chloro-2-((2-((diethylamino)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)amino) phenyl)methanesulfonamide N-(2-((5-Chloro-2-((2-(thiomorpholinomethyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)amino) phenyl)methanesulfonamide 2-((5-Chloro-2-((2-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)amino)-N ,N-Dimethylbenzamide 2-((5-Chloro-2-((2-((4-ethylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidine-4- yl)amino)-N,N-dimethylbenzamide 2-((5-Chloro-2-((2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)amino)-N ,N-Dimethylbenzamide 2-((5-Chloro-2-((2-(morpholinomethyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)amino)-N,N- Dimethylbenzamide 2-((5-chloro-2-((2-((diethylamino)methyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl )amino)-N,N-dimethylbenzamide 2-((5-Chloro-2-((2-(thiomorpholinomethyl)-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)amino)-N, N-Dimethylbenzamide Ethyl 6-((5-chloro-4-((2-(methylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-2-methyl-1H-indole-3-carboxylate ester 6-((5-Chloro-4-((2-(methylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-2-methyl-1H-indole-3-carboxylate methyl ester N-(2-((5-Chloro-2-((2-methyl-3-(4-methylpiperazine-1-carbonyl)-1H-indol-6-yl)amino)pyrimidine-4- yl)amino)phenyl)methanesulfonamide N-(2-((5-Chloro-2-((3-(4-(2-hydroxyethyl)piperazine-1-carbonyl)-2-methyl-1H-indol-6-yl)amino )pyrimidin-4-yl)amino)phenyl)methanesulfonamide 6-((5-Chloro-4-((2-(methylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-N-(2-hydroxyethyl)-2-methyl- 1H-Indole-3-carboxamide N-(2-((5-Chloro-2-((3-(4-ethylpiperazine-1-carbonyl)-2-methyl-1H-indol-6-yl)amino)pyrimidine-4- yl)amino)phenyl)methanesulfonamide N-(2-((5-Chloro-2-((2-methyl-3-(4-methylpiperidine-1-carbonyl)-1H-indol-6-yl)amino)pyrimidine-4- yl)amino)phenyl)methanesulfonamide N-(2-((5-Chloro-2-((3-(4-hydroxypiperidine-1-carbonyl)-2-methyl-1H-indol-6-yl)amino)pyrimidin-4-yl )amino)phenyl)methanesulfonamide N-(2-((5-Chloro-2-((2-methyl-3-(piperidine-1-carbonyl)-1H-indol-6-yl)amino)pyrimidin-4-yl)amino) phenyl)methanesulfonamide N-(2-((5-Chloro-2-((2-methyl-3-(morpholine-4-carbonyl)-1H-indol-6-yl)amino)pyrimidin-4-yl)amino) phenyl)methanesulfonamide N-(2-((5-Chloro-2-((2-methyl-3-(thiomorpholine-4-carbonyl)-1H-indol-6-yl)amino)pyrimidin-4-yl) Amino)phenyl)methanesulfonamide N-(2-((5-Chloro-2-((2-methyl-3-(pyrrolidine-1-carbonyl)-1H-indol-6-yl)amino)pyrimidin-4-yl)amino) Phenyl)methanesulfonamide (R)-N-(2-((5-chloro-2-((3-(2-(hydroxymethyl)pyrrolidine-1-carbonyl)-2-methyl-1H- Indol-6-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide N-(2-((5-Chloro-2-((3-(3-hydroxyazetidine-1-carbonyl)-2-methyl-1H-indol-6-yl)amino)pyrimidine- 4-yl)amino)phenyl)methanesulfonamide 6-((5-Chloro-4-((2-(methylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-N,N,2-trimethyl-1H-indole- 3-Carboxamide 2-((5-Chloro-2-((2-methyl-3-(4-methylpiperazine-1-carbonyl)-1H-indol-6-yl)amino)pyrimidin-4-yl)amino )-N-methylbenzamide 6-((5-Chloro-4-((2-(methylcarbamoyl)phenyl)amino)pyrimidin-2-yl)amino)-N,N,2-trimethyl-1H-indole- 3-Carboxamide 2-((5-Chloro-2-((2-methyl-3-(morpholine-4-carbonyl)-1H-indol-6-yl)amino)pyrimidin-4-yl)amino)-N- methylbenzamide 2-((5-Chloro-2-((2-methyl-3-(4-methylpiperidine-1-carbonyl)-1H-indol-6-yl)amino)pyrimidin-4-yl)amino )-N-methylbenzamide 2-((5-Chloro-2-((3-(4-hydroxypiperidine-1-carbonyl)-2-methyl-1H-indol-6-yl)amino)pyrimidin-4-yl)amino) -N-methylbenzamide 6-((5-Chloro-4-((2-(methylcarbamoyl)phenyl)amino)pyrimidin-2-yl)amino)-N,N-diethyl-2-methyl-1H- indole-3-carboxamide 6-((5-Chloro-4-((2-(methylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-2-methyl-1H-indole-3-carboxylic acid. 7. A pharmaceutical composition comprising the aromatic heterocycle-containing 2,4-diarylaminopyrimidine derivative of any one of claims 1-6 and optical isomers thereof, pharmaceutically acceptable salts, and solvents compound or prodrug and a pharmaceutically acceptable carrier. 8. The aromatic heterocycle-containing 2,4-diarylaminopyrimidine derivative of any one of claims 1-6 and its optical isomers, pharmaceutically acceptable salts, solvates or prodrugs or claims 7. Application of the pharmaceutical composition in the preparation of ALK and ROS1 kinase inhibitors. 9. The aromatic heterocycle-containing 2,4-diarylaminopyrimidine derivative of any one of claims 1-6 and its optical isomers, pharmaceutically acceptable salts, solvates or prodrugs or claims 7. Application of the pharmaceutical composition in the preparation of antitumor drugs. 10. The application of claim 9, wherein the tumor is lymphoma or lung cancer.