WO2017088746A1 - New epidermal growth factor receptor inhibitor and application thereof - Google Patents

Abstract

An epidermal growth factor receptor inhibitor as shown in the following formula, a pharmaceutical composition containing the receptor inhibitor, and use of the inhibitor or the pharmaceutical composition as a medicine for preventing and/or treating cancers. The groups have definitions described in the description. The compound shows good EGFR inhibition activity especially for a mutational EGFR, thereby being expected to be a medicine which resists tumors, having drug resistance due to EGFR mutations, has a specific curative effect and is less in side effects.

Description

New epidermal growth factor receptor inhibitor and its application Technical field

The invention belongs to the field of medical chemistry, and in particular relates to a novel class of epidermal growth factor receptor inhibitors, a pharmaceutical composition containing the same, and the use of the inhibitor or pharmaceutical composition as a therapeutic drug for cancer.

Background technique

The Epidermal Growth Factor Receptor (EGFR) is an expression product of the proto-oncogene C-erbB-1 and is a member of the EGFR family. The EGFR family includes four members, EGFR (HER-1), ERBB2 (HER-2), ERBB3 (HER-3), and ERBB4 (HER-4). Overexpression or mutation of EGFR has been shown to generally trigger tumors. EGFR mutations lead to sustained activation of EGFR, enhanced autocrine loops, disruption of receptor down-regulation, activation of abnormal signaling pathways, and play an important role in tumor progression.

The use of EGFR-tyrosine kinase inhibitor (EGFR-TKI) for EGFR has become the gold standard in the field of non-small cell lung cancer treatment. However, clinical use has found that most patients will have different degrees of drug resistance 6-12 months after treatment with EGFR-TKI inhibitors such as gefitinib and erlotinib, resulting in a significant reduction in drug efficacy and tumor progression. . Studies have shown that the production of EGFR-TKI resistance is associated with a second mutation in the EGFR gene, the most common of which is the mutation at position 790 of exon 20 of the EGFR gene, the T790M gene mutation. Because methionine has a larger space occupying than threonine, it forms steric hindrance and changes the affinity of ATP in EGFR kinase domain, which leads to EGFR-TKI small molecule drug can not effectively block EGFR activation signal, leading to drug resistance. The production. At the same time, the first generation of EGFR inhibitors lacked the selectivity of wild-type EGFR and mutant EGFR, and generally had side effects such as rash and diarrhea, which affected patient compliance.

Therefore, the development of drugs that are effective against tumor patients who are resistant to secondary mutations in EGFR, especially the development of drugs that can further improve the selectivity, enhance efficacy, and reduce side effects of wild-type EGFR and mutant EGFR, will have good application prospects. .

Summary of the invention

It is an object of the present invention to provide an epidermal growth factor inhibitor of the formula I, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, which exhibits good EGFR inhibitory activity, especially Mutant EGFR,

Another object of the present invention is to provide a compound of the formula II or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, which is prepared by using the compound of the formula II as a key intermediate. Compound I, mild reaction conditions, high yield and purity,

A third object of the present invention is to provide a compound of the formula III or a salt thereof, which is a key intermediate of the compound of the formula III, which has a small number of reaction steps, mild conditions, and a relatively good yield and purity. high,

A fourth object of the present invention is to provide a process for the preparation of a compound of the formula I, II or III of the present invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof.

A fifth object of the present invention is to provide a pharmaceutical composition comprising a compound of the formula I of the present invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier, and a pharmaceutical composition comprising the same A pharmaceutical composition of a compound of formula I of the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and another tumor suppressor.

A sixth object of the present invention is to provide a compound of the formula I of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a pharmaceutical composition of the present invention for treating and/or preventing cancer Methods and their use in the preparation of a medicament for the treatment and/or prevention of cancer.

In view of the above object, the present invention provides the following technical solutions:

In a first aspect, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,

among them,

Ring A is a C ₄ -C ₈ nitrogen-containing heterocyclic group optionally substituted by one or more halogen, oxo, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano , hydroxy, amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, alkyl acyl, amino acyl, a monoalkylaminoacyl group, a dialkylaminoacyl group, an aryl group, a heteroaryl group, and a heterocycloalkyl group. When two or more substituents are present, two adjacent substituents may be substituted together with the atoms to which they are attached. Or an unsubstituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl group, or two substituents attached to the same atom may form a substituted or unsubstituted cycloalkyl group with the atoms to which they are attached. Cycloalkyl;

X ₁ , X ₂ , X ₃ and X ₄ are each independently selected from C(R ₁ ) and N;

R ₁ , R _2a , R _2b , R _3a , R _3b and R _3c are each independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, Hydroxy, amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, alkyl acyl, amino acyl, single An alkylamino acyl group and a dialkylamino acyl group;

R ₄ , R ₅ and R ₆ are each independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, alkoxy and cycloalkyl, said alkyl, alkoxy and cycloalkyl optionally being one or more Halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, monoalkylamino, dialkylamino, hydroxy, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or hydroxy Alkyl substitution

R _{7 is} selected from the group consisting of hydrogen, alkyl, cycloalkyl and haloalkyl;

R _{8 is} selected from the group consisting of hydrogen, alkyl and cycloalkyl, optionally substituted by one or more halogen, alkyl, haloalkyl, alkoxy, amino, monoalkylamino, dioxane Substituted by a base or a hydroxy group; or

R ₇ , R ₈ and the N atom to which they are attached together form a nitrogen-containing heterocycloalkyl group, which is optionally substituted by one or more halogen, alkyl, haloalkyl, alkoxy, amino, Monoalkylamino, dialkylamino, hydroxy, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or hydroxyalkyl substituted.

In a second aspect, the present invention provides a compound of Formula II, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,

Wherein Rings A, X ₁ , X ₂ , X ₃ , X ₄ , R _2a , R _2b , R _3a , R _3b , R _3c , R ₇ and R ₈ have the definitions in Formula I.

In a third aspect, the present invention provides a compound of Formula III or a pharmaceutically acceptable salt thereof,

Wherein Rings A, X ₁ , X ₂ , X ₃ , X ₄ , R _2a , R _2b have the definitions in Formula I, and M is a halogen.

In some embodiments, the invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein Ring A is C ₄ -C ₈ a nitrogen-containing heteromonocycloalkyl group optionally substituted by one or more of halogen, oxo, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, hydroxy, amino, singly Alkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, alkylacyl, aminoacyl, monoalkylaminoacyl, a dialkylamino acyl group, an aryl group, a heteroaryl group and a heterocycloalkyl group. When two or more substituents are present, two adjacent substituents may form a substituted or unsubstituted naphthenic ring together with the atoms to which they are attached. A heterocyclic alkyl group, an aryl group, a heteroaryl group, or two substituents bonded to the same atom may form a substituted or unsubstituted cycloalkyl group or a heterocycloalkyl group with the atoms to which they are attached.

In some embodiments, the invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein Ring A is a nitrogen atom only C ₄ -C ₈ nitrogen-containing heteromonocycloalkyl optionally substituted by one or more halogen, oxo, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano , hydroxy, amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, alkyl acyl, amino acyl, a monoalkylaminoacyl group, a dialkylaminoacyl group, an aryl group, a heteroaryl group, and a heterocycloalkyl group. When two or more substituents are present, two adjacent substituents may be substituted together with the atoms to which they are attached. Or an unsubstituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl group, or two substituents attached to the same atom may form a substituted or unsubstituted cycloalkyl group with the atoms to which they are attached. Cycloalkyl.

n选自1、2、3、4、5和6，m选自1、2、3和4，R_a选自氢、C_1-6烷基、C_3-8环烷基、卤代C_1-6烷基、C_1-6烷氧基、卤代C_1-6烷氧基、硝基、氰基、羟基、氨基、单C_1-6烷基氨基、二C_1-6烷基氨基、氨基C_1-6烷基、单C_1-6烷基氨基C_1-6烷基、二C_1-6烷基氨基C_1-6烷基、羟基C_1-6烷基、C_1-6烷氧基C_1-6烷基、C_1-6烷基酰基、氨基酰基、单C_1-6烷基氨基酰基、二C_1-6烷基氨基酰基、C_6-10芳基、C_5-10杂芳基和C_3-8杂环烷基，当m选自2、3和4时，相邻两个碳原子上的两个R_a可以与它们所连接的碳原子一起构成C_3-8环烷基或C_3-8杂环烷基，或同一个碳原子上的两个R_a可以与它们共同连接的碳原子一起构成C_3-8环烷基或C_3-8杂环烷基。 In some preferred embodiments, the invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein Ring A is

n is selected from 1, 2, 3, 4, 5 and 6, m is selected from 1, 2, 3 and 4, and R _{a is} selected from the group consisting of hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, halogen C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, nitro, cyano, hydroxy, amino, mono C _1-6 alkylamino, di C _1-6 alkyl Amino group, amino C _1-6 alkyl group, mono C _1-6 alkylamino C _1-6 alkyl group, di C _1-6 alkylamino C _1-6 alkyl group, hydroxy C _1-6 alkyl group, C _{1 -6} alkoxy C _1-6 alkyl, C _1-6 alkyl acyl, amino acyl, mono C _1-6 alkylamino acyl, di C _1-6 alkylamino acyl, C _6-10 aryl, C _5-10 heteroaryl and C _3-8 heterocycloalkyl, when m is selected from 2, 3 and 4, two R _a on two adjacent carbon atoms may be combined with the carbon atom to which they are attached C _3-8 cycloalkyl or C _3-8 heterocycloalkyl, or two R _a on the same carbon atom may together with the carbon atom to which they are attached form a C _3-8 cycloalkyl group or C _3-8 Heterocycloalkyl.

n选自1、2、3和4，m选自1、2、3和4，R_a选自氢、C_1-3烷基、C_3-6环烷基、卤代C_1-3烷基、C_1-3烷氧基、卤代C_1-3烷氧基、硝基、氰基、羟基、氨基、单C_1-3烷基氨基、二C_1-3烷基氨基、氨基C_1-3烷基、单C_1-3烷基氨基C_1-3烷基、二C_1-3烷基氨基C_1-3烷基、羟基C_1-3烷基、C_1-3烷氧基C_1-3烷基、C_1-3烷基酰基、氨基酰基、单C_1-3烷基氨基酰基、二C_1-3烷基氨基酰基、C_6-10芳基、C_5-10杂芳基和C_3-6杂环烷基，当m选自2、3和4时，相邻两个碳原子上的两个R_a可以与它们所连接的碳原子一起构成C_3-6环烷基或C_3-6杂环烷基，或同一个碳原子上的两个R_a可以与它们共同连接的碳原子一起构成C_3-6环烷基或C_3-6杂环烷基。In some preferred embodiments, the invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein Ring A is

n is selected from 1, 2, 3 and 4, m is selected from 1, 2, 3 and 4, and R _{a is} selected from the group consisting of hydrogen, C _1-3 alkyl, C _3-6 cycloalkyl, halogenated C _1-3 alkane , C _1-3 alkoxy, halo C _1-3 alkoxy, nitro, cyano, hydroxy, amino, mono C _1-3 alkylamino, di C _1-3 alkylamino, amino C _1-3 alkyl, mono C _1-3 alkylamino C _1-3 alkyl, di C _1-3 alkylamino C _1-3 alkyl, hydroxy C _1-3 alkyl, C _1-3 alkoxy a group C _1-3 alkyl, C _1-3 alkyl acyl, amino acyl, mono C _1-3 alkylamino acyl, di C _1-3 alkylamino acyl, C _6-10 aryl, C _5-10 a heteroaryl group and a C _3-6 heterocycloalkyl group, when m is selected from 2, 3 and 4, two R _a on two adjacent carbon atoms may together with the carbon atom to which they are attached constitute a C _3-6 A cycloalkyl or C _3-6 heterocycloalkyl group, or two R _a on the same carbon atom, together with the carbon atom to which they are attached, may constitute a C _3-6 cycloalkyl group or a C _3-6 heterocycloalkyl group. .

In other embodiments, the invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein Ring A is two nitrogens A C ₄ -C ₈ nitrogen-containing heteromonocycloalkyl group of an atom optionally substituted by one or more halogen, oxo, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyanide Base, hydroxy, amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, alkyl acyl, amino acyl a monoalkylaminoacyl group, a dialkylaminoacyl group, an aryl group, a heteroaryl group, and a heterocycloalkyl group. When two or more substituents are present, two adjacent substituents may be bonded together with the atoms to which they are attached. a substituted or unsubstituted cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or two substituents bonded to the same atom may form a substituted or unsubstituted cycloalkyl group with an atom to which they are attached, Heterocycloalkyl.

m选自1、2、3和4，p选自0、1和2，q选自0、1和2，R_a选自氢、C_1-6烷基、C_3-8环烷基、卤代C_1-6烷基、C_1-6烷氧基、卤代C_1-6烷氧基、硝基、氰基、羟基、氨基、单C_1-6烷基氨基、二C_1-6烷基氨基、氨基C_1-6烷基、单C_1-6烷基氨基C_1-6烷基、二C_1-6烷基氨基C_1-6烷基、羟基C_1-6烷基、C_1-6烷氧基C_1-6烷基、C_1-6烷基酰基、氨基酰基、单C_1-6烷基氨基酰基、二C_1-6烷基氨基酰基、C_6-10芳基、C_5-10杂芳基和C_3-8杂环烷基，当m选自2、3和4时，相邻两个原子上的两个R_a可以与它们所连接的原子一起构成C_3-8环烷基或C_3-8杂环烷基，或同一个原子上的两个R_a可以与它们共同连接的原子一起构成C_3-8环烷基或C_3-8杂环烷基。In some preferred embodiments, the invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein Ring A is

m is selected from 1, 2, 3 and 4, p is selected from 0, 1 and 2, q is selected from 0, 1 and 2, and R _{a is} selected from the group consisting of hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, halo-C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, nitro, cyano, hydroxy, amino, mono-C _1-6 alkylamino, di C _{1- 6} alkylamino group, amino C _1-6 alkyl group, mono C _1-6 alkylamino C _1-6 alkyl group, di C _1-6 alkylamino C _1-6 alkyl group, hydroxy C _1-6 alkyl group , C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkyl acyl, amino acyl, mono C _1-6 alkylamino acyl, di C _1-6 alkylamino acyl, C _6-10 An aryl group, a C _5-10 heteroaryl group and a C _3-8 heterocycloalkyl group, when m is selected from 2, 3 and 4, two R _a on two adjacent atoms may be together with the atom to which they are attached C _3-8 cycloalkyl or C _3-8 heterocycloalkyl, or two R _a on the same atom may together with the atoms to which they are attached form a C _3-8 cycloalkyl or C _3-8 hetero Cycloalkyl.

m选自1、2、3和4，p选自0、1和2，q选自0、1和2，R_a选自氢、C_1-3烷基、C_3-6环烷基、卤代C_1-3烷基、C_1-3烷氧基、卤代C_1-3烷氧基、硝基、氰基、羟基、氨基、单C_1-3烷基氨基、二C_1-3烷基氨基、氨基C_1-3 烷基、单C_1-3烷基氨基C_1-3烷基、二C_1-3烷基氨基C_1-3烷基、羟基C_1-3烷基、C_1-3烷氧基C_1-3烷基、C_1-3烷基酰基、氨基酰基、单C_1-3烷基氨基酰基、二C_1-3烷基氨基酰基、C_6-10芳基、C_5-10杂芳基和C_3-6杂环烷基，当m选自2、3和4时，相邻两个原子上的两个R_a可以与它们所连接的原子一起构成C_3-6环烷基或C_3-6杂环烷基，或同一个原子上的两个R_a可以与它们共同连接的原子一起构成C_3-6环烷基或C_3-6杂环烷基。In some preferred embodiments, the invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein Ring A is

m is selected from 1, 2, 3 and 4, p is selected from 0, 1 and 2, q is selected from 0, 1 and 2, and R _{a is} selected from the group consisting of hydrogen, C _1-3 alkyl, C _3-6 cycloalkyl, Halogen C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, nitro, cyano, hydroxy, amino, mono C _1-3 alkylamino, di C _{1- 3} alkylamino group, amino C _1-3 alkyl group, mono C _1-3 alkylamino C _1-3 alkyl group, di C _1-3 alkylamino C _1-3 alkyl group, hydroxy C _1-3 alkyl group , C _1-3 alkoxy C _1-3 alkyl, C _1-3 alkyl acyl, amino acyl, mono C _1-3 alkylamino acyl, di C _1-3 alkylamino acyl, C _6-10 Aryl, C _5-10 heteroaryl and C _3-6 heterocycloalkyl, when m is selected from 2, 3 and 4, two R _a on two adjacent atoms may be together with the atom to which they are attached C _3-6 cycloalkyl or C _3-6 heterocycloalkyl, or two R _a on the same atom may together with the atoms to which they are attached form a C _3-6 cycloalkyl or C _3-6 hetero Cycloalkyl.

In other embodiments, the invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein Ring A is a nitrogen atom And a C ₄ -C ₈ nitrogen-containing heteromonocycloalkyl group having one oxygen atom, optionally substituted by one or more halogen, oxo, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, nitrate Base, cyano, hydroxy, amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, alkyl acyl , aminoacyl, monoalkylaminoacyl, dialkylaminoacyl, aryl, heteroaryl and heterocycloalkyl substituted, when two or more substituents are present, two adjacent substituents may be attached thereto The atoms together form a substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl group, or two substituents attached to the same atom may form a substituted or unsubstituted ring with the atoms to which they are attached. Alkyl, heterocycloalkyl.

m选自1、2、3和4，p选自0、1和2，q选自0、1和2，R_a选自氢、C_1-6烷基、C_3-8环烷基、卤代C_1-6烷基、C_1-6烷氧基、卤代C_1-6烷氧基、硝基、氰基、羟基、氨基、单C_1-6烷基氨基、二C_1-6烷基氨基、氨基C_1-6烷基、单C_1-6烷基氨基C_1-6烷基、二C_1-6烷基氨基C_1-6烷基、羟基C_1-6烷基、C_1-6烷氧基C_1-6烷基、C_1-6烷基酰基、氨基酰基、单C_1-6烷基氨基酰基、二C_1-6烷基氨基酰基、C_6-10芳基、C_5-10杂芳基和C_3-8杂环烷基，当m选自2、3和4时，相邻两个原子上的两个R_a可以与它们所连接的原子一起构成C_3-8环烷基或C_3-8杂环烷基，或同一个原子上的两个R_a可以与它们共同连接的原子一起构成C_3-8环烷基或C_3-8杂环烷基。In some preferred embodiments, the invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein Ring A is

m is selected from 1, 2, 3 and 4, p is selected from 0, 1 and 2, q is selected from 0, 1 and 2, and R _{a is} selected from the group consisting of hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, Halogen C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, nitro, cyano, hydroxy, amino, mono C _1-6 alkylamino, di C _{1- 6} alkylamino group, amino C _1-6 alkyl group, mono C _1-6 alkylamino C _1-6 alkyl group, di C _1-6 alkylamino C _1-6 alkyl group, hydroxy C _1-6 alkyl group , C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkyl acyl, amino acyl, mono C _1-6 alkylamino acyl, di C _1-6 alkylamino acyl, C _6-10 An aryl group, a C _5-10 heteroaryl group and a C _3-8 heterocycloalkyl group, when m is selected from 2, 3 and 4, two R _a on two adjacent atoms may be together with the atom to which they are attached C _3-8 cycloalkyl or C _3-8 heterocycloalkyl, or two R _a on the same atom may together with the atoms to which they are attached form a C _3-8 cycloalkyl or C _3-8 hetero Cycloalkyl.

m选自1、2、3和4，p选自0、1和2，q选自0、1和2，R_a选自氢、C_1-3烷基、C_3-6环烷基、卤代C_1-3烷基、C_1-3烷氧基、卤代C_1-3烷氧基、硝基、氰基、羟基、氨基、单C_1-3烷基氨基、二C_1-3烷基氨基、氨基C_1-3烷基、单C_1-3烷基氨基C_1-3烷基、二C_1-3烷基氨基C_1-3烷基、羟基C_1-3烷基、C_1-3烷氧基C_1-3烷基、C_1-3烷基酰基、氨基酰基、单C_1-3烷基氨基酰基、二C_1-3烷基氨基酰基、C_6-10芳基、C_5-10杂芳基和C_3-6杂环烷基，当m选自2、3和4时，相邻两个原子上的两个R_a可以与它们所连接的原子一起构成C_3-6环烷基或C_3-6杂环烷基，或同一个原子上的两个R_a可以与它们共同连接的原子一起构成C_3-6环烷基或C_3-6杂环烷基。在一些实施方案中，本发明提供通式I、 II或III所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中环A为含有一个氮原子和一个硫原子的C₄-C₈含氮杂单环烷基，其任选被一个或多个卤素、氧代、烷基、环烷基、卤代烷基、烷氧基、卤代烷氧基、硝基、氰基、羟基、氨基、单烷基氨基、二烷基氨基、氨基烷基、单烷基氨基烷基、二烷基氨基烷基、羟基烷基、烷氧基烷基、烷基酰基、氨基酰基、单烷基氨基酰基、二烷基氨基酰基、芳基、杂芳基和杂环烷基取代，当取代基有两个以上时，相邻的两个取代基可以与它们连接的原子一起构成取代或未取代的环烷基、杂环烷基、芳基、杂芳基，或连接在同一个原子上的两个取代基可以与它们共同连接的原子形成取代或未取代的环烷基、杂环烷基。In some preferred embodiments, the invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein Ring A is

m is selected from 1, 2, 3 and 4, p is selected from 0, 1 and 2, q is selected from 0, 1 and 2, and R _{a is} selected from the group consisting of hydrogen, C _1-3 alkyl, C _3-6 cycloalkyl, Halogen C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, nitro, cyano, hydroxy, amino, mono C _1-3 alkylamino, di C _{1- 3} alkylamino group, amino C _1-3 alkyl group, mono C _1-3 alkylamino C _1-3 alkyl group, di C _1-3 alkylamino C _1-3 alkyl group, hydroxy C _1-3 alkyl group , C _1-3 alkoxy C _1-3 alkyl, C _1-3 alkyl acyl, amino acyl, mono C _1-3 alkylamino acyl, di C _1-3 alkylamino acyl, C _6-10 Aryl, C _5-10 heteroaryl and C _3-6 heterocycloalkyl, when m is selected from 2, 3 and 4, two R _a on two adjacent atoms may be together with the atom to which they are attached C _3-6 cycloalkyl or C _3-6 heterocycloalkyl, or two R _a on the same atom may together with the atoms to which they are attached form a C _3-6 cycloalkyl or C _3-6 hetero Cycloalkyl. In some embodiments, the present invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein Ring A is a nitrogen atom and a C ₄ -C ₈ nitrogen-containing heteromonocycloalkyl group of a sulfur atom optionally substituted by one or more halogen, oxo, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, nitro , cyano, hydroxy, amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, alkyl acyl, Aminoacyl, monoalkylaminoacyl, dialkylaminoacyl, aryl, heteroaryl and heterocycloalkyl substituted, when two or more substituents are present, the two adjacent substituents may be bonded to the atom The substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl group, or two substituents attached to the same atom may form a substituted or unsubstituted cycloalkane with the atoms to which they are attached. Base, heterocycloalkyl.

In some embodiments, the invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein X ₁ , X ₂ , X ₃ And X ₄ are both C(R ₁ ).

In some specific embodiments, the invention provides a compound of formula Ia, IIa, and IIIa, or a pharmaceutically acceptable salt, isomer, solvate, crystal, or prodrug thereof,

Wherein Rings A, R ₁ , R _2a , R _2b , R _3a , R _3b , R _3c , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and M have the definitions of Formulas I, II and III above , n is selected from integers of 1, 2, 3 and 4.

In other embodiments, the invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein X ₁ , X ₂ , X At least one of ₃ and X ₄ is N.

In other embodiments, the invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein X ₁ , X ₂ , X Two of ₃ and X ₄ are N.

In other embodiments, the invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein X ₁ , X ₂ , X _{Three of 3} and X ₄ are N.

In other embodiments, the invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein X ₁ , X ₂ , X ₃ and X ₄ are both N.

In some embodiments, the present invention of general formula I, II or III compound or a pharmaceutically acceptable salt, isomer, solvate, crystallization or prodrug thereof, wherein R _1, R _2a and R _2b Each is independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, C _3-8 cycloalkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy , nitro, cyano, hydroxy, amino, mono C _1-6 alkylamino, di C _1-6 alkylamino, amino C _1-6 alkyl, mono C _1-6 alkylamino C _1-6 alkane Base, di-C _1-6 alkylamino C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkyl acyl, amino acyl, Mono C _1-6 alkylamino acyl and di C _1-6 alkylamino acyl.

In some preferred embodiments, the invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein each R ₁ , R _2a And R _2b are each independently independently selected from the group consisting of hydrogen, halogen, C _1-3 alkyl, C _3-6 cycloalkyl, halo C _1-3 alkyl, C _1-3 alkoxy, halo C _{1 -3} alkoxy, nitro, cyano, hydroxy, amino, mono C _1-3 alkyl amino, di C _1-3 alkyl amino, amino C _1-3 alkyl, mono C _1-3 alkyl amino C _1-6 alkyl, di C _1-3 alkylamino C _1-3 alkyl, hydroxy C _1-3 alkyl, C _1-3 alkoxy C _1-3 alkyl, C _1-3 alkyl An acyl group, an aminoacyl group, a mono C _1-3 alkylamino acyl group and a di C _1-3 alkylamino acyl group.

In still other preferred embodiments, the invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R ₁ , R _2a And R _2b are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, trifluoromethyl , trifluoroethyl, difluoromethyl, difluoroethyl, methoxy, ethoxy, propoxy, trifluoromethyloxy, nitro, cyano, hydroxy, amino, methylamino, ethylamino , propylamino, isopropylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, N-methyl-N-ethylamino, N-methyl-N-propylamino, N- Methyl-N-isopropylamino, N-ethyl-N-propylamino, N-ethyl-N-isopropylamino, N-propyl-N-isopropylamino, aminomethyl, amino Ethyl, aminopropyl, methylaminomethyl, methylaminoethyl, ethylaminomethyl, ethylaminoethyl, dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl, diethylaminoethyl , hydroxymethyl, hydroxyethyl, methoxy , Ethoxymethyl, propoxymethyl, methoxyethyl and ethoxyethyl.

In still other preferred embodiments, the invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R ₁ , R _2a And R _2b are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, hydroxy, amino , methylamino, ethylamino, propylamino, dimethylamino, diethylamino, aminomethyl, aminoethyl, aminopropyl, methylaminomethyl, methylaminoethyl, ethylaminomethyl, ethylaminoethyl, Dimethylaminomethyl, diethylaminomethyl, hydroxymethyl and hydroxyethyl.

In some preferred embodiments, the invention provides a compound of Formula I or II, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R _3a , R _3b and R _3c Each is independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, C _3-8 cycloalkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy , nitro, cyano, hydroxy, amino, mono C _1-6 alkylamino, di C _1-6 alkylamino, amino C _1-6 alkyl, mono C _1-6 alkylamino C _1-6 alkane Base, di-C _1-6 alkylamino C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkyl acyl, amino acyl, Mono C _1-6 alkylamino acyl and di C _1-6 alkylamino acyl.

In still other preferred embodiments, the present invention provides a compound of Formula I or II, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein each R _3a , R _3b and R _3c are each independently selected from the group consisting of hydrogen, halogen, C _1-3 alkyl, C _3-6 cycloalkyl, halo C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkane Oxy, nitro, cyano, hydroxy, amino, mono C _1-3 alkylamino, di C _1-3 alkylamino, amino C _1-3 alkyl, mono C _1-3 alkylamino C _{1- 6} alkyl, di C _1-3 alkyl amino C _1-3 alkyl, hydroxy C _1-3 alkyl, C _1-3 alkoxy C _1-3 alkyl, C _1-3 alkyl group, an amino group An acyl group, a mono C _1-3 alkylamino acyl group and a di C _1-3 alkylamino acyl group.

In still other preferred embodiments, the invention provides a compound of Formula I or II, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R _3a , R _3b and R _3c are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, trifluoromethyl, tri Fluoroethyl, difluoromethyl, difluoroethyl, methoxy, ethoxy, propoxy, trifluoromethyloxy, nitro, cyano, hydroxy, amino, methylamino, ethylamino, propyl Amino, isopropylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, N-methyl-N-ethylamino, N-methyl-N-propylamino, N-methyl -N-isopropylamino, N-ethyl-N-propylamino, N-ethyl-N-isopropylamino, N-propyl-N-isopropylamino, aminomethyl, aminoethyl , aminopropyl, methylaminomethyl, methylaminoethyl, ethylaminomethyl, ethylaminoethyl, dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl, diethylaminoethyl, hydroxy Methyl, hydroxyethyl, methoxymethyl, Ethoxymethyl, propoxymethyl, methoxyethyl and ethoxyethyl.

In still other preferred embodiments, the invention provides a compound of Formula I or II, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R _3a , R _3b and R _3c are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, hydroxy, amino, A Amino, ethylamino, propylamino, dimethylamino, diethylamino, aminomethyl, aminoethyl, aminopropyl, methylaminomethyl, methylaminoethyl, ethylaminomethyl, ethylaminoethyl, dimethyl Aminomethyl, diethylaminomethyl, hydroxymethyl and hydroxyethyl.

In some embodiments, the invention provides a compound of Formula I or II, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R _{7 is} selected from the group consisting of hydrogen, C _1-6 Alkyl, C _3-6 cycloalkyl and halogenated C _1-6 alkyl.

In some preferred embodiments, the present invention provides Formula I or II compound as shown or a pharmaceutically acceptable salt, isomer, solvate, crystallization or prodrug thereof, wherein R ₇ is selected from hydrogen, C _{1 a -3} alkyl group, a C _3-6 cycloalkyl group, and a halogenated C _1-3 alkyl group.

In some preferred embodiments, the present invention provides Formula I or II compound as shown or a pharmaceutically acceptable salt, isomer, solvate, crystallization or prodrug thereof, wherein R ₇ is selected from hydrogen, methyl , ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and trifluoromethyl.

In some preferred embodiments, the present invention provides Formula I or II compound as shown or a pharmaceutically acceptable salt, isomer, solvate, crystallization or prodrug thereof, wherein R ₇ is methyl.

In some embodiments, the present invention provides a formula I or II compound represented by or a pharmaceutically acceptable salt, isomer, solvate, crystallization or prodrug thereof, wherein R ₈ is selected from hydrogen, C _1-6 An alkyl group and a C _3-6 cycloalkyl group, said C _1-6 alkyl group and a C _3-6 cycloalkyl group optionally being one or more halogen, C _1-6 alkyl, halogenated C _1-6 Alkyl, C _1-6 alkoxy, amino, mono C _1-6 alkylamino, di C _1-6 alkylamino or hydroxy substituted.

In some preferred embodiments, the present invention provides a formula I or II or a compound represented by the pharmaceutically acceptable salts, isomers, solvates, crystalline or prodrug thereof, wherein R ₈ is selected from hydrogen, C _{1 a -3} alkyl group and a C _3-6 cycloalkyl group, said C _1-3 alkyl group and a C _3-6 cycloalkyl group optionally being one or more halogen, C _1-3 alkyl group, halogenated C _{1 a -3} alkyl group, a C _1-3 alkoxy group, an amino group, a mono C _1-3 alkylamino group, a di C _1-3 alkylamino group or a hydroxy group.

In some preferred embodiments, the present invention provides a formula I or II compound represented by or a pharmaceutically acceptable salt, isomer, solvate, crystallization or prodrug thereof, wherein R ₈ is selected from hydrogen, C _{1 -3} alkyl and C _3-6 cycloalkyl, said C _1-3 alkyl and C _3-6 cycloalkyl optionally being one or more halogen, methyl, ethyl, propyl, isopropyl Base, trifluoromethyl, difluoromethyl, trifluoroethyl, methoxy, ethoxy, propoxy, isopropyloxy, amino, methylamino, ethylamino, propylamino, dimethylamino, Diethylamine, dipropylamino, methylethylamino, methylpropylamino, ethylpropylamino or hydroxy substituted.

In some preferred embodiments, the present invention provides a formula I or II compound represented by or a pharmaceutically acceptable salt, isomer, solvate, crystallization or prodrug thereof, wherein R ₈ is selected from hydrogen, methyl , ethyl and propyl, said methyl, ethyl and propyl optionally being one or more amino, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, A Substituted by ethylamino, methylpropylamino or ethylpropylamino.

In some preferred embodiments, the present invention provides a formula I or II compound represented by or a pharmaceutically acceptable salt, isomer, solvate, crystallization or prodrug thereof, wherein R ₈ is substituted with dimethylamino Ethyl.

In other embodiments, the present invention provides a compound of general formula I or II, or a pharmaceutically acceptable salt thereof shown, isomer, solvate, crystallization or prodrug thereof, wherein R _7, R ₈ and connected N constitutes a four to eight membered azacycloalkyl group, and the four to eight membered azacycloalkyl group is optionally substituted by one or more halogen, C _1-6 alkyl, halo C _1-6 alkyl, C _{1- 6} alkoxy, amino, mono C _1-6 alkylamino, di C _1-6 alkylamino, hydroxy, amino C _1-6 alkyl, mono C _1-6 alkylamino C _1-6 alkyl, Di-C _1-6 alkylamino C _1-6 alkyl or hydroxyalkyl substituted.

In some preferred embodiments, the present invention provides a compound of Formula I or II, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R ₇ , R ₈ and their linkages N constitutes a four to eight membered azacycloalkyl group, and the four to eight membered azacycloalkyl group is optionally substituted by one or more halogen, C _1-3 alkyl, halo C _1-3 alkyl, C _{1 -3} alkoxy, amino, mono C _1-3 alkylamino, di C _1-3 alkylamino, hydroxy, amino C _1-3 alkyl, mono C _1-3 alkylamino C _1-3 alkyl , a di-C _1-3 alkylamino C _1-3 alkyl group or a hydroxyalkyl group.

In some preferred embodiments, the present invention provides a compound of Formula I or II, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R ₇ , R ₈ and their linkages N-constituting five to six yuan azacycloalkyl, said azacycloalkyl five to six yuan optionally substituted with one or more halo, C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy, amino, mono C _1-3 alkylamino, di C _1-3 alkylamino, hydroxy, amino C _1-3 alkyl, mono C _1-3 alkylamino C _1-3 Alkyl, di-C _1-3 alkylamino C _1-3 alkyl or hydroxyalkyl substituted.

In some embodiments, the invention provides a compound of Formula I, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R ₄ , R ₅ and R ₆ are each independently selected From hydrogen, halogen, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, said C _1-6 alkyl, C _1-6 alkoxy and ring The alkyl group is optionally selected from one or more of halogen, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, amino, mono C _{1 -6} alkylamino, di C _1-6 alkylamino, hydroxy, amino C _1-6 alkyl, mono C _1-6 alkylamino C _1-6 alkyl, di C _1-6 alkylamino C _{1 -6} alkyl and hydroxy C _1-6 alkyl substituted.

In some preferred embodiments, the invention provides a compound of Formula I, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R ₄ , R ₅ and R ₆ are each independently Is selected from the group consisting of hydrogen, halogen, cyano, C _1-3 alkyl, C _1-3 alkoxy, C _3-6 cycloalkyl, said C _1-3 alkyl, C _1-3 alkoxy and C _3-6 cycloalkyl optionally substituted with one or more halo, C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy, a C _1-3 alkoxy group, halo , amino, mono C _1-3 alkylamino, di C _1-3 alkylamino, hydroxy, amino C _1-3 alkyl, mono C _1-3 alkylamino C _1-3 alkyl, di C _{1- 3} alkylamino C _1-3 alkyl or hydroxy C _1-3 alkyl substituted.

In some preferred embodiments, the invention provides a compound of Formula I, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R ₄ , R ₅ and R ₆ are hydrogen.

In some embodiments, the invention provides a compound of Formula III, or a pharmaceutically acceptable salt thereof, wherein M is selected from the group consisting of fluorine, chlorine, bromine, and iodine.

In some preferred embodiments, the invention provides a compound of Formula III, or a pharmaceutically acceptable salt thereof, wherein M is selected from the group consisting of chlorine, bromine, and iodine.

In some specific embodiments, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein

Ring A is

n is selected from 1, 2, 3 and 4;

m is selected from 1, 2, 3 and 4;

R _{a is} selected from the group consisting of hydrogen, C _1-3 alkyl, C _3-6 cycloalkyl, halogenated C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, nitro , cyano, hydroxy, amino, mono C _1-3 alkylamino, di C _1-3 alkylamino, amino C _1-3 alkyl, mono C _1-3 alkylamino C _1-3 alkyl, two C _1-3 alkylamino C _1-3 alkyl, hydroxy C _1-3 alkyl, C _1-3 alkoxy C _1-3 alkyl, C _1-3 alkyl acyl, amino acyl, mono C _{1 -3} alkylaminoacyl, di C _1-3 alkylamino acyl, C _6-10 aryl, C _5-10 heteroaryl and C _3-6 heterocycloalkyl, when m is selected from 2, 3 and 4 When two R _a groups of two adjacent carbon atoms may form a C _3-6 cycloalkyl group or a C _3-6 heterocycloalkyl group together with the carbon atom to which they are attached, or two on the same carbon atom. R _a may together with the carbon atom to which they are attached together constitute a C _3-6 cycloalkyl group or a C _3-6 heterocycloalkyl group;

X ₁ , X ₂ , X ₃ and X ₄ are each independently selected from C(R ₁ ) and N;

R ₁ , R _2a , R _2b , R _3a , R _3b and R _3c are each independently selected from the group consisting of hydrogen, halogen, C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy, Halogen C _1-3 alkoxy, nitro, cyano, hydroxy, amino, mono C _1-3 alkylamino, di C _1-3 alkylamino, amino C _1-3 alkyl, mono C _{1- 3} alkylamino C _1-6 alkyl, di C _1-3 alkylamino C _1-3 alkyl, hydroxy C _1-3 alkyl, C _1-3 alkoxy C _1-3 alkyl, C _{1 a -3} alkyl acyl group, an amino acyl group, a mono C _1-3 alkylamino acyl group and a di C _1-3 alkylamino acyl group;

R ₄ , R ₅ and R ₆ are all hydrogen;

R ₇ is a methyl group;

R ₈ is an ethyl group substituted by dimethylamino.

In other specific embodiments, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein

Ring A is

m is selected from 1, 2, 3 and 4;

p is selected from 0, 1, and 2;

q is selected from 0, 1, and 2; R _{a is} selected from hydrogen, C _1-3 alkyl, C _3-6 cycloalkyl, halogenated C _1-3 alkyl, C _1-3 alkoxy, halogen C _1-3 alkoxy, nitro, cyano, hydroxy, amino, mono C _1-3 alkylamino, di C _1-3 alkylamino, amino C _1-3 alkyl, mono C _1-3 alkyl C _1-3 alkyl amino, di C _1-3 alkyl amino C _1-3 alkyl, hydroxy C _1-3 alkyl, C _1-3 alkoxy C _1-3 alkyl, C _1-3 alkoxy Alkanoyl group, aminoacyl group, mono C _1-3 alkylamino acyl group, di C _1-3 alkylamino acyl group, C _6-10 aryl group, C _5-10 heteroaryl group and C _3-6 heterocycloalkyl group, When m is selected from 2, 3 and 4, two R _a on two adjacent atoms may together with the atom to which they are attached form a C _3-6 cycloalkyl group or a C _3-6 heterocycloalkyl group, or the same Two R _a on one atom may together with the atoms to which they are attached form a C _3-6 cycloalkyl group or a C _3-6 heterocycloalkyl group;

X ₁ , X ₂ , X ₃ and X ₄ are each independently selected from C(R ₁ ) and N;

R ₁ , R _2a , R _2b , R _3a , R _3b and R _3c are each independently selected from the group consisting of hydrogen, halogen, C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy, Halogen C _1-3 alkoxy, nitro, cyano, hydroxy, amino, mono C _1-3 alkylamino, di C _1-3 alkylamino, amino C _1-3 alkyl, mono C _{1- 3} alkylamino C _1-6 alkyl, di C _1-3 alkylamino C _1-3 alkyl, hydroxy C _1-3 alkyl, C _1-3 alkoxy C _1-3 alkyl, C _{1 a -3} alkyl acyl group, an amino acyl group, a mono C _1-3 alkylamino acyl group and a di C _1-3 alkylamino acyl group;

R ₄ , R ₅ and R ₆ are all hydrogen;

R ₇ is a methyl group;

R ₈ is an ethyl group substituted by dimethylamino.

In other specific embodiments, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein

Ring A is

m is selected from 1, 2, 3 and 4;

p is selected from 0, 1, and 2;

q is selected from 0, 1, and 2; R _{a is} selected from hydrogen, C _1-3 alkyl, C _3-6 cycloalkyl, halogenated C _1-3 alkyl, C _1-3 alkoxy, halogen C _1-3 alkoxy, nitro, cyano, hydroxy, amino, mono C _1-3 alkylamino, di C _1-3 alkylamino, amino C _1-3 alkyl, mono C _1-3 alkyl Amino C _1-3 alkyl, di C _1-3 alkylamino C _1-3 alkyl, hydroxy C _1-3 alkyl, C _1-3 alkoxy C _1-3 alkyl, C _1-3 alkane an acyl group, an amino group, a mono C _1-3 alkyl amino group, a di C _1-3 alkyl amino group, C _6-10 aryl, C _5-10 heteroaryl, and C _3-6 heterocycloalkyl, When m is selected from 2, 3 and 4, two R _a on two adjacent atoms may form a C _3-6 cycloalkyl group or a C _3-6 heterocycloalkyl group together with the atom to which they are attached, or the same Two R _a on one atom may together with the atoms to which they are attached form a C _3-6 cycloalkyl group or a C _3-6 heterocycloalkyl group;

X ₁ , X ₂ , X ₃ and X ₄ are each independently selected from C(R ₁ ) and N;

R ₁ , R _2a , R _2b , R _3a , R _3b and R _3c are each independently selected from the group consisting of hydrogen, halogen, C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy, Halogen C _1-3 alkoxy, nitro, cyano, hydroxy, amino, mono C _1-3 alkylamino, di C _1-3 alkylamino, amino C _1-3 alkyl, mono C _{1- 3} alkylamino C _1-6 alkyl, di C _1-3 alkylamino C _1-3 alkyl, hydroxy C _1-3 alkyl, C _1-3 alkoxy C _1-3 alkyl, C _{1 a -3} alkyl acyl group, an amino acyl group, a mono C _1-3 alkylamino acyl group and a di C _1-3 alkylamino acyl group;

R ₄ , R ₅ and R ₆ are all hydrogen;

R ₇ is a methyl group;

R ₈ is an ethyl group substituted by dimethylamino.

In some specific embodiments, the invention provides the following compounds, or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof:

In other specific embodiments, the invention provides the following compounds, or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof:

In a fourth aspect, the invention provides a process for the preparation of a compound of formula I, II and III of the invention, comprising the steps of:

A) the starting material of formula 1 and the starting material of formula 2 are nucleophilic to produce an intermediate of formula III;

B) an intermediate of formula III is reacted with a starting material of formula 3 to produce an intermediate of formula 4;

C) an intermediate of formula 4 is subjected to a nucleophilic reaction to produce an intermediate of formula 5;

D) an intermediate of formula 5 is subjected to a reduction reaction to produce an intermediate of formula II;

E) An intermediate of formula II is reacted with a starting material of formula 6 to produce a compound of formula I.

The above rings A, X ₁ , X ₂ , X ₃ , X ₄ , R _2a , R _2b , R _3a , R _3b , R _3c , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and M have the formula Definitions in I, II, III.

In some embodiments, the invention provides a process for the preparation of a compound of formula I of the invention, which process comprises the use of a compound of formula II of the invention.

In some embodiments, the invention provides a process for the preparation of a compound of formula I of the invention, which process comprises the use of a compound of formula III of the invention.

In a fifth aspect, the invention provides a pharmaceutical composition comprising a compound of formula I of the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier.

In some embodiments, the invention provides a pharmaceutical composition comprising a compound, isomer, solvate, crystal or prodrug of Formula I of the invention, further comprising one or more compounds selected from the group consisting of: Gefitinib, erlotinib, lapatinib, afatinib, vandetanib, carnitinib, apatinib, dacomitinib, pelitinib , WZ4002, AG-490, AZD8931, AZD9291 and so on.

The compound, isomer, solvate, crystal or prodrug of the formula I of the present invention may be admixed with a pharmaceutically acceptable carrier to prepare a pharmaceutical preparation suitable for oral or parenteral administration. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes. The formulation may be administered by any route, for example by infusion or bolus injection, by a route of absorption through the epithelium or skin mucosa (e.g., oral mucosa or rectum, etc.). Administration can be systemic or topical. Examples of the orally administered preparations include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like. The formulation can be prepared by methods known in the art and comprises a carrier conventionally used in the field of pharmaceutical formulations.

In a sixth aspect, the present invention provides a method of treating and/or preventing a tumor of a compound, isomer, solvate, crystal or prodrug of the present invention or a pharmaceutical composition of the present invention, and in the preparation of a treatment and/or prevention Use in a tumor drug, comprising administering to a tumor-prone population or a tumor patient a compound, isomer, solvate, crystal or prodrug of the formula I of the invention or a compound, isomer comprising the formula I of the invention, A pharmaceutical composition of a solvate, crystal or prodrug to effectively reduce the incidence of tumors and prolong the life of a tumor patient.

In some embodiments, the invention provides a method of treating a tumor having resistance to a compound, a isomer, a solvate, a crystal or a prodrug of the invention, or a pharmaceutical composition of the invention, comprising A pharmaceutically acceptable tumor patient is administered a therapeutically effective amount of a compound, isomer, solvate, crystal or prodrug of the formula I according to the invention or a compound, isomer, solvate, crystal or pre-compound comprising the formula I of the invention Pharmaceutical composition of the drug.

In other embodiments, the invention provides a compound, isomer, solvate, crystal or prodrug of the invention, or a pharmaceutical composition of the invention, in the manufacture of a medicament for treating a tumor having drug resistance application. The drug-resistant tumor may be a tumor resistant to a plurality of drugs, preferably a tumor resistant to an EGFR inhibitor, for example, to a first, second, and third generation EGFR inhibitor, such as gefitinib. , erlotinib and lapatinib have drug-resistant tumors. Such tumors include, but are not limited to, solid tumors, preferably lung cancer, head and neck tumors, colorectal cancer, bladder cancer, pancreatic cancer, breast cancer, prostate cancer, gastric cancer, oral cancer, liver cancer, ovarian cancer. More preferably, the tumor is non-small cell lung cancer. In some embodiments, the invention provides a method of treating a tumor having resistance to a compound, isomer, solvate, crystal or prodrug of Formula I of the invention, wherein the tumor carries an EGFR mutated gene. In one embodiment, the EGFR mutated gene carried by the tumor is a T790M mutation in exon 20. In another embodiment, the EGFR mutated gene carried by the tumor is a L858R mutation and/or a deletion/insertion mutation in exon 21. In another embodiment, the EGFR mutated gene carried by the tumor is a T790M and L858R double mutation. In other embodiments, the invention provides a compound, isomer, solvate, crystal or a compound of the formula I of the invention for use in treating a tumor A prodrug or a pharmaceutical composition of the invention wherein the therapeutic effect of the tumor is manifested in a prominent therapeutic effect, a high degree of selectivity and/or less side effects. In still other embodiments, the present invention provides a method of treating a tumor of a compound, isomer, solvate, crystal or prodrug of the present invention or a pharmaceutical composition of the present invention, the method comprising administering it A therapeutically effective amount of a compound, isomer, solvate, crystal or prodrug of the present invention or a pharmaceutical composition of the present invention, which produces a therapeutic effect in the treatment of a tumor, which is highly effective. Selectivity and / or fewer side effects.

Definition of Terms

Unless otherwise defined, all technical and scientific terms used herein have the same meaning meaning meaning

"Isomers" of the present invention include cis-trans isomers of the cis or trans configuration, as well as enantiomers and diastereomers derived from chiral carbons.

The "pharmaceutically acceptable salt" of the present invention means a pharmaceutically acceptable salt formed by the compound of the present invention and an acid, and the acid may be selected from the group consisting of phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, Maleic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-toluenesulfonic acid, malic acid, methanesulfonic acid and the like.

The "solvate" of the present invention means a form of the compound of the present invention which forms a solid or liquid complex by coordination with a solvent molecule. Hydrates are a special form of solvates in which coordination occurs with water. Within the scope of the invention, the solvate is preferably a hydrate.

"Crystalline" as used in the present invention refers to various solid forms formed by the compounds of the present invention, including crystalline forms and amorphous forms.

The "prodrug" of the present invention refers to a compound which is converted into a compound of the present invention by a reaction with an enzyme, gastric acid or the like under physiological conditions of a living body, that is, a compound which is converted into the invention by oxidation, reduction, hydrolysis or the like of the enzyme and/or A compound which is converted into a compound of the invention by a hydrolysis reaction such as gastric acid or the like.

A "pharmaceutical composition" according to the invention is meant to comprise any one of the compounds described herein, including isomers, prodrugs, solvates, pharmaceutically acceptable salts or chemically protected forms thereof, and one or more A mixture of pharmaceutically acceptable carriers.

The "application in the preparation of a medicament for treating and/or preventing a tumor" of the present invention means that the growth, development and/or metastasis of a tumor can be inhibited, and a therapeutically effective dose of the present invention is mainly administered to a human or animal in need thereof. A compound inhibits, slows or reverses the growth, progression or spread of a tumor in a subject.

The term "alkyl" refers to a straight or branched saturated hydrocarbon group, preferably a hydrocarbon group of 6 or less carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 2,2-Methylbutyl and 2,3-dimethylbutyl. The term "C _1-6 alkyl" refers to a straight or branched saturated hydrocarbon group containing from 1 to 6 carbon atoms. The term "C _1-3 alkyl" means a straight or branched saturated hydrocarbon group having 1 to 3 carbon atoms.

The "cycloalkyl group" of the present invention means a cyclic saturated, partially saturated hydrocarbon group, preferably a cycloalkyl group of 12 or less carbon atoms, more preferably a cycloalkyl group of 8 or less carbon atoms, still more preferably 6 carbon atoms. The following cycloalkyl group. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. The "C _3-8 cycloalkyl group" of the present invention means a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms.

The "alkoxy group" of the present invention means an -O-alkyl group.

硫原子被一个氧代基团取代形成

硫原子被两个氧代基团取代形成

The "oxo" of the present invention means O =, for example, a carbon atom is substituted by an oxo group.

The sulfur atom is replaced by an oxo group

The sulfur atom is replaced by two oxo groups

The "halogen" of the present invention means fluorine, chlorine, bromine or iodine.

The "haloalkyl group" of the present invention means an alkyl group substituted with at least one halogen atom.

The "haloalkoxy group" of the present invention means an alkoxy group substituted with at least one halogen, preferably a C _1-6 alkoxy group substituted with at least one halogen, and further preferably a C _1-3 alkane substituted with at least one halogen. Oxyl, a suitable halogenated C _1-3 alkoxy group is chloromethoxy, fluoromethoxy, dichloromethoxy, difluoromethoxy, trichloromethoxy, trifluoromethoxy; Chloroethoxy, difluoroethoxy, trichloroethoxy, trifluoroethoxy.

The "monoalkylamino group" of the present invention means -NH-alkyl group, preferably -NH-C _1-6 alkyl group, and more preferably -NH-C _1-3 alkyl group.

The "dialkylamino group" of the present invention means -N-(alkyl)(alkyl), preferably -N-(C _1-6 alkyl)(C _1-6 alkyl), further preferably -N -(C _1-3 alkyl) (C _1-3 alkyl).

The "aminoalkyl group" of the present invention means -alkyl-NH ₂ .

The "monoalkylaminoalkyl group" of the present invention means an -alkyl-NH-alkyl group.

The "dialkylaminoalkyl group" of the present invention means -alkyl-N-(alkyl)(alkyl).

The "hydroxyalkyl group" of the present invention means -alkyl-OH.

The "alkyl acyl group" of the present invention means a -C(O)-alkyl group.

The "aminoacyl group" of the present invention means -C(O)-NH ₂ .

The "monoalkylaminoacyl" of the present invention means -C(O)-NH-alkyl.

The "dialkylaminoacyl group" of the present invention means -C(O)-N-(alkyl)(alkyl).

The "heterocycloalkyl group" of the present invention means a substituted or unsubstituted saturated, partially saturated cyclic alkyl group containing at least one hetero atom selected from N, O, and S.

The "aryl group" of the present invention means an aromatic system which may contain a monocyclic or polycondensed ring such as a bicyclic or tricyclic aromatic ring, wherein at least a part of the fused ring forms a conjugated aromatic system containing 5 to 50 One carbon atom, preferably from about 6 to about 14 carbon atoms. Suitable aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthracenyl, tetrahydronaphthyl, anthracenyl, indanyl, biphenylene, and anthracenyl. The "C ₆ -C ₁₀ aryl group" of the present invention means an aromatic system having 6 to 10 carbon atoms.

The "heteroaryl" of the present invention means an aromatic monocyclic or polycondensed ring such as an aromatic group in which at least one carbon atom of a bicyclic or tricyclic ring is replaced by a hetero atom, and the hetero atom is O, S, N. Suitable heteroaryl groups include, but are not limited to, imidazolyl, benzimidazolyl, imidazopyridyl, quinazolinone, pyrrolyl, imidazolidinyl, furyl, thienyl, pyrazolyl, oxazolyl, thiazole Base, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl and the like. The "C ₅ -C ₁₀ heteroaryl group" of the present invention means a heteroaryl group having 5 to 10 atoms.

等。The "C ₄ -C ₈ nitrogen-containing heterocyclic group" of the present invention means a substituted or unsubstituted saturated, partially saturated and fully unsaturated total ring atom number of 4, 5, 6, 7 or containing at least one nitrogen atom. The heterocyclic group of 8, for example, a C ₄ nitrogen-containing heterocyclic group means a substituted or unsubstituted saturated, partially saturated and fully unsaturated total nitrogen-containing heterocyclic group having 4 ring atoms. The "C ₄ -C ₈ nitrogen-containing heteromonocycloalkyl group" of the present invention means a substituted or unsubstituted saturated, partially saturated and fully unsaturated total ring atom number of 4, 5, 6, containing at least one nitrogen atom. Suitable heterocycloalkyl groups of 7 or 8 include, but are not limited to, substituted or unsubstituted azetidinyl, azacyclopentyl, azacyclohexyl, azepanyl, azacyclooctyl , azacyclopentyl, azacyclohexyl, aziridine, azacyclooctyl, azathiolanyl, azathioheptyl, azathioheptyl, a nitrogen sulfur a heterocyclic octyl group, a diazacyclopentyl group, a diazacyclohexyl group, a diazepanyl group or a diazacyclooctyl group; and a substituted or unsubstituted nitrogen-containing heteroaryl group, for example, substituted or unsubstituted Pyridyl, imidazolyl, pyrazolyl, pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, wherein the substituent is selected from the group consisting of alkyl, oxo, cycloalkyl, hydroxy, hydroxyalkyl, alkoxy Amino, monoalkylamino, bisalkylamino, amido, alkylamido, arylamido, heteroarylamino, halogen, haloalkyl, haloalkoxy. Herein, the C ₄ -C ₈ nitrogen-containing heterocyclic group and the anthracene ring constitute a nitrogen heterocyclic fluorene structure, for example, a suitable nitrogen heterocyclic fluorene structure includes but is not limited to

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detailed description

The following representative examples are intended to better illustrate the invention and are not intended to limit the scope of the invention.

Example 1 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(2,3-dihydro-1H-) Synthesis of pyrrolo[1,2-a]-indol-9-yl)pyrimidin-2-yl)amino)phenyl)allylamide

Step a Synthesis of 1-(3-bromopropyl)-1H-indole

Add NaH (60% content, 1.23 g, 30.73 mmol) and DMF (10 ml) in a 100 ml reaction flask, stir at room temperature for 5 min, then cool to 0-4 ° C, slowly add 10 mL of dissolved hydrazine (3 g, 25.61 mmol) The DMF solution was added and added to room temperature for 20 min to prepare a hydrazine activation solution.

Another 250 ml reaction flask was taken, and 1,3-dibromopropane (15.51 g, 76.82 mmol) and DMF (50 ml) were added. The hydrazine activating solution prepared above was slowly added dropwise at 0-4 ° C, and the reaction was carried out for 0.5 h at room temperature. After the reaction was over, water (100 ml) was added to quench the reaction. The title compound was obtained after EtOAc.

ESI-Ms m/z: 239.1 [M+H].

Step b Synthesis of 1-(3-iodopropyl)-1H-indole

In a 250 ml reaction flask, 1-(3-bromopropyl)-1H-indole (4.72 g, 19.83 mmol), sodium iodide (13.39 g, 89.93 mmol) and acetonitrile (100 ml) were obtained. Reflux overnight. After completion of the reaction, water was added, and ethyl acetate was evaporated.

ESI-Ms m/z: 286.1 [M+H].

Step c Synthesis of 2,3-dihydropyrrolo[1,2-a]indole

In a 250 ml three-necked flask, the obtained product of the step b was sequentially added 1-(3-iodopropyl)-1H-indole (5.44 g, 19.83 mmol), potassium phosphate (8.4 g, 39.67 mmol), tetratriphenylphosphine. Palladium (2.3 g, 1.98 mmol) and 1,4-dioxane (80 ml) were argon-protected and refluxed overnight. After the reaction was completed, the mixture was evaporated.

ESI-Ms m/z: 158.1 [M+H].

Synthesis of step d 9-(2-chloropyrimidin-4-yl)-2,3-dihydropyrrolo[1,2-a]indole

In a 100 ml reaction flask, aluminum trichloride (2.18 g, 16.35 mmol), ethylene glycol dimethyl ether (50 ml), 2,4-dichloropyrimidine (2.44 g, 16.35 mmol) and step 2 were successively added. 3-Dihydropyrrolo[1,2-a]indole (2.57 g, 16.35 mmol), refluxed for 2 h. After completion of the reaction, the reaction solution was cooled to room temperature, filtered, and the filter cake was washed with water and dried to give the title compound.

ESI-Ms m/z: 270.4 [M+H].

Step e N-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(2,3-dihydropyrrolo[1,2-a]indol-9-yl)-pyrimidine Synthesis of 2-amine

In a 250 ml reaction flask, 9-(2-chloropyrimidin-4-yl)-2,3-dihydropyrrolo[1,2-a]indole (2.69 g, 10 mmol), 4-fluoro, obtained in step d 2-methoxy-5-nitroaniline (1.86 g, 10 mmol) and p-toluenesulfonic acid (1.71 g, 10 mmol) were dissolved in 50 mL of sec-butanol and reacted at 110 ° C for 2 h. After the reaction was completed, cooled to room temperature. Filtration, washing with sec-butanol and drying to give the title compound.

ESI-Ms m/z: 420.4 [M+H].

Step f N-(4-((2-(Dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)-4-(2,3-dihydro Synthesis of pyrrolo[1,2-a]fluoren-9-yl)-pyrimidin-2-amine

In a 50 ml reaction flask, the resulting product of step e was sequentially added N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(2,3-dihydropyrrolo[1,2-a吲哚-9-yl)-pyrimidine-2-amine (2.5 g, 6 mmol), N,N,N'-trimethylethylenediamine (0.61 g, 6 mmol), diisopropylethylamine (2.3 g , 18 mmol), and 10 ml of dioxane, refluxing at 110 ° C for 3 h. After completion of the reaction, concentration and purification by column chromatography

ESI-Ms m/z: 502.4 [M+H].

Step g N-(4-((2-(Dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-aminophenyl)-4-(2,3-dihydropyrrole Synthesis of [1,2-a]fluoren-9-yl)-pyrimidine-2-amine

In a 50 ml reaction flask, the resulting step N was added N-(4-((2-(dimethylamino)ethyl))(methyl)amino)-2-methoxy-5-nitrophenyl) 4-(2,3-dihydropyrrolo[1,2-a]indol-9-yl)-pyrimidin-2-amine (2.5 g, 5 mmol), 10% Pd-C (20 mg) and 30 mL methanol Hydrogen was reduced for 1 h at 1 standard atmosphere. After the reaction was completed, it was filtered and concentrated to give the title compound.

ESI-Ms m/z: 472.6 [M+H].

Step h N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((5-methyl-4-(2,3-di) Synthesis of Hydrogen-1H-pyrrolo[1,2-a]-indol-9-yl)pyrimidin-2-yl)amino)phenyl)propanamide

In a 150 ml single-mouth bottle, the obtained step g was added N-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-aminophenyl)-4 -(2,3-dihydropyrrolo[1,2-a]indol-9-yl)-pyrimidin-2-amine (2 g, 4.2 mmol), diisopropylethylamine (0.53 g, 4.2 mmol) After dissolving, 20 ml of anhydrous dichloromethane was added, and 5 ml of a solution of allylic acid chloride (0.37 g, 4.2 mmol) in methylene chloride was added slowly, and the mixture was reacted for 10 min. ^{1 H NMR (300MHz, DMSO-} d 6): δ10.17 (s, 1H), 8.69 (s, 1H), 8.28-8.25 (d, 2H), 8.02 (s, 1H), 7.37-7.35 (d, 1H), 7.15-6.97 (m, 4H), 6.44-6.35 (m, 1H), 6.21-6.15 (m, 1H), 5.74-5.70 (d, 1H), 4.1-4.10 (t, 2H), 3.81 ( s, 3H), 3.35 (s, 1H), 3.30-3.25 (t, 1H), 2.90 (s, 2H), 2.73 (s, 3H), 2.60-2.56 (m, 2H), 2.33 (s, 2H) , 2.22 (s, 6H).

ESI-Ms m/z: 526.4 [M+H].

Example 2 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(6,7,8,9-tetra) Synthesis of Hydropyrido[1,2-a]indole-10-yl)-pyrimidin-2-yl)amino)phenyl)allylamide

Step a Synthesis of 1-(4-bromobutyl)-1H-indole

In a 100 mL reaction flask, NaH (60% content, 1.23 g, 30.73 mmol) and DMF (10 mL) were added sequentially, stirred at room temperature for 5 min, then cooled to 0-4 ° C, and 10 mL of dissolved hydrazine (3 g, 25.61 mmol) was slowly added. The DMF solution was added and added to room temperature for 20 min to prepare a hydrazine activation solution.

Another 250 mL reaction flask was taken, and 1,4-dibromobutane (16.59 g, 76.82 mmol) and DMF (50 mL) were added. The hydrazine activating solution prepared above was slowly added dropwise at 0-4 ° C, and the reaction was carried out for 0.5 h at room temperature. After completion of the reaction, the mixture was evaporated.

ESI-Ms m/z: 252.1 [M+H].

Step b Synthesis of 1-(4-iodobutyl)-1H-indole

In a 250 mL reaction flask, 1-(4-bromobutyl)-1H-indole (5 g, 19.83 mmol), sodium iodide (13.39 g, 89.93 mmol), acetonitrile (100 mL), and then refluxed. overnight. After completion of the reaction, water was added, and ethyl acetate was evaporated.

ESI-Ms m/z: 300.0 [M+H].

Synthesis of step c 6,7,8,9-tetrahydropyrido[1,2-a]indole

In a 250 mL three-necked flask, the obtained product of step b was added 1-(4-iodobutyl)-1H-indole (5.93 g, 19.83 mmol), potassium phosphate (8.4 g, 39.67 mmol), tetratriphenyl. Palladium phosphate (2.3 g, 1.98 mmol), 1,4-dioxane (80 mL), argon-protected, refluxed overnight. After the reaction was completed, the mixture was evaporated.

ESI-Ms m/z: 172.1 [M+H].

Step d Synthesis of 10-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydropyrido[1,2-a]indole

In a 100 mL reaction flask, aluminum trichloride (2.18 g, 16.35 mmol), ethylene glycol dimethyl ether (50 mL), 2,4-dichloropyrimidine (2.44 g, 16.35 mmol), and the obtained product of step c were successively added. , 7,8,9-tetrahydropyrido[1,2-a]indole (2.8 g, 16.35 mmol), refluxed for 2 h. After completion of the reaction, the reaction solution was cooled to room temperature, filtered, and the filter cake was washed with water and dried to give the title compound.

ESI-Ms m/z: 284.1 [M+H].

Step e N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(6,7,8,9-tetrahydro) Synthesis of pyrido[1,2-a]indol-10-ylpyrimidin-2-yl)amino)phenyl)allylamide

The product obtained in the step d is 10-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydropyrido[1,2-a]indole, 4-fluoro-2-methoxy- 5-Nitroaniline, N,N,N'-trimethylethylenediamine and allyl chloride were used as starting materials, and the title compound was obtained according

^{1 H NMR (300MHz, DMSO-} d 6) δ10.20 (s, 1H), 8.65 (s, 1H), 8.34 (d, 1H), 8.11 (s, 1H), 8.06 (d, 1H), 7.43 ( d, 1H), 7.19-7.03 (m, 3H), 6.98 (s, 1H), 6.57-6.41 (m, 1H), 6.28-6.15 (m, 1H), 5.82-5.71 (m, 1H), 4.09 ( t, 2H), 3.84 (s, 3H), 3.18 (t, 2H), 3.06-2.92 (m, 2H), 2.66 (s, 3H), 2.47-2.40 (m, 2H), 2.27 (s, 6H) , 2.08-1.96 (m, 2H), 1.87-1.74 (m, 2H).

ESI-Ms m/z: 540.3 [M+H].

Example 3 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((5-methyl-4-(6,7, Synthesis of 8,9-tetrahydropyrido[1,2-a]indol-10-ylpyrimidin-2-yl)amino)phenyl)allylamide

Step a Synthesis of 10-(2-chloro-5-methylpyrimidin-4-yl)-6,7,8,9-tetrahydropyrido[1,2-a]indole

Using the 6,7,8,9-tetrahydropyrido[1,2-a]indole and 5-methyl-2,4-dichloropyrimidine as the starting materials in the step c of Example 2, according to the procedure of Example 2 The title compound was prepared by the method of d.

Step b N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((5-methyl-4-(6,7,8) Synthesis of 9-tetrahydropyrido[1,2-a]indol-10-ylpyrimidin-2-yl)amino)phenyl)propanamide

The product obtained in the step a is 10-(2-chloro-5-methylpyrimidin-4-yl)-6,7,8,9-tetrahydropyrido[1,2-a]indole, 4-fluoro-2. -Methoxy-5-nitroaniline, N,N,N'-trimethylethylenediamine and allyl chloride as starting materials, the title compound was obtained according to the procedure of Example 1, Steps e, f, g and h .

^{1 H NMR (300MHz, DMSO-} d 6) δ10.02 (s, 1H), δ8.84 (s, 1H), 8.33 (s, 1H), 7.77 (s, 1H), 7.42 (d, 1H), 7.26(d,1H), 7.10-7.13 (m,1H), 7.04-7.07 (m,1H), 6.95 (s,1H), 6.34-6.39 (m,1H), 6.19-6.22 (m,1H), 5.73 (d, 1H), 4.11 (t, 2H), 3.83 (s, 3H), 2.99 (s, 2H), 2.83 (t, 2H), 2.67 (s, 3H), 2.25 (t, 2H), 2.17 (s, 6H), 2.07 (s, 3H), 2.04 (m, 2H), 1.79 (m, 2H).

ESI-Ms m/z: 554.3 [M+H].

Example 4 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(6,7,8,9-tetra) Synthesis of Hydropyrido[1,2-a]-5-fluoroindole-10-yl)pyrimidin-2-yl)amino)phenyl)allylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloropyrimidine, 5-fluoroindole, 1,4-dibromobutane, N,N,N'-trimethyl The title compound was obtained according to the method of Example 1 using ethylenediamine and allyl chloride as starting materials.

^{1 H NMR (300MHz, DMSO-} d 6): δ9.62 (s, 1H), 9.42 (s, 1H), 8.3-8.27 (d, 2H), 7.87 (s, 1H), 7.49 (d, 1H) , 7.14 (d, 1H), 7.06 (s, 2H), 6.71-6.63 (m, 1H), 6.22-6.16 (m, 1H) 5.73 (d, 1H), 4.13 (s, 2H), 3.84 (s, 3H), 3.32 (s, 4H), 3.22-3.20 (t, 2H), 2.83 (s, 6H), 2.64 (s, 3H), 2.02 (s, 2H), 1.85 (s, 2H).

ESI-Ms m/z: 558.4 [M+H].

Example 5 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-((2,3-dihydro-1H) Synthesis of pyrrolo[1,2-a]-5-fluoroindol-9-yl)-5-chloro-pyrimidin-2-yl)amino)phenyl)allylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4,5-trichloropyrimidine, 5-fluoroindole, 1,3-dibromopropane, N,N,N'-trimethyl The title compound was obtained by the method of Example 1 using methylenediamine and allyl chloride as starting materials.

1H NMR (300MHz, DMSO-d6) δ: 9.99 (s, 1H), 8.48 (s, 1H), 8.42 (s, 2H), 7.41-7.34 (m, 2H), 6.98-6.91 (m, 2H), 6.44–6.39 (m, 1H), 6.17 (m, 1H), 5.61 (d, 1H), 4.14 (t, 2H), 3.82 (s, 3H), 3.16–3.11 (m, 2H), 2.91-2.87 ( m, 2H), 2.68 (s, 3H), 2.57–2.54 (m, 2H), 2.39–2.35 (m, 2H), 2.23 (s, 6H).

ESI-Ms m/z: 578.2 [M+H].

Example 6 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(2,3-dihydro-1H-) Synthesis of pyrrolo[1,2-a]-5-fluoroindol-9-yl)pyrimidin-2-yl)amino)phenyl)allylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloropyrimidine, 5-fluoroindole, 1,3-dibromopropane, N,N,N'-trimethyl The title compound was obtained according to the method of Example 1 using diamine and allyl chloride as starting materials.

1H NMR (300MHz, DMSO-d6) δ 10.07 (s, 1H), 8.65 (s, 1H), 8.25 (d, 1H), 8.05 - 8.02 (m, 1H), 7.36-7.34 (m, 2H), 7.01(s,1H), 6.90–6.97(m,2H), 6.36-6.34(m,1H), 6.17-6.15(m,1H),5.69-5.67(d,1H), 4.13(t,2H), 3.79(s,3H), 2.89–2.88(t,2H), 2.73(s,3H), 2.62–2.60(t,2H),2.51–2.50(t,2H), 2.32-2.30(t,2H), 2.21(s,6H).

ESI-Ms m/z: 544.4 [M+H].

Example 7 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3,4-dihydro-1H-) Synthesis of [1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)amino)phenyl)allylamide

Step a Synthesis of 2-hydroxymethylhydrazine

In a 100 ml reaction flask, lithium tetrahydroaluminum (902.63 mg, 23.78 mmol) and THF (30 ml) were added in this order, and stirred at room temperature. After 5 min, ice bath was added, and ethyl hydrazine-2-carboxylate (3 g, 15.86 mmol) was slowly added, and the mixture was warmed to room temperature for 2 h. After completion of the reaction, the system was cooled to 0 ° C, then 20 ml of THF and 1.7 ml of 20% KOH were added thereto, stirred for 10 min, filtered, and the filter cake was washed with 20 ml of THF, and the filtrate was washed once with saturated NaCl (10 ml). It was dried, filtered and concentrated to dryness to give the title compound (2.3 g).

ESI-Ms m/z: 148.1 [M+H].

Step b Synthesis of 3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole

In a 500 ml reaction flask, the 2-hydroxymethyl hydrazine (300 mg, 2.04 mmol) obtained in the step a, KOH (285.91 mg, 5.10 mmol), and CH ₂ Cl ₂ (160 ml) were sequentially added, and cooled to about 0 ° C in an ice bath. Protected with nitrogen and stirred for 10 min. 40 mL of a solution of Diphenyl(vinyl)sulfonium trifluoromethanesulfonate (888.86 mg, 2.45 mmol) in CH ₂ Cl _{2 was} added dropwise to the above reaction system, and after completion, the mixture was allowed to react to room temperature. After the completion of the reaction, the reaction mixture was quenched with EtOAc (EtOAc)EtOAc.

ESI-Ms m/z: 174.1 [M+H].

Step c N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3,4-dihydro-1H-[ Synthesis of 1,4]oxazino[4,3-a]indole-10-ylpyrimidin-2-yl)amino)phenyl)propanamide

3-, 4-dihydro-5-nitroaniline, 2,4-dichloropyrimidine, step b, 3,4-dihydro-1H-[1,4]oxazine [4,3- The title compound was obtained according to the procedure of Example 1 using </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt;

1H NMR (300MHz, DMSO-d6) δ 10.04 (s, 1H), 8.61 (s, 1H), 8.35 (d, 1H), 8.06 (d, 1H), 8.03 (s, 1H), 7.50-7.49 ( d, 1H), 7.24–7.19 (m, 2H), 7.12-7.11 (d, 1H), 7.00 (s, 1H), 6.45 (s, 1H), 6.22–6.19 (d, 1H), 5.73-5.71 ( d,1H),5.07(s,2H),4.16–4.14(t,2H),4.06–4.04(t,2H),3.81(s,3H),2.96(s,2H),2.70(s,3H) , 2.30 (s, 6H), 2.35 (m, 2H).

ESI-Ms m/z: 542.2 [M+H].

Example 8 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(6,7,8,9-tetra) Synthesis of Hydropyrido[1,2-a]-7-chloroindole-10-yl)pyrimidin-2-yl)amino)phenyl)Allylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloropyrimidine, 7-chloroindole, 1,4-dibromobutane, N,N,N'-trimethyl The title compound was obtained according to the method of Example 1 using ethylenediamine and allyl chloride as starting materials.

1H NMR (300MHz, DMSO-d6) δ: 10.04 (s, 1H), 8.69 (s, 1H), 8.38 - 8.36 (d, 1H), 8.26 (s, 1H), 8.00 (s, 2H), 7.14 - 7.12 (m, 1H), 7.03–6.98 (m, 2H), 6.43–6.35 (m, 1H), 6.17–6.16 (d, 1H), 5.71–5.70 (d, 1H), 4.66–4.62 (m, 2H) ), 3.34–3.21 (m, 3H), 2.90–2.86 (m, 3H), 2.70 (s, 4H), 2.33–2.31 (m, 2H), 2.20 (s, 6H), 2.20–2.19 (m, 2H) ), 1.78–1.76 (m, 2H),

ESI-Ms m/z: 575.2 [M+H].

Example 9 N-(5-((4-(1,1-Dimethyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-) Synthesis of amide)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloropyrimidine, 1,3-dibromo-3-methylbutane, anthracene, N,N,N'-three The title compound was obtained according to the method of Example 1 using methylethylenediamine and allyl chloride as starting materials.

1H NMR (300MHz, DMSO-d6) δ10.00 (s, 1H), 8.58 (s, 1H), 8.36 - 8.58 (m, 1H), 7.91 - 7.96 (m, 2H), 7.35 - 7.40 (m, 1H) ), 7.09 - 7.40 (m, 4H), 6.36 - 6.45 (m, 1H), 6.18 - 6.23 (m, 1H), 5.71 - 5.74 (m, 1H) 4.12 - 4.19 (m, 2H), 3.80 (s, 3H), 2.93 (s, 2H), 2.69 (s, 3H), 2.37 - 2.44 (m, 2H), 2.28 (s, 6H), 1.56 (s, 2H), 1.37 (s, 6H).

ESI-Ms m/z: 554.3 [M+H].

Example 10 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(6,7,8,9-tetra) Synthesis of Hydropyrido[1,2-a]indole-10-yl)-5-chloro-pyrimidin-2-yl)amino)phenyl)allylamide

The product obtained in the step c of Example 2, 6,7,8,9-tetrahydropyrido[1,2-a]indole, 4-fluoro-2-methoxy-5-nitroaniline, 2,4, The title compound was obtained according to the method of Example 1 using 5-trichloropyrimidine, N,N,N'-trimethylethylenediamine and allyl chloride as starting materials.

1H NMR (300MHz, DMSO-d6) δ: 9.63 (s, 1H), 9.47 (s, 1H), 8.3 - 8.30 (d, 2H), 7.85 (s, 1H), 7.5 (d, 1H), 7.12 ( d, 1H), 7.04 (s, 2H), 6.72 - 6.61 (m, 1H), 6.23 - 6.15 (m, 1H), 5.7, 5 (d, 1H), 4.12 (s, 2H), 3.86 (s, 3H), 3.34 (s, 4H), 3.20–3.17 (t, 2H), 2.86 (s, 6H), 2.66 (s, 3H), 2.01 (s, 2H), 1.86 (s, 2H).

ESI-Ms m/z: 575.2 [M+H].

Example 11 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(6,7,8,9-tetra) Synthesis of Hydropyrido[1,2-a]-5-methoxy-indol-1-ylpyrimidin-2-yl)amino)phenyl)allylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloropyrimidine, 5-methoxyindole, 1,4-dibromobutane, N,N,N'-three The title compound was obtained according to the method of Example 1 using methylethylenediamine and allyl chloride as starting materials.

1H NMR (300MHz, DMSO-d6) δ: 10.02 (s, 1H), 9.53 (s, 1H), 8.40 - 8.45 (d, 2H), 7.92 (s, 1H), 7.52 (d, 1H), 7.18 ( d, 1H), 7.10 (s, 2H), 6.76 - 6.70 (m, 1H), 6.28 - 6.20 (m, 1H) 5.72 (d, 1H), 4.12 (s, 2H), 3.85 (s, 3H), 3.72 (s, 3H), 3.32 (s, 4H), 3.21 - 3.19 (t, 2H), 2.83 (s, 6H), 2.65 (s, 3H), 2.02 (s, 2H), 1.86 (s, 2H) .

ESI-Ms m/z: 570.4 [M+H].

Example 12 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino-4-methoxy-5-((4-(1,1a,2,8b-tetrahydro) Synthesis of cyclopropyl[3,4]pyrrolo[1,2-a]indole-8-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

Step a 1- Synthesis of 1-allyl-1H-indole-2-carbaldehyde:

In a 100 mL two-necked flask, 25 ml of anhydrous DMF was added, cooled to 0-5 ° C, 662 mg of NaH was slowly added, and stirred for 10 min. 10 mL of an anhydrous DMF solution in which 2 g of 1H-indole-2-carbaldehyde was dissolved was slowly dropped into the above reaction solution, bubbles were generated, the color of the solution became dark black, stirring was continued for 15 min, and then 5 mL was slowly added to dissolve 1.82 g of 3- Anhydrous DMF solution of bromopropene was reacted at room temperature for 3 h, added with 50 mL of water, EtOAc (EtOAc)EtOAc.

ESI-Ms m/z: 186.0 [M+H]

Step b: Synthesis of N-((1-propenyl-1H-indol-2-yl)methenyl)-4-methylbenzenesulfonylhydrazide:

In a 100 mL single-mouth bottle, 1-allyl-1H-indole-2-carbaldehyde (1.85 g, 10 mmol) obtained in Step a, p-toluenesulfonylhydrazide (1.86 g, 10 mmol), 50 mL of methanol, oil The reaction was refluxed at 85 ° C for 2 h. Concentration gave the title crude product 3.6 g, which was used directly next.

Step c: Synthesis of 1,1,2,8b-tetrahydrocyclopropyl[3,4]pyrrolo[1,2-a]indole:

In a 250 mL three-necked flask, N-((1-propenyl-1H-indol-2-yl)methenyl)-4-methylbenzenesulfonyl hydrazide (2.2 g, 6.23 mmol) obtained in step b was added, and carbonic acid was added. Potassium (1.29 g, 9.35 mmol) and 60 ml of dioxane were refluxed in an oil bath at 100 ° C for 12 h. Filtration, concentration, addition of 50 ml of water, extraction with 3X 40 ml of ethanol, washing with 30 ml of water, concentration and column chromatography to give 1.0 g of the title product. Used directly in the next step.

Step d: N-(2-((2-(Dimethylamino)ethyl)(methyl)amino-4-methoxy-5-((4(1,1a,2,8b-tetrahydrocyclo)) Synthesis of propyl[3,4]pyrrolo[1,2-a]indole-8-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

1,1a,2,8b-tetrahydrocyclopropyl[3,4]pyrrolo[1,4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloropyrimidine, step c The title compound was obtained according to the procedure of Example 1 using 2-, a, N, N, N'-trimethylethylenediamine and allyl chloride as starting materials.

^{1 H-NMR (300MHz, DMSO} -d 6) δ: 10.03 (s, 1H), 8.70 (s, 1H), 8.32-8.33 (d, 1H), 8.24-8.26 (d, 1H), 8.01 (s, 1H), 7.21-7.28 (m, 2H), 7.10-7.13 (m, 1H), 7.03-7.06 (m, 2H), 6.41-6.47 (m, 1H), 6.20-6.23 (d, 1H), 5.74 5.76 (d, 1H), 4.19-4.28 (m, 2H), 3.86 (s, 3H), 2.97 (s, 2H), 2.95 (s, 2H), 2.74 (s, 3H), 2.29-2.5 (m, 8H), 1.44-1.45 (m, 1H), 0.70-0.71 (m, 1H).

ESI-Ms m/z: 537.9 [M+H]

Example 13 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(6-oxo-6,7, Synthesis of 8,9-tetrahydropyrido[1,2-a]indole-10-yl)-pyrimidin-2-yl)amino)phenyl)allylamide

ESI-Ms m/z: 554.4 [M+H]

Example 14 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(6-fluoro-6,7,8) Synthesis of 9-tetrahydropyrido[1,2-a]indol-10-yl)-pyrimidin-2-yl)amino)phenyl)allylamide

ESI-Ms m/z: 558.3 [M+H]

Example 15 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(9-fluoro-6,7,8) Synthesis of 9-tetrahydropyrido[1,2-a]indol-10-yl)-pyrimidin-2-yl)amino)phenyl)allylamide

ESI-Ms m/z: 558.5 [M+H]

Example 16 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(9,9-difluoro-6, Synthesis of 7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)-pyrimidin-2-yl)amino)phenyl)allylamide

ESI-Ms m/z: 575.3 [M+H]

Example 17 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1,2-dihydronitrogen) Synthesis of butadieno[1,2-a]indol-8-yl)-pyrimidin-2-yl)amino)phenyl)allylamide

ESI-Ms m/z: 511.6 [M+H]

Example 18 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-fluoro-2,3-di) Synthesis of Hydrogen-1H-pyrrolo[1,2-a]-indol-9-yl)pyrimidin-2-yl)amino)phenyl)propanamide

ESI-Ms m/z: 543.8 [M+H]

Example 19 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(2-oxo-1,2-) Synthesis of dihydroazetidino[1,2-a]indol-8-yl)-pyrimidin-2-yl)amino)phenyl)allylamide

ESI-Ms m/z: 525.4 [M+H]

Example 20 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1,1-dioxo-3) Synthesis of 4-dihydro-2H-[1,2]thiazine[2,3-a]indol-5-yl)pyrimidin-2-yl)amino)phenyl)propanamide

ESI-Ms m/z: 590.4 [M+H]

Example 21 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(2,3-dimethyl-1) Synthesis of 2,3,4-tetrahydropyrazine[1,2-a]indol-10-ylpyrimidin-2-yl)amino)phenyl)allylamide

ESI-Ms m/z: 569.5 [M+H]

Example 22 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-oxo-1,2, Synthesis of 3,4-tetrahydropyrazine[1,2-a]indol-10-ylpyrimidin-2-yl)amino)phenyl)allylamide

ESI-Ms m/z: 555.7 [M+H]

Example 23 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(2-methyl-1,2, Synthesis of 3,4-tetrahydropyrazine[1,2-a]indol-10-ylpyrimidin-2-yl)amino)phenyl)allylamide

ESI-Ms m/z: 554.8 [M+H]

Experimental Example 1 Evaluation of in vitro kinase activity

1 experimental material

1.1 enzyme

EGFR ^WT kinase, purchased from Carna Corporation;

EGFR ^T790M/L858R kinase was purchased from Invitrogen.

1.2 reagent

Adenosine triphosphate (ATP), purchased from Sigma;

Peptide (Peptide FAM-P22), purchased from GL Biochem;

Ethylenediaminetetraacetic acid (EDTA) was purchased from Sigma.

1.3 instruments

Caliper EZ reader microfluidic chip instrument, purchased from Caliper Life Sciences, Inc.

2 experimental methods

2.1 Preparation of 1× Kinase Base Buffer and Stop Buffer

1×kinase base buffer (for EGFR ^WT ): 50 mM HEPES, pH 7.5, 0.0015% Brij-35, 10 mM MgCl ₂ , 10 mM MnCl ₂ , 2 mM DTT;

1×kinase base buffer (for EGFR ^T790M/L858R ): 50 mM HEPES, pH 7.5, 0.0015% Brij-35, 10 mM MgCl ₂ , 2 mM DTT;

Stop buffer: 100 mM HEPES, pH 7.5, 0.0015% Brij-35, 0.2% Coating Reagent #3, 50 mM EDTA.

2.2 Preparation of compounds

The compounds of the present invention were separately dissolved in 10 mM with 100% DMSO, diluted to 50 μM with complete medium, and then diluted to 5 μM with complete medium containing 0.1% DMSO, followed by 3-fold dilution for a total of 10 concentrations (for EGFR ^WT );

The compound of the present invention was separately dissolved to 10 mM with 100% DMSO, diluted to 50 μM with complete medium, and then diluted to 1 μM with complete medium containing 0.1% DMSO, and then diluted 3 times in total for 10 concentrations (for EGFR ^T790M/L858R );

100 μl of 100% DMSO was added to the empty wells for the preparation of a kinase-free compound control group and a non-kinase-free compound control group;

The 96-well plate used above was labeled as the source plate.

2.3 Preparing the middle board

10 μl of the solution was transferred from the source plate into a new 96-well plate as an intermediate plate, and 90 μl of 1×kinase buffer was added to each well of the intermediate plate, and vortexed and mixed for 10 minutes.

2.4 Preparing the experiment board

From the 96-well intermediate plate, transfer 5 μl of solution to each well into a 384-well plate.

2.5 kinase reaction

2.5.1. Preparation of 2.5×kinase solution: EGFR ^WT kinase and EGFR ^T790M/L858R kinase stock solution were separately added to 1×basal buffer to prepare 2.5×kinase solution;

2.5.2. Preparing a 2.5× peptide solution: adding FAM-labeled peptide and ATP to 1× base buffer to prepare a 2.5× peptide solution;

2.5.3. Transfer 10 μl of 2.5× kinase solution to a 384-well assay plate and incubate for 10 min at room temperature;

2.5.4. Transfer 10 μl of 2.5× peptide solution to a 384-well assay plate, incubate at 28 ° C for a period of time, and add 25 μl of stop buffer to stop the reaction.

A non-kinase-free compound control group (containing DMSO, 1×basal buffer and 2.5× peptide solution, and a kinase-free compound control group (including DMSO, 2.5×kinase solution, and 2.5×peptide solution) was also provided.

2.5.5. Caliper instrument readings, fitting curves, calculation of inhibition rate

Read the data on the Caliper instrument and obtain the conversion data from the Caliper program and calculate the inhibition rate according to the following formula:

Inhibition rate %=(max-com)/(max-min)×100 Calculate the inhibition rate, where “max” represents a kinase-free compound control group, “com” represents a test compound group, and “min” represents a kinase-free compound. Control group.

2.5.6. Calculate IC ₅₀ values using Graphpad 5.0 data processing software. The results are shown in Table 1.

Table 1

From the experimental results, the compound of the present invention has a good inhibitory activity against a mutant EGFR kinase such as EGFR ^L858R/T790M kinase, and has an IC ₅₀ value of less than 1 nM, and has a small effect on wild-type EGFR kinase and has good selectivity.

Experimental Example 2 Evaluation of in vitro cell viability

2. Experimental materials

1.1 cells and positive control drugs

The experimental cell line NCI-H1975 (EGFR double mutant cells with L858R and T790M mutations) and A431 (EGFR wild type cells) were purchased from ATCC.

The commercially available highly potent and selective, irreversible EGFR mutant inhibitor AZD9291 produced by AstraZeneca was used as a positive control. For the synthesis method, see PCT/GB2012/051783 (Patent No. WO 2013/014448), in the specification example 28, and passed hydrogen. Spectral and mass spectrometric confirmation.

1.2 reagent

Cell Titer-Glo luminescent cell viability assay, purchased from Promega;

RPMI1640 medium, purchased from Invitrogen;

DMEM medium, purchased from Invitrogen;

Fetal bovine serum, purchased from Invitrogen;

DMSO, purchased from Sigma;

NCI-H1975 cells were cultured in RPMI1640 medium containing 10% inactivated fetal bovine serum (GIBCO), containing penicillin 100 IU/mL and streptomycin 100 μg/mL;

A431 cells were cultured in DMEM medium containing 10% inactivated fetal bovine serum (GIBCO) containing penicillin 100 IU/mL and streptomycin 100 μg/mL.

2 experimental methods

2.1 Experimental procedure (CTG assay)

After digesting NCI-H1975 cells and A431 cells in logarithmic growth phase, they were blown into single cell suspensions, seeded in 96-well culture plates, 100 μL per well medium, and each cell line was composed of 3 96-well plates. NCI-H1975 cells were seeded with ³ ×10 ³ cells per well, and A431 cells were seeded with ⁴ ×10 ³ cells per well. The inoculated NCI-H1975 cells and A431 cells were cultured in a 5% CO ₂ incubator for 16-24 hours. After the cells were attached, the test compound was added at the following concentration (the highest test of the compound on NCI-H1975 cells). The concentration was 4 μM, 3 fold dilution, a total of 9 concentrations; the highest test concentration on A431 cells was 10 μM, 3 fold dilution, a total of 9 concentrations), and cultured for an additional 72 hours in an incubator. At the same time, a blank control group (only medium, no cell and DMSO solution) and a DMSO control group (cells and 0.5% DMSO solution were added to the medium). Add 100 μL of CTG solution, shake it for 2 min in the dark, and incubate for 10 min.

2.2 readings, calculate IC ₅₀ values

多模式微孔板检测仪读板，记录luminescence读值结果，并按照以下公式计算抑制率：Put the plate in

The multi-mode microplate reader reads the plate, records the luminescence reading results, and calculates the inhibition rate according to the following formula:

Inhibitor (%) = (1-(RLU _{com -} RLU _blank ) / (RLU _{DMSO -} RLU _blank )) × 100%,

Where RLU _com represents the absorbance of the test compound group, RLU _blank represents the absorbance of the blank control group, and RLU _DMSO represents the absorbance of the DMSO control group.

The XEFFit curve fitting software was used to plot the pharmacodynamic inhibition rate curve and calculate the IC ₅₀ value. The results are shown in Table 2.

Table 2

The results of in vitro cell experiments showed that the compounds of the present invention have a better inhibitory effect on double mutant cells (NCI-H1975), and have less inhibition on EGFR wild type cells (A431), and the selectivity is similar to or significantly superior to AZD9291. One of the major side effects of currently marketed EGFR inhibitors is rash, diarrhea, etc., which are associated with inhibition of wild-type EGFR and poor selectivity. Therefore, the compound of the present invention is expected to be a drug having a specific therapeutic effect against a tumor resistant to EGFR mutation and having a small side effect.

Experimental Example 3 Blood Sugar Impact Test

1 experimental material

1.1 compound

The compound of the present invention was dissolved in 25 mM sodium citrate-sodium citrate buffer (pH 4.5) to prepare a clear solution having a concentration of 1.25 mg/mL, and was set as a test compound group; 25 mM citric acid was used. - sodium citrate buffer (pH 4.5) was set as a vehicle control group;

1.2 animals

Female BALB/C mice, 5 in each group, weighing 18-22 g, were provided by Shanghai Xipuer-Beikai Experimental Animal Co., Ltd. The test mice were given an environmental adaptation period of 2 to 4 days before the experiment, and fasted for 8-12 hours before administration.

2 experimental methods

2.1 mice fasted but free to drink water for 12 hours;

2.2 taking 5 mice in step 2.1, intragastric administration (I.G.) administration of the compound of the invention 25mg / kg;

2.3 Blood was collected from the eyelids at 0 min, 15 min, 30 min, 1 h, 2 h after gavage, and the blood glucose level A of the animals was measured using a Roche superior blood glucose meter according to the formula AUC=[(A _15min +A ₀ )×7.5]+[(A _30min + A _15min )×7.5]+[(A _60min +A _30min )×15]+[(A _120min +A _60min )×30] Calculate the AUC value and increase %=[(AUC _compound- AUC _solvent ) according to the formula AUC/ AUC _solvent ] × 100% calculated the AUC growth rate, where “A ₀ ” represents the blood glucose level at 0 min after gavage, “A _{15 min} ” represents the blood glucose level after 15 min, and “A _{30 min} ” represents the blood glucose after 30 min. Value, "A _60min " represents the blood glucose level after _{60 minutes} of gavage, "A _120min " represents the blood glucose level after _{120 minutes} of gavage, "AUC _compound " represents the AUC value of the test compound, and "AUC _solvent " represents the AUC of the vehicle control group. Value, the results are shown in Table 3.

table 3

It is known that EGFR inhibitors may cause side effects such as hyperglycemia and impaired insulin signaling. According to the experimental report, AZD9291 and Clociletinib (CO1686) of Clovis Oncology have a certain degree of side effects on blood glucose (Management of hyperglycemia from epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) targeting T790M-mediated resistance, Jeryl Villadolid , et al. Translational Lung Cancer Research (2015), 4(5), 576-583). The above experimental results of the present invention indicate that the compound of the present invention It has little effect on blood sugar and is expected to overcome the high blood sugar side effects of existing EGFR inhibitors, thereby helping to reduce adverse reactions and improve patient compliance.

Experimental Example 4 Drug Metabolism Experiment

1 experimental material

1.1 compound

The compounds of the invention are formulated into either oral and injectable formulations. Among them, the oral drug formulation was dissolved in 25 mM sodium citrate-sodium citrate buffer (pH 4.5) to prepare a 1.25 mg/mL clear solution; the tail vein injection drug formulation was citrate-sodium citrate buffer solution. A mixed solution of (pH 4.5) and physiological saline volume ratio of 1:1 was prepared into a 0.2 mg/mL solution.

1.2 animals

Female BALB/C mice, 5 in each group, weighing 18-22 g, were provided by Shanghai Xipuer-Beikai Experimental Animal Co., Ltd. The test mice were given an environmental adaptation period of 2 to 4 days before the experiment, and were fasted for 8-12 hours before administration, and given water for 2 hours after administration, and fed after 4 hours.

1.3 reagent

Methanol (chromatographically pure): produced by Spectrum;

Acetonitrile (chromatographically pure): produced by Spectrum;

The remaining reagents were all commercially available analytical grades.

1.4 Instrument

American AB company API 4500 triple quadrupole liquid-mass instrument with electrospray ion source (ESI), LC-30AD double pump; SIL-30AC autosampler; CTO-30AC column thermostat; DGU-20A3R Degasser; Analyst QS A01.01 chromatography workstation; Milli-Q ultrapure water (Millipore Inc); Qilinbeier Vortex-5 oscillator; HITACHI CF16RXII desktop high speed refrigerated centrifuge.

2 experimental methods

2.1 mice fasted but can drink water for 12 hours, take 0 time blank plasma;

2.2 taking 5 mice in step 2.1, intragastric administration (I.G.) administration of the compound of the invention 25mg / kg;

5 mice in step 2.1, the intravenous vein (Intravenous administration, I.V.) administered the compound of the invention 2mg / kg;

2.3 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 10 h, 24 h after intragastric administration, blood was continuously taken from the fundus venous plexus in an EP tube with heparin distributed, and centrifuged at 8000 rpm/min for 5 min to obtain upper plasma, -20 Cryopreservation at °C until LC-MS/MS analysis;

5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 10 h, 24 h after tail vein injection, continuous blood was taken from the fundus venous plexus in an EP tube with heparin distributed, and the supernatant plasma was taken after centrifugation at 8000 rpm/min for 5 min. Cryopreservation at -20 ° C until LC-MS/MS analysis;

2.4 According to the plasma concentration-time data obtained in step 2.3, the pharmacokinetic parameters were calculated using WinNonlin software, as shown in Table 4.

Table 4

The compounds of the invention have good pharmacokinetic data and should have good clinical application prospects.

While the invention has been described hereinabove, it will be understood by those skilled in the art that various modifications and changes of the invention may be made without departing from the spirit and scope of the invention. The scope of the invention is not limited to the details described above, but rather to the claims.

Claims (10)

a compound of formula I or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,

among them: Ring A is a C ₄ -C ₈ nitrogen-containing heterocyclic group optionally substituted by one or more halogen, oxo, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano , hydroxy, amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, alkyl acyl, amino acyl, a monoalkylaminoacyl group, a dialkylaminoacyl group, an aryl group, a heteroaryl group, and a heterocycloalkyl group. When two or more substituents are present, two adjacent substituents may be substituted together with the atoms to which they are attached. Or an unsubstituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl group, or two substituents attached to the same atom may form a substituted or unsubstituted cycloalkyl group with the atoms to which they are attached. Cycloalkyl; X ₁ , X ₂ , X ₃ and X ₄ are each independently selected from C(R ₁ ) and N; R ₁ , R _2a , R _2b , R _3a , R _3b and R _3c are each independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, Hydroxy, amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, alkyl acyl, amino acyl, single An alkylamino acyl group and a dialkylamino acyl group; R ₄ , R ₅ and R ₆ are each independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, alkoxy and cycloalkyl, said alkyl, alkoxy and cycloalkyl optionally being one or more Halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, monoalkylamino, dialkylamino, hydroxy, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or hydroxy Alkyl substitution R _{7 is} selected from the group consisting of hydrogen, alkyl, cycloalkyl and haloalkyl; R _{8 is} selected from the group consisting of hydrogen, alkyl and cycloalkyl, optionally substituted by one or more halogen, alkyl, haloalkyl, alkoxy, amino, monoalkylamino, dioxane Substituted by a base or a hydroxy group; or R ₇ , R ₈ and the N atom to which they are attached together form a nitrogen-containing heterocycloalkyl group, which is optionally substituted by one or more halogen, alkyl, haloalkyl, alkoxy, amino, Monoalkylamino, dialkylamino, hydroxy, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or hydroxyalkyl substituted. A compound according to claim 1 or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein: Ring A is a C ₄ -C ₈ nitrogen-containing heteromonocycloalkyl group containing only one nitrogen atom, optionally substituted by one or more halogen, oxo, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkyl Oxy, nitro, cyano, hydroxy, amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl , alkyl acyl, amino acyl, monoalkylamino acyl, dialkylamino acyl, aryl, heteroaryl and heterocycloalkyl substituted, when there are two or more substituents, two adjacent substituents may Together with the atoms to which they are attached, a substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl group, or two substituents attached to the same atom may form a substitution with the atoms to which they are attached or Unsubstituted cycloalkyl or heterocycloalkyl; Preferably, Ring A is

n is selected from 1, 2, 3, 4, 5 and 6, m is selected from 1, 2, 3 and 4, and R _{a is} selected from the group consisting of hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, halogen C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, nitro, cyano, hydroxy, amino, mono C _1-6 alkylamino, di C _1-6 alkyl Amino group, amino C _1-6 alkyl group, mono C _1-6 alkylamino C _1-6 alkyl group, di C _1-6 alkylamino C _1-6 alkyl group, hydroxy C _1-6 alkyl group, C _{1 -6} alkoxy C _1-6 alkyl, C _1-6 alkyl acyl, amino acyl, mono C _1-6 alkylamino acyl, di C _1-6 alkylamino acyl, C _6-10 aryl, C _5-10 heteroaryl and C _3-8 heterocycloalkyl, when m is selected from 2, 3 and 4, two R _a on two adjacent carbon atoms may be combined with the carbon atom to which they are attached C _3-8 cycloalkyl or C _3-8 heterocycloalkyl, or two R _a on the same carbon atom may together with the carbon atom to which they are attached form a C _3-8 cycloalkyl group or C _3-8 Heterocycloalkyl. A compound according to claim 1 or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein: Ring A is a C ₄ -C ₈ nitrogen-containing heteromonocycloalkyl group containing two nitrogen atoms, optionally substituted by one or more halogen, oxo, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkyl Oxy, nitro, cyano, hydroxy, amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl , alkyl acyl, amino acyl, monoalkylamino acyl, dialkylamino acyl, aryl, heteroaryl and heterocycloalkyl substituted, when there are two or more substituents, two adjacent substituents may Together with the atoms to which they are attached, a substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl group, or two substituents attached to the same atom may form a substitution with the atoms to which they are attached or Unsubstituted cycloalkyl or heterocycloalkyl; Preferably, Ring A is

m is selected from 1, 2, 3 and 4, p is selected from 0, 1 and 2, q is selected from 0, 1 and 2, and R _{a is} selected from the group consisting of hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, Halogen C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, nitro, cyano, hydroxy, amino, mono C _1-6 alkylamino, di C _{1- 6} alkylamino group, amino C _1-6 alkyl group, mono C _1-6 alkylamino C _1-6 alkyl group, di C _1-6 alkylamino C _1-6 alkyl group, hydroxy C _1-6 alkyl group , C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkyl acyl, amino acyl, mono C _1-6 alkylamino acyl, di C _1-6 alkylamino acyl, C _6-10 An aryl group, a C _5-10 heteroaryl group and a C _3-8 heterocycloalkyl group, when m is selected from 2, 3 and 4, two R _a on two adjacent atoms may be together with the atom to which they are attached The C _3-8 cycloalkyl or C _3-8 heterocycloalkyl group, or two R _a on the same atom may form a C _3-8 cycloalkyl group or a C _3-8 heteroatom together with the atoms to which they are attached. Cycloalkyl. A compound according to claim 1 or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein: Ring A is a C ₄ -C ₈ nitrogen-containing heteromonocycloalkyl group containing one nitrogen atom and one oxygen atom, optionally substituted by one or more halogen, oxo, alkyl, cycloalkyl, haloalkyl, alkoxy , haloalkoxy, nitro, cyano, hydroxy, amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxy Alkyla, alkyl acyl, amino acyl, monoalkylamino acyl, dialkylamino acyl, aryl, heteroaryl and heterocycloalkyl substituted, when there are two or more substituents, two adjacent The substituents may, together with the atoms to which they are attached, form a substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl group, or an atom to which the two substituents attached to the same atom may be attached. Forming a substituted or unsubstituted cycloalkyl or heterocycloalkyl group; Preferably, Ring A is

m is selected from 1, 2, 3 and 4, p is selected from 0, 1 and 2, q is selected from 0, 1 and 2, and R _{a is} selected from the group consisting of hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, halo-C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, nitro, cyano, hydroxy, amino, mono-C _1-6 alkylamino, di C _{1- 6} alkylamino group, amino C _1-6 alkyl group, mono C _1-6 alkylamino C _1-6 alkyl group, di C _1-6 alkylamino C _1-6 alkyl group, hydroxy C _1-6 alkyl group , C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkyl acyl, amino acyl, mono C _1-6 alkylamino acyl, di C _1-6 alkylamino acyl, C _6-10 An aryl group, a C _5-10 heteroaryl group and a C _3-8 heterocycloalkyl group, when m is selected from 2, 3 and 4, two R _a on two adjacent atoms may be together with the atom to which they are attached C _3-8 cycloalkyl or C _3-8 heterocycloalkyl, or two R _a on the same atom may together with the atoms to which they are attached form a C _3-8 cycloalkyl or C _3-8 hetero Cycloalkyl. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein: X ₁ , X ₂ , X ₃ and X ₄ are each independently selected from C(R ₁ ) and N; R ₁ , R _1a , R _1b , R _2a , R _2b , R _3a , R _3b and R _3c are each independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, halo C _1-6 alkyl, C _{1 -6} alkoxy, halo C _1-6 alkoxy, nitro, cyano, hydroxy, amino, mono C _1-6 alkylamino, di C _1-6 alkylamino, amino C _1-6 alkane , mono C _1-6 alkylamino C _1-6 alkyl, di C _1-6 alkylamino C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy C _{1- a 6} alkyl group, a C _1-6 alkyl acyl group, an amino acyl group, a mono C _1-6 alkylamino acyl group, and a di C _1-6 alkylamino acyl group; R ₇ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkyl and halo; Preferably, R _a is selected from hydrogen, methyl, ethyl, propyl, isopropyl, , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and trifluoromethyl; R _{8 is} selected from the group consisting of hydrogen, C _1-6 alkyl and C _3-6 cycloalkyl, said C _1-6 alkyl and C _3-6 cycloalkyl optionally being one or more halogens, C _{1- 6} alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, amino, mono C _1-6 alkylamino, di C _1-6 alkylamino or hydroxy substituted; preferably, R _{b is} selected From hydrogen, C _1-3 alkyl and C _3-6 cycloalkyl, said C _1-3 alkyl and C _3-6 cycloalkyl are optionally substituted by one or more halogen, methyl, ethyl, Propyl, isopropyl, trifluoromethyl, difluoromethyl, trifluoroethyl, methoxy, ethoxy, propoxy, isopropyloxy, amino, methylamino, ethylamino, propylamino , dimethylamino, diethylamino, dipropylamino, methylethylamino, methylpropylamino, ethylpropylamino or hydroxy substituted; R ₄ , R ₅ and R ₆ are each independently selected from the group consisting of hydrogen, halogen, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, said C _1-6 Alkyl, C _1-6 alkoxy and cycloalkyl are optionally substituted by one or more halogen, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, amino, mono C _1-6 alkylamino, di C _1-6 alkylamino, hydroxy, amino C _1-6 alkyl, mono C _1-6 alkylamino C _1-6 alkane Substituted, di-C _1-6 alkylamino C _1-6 alkyl and hydroxy C _1-6 alkyl. A compound according to claim 1 or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, which is the following compound:

A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier. Use of a compound according to any one of claims 1 to 6 or a composition according to claim 7 for the preparation of a medicament for the treatment and/or prevention of a tumor, preferably the tumor is a drug-resistant tumor, more preferably The tumor is a tumor resistant to an EGFR inhibitor. a compound of formula II or a pharmaceutically acceptable salt thereof,

Wherein Rings A, X ₁ , X ₂ , X ₃ , X ₄ , R _2a , R _2b , R _3a , R _3b , R _3c , R ₇ and R ₈ have the definitions in claims 1-5. a compound of formula III or a pharmaceutically acceptable salt thereof,

Wherein Rings A, X ₁ , X ₂ , X ₃ , X ₄ , R _2a , R _2b have the definitions in claims 1-5, and M is a halogen.