TW202237581A - Compound as for kinase inhibitor and application thereof - Google Patents

Abstract

The present invention relates to a compound used as a kinase inhibitor and application thereof, belonging to the pharmaceutical technical field. The compound used as a kinase inhibitor is a compound represented by formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof. The compound has a good inhibitory activity against insertion mutation of EGFR and Her2 exon 20, deletion mutation of EGFR exon 19, and L858R point mutation of exon 21, and has a great potential to be developed into a drug for treating related diseases.

Description

Compounds as kinase inhibitors and uses thereof

The invention relates to a compound used as a kinase inhibitor and its use, belonging to the technical field of medicines.

The epidermal growth factor receptor belongs to the receptor tyrosine kinase (RTK) family, which includes EGFR/ERBB1, HER2/ERBB2/NEU, HER3/ERBB3, and HER4/ERBB4. EGFR initiates its tyrosine kinase activity through homodimerization or heterodimerization, and then phosphorylates its substrate, thereby initiating multiple downstream pathways related to it in cells, such as those involved in cell survival. PI3K-AKT-mTOR pathway and RAS-RAF-MEK-ERK pathway involved in cell proliferation, etc. The mutation or amplification of EGFR will lead to the activation of EGFR kinase, which will lead to the occurrence of various human diseases, such as malignant tumors. For example, in patients with non-small cell lung cancer, more than 10% of American patients have EGFR mutations, while the proportion of EGFR mutations in Asian patients can reach nearly 50%. At the same time, in patients with non-small cell lung cancer, the incidence of Her2 mutation is about 2-4%.

EGFR mutations mainly include deletions, insertions, and point mutations, among which exon 19 deletions and exon 21 L858R point mutations account for nearly 90% of EGFR mutations. For tumor patients with these EGFR mutations, the currently marketed EGFR-TKIs include first-generation Iressa, Tarceva, and Conmana, second-generation afatinib and dacomitinib, and third-generation osimertinib . The other 10% of EGFR mutations mainly involve exon 18 and 20 of EGFR, and the insertion mutation of EGFR exon 20 accounts for about 9% of the entire EGFR mutation. In tumor patients with Her2 mutations, the most common Her2 mutation is an insertion mutation in exon 20 of Her2. For exon 20 insertion mutations of EGFR and Her2, there are currently no drugs on the market.

It was recently reported that TAK-788 has certain activity against clinical EGFR exon 20 insertion mutations. According to the reported clinical trial results, the clinical response rate is only about 40%, and the curative effect is not satisfactory. This compound is currently in clinical research.

In order to meet the clinical needs of patients with EGFR and Her2 mutations, especially patients with EGFR and Her2 exon 20 insertion mutations, the present invention has developed a series of drugs with excellent EGFR and Her2 exon 20 insertion mutation activity and EGFR exon Compounds with 19 deletions and exon 21 L858R point mutations have great potential to be developed into drugs for treating related diseases.

The first object of the present invention is to provide a compound used as a kinase inhibitor, which has good inhibitory activity on EGFR, Her2 exon 20 insertion mutation, EGFR exon 19 deletion and exon 21 L858R point mutation .

The second object of the present invention is to provide the use of the above compounds in the preparation of medicines for treating related diseases caused by EGFR mutation and/or Her2 mutation.

In order to solve the above problems, the technical scheme adopted by the compound used as a kinase inhibitor of the present invention is:

式Ⅰ中，A選自：

或

； 其中，Z ₅、Z ₆、Z ₇、Z ₈、Z ₉、Z ₁₁和Z ₁₂各自獨立地選自N和CR ₄；Z ₁₀選自

、

、

、

、

、

、

、

；R ₈選自H、胺基、酯基、C _1-6的烷基、C _1-6的氘代烷基、C _1-6的烷氧基、C _1-6的氘代烷氧基、C _3-6的環烷基、C _3-6的環烷氧基、C _6-10的芳基、5-10元的雜芳基，或者為被1~3個R取代的胺基、酯基、C _1-6的烷基、C _1-6的烷氧基、C _3-6的環烷基、C _3-6的環烷氧基、C _6-10的芳基、5-10元的雜芳基；所述5-10元的雜芳基中含有至少1個雜原子，所述雜原子選自N、O、S或P； m為0、1、2或3；C選自4～7元的環； Z ₁、Z ₂各自獨立地選自N或者CR ₄； L選自單鍵、

、

、

、

、

、

、

、

或者

； B選自C _6-10的芳基、5-10元的雜芳基、被1~3個取代基取代的C _6-10的芳基、被1~3個取代基取代的5-10元的雜芳基；所述取代基各自獨立地選自H、鹵素、氰基、胺基、酯基、脲基、胺基甲酸酯基、醯胺基、C _1-6的烷基、C _1-6的烷氧基、C _3-6的環烷基、C _3-6的環烷氧基、C _1-6的烷胺基、C _3-12的環烷胺基、C _1-6的鹵代烷基、C _1-6的鹵代烷氧基、C _3-6的鹵代環烷基、C _3-6的鹵代環烷氧基、C _1-6的鹵代烷胺基、C _3-12的鹵代環烷胺基、C _6-10的芳基、5-10元的雜芳基，或者為被1~3個R取代的胺基、酯基、脲基、胺基甲酸酯基、醯胺基、C _1-6的烷基、C _1-6的烷氧基、C _3-6的環烷基、C _3-6的環烷氧基、C _1-6的烷胺基、C _3-12的環烷胺基、C _1-6的鹵代烷基、C _1-6的鹵代烷氧基、C _3-6的鹵代環烷基、C _3-6的鹵代環烷氧基、C _1-6的鹵代烷胺基、C _3-12的鹵代環烷胺基、C _6-10的芳基、5-10元的雜芳基； 所述R各自獨立地選自鹵素、氰基、胺基、羥基、酯基、脲基、胺基甲酸酯基、醯胺基、C _1-6的烷基、C _1-6的烷氧基、C _3-6的環烷基、C _3-6的環烷氧基、C _1-12的烷胺基、C _6-10的芳基、5-10元的雜芳基、

、

、

、

、

、

或

；其中，Y ₁、Y ₂、Y ₃、Y ₄、Y ₅各自獨立地選自氫、鹵素、C _1-12的烷基、C _3-12的環烷基、C _1-12的烷胺基，R _Y選自C _1-12的烷基、C _3-12的環烷基、C _1-12的烷基中的一個或多個碳原子被N、O、S中的一個或多個雜原子替換形成的基團、C _3-12的環烷基中的一個或多個碳原子被N、O、S中的一個或多個雜原子替換形成的基團； R ₄、R ₆、R ₇、R ₉和R ₁₀各自獨立地選自H、鹵素、氰基、胺基、酯基、碸基、脲基、胺基甲酸酯基、醯胺基、磷氧基、C _1-6的烷基、C _1-6的氘代烷基、C _1-6的烷氧基、C _3-6的環烷基、C _3-6的環烷氧基、C _6-10的芳基、5-10元的雜芳基、5-10元脂肪雜環基，或者為被1~3個所述R取代的胺基、酯基、碸基、脲基、胺基甲酸酯基、醯胺基、C _1-6的烷基、C _1-6的烷氧基、C _3-6的環烷基、C _3-6的環烷氧基、C _6-10的芳基、5-10元的雜芳基、5-10元脂肪雜環基； R ₅選自H、C _1-6的烷基、C _1-6的烷氧基、C _3-6的環烷基、C _3-6的環烷氧基、C _6-10的芳基、5-10元的雜芳基； 其中，當Z ₁、Z ₂均選自CH、A選自

、B選自被1~3個取代基取代的C _6-10的芳基、被1~3個取代基取代的5-10元的雜芳基時，B上所述1~3個取代基中的至少1個為

。 A compound used as a kinase inhibitor, which is a compound represented by formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof:

In formula I, A is selected from:

or

; Wherein, Z ₅ , Z ₆ , Z ₇ , Z ₈ , Z ₉ , Z ₁₁ and Z ₁₂ are each independently selected from N and CR ₄ ; Z ₁₀ is selected from

,

,

,

,

,

,

,

; R _is selected from H, amino, ester, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy , C _3-6 cycloalkyl, C _3-6 cycloalkoxy, C _6-10 aryl, 5-10 membered heteroaryl, or an amino group substituted by 1 to 3 R, Ester group, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, C _6-10 aryl, 5-10 A membered heteroaryl group; the 5-10 membered heteroaryl group contains at least 1 heteroatom, and the heteroatom is selected from N, O, S or P; m is 0, 1, 2 or 3; C is selected from From 4 to 7 membered rings; Z ₁ and Z ₂ are each independently selected from N or CR ₄ ; L is selected from single bonds,

,

,

,

,

,

,

,

or

; B is selected from the aryl group of C _6-10 , the heteroaryl group of 5-10 yuan, the aryl group of C _6-10 substituted by 1~3 substituents, the 5-10 substituted by 1~3 substituents Elementary heteroaryl; each of the substituents is independently selected from H, halogen, cyano, amino, ester, ureido, carbamate, amido, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, C _1-6 alkylamino, C _3-12 cycloalkylamino, C _{1- 6} haloalkyl, C _1-6 haloalkoxy, C _3-6 halocycloalkyl, C _3-6 halocycloalkoxy, C _1-6 haloalkylamino, C _3-12 Halogenated cycloalkylamino, C _6-10 aryl, 5-10 membered heteroaryl, or amine, ester, urea, carbamate substituted by 1~3 R , amido, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, C _1-6 alkylamino, C _3-12 cycloalkylamino, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 halocycloalkyl, C _3-6 halocycloalkoxy, C _1-6 haloalkylamino, C _3-12 halocycloalkylamino, C _6-10 aryl, 5-10 membered heteroaryl; each of the Rs is independently selected from halogen, cyano , amino group, hydroxyl group, ester group, urea group, urethane group, amido group, C _1-6 alkyl group, C _1-6 alkoxy group, C _3-6 cycloalkyl group, C _3-6 cycloalkoxy, C _1-12 alkylamino, C _6-10 aryl, 5-10 membered heteroaryl,

,

,

,

,

,

or

; Wherein, Y ₁ , Y ₂ , Y ₃ , Y ₄ , Y ₅ are each independently selected from hydrogen, halogen, C _1-12 alkyl, C _3-12 cycloalkyl, C _1-12 alkylamine One or more carbon atoms selected from C _1-12 alkyl, C _3-12 cycloalkyl, C _1-12 alkyl are replaced by one or more of N, O, _S A group formed by heteroatom replacement, a group formed by replacing one or more carbon atoms in a C _3-12 cycloalkyl group with one or more heteroatoms in N, O, and S; R ₄ , R ₆ , R ₇ , R ₉ and R ₁₀ are each independently selected from H, halogen, cyano, amine, ester, pyl, ureido, carbamate, amido, phosphorus oxy, C _{1- 6} alkyl, C _1-6 deuterated alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, C _6-10 aryl , a 5-10 membered heteroaryl group, a 5-10 membered aliphatic heterocyclic group, or an amine group, ester group, pylori group, urea group, carbamate group, Amino group, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, C _6-10 aryl, 5- 10-membered heteroaryl, 5-10 membered aliphatic heterocyclic group; R ₅ is selected from H, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _{3 -6} cycloalkoxy group, C _6-10 aryl group, 5-10 membered heteroaryl group; wherein, when Z ₁ and Z ₂ are both selected from CH, A is selected from

When B is selected from a _C6-10 aryl group substituted by 1 to 3 substituents, and a 5-10 membered heteroaryl group substituted by 1 to 3 substituents, the 1 to 3 substituents mentioned above on B At least 1 of the

.

The compounds used as kinase inhibitors provided by the present invention have good inhibitory activity on EGFR and Her2 exon 20 insertion mutations, EGFR exon 19 deletions and exon 21 L858R point mutations, and have great potential to be developed into therapeutic Drugs for related diseases.

式中，Z ₃、Z ₄各自獨立地選自N、CR ₄； R ₁、R ₂各自獨立地選自H、鹵素、氰基、胺基、酯基、脲基、胺基甲酸酯基、醯胺基、C _1-6的烷基、C _1-6的烷氧基、C _3-6的環烷基、C _3-6的環烷氧基、C _1-6的烷胺基、C _3-12的環烷胺基、C _1-6的鹵代烷基、C _1-6的鹵代烷氧基、C _3-6的鹵代環烷基、C _3-6的鹵代環烷氧基、C _1-6的鹵代烷胺基、C _3-12的鹵代環烷胺基、C _6-10的芳基、5-10元的雜芳基，或者為被1~3個所述R取代的胺基、酯基、脲基、胺基甲酸酯基、醯胺基、C _1-6的烷基、C _1-6的烷氧基、C _3-6的環烷基、C _3-6的環烷氧基、C _1-6的烷胺基、C _3-12的環烷胺基、C _1-6的鹵代烷基、C _1-6的鹵代烷氧基、C _3-6的鹵代環烷基、C _3-6的鹵代環烷氧基、C _1-6的鹵代烷胺基、C _3-12的鹵代環烷胺基、C _6-10的芳基、5-10元的雜芳基； R ₃選自

、

、

、

、

或

；其中，Y ₁、Y ₂、Y ₃、Y ₄、Y ₅各自獨立地選自氫、鹵素、C _1-12的烷基、C _1-12的烷氧基、C _3-12的環烷基、C _1-12的烷胺基、所述R取代的C _1-12的烷胺基。 In order to further optimize the inhibitory effect on EGFR and Her2 exon 20 insertion mutations, preferably, the compound used as a kinase inhibitor is a compound as shown in formula II or a pharmaceutically acceptable salt, solvate or pro- medicine:

In the formula, Z ₃ and Z ₄ are each independently selected from N and CR ₄ ; R ₁ and R ₂ are each independently selected from H, halogen, cyano, amine, ester, urea, and carbamate , amido, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, C _1-6 alkylamino, C _3-12 cycloalkylamino, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 halocycloalkyl, C _3-6 halocycloalkoxy, C _1-6 haloalkylamino group, C _3-12 halocycloalkylamino group, C _6-10 aryl group, 5-10 membered heteroaryl group, or substituted by 1 to 3 R Amino group, ester group, urea group, urethane group, amido group, C _1-6 alkyl group, C _1-6 alkoxy group, C _3-6 cycloalkyl group, C _3-6 Cycloalkoxy, C _1-6 alkylamino, C _3-12 cycloalkylamino, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 halo ring Alkyl, C _3-6 halocycloalkoxy, C _1-6 haloalkylamino, C _3-12 halocycloalkylamino, C _6-10 aryl, 5-10 membered hetero Aryl; _R3 is selected from

,

,

,

,

or

; Wherein, Y ₁ , Y ₂ , Y ₃ , Y ₄ , and Y ₅ are each independently selected from hydrogen, halogen, C _1-12 alkyl, C _1-12 alkoxy, C _3-12 cycloalkane group, a C _1-12 alkylamino group, and the R-substituted C _1-12 alkylamino group.

、

、

、

、

、

、

或

； R ₁₂、R ₁₃各自獨立地選自H、酯基、醯基、C _1-6的烷基、C _3-6的環烷基、C _3-6的環烷氧基、C _6-10的芳基、5-9元的雜芳基，或者為被1~3個所述R取代的酯基、醯基、C _1-6的烷基、C _3-6的環烷基、C _3-6的環烷氧基、C _6-10的芳基、5-9元的雜芳基。 In order to further optimize the inhibitory effect on EGFR and Her2 exon 20 insertion mutations, preferably, Z ₁ is CR ₄ , Z ₂ is CH, wherein, R ₄ is selected from H, 5-9 membered heterogeneous compounds containing more than one nitrogen atom Aromatic ring, 5-9 membered heteroaryl group containing more than one nitrogen atom with 1~3 substituents _R12 , cyano group,

,

,

,

,

,

,

or

; R ₁₂ and R ₁₃ are each independently selected from H, ester group, acyl group, C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 cycloalkoxy group, C _6-10 aryl group, 5-9 membered heteroaryl group, or ester group, acyl group, C _1-6 alkyl group, C _3-6 cycloalkyl group, C _{3 -6} cycloalkoxy, C _6-10 aryl, 5-9 membered heteroaryl.

式Ⅲ中，R ₈為氫、C _3-6的環烷基、C _1-3的烷基、C _1-3的氘代烷基、C _1-3的鹵代烷基； R ₄選自H、

、

、

、

、

、

、

、

、

、

、

、

；其中，R ₁₄為C _1-3的烷基，n為1-3的整數，R ₁₂、R ₁₃、R ₁₅各自獨立選自H或C _1-3的烷基； Z ₃、Z ₄各自獨立地選自CH或N； R ₁選自氫、C _1-3的烷氧基、C _1-3的鹵代烷氧基、C _1-3的氘代烷氧基、C _3-6的環烷基； R ₂選自

，其中，D環為4-6元的環烷胺基； R ₃選自

、

； 其中，當R ₄選自

、

、

、

、

、

、

、

，Z ₃、Z ₄同時選擇CH時，R ₂選自

； 當R ₄選自H時，R ₂選自

。 In order to further optimize the inhibitory effect on EGFR and Her2 exon 20 insertion mutations, preferably, the compound shown in formula III:

In formula III, R ₈ is hydrogen, C _3-6 cycloalkyl, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl; R ₄ is selected from H,

,

,

,

,

,

,

,

,

,

,

,

; Wherein, R ₁₄ is C _1-3 alkyl, n is an integer of 1-3, R ₁₂ , R ₁₃ , R ₁₅ are each independently selected from H or C _1-3 alkyl; Z ₃ , Z ₄ are each independently selected from CH or N; R is selected from hydrogen, C _1-3 alkoxy, C _1-3 haloalkoxy, C _{1-3 deuterated} alkoxy, C _3-6 cycloalkane base _; R2 is selected from

, wherein, the D ring is a 4-6-membered cycloalkylamino group; R ₃ is selected from

,

; Wherein, when R ₄ is selected from

,

,

,

,

,

,

,

, when Z ₃ and Z ₄ select CH at the same time, R ₂ is selected from

; when R ₄ is selected from H, R ₂ is selected from

.

式Ⅲ’中，R ₈為氫、C _3-6的環烷基、C _1-3的烷基、C _1-3的氘代烷基、C _1-3的鹵代烷基； R ₄選自

、

、

、

、

、

、

、

、

、

、

、

；其中，R ₁₄為C _1-3的烷基，n為1-3的整數，R ₁₂、R ₁₃、R ₁₅各自獨立選自H或C _1-3的烷基； Z ₃、Z ₄各自獨立地選自CH或N，且至少有一個選自N； R ₁選自氫、C _1-3的烷氧基、C _1-3的鹵代烷氧基、C _1-3的氘代烷氧基、C _3-6的環烷基； R ₂選自

，其中，D環為4-6元的環烷胺基； R ₃選自

。 Preferably, it is a compound shown in formula III':

In formula III', R ₈ is hydrogen, C _3-6 cycloalkyl, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl; R ₄ is selected from

,

,

,

,

,

,

,

,

,

,

,

; Wherein, R ₁₄ is C _1-3 alkyl, n is an integer of 1-3, R ₁₂ , R ₁₃ , R ₁₅ are each independently selected from H or C _1-3 alkyl; Z ₃ , Z ₄ are each independently selected from CH or N, and at least one is selected from N; R is selected from hydrogen, C _1-3 alkoxy, C _1-3 haloalkoxy, C _{1-3 deuterated} alkoxy , C _3-6 cycloalkyl; R ₂ is selected from

, wherein, the D ring is a 4-6-membered cycloalkylamino group; R ₃ is selected from

.

；

；

；

；

；

； 式Ⅳ、式Ⅴ、式Ⅵ、式Ⅶ、式Ⅷ、式Ⅸ中，R ₁選自氫、C _1-3的烷氧基、C _1-3的鹵代烷氧基、C _1-3的氘代烷氧基、C _3-6的環烷基； R ₂選

，其中，D環為4-6元的烷胺環； R ₃選自

、

； R ₄選自H、

、

、

、

、

、

、

、

、

、

、

、

；其中，R ₁₄為C _1-3的烷基，n為1-3的整數，R ₁₂、R ₁₃、R ₁₅各自獨立選自H或C _1-3的烷基； R ₁₆選自H或C _1-3的烷基。 In order to further optimize the inhibitory effect on EGFR and Her2 exon 20 insertion mutations, preferably, the compounds represented by formula IV, formula V, formula VI, formula VII, formula VIII, and formula IX:

;

;

;

;

;

; In formula IV, formula V, formula VI, formula VII, formula VIII, and formula IX, R is selected from hydrogen, C _1-3 alkoxy, C _{1-3 haloalkoxy, C 1-3 deuterium} Substituted alkoxy, C _3-6 cycloalkyl; R ₂ select

, wherein, ring D is a 4-6 membered alkylamine ring; R ₃ is selected from

,

_{; R is} selected from H,

,

,

,

,

,

,

,

,

,

,

,

; wherein, R ₁₄ is C _1-3 alkyl, n is an integer of 1-3, R ₁₂ , R ₁₃ , R ₁₅ are each independently selected from H or C _1-3 alkyl; R ₁₆ is selected from H or C _1-3 alkyl.

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

。 In order to further optimize the inhibitory effect on EGFR and Her2 exon 20 insertion mutations, preferably, the structural formula of the compound used as a kinase inhibitor is selected from the following structures:

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

.

In addition to the EGFR exon 20 insertion mutation, the compound with the above structure also has a good inhibitory effect on exon 19 deletion and exon 21 L858R point mutation.

； 式Ⅹ中，R ₈選自H、C _1-4的烷基、C _1-4的氘代烷基、C _1-4的鹵代烷基； Y ₁、Y ₂、Y ₃各自獨立地選自H、D、鹵素、C _1-4的鹵代烷基、C _1-4的氘代烷基、-CH ₂NR ₁₁₁R ₁₁₂或

，其中，D環為4-6元的環烷胺基或4-6元的雜環烷胺基，所述雜環烷胺基為環烷胺基上的1-3個環碳原子被雜原子取代，雜原子選自O、S或N； R ₄選自

、

、

、

、

、

、

、

、

、

、

；其中R ₄₀選自H、C _1-4的烷基、或C _1-4的氘代烷基、或C _1-4的鹵代烷基； R ₁₁選自

、

、

、

、

、

、

、

、

、

、

；其中R ₁₁₀、R ₁₁₁、R ₁₁₂各自獨立地選自H、C _1-4的烷基、或C _1-4的氘代烷基、或C _1-4的鹵代烷基； 其中，當R ₁₁選自

，Y ₁、Y ₂、Y ₃均為H，R ₈為甲基，R ₄為

或

時，R ₄₀選自H、C _2-4的烷基、C _1-4的氘代烷基或C _1-4的鹵代烷基。 Preferably, the above compound has the structure shown in IX:

; In formula X, R ₈ is selected from H, C _1-4 alkyl, C _1-4 deuterated alkyl, C _1-4 haloalkyl; Y ₁ , Y ₂ , Y ₃ are each independently selected from H, D, halogen, C _1-4 haloalkyl, C _1-4 deuterated alkyl, -CH ₂ NR ₁₁₁ R ₁₁₂ or

, wherein, the D ring is a 4-6 membered cycloalkylamino group or a 4-6 membered heterocycloalkylamino group, and the heterocycloalkylamino group is that 1-3 ring carbon atoms on the cycloalkylamino group are heterocycloalkylamino Atom substitution, heteroatoms are selected from O, S or N; R ₄ is selected from

,

,

,

,

,

,

,

,

,

,

; wherein R ₄₀ is selected from H, C _1-4 alkyl, or C _1-4 deuterated alkyl, or C _1-4 haloalkyl; R ₁₁ is selected from

,

,

,

,

,

,

,

,

,

,

; wherein R ₁₁₀ , R ₁₁₁ , and R ₁₁₂ are each independently selected from H, C _1-4 alkyl, or C _1-4 deuterated alkyl, or C _1-4 haloalkyl; wherein, when R ₁₁ selected from

, Y ₁ , Y ₂ , Y ₃ are all H, R ₈ is methyl, R ₄ is

or

When, R ₄₀ is selected from H, C _2-4 alkyl, C _1-4 deuterated alkyl or C _1-4 haloalkyl.

；

； 式Ⅺ、式Ⅻ中，R ₁₁選自

、

、

、

。 More preferably, it is the compound shown in formula XI and formula XII:

;

; In formula XI and formula XII, R ₁₁ is selected from

,

,

,

.

。 Preferably, be the compound of following structural formula:

.

； 式Ⅹ’中，R ₈選自H、C _1-4的烷基、C _1-4的氘代烷基、C _1-4的鹵代烷基； Y ₁、Y ₂、Y ₃各自獨立地選自H、D、鹵素、C _1-4的鹵代烷基、C _1-4的氘代烷基、-CH ₂NR ₁₁₁R ₁₁₂或

，其中，D環為4-6元的環烷胺基或4-6元的雜環烷胺基，所述雜環烷胺基為環烷胺基上的1-3個環碳原子被雜原子取代，雜原子選自O、S或N； R ₁₁選自

、

、

、

、

、

；其中R ₁₁₀、R ₁₁₁、R ₁₁₂各自獨立地選自H、C _1-4的烷基、或C _1-4的氘代烷基、或C _1-4的鹵代烷基。 Preferably, it is a compound represented by formula X':

; In formula X', R ₈ is selected from H, C _1-4 alkyl, C _1-4 deuterated alkyl, C _1-4 haloalkyl; Y ₁ , Y ₂ , Y ₃ are each independently selected from H, D, halogen, C _1-4 haloalkyl, C _1-4 deuterated alkyl, -CH ₂ NR ₁₁₁ R ₁₁₂ or

, wherein, the D ring is a 4-6 membered cycloalkylamino group or a 4-6 membered heterocycloalkylamino group, and the heterocycloalkylamino group is that 1-3 ring carbon atoms on the cycloalkylamino group are heterocycloalkylamino Atom substitution, the heteroatom is selected from O, S or N; R ₁₁ is selected from

,

,

,

,

,

; wherein R ₁₁₀ , R ₁₁₁ , and R ₁₁₂ are each independently selected from H, C _1-4 alkyl, or C _1-4 deuterated alkyl, or C _1-4 haloalkyl.

、

、

、

、

、

、

、

。 More preferably, be the compound of following structural formula:

,

,

,

,

,

,

,

.

Unless otherwise stated, the following terms used in this specification and claims have the following meanings:

The C _6-10 aryl group is a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 10 ring atoms, for example, phenyl or naphthyl.

5-10 membered heteroaryl refers to a monocyclic or bicyclic aromatic group having 5 to 10 ring atoms, wherein one or more, preferably one, two or three ring atoms are Heteroatoms selected from N, O, S, remaining ring atoms are carbon. Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazole base, quinolinyl, isoquinolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, etc.

5-10 membered aliphatic heterocyclic group refers to a monocyclic or bicyclic non-aromatic group with 5 to 10 ring atoms, one or more, preferably one, two or three ring atoms is a heteroatom selected from N, O, S, and the remaining ring atoms are carbon.

Alkylamino refers to a -NR'R'' group, wherein R' and R'' are selected from hydrogen or alkyl, and R' and R'' are not hydrogen at the same time, for example, methylamino, ethylamino, Propylamino, dimethylamino, diethylamino, ethylmethylamino, propylmethylamino, etc.

、

、

、

、

、

、

等，其中R為烷基，m、n、m’和n’各自獨立地選自0、1、2、3或4，但m和n不同時為0，m’和n’不同時為0。 Cycloalkylamino group refers to the following structure

,

,

,

,

,

,

etc., wherein R is an alkyl group, m, n, m' and n' are each independently selected from 0, 1, 2, 3 or 4, but m and n are not 0 at the same time, and m' and n' are not 0 at the same time .

結構的基團，R ₁₂、R ₁₃的含義如上所述。 Phosphate has

The meanings of R ₁₂ and R ₁₃ are as above.

Haloalkyl, haloalkoxy, halocycloalkyl, halocycloalkoxy, haloalkylamino, halocycloalkylamino are groups in which hydrogen in corresponding groups such as alkyl is replaced by halogen, specifically The number of substitutions may be one or more.

The haloalkyl group can be monosubstituted, disubstituted or trisubstituted, preferably the substituted halogen is fluorine. The number of deuterated groups in the deuterated alkyl group can be one, two, three... or all.

”代表化學鍵連接位置。 "

" represents the chemical bond connection position.

The above compounds have been confirmed by biological activity experiments to have good inhibitory activity against EGFR and Her2 exon 20 insertion mutation, exon 19 deletion and exon 21 L858R point mutation, and can be used as the original drug of related drugs.

On the basis of the above original drug, "pharmaceutically acceptable salt" of the original drug refers to a salt that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Such salts include:

Acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc., typical inorganic acid salts are selected from hydrochloride, hydrobromide, hydroiodide salts, sulfates, bisulfates, nitrates, phosphates, acid phosphates. Acid addition salts with organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, malic acid, Toric acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedi Sulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4'-methylene Bis-(3-hydroxy 2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, Salicylic acid, stearic acid, muconic acid, etc.; or an acidic proton present in the parent compound with an organic base (e.g. ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc.) Coordinated salts. Typical organic acid salts are selected from formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate , lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, isethionate, benzenesulfonate, salicylate, picrate, glutamate, Ascorbate, camphorate, camphorsulfonate. It is readily understood that the pharmaceutically acceptable salts are non-toxic.

Solvates are compounds containing solvents, such as hydrates, dimethylsulfoxides, and the like.

A prodrug refers to a compound that produces the compound, salt, or solvate of the present invention through metabolic or chemical transformation during the treatment of related diseases.

The technical scheme of the application of above-mentioned compound of the present invention is:

Use of the above-mentioned compound used as a kinase inhibitor in the preparation of medicines for treating related diseases caused by EGFR mutation and/or Her2 mutation.

Based on the good inhibitory activity of the above compounds on the exon 20 insertion mutation of EGFR and Her2, and the expected good inhibitory activity on the EGFR exon 19 deletion and the L858R point mutation of exon 21, the drugs based on the above compounds are expected to be effective against related The disease has a better therapeutic effect.

Preferably, the EGFR mutation and/or Her2 mutation is exon 20 insertion mutation, EGFR exon 19 deletion, EGFR exon 21 L858R point mutation. It is confirmed by biological activity experiments that the above compound has a good inhibitory effect on the above mutation types of exon 20 of the above two kinases.

The above compounds can also be used in combination with other drugs for the treatment of cancer. Other drugs used in combination can be ERK inhibitors or MEK inhibitors. The cancer is preferably lung cancer, more preferably lung cancer caused by EGFR and Her2 exon 20 insertion mutation, EGFR exon 19 deletion and exon 21 L858R point mutation.

The technical solution of the present invention will be further described below, but the protection scope of the present invention is not limited thereto. It mainly includes the chemical experiment part and the biological experiment part.

1. Chemical experiment part

1. The intermediates involved in the examples are described below.

intermediate 1

synthetic route:

Add indole (20g, 170.9mmol), methyl iodide (48.5g, 341.8mmol) and cesium carbonate (111g, 341.8mmol) into N,N-dimethylformamide, react at room temperature for 16h, TLC monitor. After the raw materials were reacted, water and ethyl acetate were added to the reaction system, the water phase was extracted three times, spin-dried, and purified by column to obtain 22 g of the product. ¹ HNMR (400MHz, CDCl ₃ ) δ 7.62 (dt, J = 8.0, 1.2Hz, 1H), 7.29 (dt, J = 8.0, 1.2Hz, 1H), 7.21 (ddd, J = 8.0, 6.8, 1.2Hz, 1H), 7.10 (ddd, J = 8.0, 6.8, 1.2Hz, 1H), 7.00 (d, J = 3.2Hz, 1H), 6.47 (dd, J = 3.2, 0.8Hz, 1H), 3.72 (s, 3H ).

intermediate 2

synthetic route:

Add indole (5g, 42.7mmol), deuterated methyl iodide (9.3g, 64.1mmol) and cesium carbonate (21g, 64.6mmol) into N,N-dimethylformamide and react at room temperature 16h, TLC monitoring. After the raw materials were reacted, water and ethyl acetate were added to the reaction system, the water phase was extracted three times, spin-dried, and 5.3 g of the product was obtained after column purification. ¹ HNMR (400MHz, CDCl ₃ ) δ 7.63 (dq, J = 8.1, 1.1Hz, 1H), 7.27 (dt, J = 8.2, 1.0Hz, 1H), 7.21 (ddd, J = 8.3, 6.8, 1.2Hz, 1H), 7.11 (ddd, J = 8.2, 6.8, 1.2Hz, 1H), 6.97 (d, J = 3.1Hz, 1H), 6.47 (dd, J = 3.0, 1.3Hz, 1H).

intermediate 3

synthetic route:

Indole (5.3g, 45.3mmol), bromocyclopropane (9.8g, 81.5mmol) and potassium hydroxide (5.4g, 81.5mmol) were added to N,N-dimethylformamide, and at 0 The reaction was carried out at ℃ for 2 h, monitored by TLC. After the raw materials were reacted, ice water and ethyl acetate were added to the reaction system, the water phase was extracted three times, spin-dried, and purified by column to obtain 2.8 g of the product.

intermediate 4

synthetic route:

Synthesis of Compound 2: Compound 1 (20g, 107.5mmol) and DMAP (2.62g, 21.5mmol) were dissolved in dichloromethane, cooled to 0°C under nitrogen protection, and then Boc ₂ O (25.78g, 118.2 mmol) in dichloromethane solution. After the dropwise addition was completed, it was raised to room temperature and reacted for 16h. After the raw materials were reacted, they were spin-dried and purified through a column to obtain 25 g of the product. ¹ HNMR (400MHz, CDCl ₃ ) δ 8.88 (d, J = 8.4Hz, 1H), 6.99 (s, 1H), 6.72 (d, J = 12.0Hz, 1H), 3.98 (s, 3H), 1.54 (s , 9H).

Synthesis of Compound 3: Compound 2 (20g, 69.9mmol), N,N,N-trimethylethylenediamine (10.68g, 104.8mmol) and DIPEA (18.16g, 139.8mmol) were dissolved in N,N-di In methyl acetamide, the temperature was raised to 90°C for 16 hours. After the reaction was completed, water and ethyl acetate were added to the reaction system for extraction, and the organic phases were combined, dried and spin-dried to obtain 30 g of the product.

Synthesis of Compound 4: Compound 3 (30g, 81.3mmol), iron powder (31.8g, 56.9mmol) and ammonium chloride (30.4g, 56.9mmol) were dissolved in ethanol/water, heated to 85°C for 3h. After the reaction was completed, filter and spin off most of the solvent, then add ammonia water to the reaction system to adjust the pH to 9-10, extract three times with dichloromethane, and spin dry to obtain 24 g of the product. ¹ HNMR (400MHz, CDCl ₃ ) δ 7.54 (s, 1H), 6.97 (s, 1H), 6.62 (s, 1H), 3.79 (s, 3H), 3.54(m, 4H), 3.09(t, J = 6.4Hz, 2H), 2.68 (d, J = 6.4Hz, 2H), 2.65 (s, 3H), 2.50 (s, 6H), 1.50 (s, 9H).

Synthesis of INT 4: Compound 4 (5g, 14.7mmol) and triethylamine (4.48g, 44.3mmol) were dissolved in dichloromethane, and cooled to 0°C under nitrogen protection. Then slowly add acryloyl chloride (1.48g, 16.2mmol) in dichloromethane solution dropwise, and keep it at 0°C for 2 hours. After the reaction is completed, add water and dichloromethane to the reaction system, extract, spin dry, and pass column purification to obtain 3.3g product. ¹ HNMR (400MHz, CDCl ₃ ) δ 10.05 (s, 1H), 9.12 (s, 1H), 6.91 (s, 1H), 6.71 (s, 1H), 6.43 (dd, J = 17.2, 1.6Hz, 1H) , 6.27 (dd, J = 16.8, 10.0Hz, 1H), 5.66 (dd, J = 10.0, 1.6Hz, 1H), 3.82 (s, 3H), 2.89-2.82 (m, 2H), 2.66 (s, 3H ), 2.30-2.26 (m, 2H), 2.25 (s, 6H), 1.52 (s, 9H).

intermediate 5

synthetic route:

The raw material INT 4 is 23g, which is dissolved in 50ml of THF. Cool in an ice-salt bath to -5°C, add dropwise to 100ml of concentrated hydrochloric acid at a temperature T<10°C, stir for 2 hours, and the spotting reaction is complete. Process, pass the column. 5.2 g of product are obtained. ¹ HNMR (CDCl ₃ ) δ 10.10 (s, 1H), 7.97 (s, 1H), 6.68 (s, 1H), 6.41-6.21 (m, 2H), 5.65 (m, 1H), 3.81 (s, 3H) , 3.76 (s, 2H), 2.82 (m, 2H), 2.65 (s, 3H), 2.20 (s, 6H).

intermediate 6

The synthetic route is as follows:

Synthesis of Compound 2: Add Compound 1 (50g, 0.26mol), trifluoroethanol (29.61g, 0.26mol), and dry THF 700 mL into a 2000mL three-necked flask, and add them in batches at 0°C under nitrogen protection. NaH (12g, 0.286mol), then stirred overnight at room temperature. TLC detected that the reaction was complete, adding saturated aqueous ammonium chloride solution, extracting with ethyl acetate three times, washing with saturated brine, drying, spin-drying, and passing through the column to obtain 53 g of the product. ¹ HNMR: (CDCl ₃ , 400MHz) δ 8.36 (d, J = 8.0Hz, 1H), 7.19 (d, J = 8.4Hz, 1H), 4.94~4.88 (m, 2H).

Synthesis of compound 3: Add compound 2 (40g, 0.156mol), NH ₄ Cl (42g, 0.78mol), 600mL ethanol and 200mL water into a 2000mL three-neck flask, raise the temperature to 80°C under nitrogen protection, and add iron in batches Powder (44g, 0.78mol), after the addition was completed, the reaction was stirred for 2h, and TLC showed that the reaction was complete. Cool down to room temperature, filter, and spin dry the filtrate, add 1000 mL of ethyl acetate, wash with water, dry, and spin dry to obtain 30 g of the product. ¹ HNMR: (CDCl ₃ , 400MHz) δ 6.93 (d, J = 7.6Hz, 1H), 6.83 (d, J = 8.0Hz, 1H), 4.78~4.74 (m, 2H), 3.82 (s, 2H).

Synthesis of compound 4: In a 1000mL three-necked flask, add compound 3 (30g, 0.132mol), DIPEA (33mL, 0.192mol), 600mL of dichloromethane, and cool down to 0°C under nitrogen protection. Acetyl chloride (12g, 0.169mol) was added dropwise. After the dropwise addition was completed, the reaction was stirred at 0°C for 3h, followed by tracking and monitoring with a spot plate. After the reaction was completed, 100 mL of water and 400 mL of 1N hydrochloric acid aqueous solution were added, extracted three times with dichloromethane, the organic phases were combined, washed with water, dried, and spin-dried to obtain 24 g of the product. ¹ HNMR: (CDCl ₃ , 400MHz) δ 8.67 (d, J = 8.0Hz, 1H), 7.43 (s, 1H), 7.03 (d, J = 8.4Hz, 1H), 4.85~4.79(m, 2H), 2.24 (s, 3H).

Synthesis of compound 5: In a 500mL three-necked flask, add trifluoroacetic anhydride (200mL), compound 4 (20g, 75mmol), then cool down to -10°C, slowly add fuming nitric acid (3.5mL), keep the temperature at -5 °C, under this temperature condition, stir for 1 h, spot plate tracking, and the reaction is complete. The reaction solution was poured into crushed ice, extracted three times with ethyl acetate, dried, spin-dried, and passed through the column to obtain 16 g of the product. ¹ HNMR: (DMSO-d6, 400MHz) δ 9.95 (s,1H), 9.18 (s,1H), 5.17~5.15 (m, 2H), 2.18 (s, 3H).

Synthesis of Compound 6: Add Compound 5 (10.4 g, 33.2 mmol), N,N,N-trimethylethylenediamine (5.08 g, 49.8 mmol ), and 100 mL of acetonitrile into a 250 mL single-necked bottle. Then the temperature was raised to 80°C under the protection of nitrogen, and stirred overnight. After the reaction is completed, spin the reaction solution to dryness, add methyl tert-butyl ether to make a slurry, filter, and dry to obtain 8.6 g of the product. ¹ HNMR: (DMSO-d6, 400MHz) δ 9.50 (s, 1H), 8.60 (s, 1H), 5.17~5.15 (m, 2H), 4.05 (t, d = 7.6Hz, 2H), 3.36 (t, d = 7.4Hz, 2H), 2.83 (s, 3H), 2.79 (s, 6H), 2.08 (s, 3H).

Synthesis of Compound 7: Add THF 160mL, Compound 6 (8g, 20.8mmol), DMAP (0.72g, 2.08mmol), Boc ₂ O (44.8g, 208mmol) into a 250mL single-necked bottle, and then raise the temperature to 80 ℃, stirred the reaction for 2h, tracked the plate, and the reaction was completed. After processing and passing through the column, 8 g of the product was obtained, with a yield of 83%.

Synthesis of compound 8: In a 250mL three-neck flask, add 150mL of anhydrous methanol, compound 7 (8g, 16.6mmol), under nitrogen protection, cool down to 0°C, add sodium methoxide (1.18g, 21.9mmol) in batches, and then Under this condition, the reaction was stirred for 1 h, tracked by pointing plate, after the reaction was completed, water was added, extracted three times with ethyl acetate, the organic phases were combined, washed with water, dried, and spin-dried to obtain product 7.2 with a yield of 90%.

Synthesis of Compound 9: Add Compound 8 (6.1g, 14mmol), NH ₄ Cl (3.7g, 53.4mmol), 90mL of ethanol and 30mL of water into a 250mL three-neck flask, raise the temperature to 80°C under nitrogen protection, and add in batches After the addition of iron powder (3.9g, 70mmol), the mixture was stirred and reacted for 2h under these conditions. Point board tracking, the reaction is complete. Cool down to room temperature, filter, spin dry the filtrate, add ethyl acetate and brine, process, spin dry to obtain 3.6g of product, yield 64%.

Synthesis of INT 6: In a 250mL three-neck flask, add 100mL of dichloromethane, compound 9 (3.5g, 8.6mmol), triethylamine (1.74g, 17.2mmol), under the protection of nitrogen, cool down to -5°C, divide Add acryloyl chloride (0.851g, 9.4mmol) in batches, stir the reaction for 0.5h, and track with a spot plate. After the reaction was completed, saturated aqueous sodium bicarbonate solution was added, extracted three times with dichloromethane, washed with water, dried, spin-dried and passed through the column to obtain 1.9 g of product. ¹ HNMR: (CDCl ₃ , 400MHz) δ 10.13 (s, 1H), 9.38 (s, 1H), 6.60 (s, 1H), 6.43 (d, J = 5.6Hz, 1H), 5.17~5.15 (m, 2H ), 4.05 (t, d = 7.6Hz, 2H), 3.36 (t, d = 7.4Hz, 2H), 2.83 (s, 3H), 2.79 (s, 6H), 2.08 (s, 3H).

intermediate 7

synthetic route:

Compound 1 (20g, 107.5mmol), N,N,N-trimethylethylenediamine (12g, 118.2mmol) and potassium carbonate (30g, 215mmol) were added into acetonitrile, then heated to 80°C for 16h. After the reaction was completed, filter, and the filter cake was stirred and washed three times with ethyl acetate, and the filtrates were combined, dried, and spin-dried to obtain 37 g of the product. ¹ HNMR (400MHz, CDCl ₃ ) δ 7.25 (s, 1H), 6.59 (s, 1H), 3.89 (s, 3H), 3.75 (s, 2H), 3.18-3.09 (m, 2H), 2.79 (s, 3H), 2.50-2.43 (m, 2H), 2.21 (s, 6H).

intermediate 8

synthetic route:

Synthesis of compound 2: Dissolve compound 1 (13g, 62.8mmol) and aluminum trichloride (9.9g, 94.2mmol) in dry THF 200mL, raise the temperature to 80°C for 1h under the protection of nitrogen, and slowly add INT under stirring -1 THF solution (12.5g, 75.3mmol), continue to react at 80°C for 3h after adding, spot plate tracking. After completion of the reaction, process and pass through the column to obtain 8.6g of product. ¹ HNMR (400MHz, CDCl ₃ ) δ 8.83 (d, J = 0.8Hz, 1H), 8.19-8.13 (m, 1H), 7.98 (s, 1H), 7.40-7.28 (m, 3H), 3.89 (s, 3H), 3.86 (s, 3H).

Synthesis of INT 8: Dissolve compound 2 (8.6g, 28.5mmol) and intermediate 7 (9.2g, 34.2mmol) in dioxane and water, add p-toluenesulfonic acid monohydrate (8.14g, 42.8 mmol), heated to 80 °C and reacted for 16 h. Spot plate tracking, after the reaction was completed, the reaction solution was spin-dried, and 2N aqueous sodium hydroxide solution was added to make it alkaline, then extracted three times with ethyl acetate, dried, spin-dried, and passed through the column to obtain 9g of product. ¹ HNMR (400MHz, CDCl ₃ ) δ 9.44 (s, 1H), 8.90 (s, 1H), 8.07 (s, 1H), 7.78 (s, 1H), 7.68 (s, 1H), 7.41-7.35 (m, 1H), 7.30 (d, J = 1.2Hz, 1H), 7.23-7.18 (m, 2H), 6.72 (s, 1H), 4.00 (s, 3H), 3.94 (s, 3H), 3.71 (s, 3H ), 3.37 (d, J = 7.2Hz, 2H), 2.90 (s, 3H), 2.70 (s, 2H), 2.37 (s, 6H).

intermediate 9

synthetic route:

Compound 1 (1g, 3.07mmol), AZD9291 intermediate (0.686g, 3.69mmol), and p-toluenesulfonic acid monohydrate (0.76g, 3.99mmol) were added to dry dioxane, and the temperature was raised to 80°C, react for 16h. Spot plate tracking, the reaction was completed, processed, and passed through the column to obtain 0.23g product. ¹ HNMR (400MHz, CDCl ₃ ) δ 9.74 (d, J = 8.4Hz, 1H), 8.88 (s, 1H), 8.02 (s, 1H), 7.89 (s, 1H), 7.38 (m, 2H), 7.26 (m, 1H), 7.11 (t, J = 7.6Hz, 1H), 6.79 (d, J = 12.0Hz, 1H), 4.05 (s, 3H), 3.93 (s, 3H), 2.33 (s, 3H) .

intermediate 10

synthetic route:

Synthesis of compound 2: INT 8 (4.06g, 7.62mmol) and lithium hydroxide monohydrate (1.6g, 38.1mmol) were added to a mixed solvent of methanol, tetrahydrofuran and water, reacted at 40°C for 16h, monitored by TLC, After the reaction of the raw materials, spin dry directly, then add anhydrous methanol and concentrated hydrochloric acid to neutralize, spin dry the solvent, and then add water with toluene three times to obtain 6.5 g of crude product, which is directly injected into the next step.

Synthesis of INT 10: Dissolve compound 2 (6.5g), DIPEA (5.8g, 45mmol) and tert-butyl carbazate (2.97g, 22.5mmol) in dry DMF, react at room temperature for 15min, then add PyBop (4.68g, 9mmol), under the protection of nitrogen, react at room temperature for 16h, spot plate tracking, after the reaction is completed, add water and ethyl acetate to the reaction system for extraction, combine the organic phases, dry, spin dry, and pass through the column to obtain 1.9g product. ¹ HNMR (400MHz, DMSO-d6) δ 10.32 (s, 1H), 9.26 (m, 1H), 9.11 (s, 1H), 8.71 (s, 1H), 8.40 (s, 1H), 8.35 (s, 1H ), 8.30 (s, 1H), 8.16 (m, 1H), 7.48 (d, J = 8.2Hz, 1H), 7.22 (ddd, J = 8.2, 7.0, 1.2Hz, 1H), 7.04 (t, J = 7.6Hz, 1H), 6.94 (s, 1H), 3.96 (s, 3H), 3.83 (s, 3H), 3.48 (t, J = 6.9Hz, 2H), 3.31 (m, 2H), 2.86 (s, 3H), 2.80 (s, 6H), 1.49 (s, 9H).

2. The specific examples of compounds used as kinase inhibitors are described below:

Example 1

The structural formula of the compound used as a kinase inhibitor of the present embodiment is:

synthetic route:

Synthesis of compound 2: Add compound 1 (0.234g, 1mmol), AlCl ₃ (0.186g, 1.4mol), 15mL of 1,2-dichloroethane to a 100mL single-necked bottle, heat the oil bath to 80°C and stir for 1h. After that, cyclopropylindole (0.16g, 1mmol) was added, stirred at 80°C for 4h, tracked by spot plate, after the reaction was completed, cooled down, poured into ice water, extracted with ethyl acetate, extracted 3 times, combined the organic phases, dried, and passed column, 0.2 g of product was obtained.

Synthesis of Example 1: compound 2 (50mg, 0.141mmol), INT 6 (65mg, 0.141mmol), p-toluenesulfonic acid monohydrate (45.5mg, 0.24mmol), NMP1.5mL and ethylene glycol monomethyl ether 3mL was added to a 5mL reactor, heated to 120°C, and reacted for 6h. After spot plate tracking, the reaction was complete, cooled to room temperature, added 10 mL of ethyl acetate, washed with aqueous sodium bicarbonate solution, washed once with saturated saline, and dried. After purification, 20 mg of the product was obtained with a yield of 51%. MS+1: 681.51.

Example 2

The structural formula of the compound used as a kinase inhibitor of the present embodiment is:

synthetic route:

Synthesis of compound 2: Add compound 1 (0.234g, 1mmol), AlCl ₃ (0.186g, 1.4mol), 15ml of 1,2-dichloroethane to a 100mL single-necked bottle, heat the oil bath to 80°C and stir for 1h. Then add INT 2 (0.138g, 1mmol), stir at 80°C for 4 hours, point the plate to track, after the reaction is complete, cool down, pour into ice water, extract with ethyl acetate, extract 3 times, combine the organic phases, dry, and pass through the column , 0.19 g of product was obtained.

Synthesis of Example 2: compound intermediate 2 (50mg, 0.152mmol), INT 6 (70.1mg, 0.152mmol), p-toluenesulfonic acid monohydrate (49.1mg, 0.26mmol), NMP 1mL and ethylene glycol mono Add 2mL of methyl ether into a 5mL reactor, heat to 120°C, react for 6h, spot plate tracking, the reaction is complete, cool to room temperature, add 10mL of ethyl acetate, wash with sodium bicarbonate aqueous solution and saturated saline once, dry, and purify , to obtain the product 22mg. MS+1: 655.53.

Example 3

The structural formula of the compound used as a kinase inhibitor of the present embodiment is:

synthetic route:

Synthesis of compound 2: Add compound 1 (5.53g, 31mmol), acetylhydrazine (2.76g, 37mmol) into a 250mL one-necked bottle, add 93mL of 1N sodium hydroxide aqueous solution, react at 80°C for 4h, and a large amount of yellow solid Precipitate. Cool down, stir at a low temperature around 5°C for 30 minutes, filter with suction, wash the filter cake once with water, and dry it under vacuum at 55°C overnight to obtain 2.75 g of the product.

Synthesis of Compound 3: Add Compound 2 (2.75g, 14.2mmol), DIPEA (12.8g, 0.1mol), 150ml of toluene into a 250mL single-necked bottle, and add 20mL of phosphorus oxychloride at room temperature, and white fog will form. Put it in an oil bath and heat it to 80°C, under nitrogen protection, stir overnight, the next day, pour the reaction solution into crushed ice, add ethyl acetate for extraction, extract three times, combine the organic phases, dry, and pass through the column to obtain 1.1g product. ¹ HNMR (400MHz, CDCl ₃ ) δ 9.18 (s, 1H), 2.70 (s, 3H).

Synthesis of Compound 4: Add Compound 3 (2.38g, 10.3mmol) and 120mL of 1,2-dichloroethane into a 250mL single-necked bottle, add anhydrous aluminum trichloride (2.318g, 17.5mmol), and stir at room temperature for 30min. Then cool down to 0°C, add 1.5g of INT 2 dropwise, stir at low temperature for 30 minutes, then raise the temperature to 50°C, react for 2 hours, and monitor by spotting. Cool down, pour it into ice water, add dichloromethane to extract twice, dry, spin dry, and pass through the column to obtain 1.24 g of the product. ¹ HNMR (400MHz, CDCl ₃ ) δ 8.84 (s, 1H), 8.05-8.00 (m, 1H), 7.96 (s, 1H), 7.42-7.26 (m, 3H), 2.50 (s, 3H).

Synthesis of Example 3: INT 6 (50mg, 0.11mmol), compound 4 (35mg, 0.11mmol), p-toluenesulfonic acid (31mg, 0.17mmol), NMP 1mL and ethylene glycol monomethyl ether 2mL were added to 5 In a mL reactor, heat to 120°C, react for 6 hours, cool to room temperature, add 10 mL of ethyl acetate, wash with aqueous sodium bicarbonate solution, wash once with saturated brine, dry, spin dry, and purify to obtain 5 mg of the product. MS+1: 651.50.

Example 4

The structural formula of the compound used as a kinase inhibitor of the present embodiment is:

synthetic route:

Synthesis of compound 2: Add compound 3 (2.38g, 10.3mmol), 120mL of 1,2-dichloroethane, anhydrous aluminum trichloride (2.33g, 17.5mmol) into a 250mL single-necked bottle, stir at room temperature for 30min, then Cool down to 0°C, add 1.62g INT 3 dropwise, stir at low temperature for 30 minutes, then raise the temperature to 50°C, react for 2 hours, cool down, pour into ice water, add dichloromethane to extract twice, dry, spin dry, pass through the column, 1.5 g of product were obtained.

Synthesis of Example 4: INT 6 (50mg, 0.11mmol), compound 2 (39mg, 0.11mmol), p-toluenesulfonic acid monohydrate (35.5mg, 0.187mmol), NMP 1mL and ethylene glycol monomethyl ether 2mL Add it into a 5mL reactor, heat to 120°C, react for 6h, cool to room temperature, add 10mL of ethyl acetate, wash with aqueous sodium bicarbonate solution, wash once with saturated brine, dry, and purify to obtain 5mg of the product. MS+1: 677.50.

Example 5

The structural formula of the compound used as a kinase inhibitor of the present embodiment is:

synthetic route:

Synthesis of Example 5: Add the compound of Example 1 (50mg, 0.073mmol), NaOH (5.3mg, 0.13mmol), and methanol 2mL into a 5mL reactor, heat to 70°C, react for 6h, cool to room temperature, Add 10 mL of ethyl acetate, wash with aqueous sodium bicarbonate solution, wash once with saturated brine, dry, and purify to obtain 5 mg of the product. MS+1: 671.51.

Example 6 and example 7

；實施例7：

The structural formula of the compounds used as kinase inhibitors of Examples 6 and 7 is: Example 6:

; Embodiment 7:

synthetic route:

Synthesis of Compound 2: Add sodium hydride (0.55g, 13.75mmol, 60%) and toluene 20mL respectively in a 50mL three-necked flask, at 0°C, under nitrogen protection, slowly add ethyl formate (1.1g, 14.86mmol) dropwise, add After completion, stir at 0°C for 10 minutes, continue to dropwise add a solution of 2-indanone (1.5g, 11.36mmol) in toluene (10mL), and then warm to room temperature and stir overnight. The next day, dilute with water, adjust the pH to 4 with concentrated hydrochloric acid, extract the aqueous phase three times with ethyl acetate, combine the organic phases, wash with water, dry, and spin dry to obtain 3.5 g of crude product.

Synthesis of Compound 3: Add 3.5g of the crude product of Compound 2, hydrazine hydrate (1.8g, 27.95mmol), glacial acetic acid (1.61g, 26.81mmol), and 30mL of ethanol to a 50mL three-neck flask, and heat at 85°C for 3h under nitrogen protection . Concentrate, dilute with water, extract three times with ethyl acetate, wash with water, dry, pass through the column to obtain 1.35g of product.

Synthesis of Compound 4 and Compound 5: Add Compound 3 (156mg, 1mmol), N,N-Dimethylformamide 5mL into a 10mL reactor, nitrogen protection, add sodium hydride at 0°C, and stir for 0.5 h, continue to add isopropyl 2,4-dichloropyrimidine-5-carboxylate (280mg, 1.2mmol) dropwise, after the addition, warm to room temperature and stir overnight. The next day, it was quenched with water, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, washed with water, dried, and passed through the column to obtain 85 mg of compound 4 and compound 5 in total.

Synthesis of Example 6 and Example 7: Compound 4 (50mg, 0.14mmol), Compound 5 (50mg, 0.14mmol), INT 5 (82mg, 0.28mmol), and p-toluenesulfonic acid monohydrate were added to a 10mL reactor Compound (26.8mg, 0.14mmol), DCE (5mL), n-pentanol (5mL), heated to 95°C under nitrogen protection and stirred overnight. The next day, water was added to quench, and the aqueous phase was extracted three times with dichloromethane. The organic phases were combined, concentrated, passed through a column, and then purified to obtain 5 mg of Example 6 and 9 mg of Example 7. Example 6: ¹ HNMR (400MHZ, CDCl ₃ ) δ 13.20 (s, 1H), 9.78 (s, 1H), 9.33 (s, 1H), 9.11 (S, 1H), 8.55 (s, 1H), 8.11 ( s, 1H), 7.63 (d, J = 4Hz, 1H), 7.46 (d, J = 2Hz, 1H), 7.31 (dd, J = 8Hz, 1H), 7.06-6.99 (m, 1H), 6.71 (s , 1H), 6.62 (d, J = 8Hz, 1H), 5.82 (d, J = 6Hz, 1H), 5.29-5.25 (m, 1H), 3.89 (s, 3H), 3.79 (s, 2H), 3.28 (s, 2H), 3.17 (s, 2H), 2.83 (s, 6H), 2.65 (s, 3H), 1.30 (d, J = 2Hz, 1H). Example 7: ¹ HNMR (400MHZ, CDCl ₃ ) δ 12.98(s, 1H), 11.10 (s, 1H), 9.85 (s, 1H), 9.44-9.34 (m, 1H), 9.11 (s, 1H), 7.64 (s, 1H), 7.46 (s, 1H ), 6.99-6.96 (m, 1H), 6.76 (s, 1H), 6.59 (d, J = 8Hz, 1H), 5.82 (d, J = 4Hz, 1H), 5.34-5.33 (m, 1H), 4.58 (s, 2H), 3.97 (s, 3H), 3.89-3.88 (m, 2H), 3.31 (s, 2H), 3.20 (s, 2H), 2.86 (s, 7H), 2.67 (s, 3H), 1.42 (S, 6H).

Example 8

The structural formula of the compound used as a kinase inhibitor of the present embodiment is:

synthetic route:

Synthesis of Compound 2: Add Compound 1 (0.94g, 4.3mmol) and 20mL of 1,2-dichloroethane to a 100mL single-necked bottle, add aluminum trichloride (1.06g, 8mmol) in an ice bath, and stir After 5 minutes, INT 1 (0.52g, 4mmol) was added, and the reaction was heated at 50°C for 1.5h. After the reaction, water was added, extracted three times with dichloromethane, the organic phases were combined, washed with water, dried, and passed through a column to obtain 0.6 g of the product. ¹ HNMR (400MHZ, CDCl ₃ ) δ 8.81 (s, 1H), 8.16 (t, J = 4Hz, 1H), 7.96 (s, 1H), 7.38-7.36 (m, 1H), 7.33-7.29 (m, 2H ), 4.35-4.30 (m, 2H), 3.87 (s, 1H), 1.24 (t, J = 8Hz, 3H).

Synthesis of compound 3: Add compound 2 (0.6g, 1.904mmol), INT 5 (0.50g, 1.713mmol), p-toluenesulfonic acid monohydrate (0.361g, 1.904mmol), 1,2 - Dichloroethane 5mL and 1-pentanol 5mL, heated at 70°C for 36h. After the reaction, the reaction solution was evaporated to dryness, dissolved in dichloromethane, washed with water, dried, and passed through a column to obtain 0.6 g of the product. ¹ HNMR (400MHZ, CDCl ₃ ) δ 9.75 (s, 1H), 8.90 (s, 1H), 8.65 (s, 1H), 7.89 (s, 1H), 7.52 (s, 1H), 7.32 (d, J = 4Hz, 1H), 7.20 (t, J = 8Hz, 1H), 7.12 (t, J = 8Hz, 1H), 3.75 (s, 1H), 6.46 (d, J = 8Hz, 1H), 5.70 (d, J = 8Hz, 1H), 3.93 (s, 1H), 3.87 (s, 1H), 2.99 (s, 2H), 2.70 (s, 3H), 2.41 (s, 7H), 0.93 (t, J = 4Hz, 3H ).

Synthesis of compound 4: Add compound 3 (0.4g, 0.70mmol), sodium hydroxide (0.084g, 2.1mmol), 10mL water and 10mL tetrahydrofuran into a 100 mL single-necked bottle, and stir at room temperature for 30 h. After the reaction is complete, spin the reaction solution to dryness, then add water to dissolve it, filter out the insoluble matter, adjust the pH of the water phase to about 5 with 1N dilute hydrochloric acid, and spin the water phase to obtain 0.4 g of crude product.

Synthesis of Example 8: Compound 4 (0.2g, 0.368mmol), methanesulfonamide (0.106g, 1.1mmol), 2-chloro-1-methylpyridinium iodide (0.112g, 0.44mmol), triethylamine (0.112g, 1.1mmol), DMAP (2.24mg, 0.002mmol) and N,N-dimethylformamide 5mL, stirred at room temperature for 36h. After the reaction was completed, saturated brine was added, extracted three times with dichloromethane, washed with water, dried, and purified to obtain 34 mg of the product. MS+1: 621.48.

Example 9

The structural formula of the compound used as a kinase inhibitor of the present embodiment is:

synthetic route:

Synthesis of Example 9: Compound 1 (0.2g, 0.368mmol), methylsulfonamide (0.12g, 1.1mmol), 2-chloro-1-methylpyridinium iodide (0.112 g, 0.44mmol), triethylamine (0.112g, 1.1mmol), DMAP (2.24mg, 0.002mmol) and N,N-dimethylformamide 5mL, stirred at room temperature for 24h. After the reaction was completed, saturated brine was added, extracted three times with dichloromethane, washed with water, dried, and purified to obtain 20 mg of the product. MS+1: 635.48.

Example 10

The structural formula of the compound used as a kinase inhibitor of the present embodiment is:

synthetic route:

Synthesis of Compound 2: Add Compound 1 (1.85g, 8.4mmol) and 40mL of 1,2-dichloroethane to a 100mL single-necked bottle, add aluminum trichloride (2.13 g, 16mmol) under ice bath, and stir After 5 minutes, INT 2 (1.2 g, 9 mmol) was added, and the reaction was heated at 50° C. for 1.5 h. After the reaction was completed, ice water was added, extracted three times with dichloromethane, washed with water, dried, and passed through a column to obtain 1.3 g of the product.

Synthesis of Compound 3: Add Compound 2 (100mg, 0.32mmol) and tetrahydrofuran (8mL) into a 50mL three-neck flask, cool down to 0°C, add Lithium Aluminum Hydride (24mg, 0.631mmol) under nitrogen protection, and stir overnight . The next day, the temperature was lowered, quenched by dropwise addition of saturated ammonium chloride aqueous solution, and extracted three times with ethyl acetate. Dried, spin-dried, and passed through the column to obtain 40 mg of product. ¹ HNMR: (CDCl ₃ , 400MHz) δ 8.57~8.50 (m, 1H), 8.03 (s, 1H), 7.37~7.33 (m, 3H), 4.77 (d, J = 2.4Hz, 2H).

Synthesis of Example 10: In a 10mL single-necked bottle, sequentially add compound 3 (32mg, 0.12mmol), INT 6 (64.5mg, 0.14mmol), Pd ₂ dba ₃ (14.8mg, 0.016mmol), X-Phos (18.4 mg, 0.032mmol), potassium phosphate (56mg, 0.3mmol), dioxane (3.2mL). Under the protection of nitrogen, heat to 100°C and stir for 12h. After the reaction was completed, water and ethyl acetate were added, extracted three times, the organic phases were combined, dried, spin-dried, and purified to obtain 10 mg of the product. ¹ HNMR: (CD ₃ OD, 400MHz) δ8.49 (s, 1H), 8.34 (s, 1H), 8.26~8.23 (m, 2H), 7.50 (d, J = 8.0Hz, 1H), 7.27~7.23 (m, 1H), 7.10~7.06 (m, 1H), 6.50~6.35 (m, 2H), 5.88~5.85 (m, 1H), 4.97~4.85 (m, 2H), 4.69 (s, 2H), 3.84 ~3.81 (m, 2H), 3.36~3.31 (m, 2H), 3.91 (s, 6H), 2.84 (s, 3H).

Example 11

The structural formula of the compound used as a kinase inhibitor of the present embodiment is:

synthetic route:

Synthesis of Compound 2: Add NaH (5.7g, 142.4mmol) and toluene (50mL) into a 250mL three-neck flask, cool the inner temperature to about 5°C in an ice bath, add ethyl formate (10.54g, 142.4mmol), and complete the addition The reaction solution was cooled to about 2°C, and 50 mL of toluene solution of compound 1 (9.4 g, 71.2 mmol) was added dropwise. During the period, the internal temperature was controlled between 0 and 4°C, and the drop was completed in about 30 minutes. After the drop, the reaction solution was removed from the ice bath and naturally Warm to room temperature and stir the reaction overnight. The next day, a large amount of solids were precipitated, and 70 mL of water was added thereto, the pH was adjusted to 1~2 with concentrated hydrochloric acid, extracted twice with ethyl acetate, dried, and concentrated to obtain 13.64 g of crude product.

Synthesis of Compound 3: Take 13.64 g of the crude product from the previous step, add 100 mL of ethanol, 80% hydrazine hydrate (11.83 g, 175.2 mmol) and glacial acetic acid (10.1 g, 168 mmol), and react the mixture under reflux for 3 h, and evaporate the solvent under reduced pressure. Add 80 mL of ethyl acetate and 60 mL of water to the residue, extract twice more with ethyl acetate, combine the organic phases, dry, concentrate, and beat to obtain 9.1 g of the product. ¹ HNMR: (CDCl ₃ , 400MHz) δ 7.80~7.78 (d, J = 7.6Hz, 1H), 7.51~7.48 (m, 2H), 7.38~7.34 (m, 1H), 7.31~7.27 (m, 1H) , 3.67 (s, 2H).

Synthesis of Compound 4: Add Compound 3 (200mg, 1.28mmol) and 6mL DMF to a 100mL single-necked bottle, under nitrogen protection, cool to about 5°C in an ice bath, add NaH (61.5mg, 1.54mmol), a small amount of bubbles escape After the addition, the reaction solution was stirred and reacted in an ice bath for 20 minutes, and then 2 mL of a DMF solution of isopropyl 2,4-dichloropyrimidine-5-carboxylate (330 mg, 1.41 mmol) was added. After the addition, the reaction solution was brownish red , raised to room temperature and stirred overnight. The next day, add water and ethyl acetate, separate the layers, extract the aqueous phase with ethyl acetate twice, combine the organic phases, dry, concentrate, and pass through the column to obtain 138 mg of the product. ¹ HNMR: (CDCl ₃ , 400MHz) δ 9.06 (s, 1H), 8.35 (s, 1H), 7.94 (d, J = 7.6Hz, 1H), 7.41 (d, J = 7.2Hz, 1H), 7.36~ 7.28 (m, 2H), 5.29~5.23 (m, 1H), 3.68 (s, 2H), 1.38 (d, J = 6.4Hz, 6H).

Synthesis of Example 11: In a 25mL single-necked bottle, add compound 4 (138g, 0.39mmol) and INT 5 (113.8mg, 0.39mmol), then add p-toluenesulfonic acid monohydrate (74.1mg, 0.39mmol), and Pentanol (5.5mL) and 1,2-dichloroethane (5.5mL), the mixture was heated and stirred overnight in an oil bath at 90°C, and the next day, water and methylene chloride were added, separated, and the water phase was reused Extracted twice with dichloromethane, combined the organic phases, dried, concentrated, passed through the column to obtain 108 mg of relatively pure crude product, and then purified to obtain 43 mg of pure product. ¹ HNMR: (CDCl ₃ , 400MHz) δ 11.14 (s, 1H), 9.68 (s, 1H), 9.20~9.0 (m, 3H), 7.93 (s, 1H), 7.49(s, 1H), 7.37~7.34 (m, 2H), 6.98~6.91 (m, 1H), 6.72 (s, 1H), 6.55~6.51 (m, 1H), 5.83~5.80 (m, 1H), 5.37~5.32 (m, 1H), 3.91 (s, 3H), 3.73 (s, 2H), 3.32~3.30 (m, 2H), 3.27~3.26 (m, 2H), 2.89 (s, 1H), 2.67 (s, 3H), 1.44 (d, J = 6Hz, 6H).

Example 12

The structural formula of the compound used as a kinase inhibitor of the present embodiment is:

synthetic route:

Synthesis of Compound 2: Add Compound 1 (200mg, 1.28mmol) and 6mL DMF into a 100mL single-necked bottle, cool in an ice bath under nitrogen protection to an internal temperature of about 5°C, add NaH (61.5mg, 1.54mmol), a small amount of bubbles escape After the addition, the reaction solution was stirred in an ice bath for 20 minutes, and then 2 mL of a DMF solution of isopropyl 2,4-dichloropyrimidine-5-carboxylate (330 mg, 1.41 mmol) was added with a syringe to complete the reaction. The solution was brownish-red, and was allowed to rise to room temperature without removing the ice bath and stirred overnight. Water and ethyl acetate were added to the reaction solution, and the liquids were separated after stirring. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined. It was dried, concentrated, and passed through the column to obtain 2108 mg of compound. ¹ HNMR: (CDCl ₃ , 400MHz) δ 8.59 (s, 1H), 8.34 (s, 1H), 7.71~7.69 (m, 1H), 7.49~7.47 (m, 1H), 7.39~7.35 (m, 2H) , 5.40~5.33 (m, 1H), 3.74 (s, 2H), 1.40 (d, J = 6.8Hz, 6H).

Synthesis of Example 12: Add compound 2 (108g, 0.31mmol) and INT 5 (89.1mg, 0.31mmol) to a 25mL single-necked bottle, and then add p-toluenesulfonic acid monohydrate (57.9mg, 0.31mmol) , 4.3mL of n-pentanol and 4.3mL of 1,2-dichloroethane, the mixture was heated and stirred in an oil bath at 90°C overnight, and dichloromethane was added to the residue, stirred and separated, and the water phase was reused Extracted twice with dichloromethane, combined the organic phases, dried, concentrated, passed through the column to obtain 25 mg of relatively pure crude product, and purified the crude product again to obtain 9 mg of pure product. ¹ HNMR: (CDCl ₃ , 400MHz) δ 12.43 (s, 1H), 9.48(s, 1H), 9.11~9.02 (m, 3H), 8.48 (s, 1H), 7.72 (d, J = 4.8Hz, 1H ), 7.51 (d, J = 4.8Hz, 1H), 7.38~7.36 (m, 2H), 6.97~6.91 (m, 1H), 6.72 (s, 1H), 6.54~6.50 (m, 1H), 5.80( d, J = 9.6Hz, 1H), 5.30~5.29 (m, 1H), 3.89 (s, 3H), 3.78 (s, 2H), 3.30 (s, 2H), 3.20 (s, 2H ), 2.85 (s , 6H), 2.65 (s, 3H), 1.34 (d, J = 6.4Hz, 6H).

Example 13

The structural formula of the compound used as a kinase inhibitor of the present embodiment is:

synthetic route:

Synthesis of compound 2: Add compound 1 (200mg, 1.28mmol) and 6mL of DMF to a 100mL single-necked bottle, under nitrogen protection, stir and cool in an ice bath to an internal temperature of about 5°C, add NaH (61.5mg, 1.54mmol) , a small amount of bubbles escaped, and the reaction solution was stirred and reacted in an ice bath for 20 minutes, and then 2mL of a DMF solution of 2,4-dichloropyrimidine (210mg, 1.41mmol) was added to it with a syringe, and the reaction solution was brownish red after the addition. , without removing the ice bath, let it rise to room temperature and stir overnight, add water and ethyl acetate to the reaction solution, separate the liquid, extract twice with ethyl acetate, combine the organic phases, dry, concentrate, and pass through the column to obtain 83 mg of the product.

Synthesis of Example 13: Add compound 2 (50mg, 0.19mmol) and INT 5 (54.4mg, 0.19mmol) to the reaction flask, then add p-toluenesulfonic acid monohydrate (35.5mg, 0.19mmol), 2mL n-pentyl Alcohol and 2 mL of 1,2-dichloroethane, and the mixture was heated and stirred in an oil bath at 90°C to react overnight. The next day, water and dichloromethane were added, separated, and dichloromethane was extracted twice again. The organic phases were combined, dried, concentrated, and passed through a column to obtain 79 mg of the product. ¹ HNMR: (CDCl ₃ , 400MHz) δ 10.09 (s, 1H), 9.79 (s, 1H), 9.37 (s, 1H), 8.43 (d, J = 5.2Hz, 1H), 7.89 (d, J = 7.2 Hz, 1H), 7.84 (s, 1H), 7.52 (d, J = 7.6Hz, 1H), 7.41~7.32 (m, 3H), 6.79 (s, 1H), 6.56~6.51 (m, 1H), 6.44 ~6.38 (m , 1H), 5.76~5.73 (m, 1H), 3.89 (s, 3H), 3.81 (s, 2H), 2.92~2.89 (m, 2H), 2.70 (s, 3H ), 2.36~2.33 (m, 2H), 2.29 (s, 6H), 2.03 (d, J = 3.6Hz, 1H).

Example 14

The structural formula of the compound used as a kinase inhibitor of the present embodiment is:

synthetic route:

Synthesis of compound 2: Dissolve compound 1 (1g, 6.40mmol) in 25mL DMF, then add NIS (1.73g, 7.68mmol), react at 80°C overnight, and spot plate tracking. The next day, when the reaction was over, the reaction solution was cooled to room temperature, extracted with water and ethyl acetate, and the organic phase was washed with saturated brine, dried, concentrated, and passed through a column to obtain 1.17 g of the product. ¹ HNMR: (DMSO-d6, 400MHz) δ 13.50 (s, 1H), 7.63~7.53 (m, 2H), 7.37~7.27 (m, 2H), 3.54 (s, 2H).

Synthesis of compound 3: Dissolve compound 2 (600mg, 2.13mmol) in anhydrous THF, lower the reaction temperature to 0-5°C, add NaH (94mg, 2.34mmol), react at 0-5°C for 30 minutes, then Add methyl iodide (5.54 mmol) dropwise at 5°C. After the drop is complete, slowly warm to room temperature and react overnight. The next day, when the reaction was completed, water was added to quench the reaction, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried, concentrated, and passed through a column to obtain 279 mg of the product. ¹ HNMR: (DMSO-d6, 400MHz) δ 7.56 (d, J = 7.6Hz, 1H), 7.52~7.37 (m, 1H), 7.34~7.33 (m, 1H), 7.31~7.26 (m, 1H), 4.08 (s, 3H), 3.47 (s, 2H).

Synthesis of compound 4: Dissolve compound 3 (109mg, 0.37mmol) in 4mL dry 1,4-dioxane, add hexa-n-butylditin (0.43g, 0.74mmol), tetrakis(triphenylphosphine) Palladium (20.8mg, 0.018mmol), react overnight at 100°C. The next day, add 2 mL of 1N cesium fluoride aqueous solution, stir at room temperature for 5 min, filter, and extract the filtrate with ethyl acetate, wash the organic phase with saturated brine, dry, concentrate, and pass through the column to obtain 49 mg of the product. ¹ HNMR: (CDCl ₃ , 400MHz) δ 7.54~7.48 (m, 2H), 7.35~7.29 (m, 1H), 7.25~7.21 (m, 1H), 4.17 (s, 3H), 3.53 (s, 2H) , 1.67~1.53 (m, 10H), 1.40~1.36 (m, 7H), 1.34~1.16 (m, 6H), 1.14~1.13 (m, 5H),1.11~0.93 (m, 11H).

Synthesis of compound 5: Dissolve compound 4 (50mg, 0.11mmol) in 2mL of anhydrous 1,4-dioxane, add 2,4-dichloropyrimidine-5-carboxylate isopropyl ester (35mg, 0.15mmol), Tris(dibenzylideneacetone)dipalladium (41mg, 0.045mmol), react at 80°C for 3.5h, add water and ethyl acetate to extract after the reaction, wash the organic phase with saturated brine, dry, concentrate, and pass through the column to obtain 25mg of the product . ¹ HNMR: (CDCl ₃ , 400MHz) δ 8.63 (s, 1H), 7.59~7.56 (m, 2H), 7.39~7.30 (m, 2H), 5.38~5.29 (m, 1H), 4.17 (s, 3H) , 3.89 (s, 2H), 1.39 (d, J = 6.4Hz, 6H).

Synthesis of Example 14: Dissolve compound 5 (25mg, 0.068mol) in 1mL 1,2-dichloroethane and 1mL n-pentanol, add INT 5 (20mg, 0.068mmol), p-toluenesulfonic acid monohydrate (13mg, 0.068mmol), react overnight at 90°C, after the reaction, concentrate the reaction solution, wash with saturated aqueous sodium bicarbonate, extract with dichloromethane, wash the organic phase with saturated brine, dry, concentrate, and pass through the column to obtain 21mg of product . ¹ HNMR: (CDCl ₃ , 400MHz) δ 8.64 (s, 1H), 8.42 (s, 1H), 7.71 (d, J = 7.6Hz, 1H), 7.56 (d, J = 7.6Hz, 1H), 7.40 ( t, J = 7.2Hz, 1H), 7.30 (t, J = 8.4Hz, 1H), 6.97 (s, 1H), 6.49~6.47 (m, 2H), 5.84 (dd, J = 3.6, 7.6Hz, 1H ), 5.20~5.14 (m, 1H), 4.17 (s, 3H), 4.01 (s, 3H), 3.73 (s, 2H), 3.51~3.48 (m, 2H), 3.28~3.25 (m, 2H), 2.86 (s, 6H), 2.72 (s, 3H), 1.28 (d, J = 6.4Hz, 6H).

Example 15

The structural formula of the compound used as a kinase inhibitor of the present embodiment is:

synthetic route:

Synthesis of Compound 2: Compound 1 (1g, 6.40mmol) was dissolved in 25mL DMF, then NIS (1.73g, 7.68mmol) was added, reacted overnight at 80°C, followed by spotting. The next day, when the reaction was over, the reaction solution was cooled to room temperature, extracted with water and ethyl acetate, and the organic phase was washed with saturated brine, dried, concentrated, and passed through a column to obtain 1.17 g of the product. ¹ HNMR: (DMSO-d6, 400MHz) δ 13.50(s, 1H), 7.63~7.53 (m, 2H), 7.37~7.27 (m, 2H), 3.54 (s, 2H).

Synthesis of compound 3: Dissolve compound 2 (3.18g, 11.3mmol) in anhydrous 50mL THF, lower the reaction temperature to 0-5°C, add NaH (0.5g, 12.4mmol), react at 0-5°C for 30min, and then Add iodomethane (4.2g, 29.3mmol) dropwise at 0-5°C, slowly rise to room temperature, and react overnight. The next day, water was added to quench the reaction, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried, concentrated, and passed through the column to obtain 195 mg of the product. ¹ HNMR: (DMSO-d6, 400MHz) δ 7.60 (d, J = 7.2Hz, 1H), 7.54 (d, J = 7.2Hz, 1H), 7.35 (t, J = 7.2Hz, 1H), 7.31~7.27 (m, 1H), 3.93 (s, 3H), 3.55 (s, 2H).

Synthesis of Compound 4: Dissolve Compound 3 (156mg, 0.53mmol) in 5.3mL of anhydrous 1,4-dioxane, add hexa-n-butylditin (0.61g, 1.05mmol), tetrakis(triphenylphosphine) Palladium (30mg, 0.026mmol), react overnight at 100°C. The next day, water and ethyl acetate were added for extraction, and the organic phase was washed with saturated brine, dried, concentrated, and passed through a column to obtain 128 mg of the product. ¹ HNMR: (CDCl ₃ , 400MHz) δ 7.75 (d, J = 7.6Hz, 1H), 7.47 (d, J = 7.2Hz, 1H), 7.35~7.31 (m, 1H), 7.25~7.21 (m, 1H ), 4.01 (s, 3H), 3.61 (s, 2H), 1.68~1.52 (m, 25H), 1.41~1.18 (m, 49H), 0.94~0.88 (m, 32H).

Synthesis of compound 5: Dissolve compound 4 (122mg, 0.26mmol) in 5mL of anhydrous 1,4-dioxane, add 2,4-dichloropyrimidine-5-carboxylate isopropyl ester (87mg, 0.37mmol), Tris(dibenzylideneacetone)dipalladium (48.5mg, 0.053mmol), react at 80°C for 3.5h, after the reaction, add water and ethyl acetate to extract, wash the organic phase with saturated brine, dry, concentrate, and pass through the column to obtain 29mg product. ¹ HNMR: (CDCl ₃ , 400MHz) δ 9.08 (s, 1H), 7.79 (d, J = 7.6Hz, 1H), 7.45 (d, J = 7.6Hz, 1H), 7.39~7.35 (m, 1H), 7.30~7.28 (m, 1H), 5.19~5.10 (m, 1H), 4.11 (s, 3H), 3.54 (s, 2H), 1.16 (d, J = 6.4Hz, 6H).

Synthesis of Example 15: Dissolve compound 5 (30 mg, 0.08 mol) in 1.2 mL 1,2-dichloroethane and 1.2 mL n-pentanol, add INT 5 (23.3 mg, 0.08 mmol), p-toluenesulfonic acid Monohydrate (13mg, 0.068mmol), react overnight at 90°C, after the reaction is completed, the reaction solution is concentrated, washed with saturated aqueous sodium bicarbonate, extracted with dichloromethane, washed with saturated brine, dried, concentrated, and passed through the column 22 mg of product were obtained. ¹ HNMR: (CDCl ₃ , 400MHz) δ 9.01 (s, 1H), 8.22 (s, 1H), 7.70 (d, J = 7.6Hz, 1H), 7.49 (d, J = 7.2Hz, 1H), 7.36 ( t, J = 7.6Hz, 1H), 7.29 (t, J = 6.8Hz, 1H), 6.95 (s, 1H), 6.51~6.37 (m, 2H), 5.80 (d, J = 9.6Hz, 1H), 5.06~4.99 (m, 1H), 3.97 (s, 3H), 3.92 (s, 3H), 3.65~3.63 (m, 1H), 3.56 (s, 2H), 3.49~3.46 (m, 2H), 3.41 ( s, 1H), 3.31~3.21(m, 2H), 2.83 (s, 6H), 2.70 (s, 3H), 1.10 (d, J = 6.4Hz, 6H).

Example 16

The structural formula of the compound used as a kinase inhibitor of the present embodiment is:

synthetic route:

Synthesis of Compound 2: Add Compound 1 (1.85g, 8.4mmol) and DCE (40mL) to a 100mL single-necked bottle, add aluminum trichloride (2.13g, 16mmol) in an ice bath, stir for 5 minutes, and then add INT 2 (1.2g, 9mmol), then heated at 50°C for 1.5h. After the reaction, water was added, extracted three times with dichloromethane, the organic phases were combined, washed once with saturated brine, dried, and passed through a column to obtain 1.3 g of the product.

Synthesis of Example 16: INT 6 (50mg, 0.11mmol), compound 2 (36mg, 0.11mmol), p-toluenesulfonic acid monohydrate (31mg, 0.17mmol), 1mL of NMP and 2mL of ethylene glycol monomethyl ether , added to a 5mL reactor, heated to 120°C, reacted for 6h, cooled to room temperature, added 10mL of ethyl acetate, washed with aqueous sodium bicarbonate solution, washed once with saturated brine, dried, and purified to obtain 20mg of the product. MS+1: 641.52.

Example 17

The structural formula of the compound used as a kinase inhibitor of the present embodiment is:

synthetic route:

Synthesis of Example 17: Add the compound of Example 16 (50 mg, 0.078 mmol), NaOH (36 mg, 0.9 mmol), and 2 mL of ethanol into a 5 mL reactor, heat to 70 ° C, react for 6 h, cool to room temperature, After the reaction of the raw material was complete, 10 mL of ethyl acetate was added, washed with aqueous sodium bicarbonate solution, washed once with saturated brine, dried, and purified to obtain 15 mg of the product. MS+1: 613.48.

Example 18

The structural formula of the compound used as a kinase inhibitor of the present embodiment is:

synthetic route:

Synthesis of Compound 2: Dissolve Compound 1 (2g, 10.1mmol) in dichloromethane, cool down to 0°C under nitrogen protection, slowly add Boc ₂ O (2.42g, 11.1mmol) in dichloromethane solution dropwise, and then add DMAP (0.25g, 2.05mmol) was slowly heated to room temperature for 16h. After the raw materials were reacted, they were concentrated and passed through the column to obtain 1.6 g of compound 2. ¹ HNMR (400MHz, CDCl ₃ ) δ 4.76 (s, 1H), 3.66 (d, J = 11.2Hz, 2H), 3.37 (td, J = 11.6, 4.0Hz, 2H), 2.28 (s, 1H), 1.65 (dt, J = 7.6, 5.2Hz, 2H), 1.43 (d, J = 8.8Hz, 18H).

Synthesis of Compound 3: Add Lithium Aluminum Hydride (1.75g, 46mmol) into dry tetrahydrofuran, lower the temperature to 0°C under the protection of nitrogen, slowly add the tetrahydrofuran solution of Compound 2 (1.6g, 5.36mmol) dropwise, and then raise the temperature to Reaction at 70°C for 16h. After the raw materials were reacted, the temperature was lowered to 0°C, and 2 mL of water and 2 mL of 20% aqueous sodium hydroxide solution were slowly added dropwise, and 1.48 g of compound 3 was obtained by filtration.

Synthesis of Compound 4: INT 9 (250mg, 0.526mmol), Compound 3 (100mg, 0.793mmol) and DIPEA (203mg, 1.57mmol) were added to N,N-dimethylacetamide and reacted at 100°C for 16h. After the raw materials were reacted, water was added to the reaction system, extracted three times with ethyl acetate, the organic phases were combined, washed with brine, dried, concentrated, and passed through the column to obtain 280 mg of the product.

Synthesis of Compound 5: Compound 4 (280mg, 0.481mmol) and palladium on carbon (56mg, 20%) were added to methanol, and reacted at room temperature for 2h under hydrogen atmosphere. After the raw materials were reacted, diatomaceous earth was added to filter, the filter cake was washed three times with methanol, and the filtrates were combined and spin-dried to obtain 190 mg of compound 5.

Synthesis of Example 18: Compound 5 (190mg, 0.345mmol) and triethylamine (104mg, 1.03mmol) were dissolved in dichloromethane, cooled to 0°C under nitrogen protection, and then acryloyl chloride (41mg, 0.45 mmol) in dichloromethane and kept at 0°C for 2h. After the raw materials were reacted, saturated aqueous sodium bicarbonate solution was added, extracted three times with dichloromethane, the organic phases were combined, washed with brine, dried, concentrated, and passed through the column to obtain 30 mg of the product. ¹ HNMR (400MHz, CDCl ₃ ) δ 10.54 (s, 1H), 9.66 (s, 1H), 8.89 (m, 2H), 7.97 (s, 1H), 7.32 (d, J = 8.0Hz, 1H), 7.16 (t, J = 8.0Hz, 1H), 6.98 (m, 2H), 6.84 (s, 1H), 6.44 (dd, J = 16.8, 2.0Hz, 1H), 6.36- 6.24 (m, 1H), 5.69 ( dd, J = 10.0, 2.0Hz, 1H), 3.99 (s, 3H), 3.90 (s, 3H), 3.05 (m, 1H), 2.65 (m, 7H), 2.32 (s, 3H), 2.20 (s , 3H), 1.08 (s, 2H).

Example 19

The structural formula of the compound used as a kinase inhibitor of the present embodiment is:

synthetic route:

Synthesis of compound 2: Dissolve compound 1 (5g, 28.9mmol) and AlCl ₃ (5.76g, 43.3mmol) in 50mL of dry 1,2-dichloroethane, raise the temperature to 80°C under nitrogen protection and react for 1h, Subsequently, a solution of methyl indole in dichloroethane (4.53 g, 34.6 mmol) was slowly added dropwise under stirring, and the reaction was continued at 80°C for 3 h after the addition was completed. After the reaction, the temperature was lowered, slowly poured into ice water, and extracted three times with dichloromethane, the organic phases were combined, dried, and passed through the column to obtain 2.6 g of the product.

Synthesis of Compound 3: Compound 2 (1.5g, 5.6mmol) and INT-7 (1.8g, 6.71mmol) were dissolved in dioxane and water, and p-toluenesulfonic acid monohydrate (1.59g, 8.37mmol) was added , heated to 80 °C for 16 h. After the reaction of the raw materials, the reaction solution was spin-dried, and 2N aqueous sodium hydroxide solution was added to adjust the alkalinity, and then extracted three times with ethyl acetate, the organic phases were combined, dried, concentrated, and passed through the column to obtain 2.5 g of the product.

Synthesis of Compound 4: Dissolve Compound 3 (0.5g, 1mmol) in a mixed solvent of ethanol and water, add iron powder (0.448g, 8mmol) and ammonium chloride (0.43g, 8mmol) under stirring, and heat up to 80°C Reaction 2h. After the reaction of the raw materials, ethanol was spun off, ammonia water was added to adjust the alkalinity, and then extracted three times with ethyl acetate, the organic phases were combined, dried, and concentrated to obtain 0.45 g of crude product.

Synthesis of Compound 5: Compound 4 (0.45g), hydroxylamine hydrochloride (0.4g, 5.74mmol) and anhydrous potassium acetate (1.125g, 11.4mmol) were added to a mixed solvent of ethanol and dioxane, and the reaction was refluxed at 80 °C After 16 hours, after the reaction of the raw materials, most of the solvent was spun off, then water and ethyl acetate were added, extracted three times, the organic phases were combined, dried, concentrated, and passed through the column to obtain 0.37 g of the product.

Synthesis of Compound 6: Compound 5 (0.37g, 0.734mmol) and 2,2-dimethoxypropane (0.61g, 5.87mmol) were dissolved in a mixed solvent of 1,2 dichloroethane and acetic acid, 80 ℃ reflux reaction for 2h. After the raw materials were reacted, most of the solvent was spun off. Subsequently, saturated sodium bicarbonate solution was added to adjust the pH to 8, extracted three times with dichloromethane, the organic phases were combined, dried, concentrated, and passed through the column to obtain 0.17 g of the product.

Synthesis of Example 19: Dissolve compound 6 (0.17g, 0.312mmol) and triethylamine (47mg, 0.468mmol) in dry dichloromethane, lower the temperature to 0°C, and then add acryloyl chloride in dichloromethane dropwise Solution (31mg, 0.343mmol), kept at 0℃ for 2h. After the raw materials were reacted, water and dichloromethane were added, extracted three times, the organic phases were combined, dried, concentrated, and passed through a column to obtain 60 mg of the product. ¹ HNMR (400MHz, CDCl ₃ ): δ 10.15 (s, 1H), 10.13 (s, 1H), 9.92 (s, 1H), 9.16 (s, 1H), 8.62-8.60 (m, 1H), 8.54 (s , 1H), 7.367.34 (m, 1H), 7.247.23 (m, 3H), 6.82 (m, 1H), 6.506.37 (m, 2H), 5.71 (dd, J = 22.64, 2.6Hz, 1H ), 3.97 (s, 3H), 3.93 (s, 3H), 2.92 (t, J = 5.4, 5.8Hz, 2H), 2.71 (s, 3H), 2.32 (t, J = 5.72, 5.64Hz, 2H) , 2.28 (s, 6H), 1.63 (s, 6H).

Example 20

The structural formula of the compound used as a kinase inhibitor of the present embodiment is:

synthetic route:

Synthesis of Compound 2: Dissolve INT 8 (5g, 9.38mmol) in ethanol and water, add iron powder (4.2g, 75.1mmol) and ammonium chloride (4.1g, 75.1mmol) under stirring, after the addition is complete, heat up to 80 ℃ reaction 2h. After the reaction of the raw materials, most of the ethanol in the reaction solution was spun off, then ammonia water was added to adjust the alkalinity, and then extracted three times with ethyl acetate, the organic phases were combined, dried, and concentrated to obtain 5 g of crude product.

Synthesis of compound 3: compound 2 (5 g) and lithium hydroxide (2.08 g, 49.7 mmol) were added into a mixed solvent of methanol, tetrahydrofuran and water, and reacted at room temperature for 16 h. After the raw materials were reacted, most of the solvent was spun off, and then 4.6 g of crude product was obtained after carrying water with toluene three times.

Synthesis of Compound 4: Dissolve the crude product of Compound 3 (2g), DIPEA (1.58g, 12.2mmol) and hydroxylamine hydrochloride (0.84g, 12.2mmol) in dry DMF, react at room temperature for 15 minutes, add PyBop (2.5 g, 4.91mmol), under the protection of nitrogen, react at room temperature for 16h, monitor by TLC, add water and ethyl acetate to the reaction system for extraction, combine the organic phases, dry, concentrate, and pass through the column to obtain 0.6g product.

Synthesis of Compound 5: Compound 4 (0.6g, 1.18mmol) and 2,2-dimethoxypropane (0.99g, 9.51mmol) were dissolved in a mixed solvent of 1,2-dichloroethane and acetic acid, 80 ° C reflux reaction for 2h. After the reaction of the raw materials, most of the solvent was spun off, then a saturated sodium bicarbonate solution was added to adjust the pH=8, and then extracted with dichloromethane three times, the organic phases were combined, dried, the solvent was spun off, and 0.13 g of the product was obtained by passing through the column.

Synthesis of Example 20: Dissolve compound 5 (0.13g, 0.238mmol) and triethylamine (36mg, 0.357mmol) in dry dichloromethane, cool down to 0°C, and then add acryloyl chloride in dichloromethane dropwise Solution (0.0238g, 0.262mmol), kept at 0°C for 2h. After the raw materials were reacted, water was added, extracted three times with dichloromethane, the organic phases were combined, dried, concentrated, and passed through the column to obtain 14 mg of the product. ¹ HNMR (400MHz, CDCl3): δ 8.95 (s, 1H), 8.54 (s, 1H), 8.20 (s, 1H), 2.92 (d, J = 8.12Hz, 2H), 7.86 (s, 1H), 7.31 -7.22 (m, 2H), 7.10 (t, J = 7.64, 7.32Hz, 1H), 6.63 (s, 1H), 6.59-6.53 (m, 1H), 6.30 (d, J = 16.52Hz, 1H), 5.71 (d, J = 10.24Hz, 1H), 3.86 (s, 3H), 3.80 (s, 3H), 3.31 (t, J = 5.4, 5.8Hz, 2H), 3.16 (t, J = 5.72, 5.64Hz , 2H), 2.73 (s, 6H), 2.60 (s, 3H), 1.48 (s, 6H).

Example twenty one

The structural formula of the compound used as a kinase inhibitor of the present embodiment is:

synthetic route:

Synthesis of Compound 2: Add 90ml of dioxane hydrochloride to a 250mL single-necked bottle, and protect it under nitrogen. Dissolve INT 10 (1.52g, 2.40mmol) in 50mL of dry THF, add dropwise to the reaction flask, then take 10ml of dry THF, also drop into the reaction flask, stir at 40°C for 4h, cool down At 0°C, filter with suction, wash the filter cake with dry THF, and dry in vacuum to obtain 1.324 g of the product.

Synthesis of Compound 3: Take Compound 2 (0.843g, 1.48mmol), add 16mL of triethyl orthoformate, and react under reflux at 160°C for 2 hours. The solvent was distilled off under reduced pressure, the temperature was lowered, a mixture of methanol and dichloromethane was added to dissolve, and the column was passed to obtain 0.154 g of pure product. ¹ HNMR (400MHz, DMSO-d6) δ 9.27 (s, 1H), 8.99 (s, 1H), 8.62 (s, 1H), 8.26 (s, 1H), 7.86 (s, 1H), 7.48 (d, J = 8.3Hz, 1H), 7.44 (s, 1H), 7.21 (d, J = 15.2Hz, 1H), 7.01 (s, 1H), 6.84 (s, 1H), 3.91 (s, 3H), 3.78 (s , 3H), 3.33 (s, 13H), 2.87 (s, 3H), 2.50 (p, J = 1.9Hz, 14H), 2.19 (s, 5H).

Synthesis of Compound 4: Compound 3 (154mg, 0.284mmol), zinc powder (110mg, 1.69mmol) and ammonium chloride (149mg, 2.78mmol) were added to 3mL acetone and 0.3mL water, after the addition was complete, the temperature was raised to 26°C Reaction 2h. Add a saturated aqueous solution of sodium bicarbonate, dichloromethane and a little methanol, extract twice, dry, and spin dry to obtain 0.235 g of crude product, which is directly used in the next step.

Synthesis of Example 21: Add crude compound 4 (0.235g), 10mL of dichloromethane, and triethylamine (85mg, 0.84mmol) to a 100mL single-necked bottle, cool down to 0°C, and dropwise add acryloyl chloride (33mg, 0.37mmol) , Keep the reaction at 0°C for 3h. After the raw materials were reacted, a saturated aqueous sodium bicarbonate solution was added, extracted twice with dichloromethane, dried, concentrated, and passed through a column to obtain 15 mg of the product. ¹ HNMR (400MHz, CDCl ₃ ) δ 10.17 (s, 1H), 9.78 (s, 1H), 8.92 (s, 1H), 8.85 (m, 1H), 8.16 (s, 1H), 7.97 (s, 1H) , 7.31 (d, J = 8.2Hz, 1H), 7.15 (t, J = 6.2Hz, 1H), 6.94 (d, J = 7.2Hz, 2H), 6.80 (m, 2H), 6.53-6.35 (m, 2H), 5.81-5.64 (m, 1H), 3.95 (s, 3H), 3.89 (s, 4H), 2.90 (t, J = 5.5Hz, 2H), 2.70 (s, 3H), 2.32 (s, 2H ), 2.28 (s, 6H).

Example twenty two with twenty three

Referring to Example 18, Examples 22 and 23 were synthesized, see Table 1 below:

MS+1 = 608.3 實施例23

MS+1 = 608.3 Compounds of Table 1 Examples 22 and 23 serial number structure characterize Example 22

MS+1 = 608.3 Example 23

MS+1 = 608.3

Example twenty four

The structural formula of the compound used as a kinase inhibitor of the present embodiment is:

synthetic route:

Synthesis of compound 2: Add compound 1 (24g, 133mmol) and acetylhydrazine (12.7g, 172mmol) into a 1000mL single-necked bottle, add 400mL of 1N sodium hydroxide aqueous solution, react at 80°C for 4h, and there are a lot of yellow solids Precipitate. Cool down, add 33 mL of concentrated hydrochloric acid, stir at a low temperature around 0°C for 30 minutes, filter with suction, wash the filter cake once with water, and dry under vacuum at 55°C overnight to obtain 18.8 g of a yellow solid product.

Synthesis of compound 3: Add compound 2 (18.8g, 97mmol) to a 1000mL single-necked bottle, add toluene 450mL, phosphorus oxychloride (89.3g, 583mmol), DIPEA (50.1g, 389mmol) at room temperature, Fog is generated. Heated to 80°C under nitrogen protection and stirred overnight. The next day, most of the solvent was spun off, the reaction solution was poured into crushed ice, extracted three times with ethyl acetate, the organic phases were combined, dried, concentrated, and passed through the column to obtain 12.08 g of the product.

Synthesis of Compound 4: Add Compound 3 (2.38g, 10.3mmol) to a 250mL single-necked bottle, dissolve it in 120mL 1,2-dichloroethane, add anhydrous aluminum trichloride (2.33g, 17.5mmol), and stir at room temperature 30 minutes. Cool down to 0°C, add INT 2 (1.52g, 11.33mmol) dropwise, stir at low temperature for 30min, then raise the temperature to 50°C for 2h. The temperature was lowered, poured into ice water, extracted twice with dichloromethane, dried, spin-dried, and passed through the column to obtain 1.24 g of the product. ¹ HNMR (400MHz, CDCl ₃ ) δ 8.84 (s, 1H), 8.05-8.00 (m, 1H), 7.96 (s, 1H), 7.42-7.26 (m, 3H), 2.50 (s, 3H).

Synthesis of Example 24: Add compound 4 (0.397g, 1.22mmol), p-toluenesulfonic acid monohydrate (0.3g, 1.58mol), INT 4 (0.526g, 1.34mmol), NMP 20mL into a 100mL single-necked bottle and ethylene glycol monomethyl ether 40mL. Under nitrogen protection, stir overnight at 120°C. The next day, add 0.2 mL of 1N sodium hydroxide, extract three times with ethyl acetate, dry, concentrate, and pass through a column to obtain 40 mg of the product. ¹ HNMR (400MHz, CDCl ₃ ) δ 10.22 (s, 1H), 9.78 (s, 1H), 8.89 (m, 2H), 7.95 (s, 1H), 7.31 (d, J = 8.Hz, 1H), 7.15 (m, 1H), 6.97 (t, J = 7.8Hz, 2H), 6.80 (s, 1H), 6.46 (dd, J = 16.9, 2.1Hz, 1H), 6.36 (dd, J = 17.0, 9.9Hz , 1H), 5.71 (dd, J = 9.8, 2.1Hz, 1H), 3.88 (s, 3H), 2.88 (t, J = 5.6Hz, 2H), 2.70 (s, 3H), 2.26 (s, 8H) , 2.19 (s, 3H).

Example 25

The structural formula of the compound used as a kinase inhibitor of the present embodiment is:

synthetic route:

Synthesis of Compound 2: Add 120 mL of dioxane hydrochloride to a 250 mL single-necked bottle, and protect with nitrogen. Dissolve INT 10 (2.08g) in 55mL of dry THF, add dropwise to the reaction flask, stir at 40°C for 4 hours, cool down to 0°C, filter with suction, wash the filter cake with THF, and dry in vacuo to obtain 3.3 g products.

Synthesis of Compound 3: Compound 2 (0.871g, 1.53mmol) and triethylamine (0.463g, 4.59mmol) were dissolved in dichloromethane, stirred for 5 minutes, cooled to 0°C in an ice bath, and acetic anhydride ( 0.172g, 1.683mmol), stirred at low temperature for 30 minutes, and then stirred overnight at 25°C. The next day, the raw material disappeared, and aqueous sodium bicarbonate solution was added, extracted twice with dichloromethane, the organic phases were combined, dried, and passed through a column to obtain 0.73 g of the product.

Synthesis of compound 4: take compound 3 (0.133 g), add 0.4 g of Lawson's reagent, and then add 20 mL of THF, reflux at 80° C. for 2 hours, and the raw materials disappear. Cool down, process, and pass through the column to obtain 0.13 g of the product.

Synthesis of Compound 5: Compound 4 (1.4g, 2.44mmol), zinc powder (0.955g, 14.7mmol) and ammonium chloride (1.31g, 24.5mmol) were added and heated to 26°C for 2h. The raw material disappeared, adding a saturated aqueous solution of sodium bicarbonate, extracting twice with dichloromethane, drying, and concentrating to obtain 0.6 g of crude product, which was directly used in the next step.

Synthesis of Example 25: Dissolve compound 5 (0.6g) and triethylamine (0.33g, 3.26mmol) in 50mL of dichloromethane, cool down to 0°C, add acryloyl chloride (130mg, 1.44mmol) dropwise, keep React at 0°C for 3h, and the reaction of the raw materials is complete. Add saturated aqueous sodium bicarbonate, extract twice with dichloromethane, dry, concentrate, pass through a column, and then purify to obtain 200 mg of the product. ¹ HNMR (400MHz, CDCl ₃ ) δ 9.77 (s, 1H), 9.57 (m, 1H), 8.90 (s, 1H), 8.56 (m, 1H), 7.89 (s, 1H), 7.30 (d, J = 8.2Hz, 1H), 7.14 (t, J = 7.6Hz, 1H), 6.95 (t, J = 7.5Hz, 2H), 6.71 (s, 1H), 6.50 (dd, J = 16.8, 2.0Hz, 1H) , 5.76 (ddd, J = 10.0, 7.9, 1.9Hz, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.16 (m, 2H), 2.86 (m, 2H), 2.69 (s, 4H ), 2.61 (s, 9H).

Example 26

The structural formula of the compound used as a kinase inhibitor of the present embodiment is:

synthetic route:

Synthesis of compound 2: In a 100mL single-necked bottle, dissolve compound 1 (0.624g, 2.71mmol) in 40mL of 1,2-dichloroethane, add aluminum trichloride (0.613g, 4.61mmol), and stir at room temperature For 30 minutes, cool down in an ice-salt bath, add indole (0.349g, 2.98mmol) dichloroethane solution dropwise, stir at low temperature for 30 minutes, raise the temperature to 50°C and stir for 2h, cool down, pour into ice water, and wash with ethyl acetate Extracted 3 times, combined the organic phases, dried, and passed through the column to obtain 0.245 g of solid product.

Synthesis of Example 26: Add compound 2 (0.245g, 0.79mmol), p-toluenesulfonic acid (0.195g, 1.03mol), INT 4 (0.34g, 0.87mmol), NMP10mL, ethylene glycol to a 100mL single-necked bottle 20 mL of monomethyl ether, under nitrogen protection, stirred overnight at 120°C. The next day, add sodium hydroxide aqueous solution, and extract with ethyl acetate three times. The ethyl ester phases were combined, concentrated, dried, and passed through a column to obtain 20 mg of the product. ¹ HNMR (400MHz, CDCl ₃ ) δ 10.27 (m, 1H), 9.69 (s, 1H), 9.27 (s, 1H), 8.85 (s, 1H), 8.43 (m, 1H), 7.93 (s, 1H) , 7.34 (d, J = 8.1Hz, 1H), 7.10 (t, J = 7.6Hz, 1H), 6.99 (m, 2H), 6.80 (s, 1H), 6.54-6.27 (m, 2H), 5.70 ( dd, J = 9.9, 1.9Hz, 1H), 3.88 (s, 3H), 2.89 (t, J = 5.5Hz, 2H), 2.71 (s, 3H), 2.26 (m, 11H).

Example 27

The structural formula of the compound used as a kinase inhibitor of the present embodiment is:

synthetic route:

Synthesis of Compound 2: Add 90 mL of dioxane hydrochloride to a 250 mL single-necked bottle, and protect with nitrogen. Dissolve INT 10 (1.52g) in 50mL of dry THF, add dropwise to the reaction flask, then take 10mL of THF, also drop into the reaction flask, stir at 40°C for 4h, cool down to 0°C, Suction filtration, the filter cake was washed with THF, and vacuum-dried to obtain 1.324 g of the product.

Synthesis of Compound 3: Take Compound 2 (1.324 g), add 17 mL of triethyl orthoacetate, and react under reflux at 160°C for 2 hours, and the raw materials disappear. The solvent was distilled off under reduced pressure, the temperature was lowered, a mixture of methanol and dichloromethane was added to dissolve, and the column was passed to obtain 0.42 g of pure product. ¹ HNMR (400MHz, DMSO-d6) δ 9.01 (s, 1H), 8.60 (s, 1H), 8.35 (s, 1H), 7.94 (m, 1H), 7.53 (s, 1H), 7.49 (d, J = 8.2Hz, 1H), 7.27-7.19 (m, 1H), 7.04 (d, J = 7.8Hz, 1H), 6.91 (s, 1H), 3.95 (s,3H), 3.80 (s, 3H), 3.48 (t, J = 7.0Hz, 2H), 3.03 (m, 2H), 2.86 (s, 6H), 2.56 (s, 3H), 2.47 (s, 3H).

Synthesis of Compound 4: After adding Compound 3 (420mg, 0.75mmol), zinc powder (294mg, 4.5mmol) and ammonium chloride (403mg, 7.5mmol), the temperature was raised to 26°C for 2h. The raw material disappeared, and a saturated aqueous solution of sodium bicarbonate was added, extracted twice with dichloromethane, dried, and spin-dried to obtain 667 mg of crude product, which was directly used for the next step.

Synthesis of Example 27: In a 100 mL single-necked bottle, 0.177 g of 2-fluoroacrylic acid and 10 mL of dichloromethane were added. Cool down to -5°C in an ice-salt bath under the protection of nitrogen, add 0.25 g of oxalyl chloride and 2 drops of dry DMF dropwise, and react at low temperature for 2 hours. Take another 250mL one-mouth bottle, take the crude compound 4 (667mg) and DIPEA (490mg, 3.8mmol) and dissolve it in 100mL of dichloromethane, cool down to 0°C, then add homemade 2-fluoroacryloyl chloride dropwise, and keep at 0°C After reacting for 3 hours, after the raw materials were reacted, a saturated aqueous sodium bicarbonate solution was added, extracted twice with dichloromethane, dried, concentrated, and passed through a column to obtain 120 mg of the product. ¹ HNMR (400MHz, Chloroform-d) δ 10.48 (s, 1H), 9.61 (s, 1H), 8.89 (s, 1H), 8.63 (s, 1H), 7.98 (s, 1H), 7.32 (dt, J = 8.4, 0.9Hz, 1H), 7.17 (t, J = 8.0Hz, 1H), 7.00 (d, J = 7.4Hz, 1H), 6.82 (s, 1H), 5.76 (dd, J = 46.5, 3.0Hz , 1H), 5.21 (dd, J = 14.9, 3.0Hz, 1H), 3.95 (s, 3H), 3.91 (s, 3H), 2.97 (t, J = 6.3Hz, 2H), 2.68 (s, 3H) , 2.21 (s, 11H).

Example 28

The structural formula of the compound used as a kinase inhibitor of the present embodiment is:

synthetic route:

Synthesis of Compound 3: Compound 1 (1g, 3.49mmol), Compound 2 (0.528g, 4.19mmol) and DIPEA (1.35g, 10.46mmol) were added to N,N-dimethylacetamide and reacted at 80 °C 16h. After the raw materials were reacted, water was added, extracted three times with ethyl acetate, the organic phases were combined, washed with brine, dried, concentrated, and passed through the column to obtain 1.2 g of the product.

Synthesis of Compound 4: Compound 3 (1.2g, 3.06mmol) and palladium on carbon (240mg, 20%) were added to methanol, and reacted at room temperature for 2h under hydrogen atmosphere. After the raw materials were reacted, diatomaceous earth was added to filter, the filter cake was washed three times with methanol, and the filtrates were combined and concentrated to obtain 1.1 g of crude product.

Synthesis of compound 5: Dissolve compound 4 (1.1g, 3.04mmol) and triethylamine (0.92g, 9.11mmol) in dichloromethane, cool down to 0°C under nitrogen protection, then add acryloyl chloride (0.329g , 3.95mmol) in dichloromethane solution, kept at 0°C for 2h. After the raw materials were reacted, saturated aqueous sodium bicarbonate solution was added, extracted three times with dichloromethane, the organic phases were combined, washed with brine, dried, concentrated, and passed through the column to obtain 0.84 g of the product. ¹ HNMR (400MHz, CDCl ₃ ) δ 8.90 (s, 1H), 8.66 (s, 1H), 6.87 (s, 1H), 6.65 (s, 1H), 6.42 (dd, J = 16.8, 1.6Hz, 1H) , 6.30 (dd, J = 16.8, 10.0Hz, 1H), 5.69 (dd, J = 10.0, 1.6Hz, 1H), 3.81 (s, 3H), 3.00-2.86 (m, 4H), 2.82 (d, J = 9.6Hz, 2H), 2.66-2.54 (m, 2H), 2.44 (s, 3H), 1.51 (m, 11H).

Synthesis of Example 28: Compound 5 (0.256g, 0.615mmol), Compound 6 (0.2g, 0.615mmol) and p-toluenesulfonic acid monohydrate (0.14g, 0.737mmol) were added to ethylene glycol methyl ether and N - In a mixed solvent of methylpyrrolidone, under the protection of nitrogen, the temperature was raised to 120°C for 16 hours. After the reaction was completed, water and ethyl acetate were added to the reaction system, and the aqueous phase was extracted three times. The organic phase was combined, spin-dried, and purified 1.28 mg of product were obtained. MS+1: 606.52.

Example 29

The structural formula of the compound used as a kinase inhibitor of the present embodiment is:

synthetic route:

Synthesis of Compound 2: Add 30 mL of dioxane hydrochloride to a 100 mL single-necked bottle, and protect with nitrogen. Dissolve INT 10 (0.5g) in 15mL dry THF, add dropwise to the reaction flask, then take 5mL THF, also dropwise add to the reaction flask, stir at 40°C for 4h, cool down to 0°C, pump Filtered, the filter cake was washed with THF, and vacuum-dried to obtain 0.44 g of product.

Synthesis of compound 3: Dissolve compound 2 (0.44g, 0.77mmol) and triethylamine (0.252g, 2.5mmol) in dichloromethane, stir for 5 minutes, cool down to 0°C in an ice bath, add difluoroethyl Acid anhydride (0.147g, 0.85mmol), stirred at low temperature for 30 minutes, then stirred overnight at 25°C. The next day, the raw material disappeared, and aqueous sodium bicarbonate solution was added, extracted twice with dichloromethane, the organic phases were combined, dried, and passed through a column to obtain 0.3 g of the product. ¹ HNMR (400MHz, DMSO-d6) δ10.7 (m, 2H) 8.71 (s, 1H), 8.24 (m, 4H), 7.47 (d, J = 8.2Hz, 1H), 7.21 (t, J = 7.8 Hz, 1H), 7.01 (s, 1H), 6.84 (s, 1H), 6.50 (t, J = 52.9Hz, 1H), 3.90 (s, 3H), 3.82 (s, 3H), 2.90 (m, 5H ), 2.53 (m, 2H), 2.19 (s, 6H).

Synthesis of compound 4: take compound 3 (0.3g), add 1.5g of Lawson's reagent, then add 70mL THF, and react under reflux at 80°C for 2 hours. The raw material disappeared, the temperature was lowered, processed, and passed through the column to obtain 0.185g of pure product.

Synthesis of Compound 5: Compound 4 (185mg, 0.304mmol), zinc powder (120mg, 1.84mmol) and ammonium chloride (160mg, 2.99mmol) were added and heated to 26°C for 2h. The raw material disappeared, directly added a saturated aqueous solution of sodium bicarbonate, extracted twice with dichloromethane, dried, and concentrated to obtain 155.4 mg of crude product, which was directly used for the next step.

Synthesis of Example 29: Compound 5 (416.2mg) and triethylamine (250mg) were dissolved in 40mL of dichloromethane, cooled to 0°C, then acryloyl chloride (90mg) was added dropwise, and kept at 0°C for 3h. After the raw materials were reacted, saturated aqueous sodium bicarbonate was added, extracted twice with dichloromethane, dried, concentrated, and purified to obtain 66 mg of the product. ¹ HNMR (400MHz, CDCl ₃ ) δ 9.79 (s, 1H), 9.51 (s, 1H), 8.99 (s,1H), 8.71 (m,1H), 7.97 (s, 1H), 7.31 (d, J = 8.2Hz, 1H), 7.17-7.12 (m, 1H), 7.03 (m, 1H), 6.92(m,2H), 6.91 (s, 1H), 6.70 (s, 1H), 6.50 (dd, J = 16.9 , 2.0Hz, 1H), 5.74 (d, J = 10.2Hz, 1H), 3.93 (s, 3H), 3.88 (s, 3H), 3.18 (t, J = 5.8Hz, 2H), 2.92 (m, 2H ), 2.68 (s, 3H), 2.65 (m, 6H).

Example 30

The structural formula of the compound used as a kinase inhibitor of the present embodiment is:

synthetic route:

Synthesis of Compound 2: Dissolve Compound 1 (3g, 14.15mmol) in dichloromethane, lower the temperature to 0°C under nitrogen protection, slowly add Boc ₂ O (3.3g, 15.14mmol) in dichloromethane dropwise under stirring, Then DMAP (0.34 g, 2.79 mmol) was added, and the temperature was slowly raised to room temperature to continue the reaction for 16 h. After the raw materials were reacted, they were concentrated and passed through the column to obtain 3.7 g of the product. ¹ HNMR (400MHz, CDCl ₃ ) δ 4.62 (s, 1H), 3.99 (d, J = 8.0Hz, 1H), 3.93 (s, 2H), 3.83 (s, 2H), 2.61-2.51 (m, 2H) , 1.99 (ddt, J = 11.2, 8.4, 2.4Hz, 2H), 1.43 (d, J = 1.2Hz, 18H).

Synthesis of Compound 3: Add Lithium Aluminum Hydride (1.87g, 49.2mmol) into dry THF, lower the temperature to 0°C under the protection of nitrogen, slowly add the tetrahydrofuran solution of Compound 2 (2.56g, 8.2mmol) dropwise, and then raise the temperature React at 70 °C for 16 h. After the raw materials were reacted, the temperature was lowered to 0°C, and 2 mL of water and 2 mL of 20% aqueous sodium hydroxide solution were slowly added dropwise, followed by filtration to obtain 1.72 g of compound 3.

Synthesis of Compound 4: INT 9 (200mg, 0.421mmol), Compound 3 (88mg, 0.628mmol) and DIPEA (162mg, 1.26mmol) were added to N,N-dimethylacetamide and reacted at 100°C for 16h. After the raw materials were reacted, water and ethyl acetate were added, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, washed with brine, dried, concentrated, and passed through the column to obtain 180 mg of compound 4.

Synthesis of Compound 5: Compound 4 (180mg, 0.321mmol) and palladium on carbon (36mg, 20%) were added to methanol, and reacted at room temperature for 2h under hydrogen atmosphere. After the raw materials were reacted, diatomaceous earth was added to filter, the filter cake was washed three times with methanol, and the filtrates were combined and spin-dried to obtain 130 mg of compound 5.

Synthesis of Example 30: Compound 5 (130mg, 0.23mmol) and triethylamine (70mg, 0.69mmol) were dissolved in dichloromethane, cooled to 0°C under nitrogen protection, and then acryloyl chloride (27mg, 0.299 mmol) in dichloromethane and kept at 0°C for 2h. After the raw materials were reacted, saturated aqueous sodium bicarbonate solution was added, extracted three times with dichloromethane, the organic phases were combined, washed with brine, dried, concentrated, and passed through the column to obtain 15 mg of the product. ¹ HNMR (400MHz, CDCl ₃ ) δ 9.78 (s, 1H), 8.90 (s, 1H), 8.83 (m, 2H), 7.95 (s, 1H), 7.32 (d, J = 8.0Hz, 1H), 7.17 (t, J = 7.6Hz, 1H), 6.97 (m, 2H), 6.80 (s, 1H), 6.45 (dd, J = 16.8, 1.7Hz, 1H), 6.34 (dd, J = 16.8, 10.0Hz, 1H), 5.79 (dd, J = 10.0, 1.6Hz, 1H), 3.97 (s, 3H), 3.90 (s, 3H), 3.25 (d, J = 1.6Hz, 1H), 3.13 (s, 2H), 2.63 (s, 3H), 2.58 (s, 2H), 2.40 (s, 3H), 2.20 (s, 3H),1.5 (m, 4H).

Example 31

The structural formula of the compound used as a kinase inhibitor of the present embodiment is:

synthetic route:

Synthesis of compound 2: Add compound 1 (5.32g, 29.56mmol) and hydrazine isobutyrate (3.576g, 35.1mmol) into a 250mL single-necked bottle, add 90mL of 1N sodium hydroxide aqueous solution, react at 85°C for 5h, cool down, add Adjust the pH with 8 mL of concentrated hydrochloric acid, stir in an ice-water bath for 20 minutes, filter with suction, and dry the filter cake under vacuum at 55°C overnight to obtain 2.05 g of the product.

Synthesis of Compound 3: Add Compound 2 (0.94g, 4.23mmol), 20mL of toluene, POCl ₃ (2.4ml), DIPEA (2.8ml) into a 100mL single-necked bottle, and react overnight at 80°C. Cool down, spin out most of the solvent, pour the mother liquor into ice water, extract twice with ethyl acetate, dry, spin dry, and pass through the column to obtain 0.395 g of the product. ¹ HNMR (400MHz, CDCl ₃ ) δ 9.20 (s, 1H), 3.33 (p, J = 7.0Hz, 1H), 1.48 (d, J = 7.0Hz, 6H).

Synthesis of Compound 4: Dissolve Compound 3 (0.4g, 1.54mmol) in 40mL 1,2-dichloroethane in a 100mL single-necked bottle, add anhydrous aluminum trichloride (0.35g, 2.63mmol), and stir at room temperature for 30 minutes , then cooled to 0°C, added dropwise INT 1 (0.224g, 1.71mmol), stirred at low temperature for 30min, then raised the temperature to 50°C, and reacted for 2h. Cool down, pour into ice water, add dichloromethane to extract twice, dry, concentrate, and pass through the column to obtain 130 mg of the product. ¹ HNMR (400MHz, CDCl ₃ ) δ 8.88 (s, 1H), 7.89 (d, J = 8.1Hz, 1H), 7.83 (s, 1H), 7.37 (dt, J = 8.2, 1.1Hz, 1H), 7.30 (ddd, J = 8.3, 6.9, 1.2Hz, 1H), 7.23 (ddd, J = 8.1, 7.0, 1.2Hz, 1H), 3.85 (s, 3H), 3.11 (p, J = 7.0Hz, 1H), 1.20 (d, J = 7.0Hz, 6H).

Synthesis of Example 31: Compound 4 (130mg, 0.368mmol), p-toluenesulfonic acid monohydrate (91mg, 0.478mmol) and INT 4 (159mg, 0.406mmol) were added to 16mL of ethylene glycol monomethyl ether and 8mL of NMP , reflux at 120°C overnight. The next day, add sodium hydroxide aqueous solution, extract three times with ethyl acetate, dry, concentrate, and pass through the column to obtain 25 mg of the product. ¹ HNMR (400MHz, CDCl ₃ ) δ 10.24 (s, 1H), 9.80 (s, 1H), 8.91 (m, 2H), 7.94 (s, 1H), 7.30 (d, J = 8.2Hz, 1H), 7.16 – 7.08 (m, 1H), 6.94 (m, 2H), 6.80 (s, 1H), 6.48 (dd, J = 16.9, 2.0Hz, 1H), 6.36 (t, J = 13.6Hz, 1H), 5.72 ( dd, J = 9.8, 2.1Hz, 1H), 3.96 (s, 3H), 3.89 (s, 3H), 2.87 (q, J = 8.7, 7.3Hz,3H), 2.71 (s, 3H), 2.26 (s , 8H), 1.25 (s, 6H).

Example 32

The structural formula of the compound used as a kinase inhibitor of the present embodiment is:

synthetic route:

Synthesis of compound 2: Dissolve compound 1 (3g, 15.0mmol) in dichloromethane, cool down to 0°C under nitrogen protection, then slowly add Boc ₂ O (3.59g, 16.5mmol) in dichloromethane dropwise under stirring solution, followed by adding DMAP (0.37g, 3.0mmol) and slowly warming up to room temperature to continue the reaction for 16 h. After the raw materials were reacted, they were concentrated and passed through the column to obtain 2.5 g of the product.

Synthesis of Compound 3: Add Lithium Aluminum Hydride (1.89g, 49.98mmol) into dry THF, lower the temperature to 0°C under the protection of nitrogen, then slowly add Compound 2 (2.5g, 8.33mmol) in THF under stirring solution, and then heated to 70 °C for 16 h. After the reaction of the raw materials, the temperature was lowered to 0°C, and 2 mL of water and 2 mL of 20% aqueous sodium hydroxide solution were slowly added dropwise, followed by filtration to obtain 2.1 g of the product.

Synthesis of compound 4: INT 9 (300mg, 0.631mmol), compound 3 (122mg, 0.947mmol) and DIPEA (245mg, 1.89mmol) were added to N,N-dimethylacetamide and reacted at 100°C for 16h. After the raw materials were reacted, water and ethyl acetate were added to the reaction system, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, washed with brine, dried, concentrated, and passed through the column to obtain 370 mg of the product.

Synthesis of Compound 5: Compound 4 (300mg, 0.514mmol) and palladium on carbon (60mg, 20%) were added to methanol, and reacted at room temperature for 2h under hydrogen atmosphere. After the raw materials have been reacted, filter with diatomaceous earth, wash the filter cake three times with methanol, combine the filtrates, and concentrate to obtain 310 mg of the product.

Synthesis of Example 32: Compound 6 (270mg, 0.488mmol) and triethylamine (147mg, 1.46mmol) were dissolved in dichloromethane, cooled to 0°C under nitrogen protection, and then acryloyl chloride (58mg, 0.634 mmol) in dichloromethane and kept at 0°C for 2h. After the raw materials were reacted, dichloromethane and saturated aqueous sodium bicarbonate were added, the aqueous phase was extracted three times with dichloromethane, the organic phases were combined, washed with brine, dried, spin-dried to dry the solvent, and passed through the column to obtain 15 mg of the product. ¹ HNMR (400MHz, CDCl ₃ ) δ 9.71 (s, 1H), 8.89 (s, 1H), 8.80 (m, 1H), 8.65 (s, 1H), 7.92 (s, 1H), 7.34-7.30 (m, 1H), 7.16 (t, J = 7.6Hz, 1H), 6.98 (m, 2H), 6.76 (s, 1H), 6.42 (dd, J = 16.8, 1.6Hz, 1H), 6.31 (dd, J = 16.8 , 10.0Hz, 1H), 5.78 (dd, J = 10.0, 1.6Hz, 1H), 3.96 (s, 3H), 3.89 (s, 3H), 3.09-2.99 (m, 2H), 2.73 (td, J = 11.6, 2.0Hz, 2H), 2.37 (s, 6H), 2.26-2.17 (m,4H), 2.07 (s, 2H), 1.66 (dd, J = 12.0, 4.0Hz, 2H).

Example 33

The structural formula of the compound used as a kinase inhibitor of the present embodiment is:

synthetic route:

Synthesis of compound 2: Add compound 1 (18.8g, 103.2mmol) and hydrazine propionate (10.6g, 123.8mmol) into a 250mL single-necked bottle, add 310mL of 1N sodium hydroxide aqueous solution, react at 85°C for 5h, cool down, add 8ml Adjust the pH with concentrated hydrochloric acid, stir in an ice-water bath for 2 h, filter with suction, and dry the filter cake in vacuum at 55°C overnight to obtain 6.7 g of the product. ¹ H NMR (400MHz, DMSO-d6) δ 11.58 (m, 2H), 8.14 (s, 1H), 2.87 (q, J = 7.6Hz, 2H), 1.27 (t, J =7.5 Hz, 3H).

Synthesis of compound 3: Add compound 2 (6.7g, 32.2mmol), toluene 160mL, POCl ₃ (18ml, 0.2mol ), DIPEA (21ml, 0.13mol ) to a 500mL single-necked bottle, and react overnight at 80°C. Cool down, spin out most of the solvent, pour into ice water, add ethyl acetate to extract twice, dry, concentrate, and pass through the column to obtain 1.907g of the product. ¹ HNMR (400MHz, CDCl ₃ ) δ 9.18 (s, 1H), 3.02 (q, J = 7.6Hz, 2H), 1.46 (t, J = 7.6Hz, 3H).

Synthesis of Compound 4: Dissolve Compound 3 (1.95g, 8.0mmol) in 180mL 1,2-dichloroethane in a 250mL single-necked bottle, add anhydrous aluminum trichloride (1.81g, 13.61mmol), and stir at room temperature for 30 Minutes, then lower the temperature to 0°C, add INT 1 (1.15g, 8.78mmol) dropwise, stir at low temperature for 30min, then raise the temperature to 50°C, and react for 2h. Cool down, pour into ice water, add dichloromethane to extract twice, dry, concentrate, and pass through the column to obtain 0.8g of the product. ¹ HNMR (400MHz, CDCl ₃ ) δ 8.85 (s, 1H), 7.94 (dt, J = 8.0, 1.0Hz, 1H), 7.90 (s, 1H), 7.42-7.17 (m, 3H), 3.84 (s, 3H), 2.81 (q, J = 7.6Hz, 2H), 1.19 (t, J = 7.6Hz, 3H).

Synthesis of Example 33: Compound 4 (291mg, 0.86mmol), p-toluenesulfonic acid monohydrate (213mg, 1.12mmol) and INT 4 (376mg, 0.96mmol) were added to the mixture of ethylene glycol monomethyl ether and NMP In the solvent, reflux at 120°C overnight. The next day, add sodium hydroxide aqueous solution and ethyl acetate, extract three times, dry, concentrate, and pass through the column to obtain 40 mg of the product. ¹ HNMR (400MHz, CDCl ₃ ) δ 9.83 (s, 1H), 9.75 (m, 1H), 8.88 (s, 1H), 8.75 (m, 1H), 7.91 (s, 1H), 7.38-7.20 (m, 1H), 7.18-7.06 (m,1H), 6.95 (t, J = 7.3Hz, 3H), 6.71 (s, 1H), 6.46 (dd, J = 16.8, 2.0Hz, 1H), 5.73 (dd, J = 9.9, 2.1Hz, 1H), 3.92 (s, 3H), 3.87 (s, 3H), 3.05 (m, 2H), 2.69 (m, 5H), 2.50 (m, 8H), 0.81 (d, J = 8.0Hz, 3H).

Example 34

The structural formula of the compound used as a kinase inhibitor of the present embodiment is:

synthetic route:

Synthesis of Example 34: Dissolve 2-fluoroacrylic acid (200mg, 2.22mmol) in dichloromethane, add a drop of DMF to catalyze, lower the temperature to 0°C under nitrogen protection, and then slowly add oxalyl chloride (198mg, 1.55mmol) dropwise , after the dropwise addition was completed, the temperature was slowly raised to room temperature, and the reaction was continued for 2 hours, monitored by TLC. After the reaction of the raw materials was completed, the reaction was stopped and set aside. Compound 1 (150mg, 0.272mmol) and DIPEA (105mg, 0.816mmol) were dissolved in dichloromethane, the temperature was lowered to 0°C under nitrogen protection, and then the prepared 2-fluoroacryloyl chloride (39mg, 0.353mmol) was added dropwise dichloromethane solution, kept at 0 ° C for 2h. After the raw materials were reacted, dichloromethane and saturated aqueous sodium bicarbonate were added, extracted three times with dichloromethane, the organic phases were combined, washed with brine, dried, concentrated, and passed through the column to obtain 20 mg of the product. ¹ HNMR (400MHz, CDCl ₃ ) δ 10.67 (s, 1H), 9.55 (s, 1H), 8.89 (s, 1H), 8.72 (m, 1H), 7.98 (s, 1H), δ 7.32 (dt, J = 8.3, 0.9Hz, 1H), 7.17 (t, J = 8.0Hz, 1H), 7.00 (m, 2H), 6.84 (s, 1H), 5.71 (dd, J = 46.4, 2.8Hz, 1H), 5.18 (dd, J = 14.8, 2.8Hz, 1H), 3.97 (s, 3H), 3.91 (s, 3H), 2.83 (m, 2H), 2.67 (s, 3H), 2.63 (t, J = 6.4Hz, 1H), 2.55 (m, 2H), 2.20 (d, J = 2.0Hz, 6H), 1.64 (dd, J = 7.2, 2.8Hz, 2H).

Example 35

The structural formula of the compound used as a kinase inhibitor of the present embodiment is:

synthetic route:

Synthesis of Compound 2: Add 40 mL of dioxane hydrochloride to a 100 ml single-necked bottle, and protect with nitrogen. Dissolve INT 10 (0.9g) in 20mL of dry THF, add dropwise to the reaction flask, then take 5mL THF, add dropwise to the reaction flask, stir at 40°C for 4h, then cool down to 0°C, Suction filtration, the filter cake was washed with THF, and vacuum-dried to obtain 0.67 g of the product.

Synthesis of compound 3: Dissolve compound 2 (0.458g, 0.81mmol) and triethylamine (0.243g, 2.41mmol) in 30mL of dichloromethane, stir for 5 minutes, cool down to 0°C in an ice-water bath, add trifluoro Acetic anhydride (0.204g, 0.97mmol), stirred at low temperature for 30 minutes, then stirred overnight at 25°C. The next day, the raw material disappeared, adding a saturated aqueous solution of sodium bicarbonate, and then adding a little methanol, dichloromethane extracted 3 times, the organic phase was combined, dried, and passed through the column to obtain 0.3 g of the product.

Synthesis of compound 4: take compound 3 (0.3 g), add 1.5 g of Lawson's reagent, then add 70 mL of THF, and react at reflux at 80° C. for 48 h. Cool down, process, and pass through the column to obtain 0.66g of crude product.

Synthesis of Compound 5: Compound 4 (0.66g, 1.05mmol), zinc powder (0.41g, 6.31mmol) and ammonium chloride (0.563g, 10.5mmol) were added and heated to 26°C for 2h. The raw material disappeared, directly added a saturated aqueous solution of sodium bicarbonate, DCM and a little methanol, extracted twice, dried, and spin-dried to obtain 0.64g of crude product, which was directly used for the next step.

Synthesis of Example 35: Compound 5 (0.64g) and triethylamine (0.33g, 3.26mmol) were dissolved in 50mL of dichloromethane, cooled to 0°C, and then acryloyl chloride (0.126g, 1.4mmol) was added dropwise ), keep at 0℃ for 3h. After the raw materials were reacted, dichloromethane and saturated aqueous sodium bicarbonate were added, extracted twice, dried, concentrated, and passed through a column to obtain 7 mg of the product. ¹ HNMR (400MHz, CDCl ₃ ) δ 9.80 (m, 2H), 9.04 (s, 1H), 8.76 (m, 1H), 7.96 (s, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.15 (t, J = 7.7Hz, 1H), 6.93 (m, 2H), 6.72 (s, 1H), 6.51 (dd, J = 16.7, 2.1Hz, 1H), 5.77 (d, J = 11.5Hz, 1H) , 3.94 (s, 3H), 3.89 (s, 3H), 3.14 (m, 2H), 2.73 (s, 3H), 2.60 (m, 8H).

Example 36

The structural formula of the compound used as a kinase inhibitor of the present embodiment is:

synthetic route:

Synthesis of Compound 3: Compound 1 (1g, 3.49mmol), Compound 2 (0.528g, 4.19mmol) and DIPEA (1.35 g, 10.46mmol) were added to N,N-dimethylacetamide and reacted at 80 °C 16h. After the raw materials were reacted, water was added, extracted three times with ethyl acetate, the organic phases were combined, washed with brine, dried, concentrated, and passed through the column to obtain 1.2 g of the product.

Synthesis of Compound 4: Compound 3 (1.2g, 3.06mmol) and palladium on carbon (240mg, 20%) were added to methanol, and reacted at room temperature for 2h under hydrogen atmosphere. After the raw materials were reacted, diatomaceous earth was added to filter, the filter cake was washed three times with methanol, and the filtrates were combined and concentrated to obtain 1.1 g of crude product.

Synthesis of compound 5: Dissolve compound 4 (1.1g, 3.04mmol) and triethylamine (0.92g, 9.11mmol) in dichloromethane, cool down to 0°C under nitrogen protection, then add acryloyl chloride (0.329g , 3.95mmol) in dichloromethane solution, kept at 0°C for 2h. After the raw materials were reacted, saturated aqueous sodium bicarbonate solution was added, extracted three times with dichloromethane, the organic phases were combined, washed with brine, dried, concentrated, and passed through the column to obtain 0.84 g of the product. ¹ HNMR (400MHz, CDCl ₃ ) δ 8.90 (s, 1H), 8.66 (s, 1H), 6.87 (s, 1H), 6.65 (s, 1H), 6.42 (dd, J = 16.8, 1.6Hz, 1H) , 6.30 (dd, J = 16.8, 10.0Hz, 1H), 5.69 (dd, J = 10.0, 1.6Hz, 1H), 3.81 (s, 3H), 3.00-2.86 (m, 4H), 2.82 (d, J = 9.6Hz, 2H), 2.66-2.54 (m, 2H), 2.44 (s, 3H), 1.51 (m, 11H).

Synthesis of Example 36: Compound 5 (30mg, 0.072mmol), Compound 6 (23.7mg, 0.072mmol) and p-toluenesulfonic acid monohydrate (20.5mg, 0.11mmol) were added to ethylene glycol methyl ether and N- In a mixed solvent of methylpyrrolidone, under the protection of nitrogen, the temperature was raised to 120°C for 6 hours. After the reaction was completed, water and ethyl acetate were added to the reaction system, and the aqueous phase was extracted three times. The organic phases were combined, spin-dried, and purified to obtain 9mg product.

Referring to Example 36, the compounds of Examples 37, 38 and 39 were synthesized and shown in Table 2.

MS+1 = 613.4 實施例38

MS+1 = 679.5 實施例39

MS+1 = 682.5 Compounds of Table 2 Examples 37-39 serial number structure characterize Example 37

MS+1 = 613.4 Example 38

MS+1 = 679.5 Example 39

MS+1 = 682.5

Example 40

The structural formula of the compound used as a kinase inhibitor of the present embodiment is:

synthetic route:

Synthesis of Compound 2:

Compound 1 (3g, 22.9mmol, 1eq) and aluminum trichloride (4.56g, 34.3mmol, 1.5eq) were dissolved in dry tetrahydrofuran, heated to 70°C under nitrogen protection and reacted for 1h, then slowly dropped under stirring Add a tetrahydrofuran solution of methyl indole (6.45g, 37.4mmol, 1.2eq), continue to react at 70°C for 3 h after the addition is complete, monitor by TLC, cool to 0°C after the reaction of the raw materials, slowly add ice water to quench, add Extracted three times with ethyl acetate, combined the organic phases, dried over anhydrous Na2SO4, and purified by column (petroleum ether/ethyl acetate=10/1) to obtain 3.5g of compound 2. 1HNMR (400MHz, Chloroform-d) δ 8.71 (s, 1H ), 8.13-8.06 (m, 1H), 7.88 (s, 1H), 7.32-7.28 (m, 1H), 7.24 (m, 2H), 5.12 (m, 1H), 3.80 (s, 3H), 1.18 ( d, J = 6.0Hz, 6H).

Synthesis of compound 3:

Compound 2 (3.5g, 10.6mmol, 1eq) and AZD9291 intermediate (2.96g, 15.9mmol, 1.5eq) were dissolved in dioxane/water, p-toluenesulfonic acid (3.53g, 18.6mmol, 1.75 eq), then heated to 80 °C for 16 h, TLC monitoring, after the reaction of the raw materials, the reaction system was spin-dried, and 2N sodium hydroxide aqueous solution was added to adjust the alkalinity, and then extracted three times with ethyl acetate, the organic phase was combined, anhydrous Na2SO4 After drying, the solvent was spin-dried, and purified by column (dichloromethane/methanol=20/1) to obtain 4.1g of compound 3. 1HNMR (400MHz, Chloroform-d) δ 9.59 (d, J = 8.4Hz, 1H), 8.79 ( s, 1H), 7.97 (s, 2H), 7.65 (d, J = 8.0Hz, 1H), 7.30 (dt, J = 8.4, 1.2Hz, 1H), 7.24-7.19 (m, 1H), 7.12 (ddd , J = 8.0, 7.2, 1.2Hz, 1H), 6.68 (d, J = 12.0Hz, 1H), 5.02 (m, 1H), 3.93 (s, 3H), 3.85 (s, 3H), 1.07 (d, J = 6.Hz, 6H).

Synthesis of compound 4:

Add compound 3 (557mg, 1.19mmol), amine (compound 3 in Example 18) (224mg, 1.78mmol) and DIPEA (307mg, 2.38mmol) into N,N-dimethylacetamide, react at 80°C 16h. The reaction solution was poured into ice water to precipitate a solid, which was filtered by suction (with filter aid added), and the filter cake was dissolved in dichloromethane, dried with dichloromethane, concentrated, and passed through a column to obtain 230 mg of the product.

Synthesis of compound 5:

Compound 4 (230mg, 0.393mmol) and palladium on carbon (50mg, 20%) were added to methanol, and reacted at room temperature for 2h under hydrogen atmosphere. After the raw materials were reacted, diatomaceous earth was added to filter, the filter cake was washed three times with methanol, and the filtrates were combined and spin-dried to obtain 180 mg of compound 5.

Synthesis of Example 40:

Compound 5 (180mg, 0.324mmol) and triethylamine (104mg, 1.03mmol) were dissolved in dichloromethane, the temperature was lowered to 0°C under nitrogen protection, and then acryloyl chloride (36mg, 0.40mmol) was added dropwise in dichloromethane The solution was kept at 0°C for 2h. After the raw materials were reacted, saturated aqueous sodium bicarbonate solution was added, extracted three times with dichloromethane, the organic phases were combined, washed with brine, dried, concentrated, and passed through the column to obtain 5 mg of the product. MS+1: 610.4.

Compounds of Examples 41, 42, 43, 44, 45, 46 and 47 were synthesized with reference to Example 40, as shown in Table 3.

MS+1 = 612.3 實施例 42

MS+1 = 612.2 實施例 43

MS+1 = 638.3 實施例 44

MS+1 = 615.3 實施例 45

MS+1 = 615.3 實施例 46

MS+1 = 641.3 實施例 47

MS+1 = 613.2 Compounds of Table 3 Examples 41-47 serial number structure characterize Example 41

MS+1 = 612.3 Example 42

MS+1 = 612.2 Example 43

MS+1 = 638.3 Example 44

MS+1 = 615.3 Example 45

MS+1 = 615.3 Example 46

MS+1 = 641.3 Example 47

MS+1 = 613.2

2. Biological experiment part

1. Kinase activity assay

Use the Kinase activity assay (Kinase activity Assay) to screen the activity of the compounds prepared in the examples against the EGFR exon 20 insertion mutant kinase at the concentration of ATP Km, and use Staurosporine and the one with the best activity disclosed in WO2015195228A1 The compound (TAK788) was used as the reference substance, and the biological activity screening of the compound will be repeatedly determined at 10 concentrations.

（TAK788）

(TAK788)

1. Test sample

Each sample was made into a solution with a concentration of 10 mM.

2. Experimental method

(1) Prepare the basic buffer solution and quenching buffer solution for the kinases used in the experiment

20 mM Hepes (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO.

(2) Preparation of compounds for experimental kinases

Test compounds were dissolved in 100% dimethylsulfoxide to specific concentrations. (Serial) dilutions were performed with Integra Viaflo Assist assisted DMSO.

(3) Reaction steps

Add kinase to freshly prepared base reaction buffer and add any desired cofactors to the above substrate solution.

Add EGFR exon 20 insertion mutant kinase to the substrate solution, mix gently; use Acoustic technology (Echo550; nanoliter range) to send the compound in 100% dimethyl sulfide into the kinase reaction mixture, and incubate at room temperature for 20 minute.

33P-ATP (Specific activity 10 Ci/l) was added to the reaction mixture to start the reaction, incubated at room temperature for 2 hours, and radioactivity was detected by filter-binding method.

Kinase activity data are expressed as the percentage of remaining kinase activity in test samples compared to the vehicle (dimethylsulfoxide) reaction. IC50 values and curve fitting were obtained using Prism (GRAPHPAD software).

Table 4 shows the IC50 (nM) values of the inhibitory activity of the test samples against EGFR exon 20 insertion mutant kinase.

Table 4 The inhibitory activity of different compounds on EGFR exon 20 insertion mutant kinase compound A763_Y764insFHEA IC50 (nM) D770-N771ins NPG IC50 (nM) Staurosporine 160.4 46.9 TAK788 4.19 0.731 Example 3 6.07 1.48 Example 4 15.3 2.79 Example 6 9.00 1.38 Example 7 5600 1190 Example 9 10.4 1.83 Example 10 36.4 7.66 Example 11 NA 7360 Example 12 2.27 0.30 Example 13 61.1 169 Example 14 44.6 10.1 Example 17 22.7 7.47 (NA: No activity.)

It can be seen from Table 4 that through in vitro biological activity screening, with Staurosporine as the reference substance, the compounds we used as kinase inhibitors have good inhibitory ability to EGFR exon 20 insertion mutant kinases, and most of them are better than The inhibitory activity of staurosporine was much higher. And it is equivalent to the activity of the compound with the best activity disclosed in WO2015195228A1, but the activity of our compound in Example 12 is 2-3 times that of the compound with the best activity disclosed in WO2015195228A1. It is very expected to be further developed into a drug for regulating the activity of EGFR exon 20 insertion mutation kinase or treating diseases related to EGFR exon 20 insertion mutation kinase.

2. EGFR exon 20 Cell Proliferation Inhibitory Activity Test Experiment of Insertion Mutation:

1. Experimental materials:

RPMI-1640 was purchased from BI.

Fetal bovine serum was purchased from BI.

CellTiter-Glo® was purchased from Promega.

Dimethyl sulfoxide (DMSO) was purchased from TCI.

Ba/F3-FL-EGFR-V769-D770 ins ASV, Ba/F3-FL-EGFR-D77-N771 ins SVD, Ba/F3-FL-EGFR-H773-V774 ins NPH, Ba/F3-FL-EGFR- Cells such as A763-Y764 ins FQEA were constructed by Hefei Zhongke Ruisheng Biomedical Technology Co., Ltd.

2. Experimental steps:

2.1 Compound dilution and administration

Prepare 1000X compound stock solution with DMSO, and dilute with culture medium to 20X final concentration for later use.

2.2 Cell Seeding

The cells obtained after centrifugation were suspended with a certain amount of medium and counted. Adjust the cell suspension to the specified density with the medium, take the diluted cell suspension into a 96-well plate; add 5 μl of 20X compound solution to each well of the 96-well plate, and the content of DMSO in the final system is 0.1%; The 96-well plate was placed in a 37°C, 5% CO2 cell incubator and incubated for 72h.

2.3 Detection

Bring the 96-well plate to room temperature before detection, add 50 µl of CellTiter-Glo® reagent to each well, shake it on a shaker for 2 minutes, and then place it at room temperature for 10 minutes to read the plate.

3. Data analysis

Calculate the inhibition rate (Inh%) relative to vehicle (DMSO)-treated control wells using the following formula:

Inhibition rate (Inh%)=100-(RLU compound-RLU blank)/(RLU control-RLU blank)*100%

Use GraphPad7.0 software to analyze the data, use the fitting data to draw the dose-response curve, and calculate the IC50 value. Where A<5nM, 5nM≤B≤50nM, C>50nM, as shown in Table 5.

The results of the cell proliferation inhibitory activity test of the EGFR exon 20 insertion mutation of different compounds in table 5 compound Ba/F3-FL-EGFR IC50 (nM) V769-D770ins ASV D77-N771ins SVD H773-V774ins NPH A763-Y764ins FQEA AZD-9291 B B B B Example 18 A A A A Example 19 C -- -- -- Example 20 C -- -- -- Example 21 A -- -- -- Example 22 A -- -- -- Example 23 A A A A Example 24 A A A A Example 25 A B B A Example 26 A A A A Example 27 B -- -- -- Example 28 C -- -- -- Example 29 B A B A Example 30 C -- -- -- Example 31 A -- -- -- Example 32 B -- -- -- Example 33 A A A A Example 34 A A B A Example 36 A A A A Example 38 A -- -- -- Example 40 A A A A Example 41 A A A A Example 42 A -- -- -- Example 43 A -- -- -- Example 47 A A A A

It can be seen from Table 5 that the compounds we synthesized all have good inhibitory ability to EGFR exon 20 insertion mutation. Most of them are much more active than AZD9291. Compared with the activity of TAK-788, most of the compounds of the present invention are more active than them. For example, the activity of our compound (Example 18) is 2 times that of TAK-788 left and right (see Table 6). It is very expected to be further developed into a drug for regulating the activity of EGFR exon 20 insertion mutation or treating diseases related to EGFR exon 20 insertion mutation.

The cell proliferation inhibitory activity comparison of different compounds of table 6 compound Ba/F3-FL-EGFR IC50 (nM) V769-D770ins ASV D77-N771ins SVD H773-V774ins NPH A763-Y764ins FQEA TAK-788 4.0 3.9 3.6 3.3 AZD-9291 24.6 41.4 38.7 13.7 Example 18 1.9 2.8 2.8 1.8

3. relevant EGFR Mutant cell proliferation inhibitory activity test experiment:

1. Experimental materials:

RPMI was purchased from Nanjing Shenghang.

WST-8 was purchased from Jinruimeixiang.

Dimethyl sulfoxide (DMSO) was purchased from Aike.

Ba/F3 (EGFRdel19/L858R/C797S) was purchased from Kangyuan Borch.

PC9 (EGFRdel19) and H-1975 (EGFRL858R/T790M) cells were purchased from Beina Mall.

2. Experimental steps:

Cell culture medium: RPMI containing 10% fetal bovine serum, 5mM HEPES and 2mM glutamine.

Dilute the cell suspensions of Ba/F3 (EGFRdel19/L858R/C797S), PC9 (EGFRdel19) and H-1975 (EGFRL858R/T790M) to 5000 cells/80 microliters, 1500 cells/80 microliters and 4000 cells/80 microliter. Add 80 microliters/well to a 96-well culture plate. Incubate overnight at 37°C in an incubator filled with 5% carbon dioxide.

The compound was diluted to the desired concentration with culture medium according to five times the final concentration. Twenty microliters of the compound dilutions were transferred to culture plates containing 80 microliters of the cells incubated overnight above and incubated for an additional 72 hours.

After 72 hours, add 10 microliters of 6mg/ml WST8 solution dissolved in phosphate buffer, and incubate at 37°C with 5% carbon dioxide for 3 hours. Read the absorbance at 450nm and subtract the absorbance at 650nm.

The obtained light absorbance value was calculated according to the following formula:

Cell survival rate%=(OD measured value/OD drug-free cells) X100

The % cell survival rate corresponding to the compound concentration was calculated with Prizm8.2 software IC50, and the results are shown in Table 7.

Table 7 Cell Proliferation Inhibitory Activity Experiments Related to EGFR Mutations Cell line/IC ₅₀ (nM) TAK-788 AZD-9291 Example 18 H-1975 (EGFRL858/T790M) 101.4 20.19 91.16 PC-9 (EGFRdel19) 24.05 7.846 6.612 Ba/F3 (EGFRdel19/L858/797s) 2627 2704 3977

It can be seen from Table 7 that the cytostatic activity and osimertinib activity of Example 18 to H-1975 (EGFRL858/T790M) and C-9 (EGFRdel19) have little difference, and are better than TAK788. Therefore, our compound also has a certain therapeutic effect on the treatment of related diseases caused by EGFR mutation.

The above descriptions are only examples of the present invention, and are not intended to limit the patent scope of the present invention. All equivalent transformations made using the content of the description of the present invention, or directly or indirectly used in other related technical fields, are included in the scope of the present invention. within the scope of patent protection.

none

none.

Claims (14)

A compound used as a kinase inhibitor, which is a compound represented by formula I, or a tautomer, or a mesoform, a racemate, and a mixture of a mesoform and a racemate, or Enantiomers, diastereomers and mixtures of enantiomers and diastereomers thereof, or deuterated compounds thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof:

In formula I, A is selected from:

or

; Wherein, Z ₅ , Z ₆ , Z ₇ , Z ₈ , Z ₉ , Z ₁₁ and Z ₁₂ are each independently selected from N and CR ₄ ; Z ₁₀ is selected from

,

,

,

,

,

,

,

; R _is selected from H, amino, ester, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy , C _3-6 cycloalkyl, C _3-6 cycloalkoxy, C _6-10 aryl, 5-10 membered heteroaryl, or an amino group substituted by 1 to 3 R, Ester group, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, C _6-10 aryl, 5-10 A membered heteroaryl group; the 5-10 membered heteroaryl group contains at least 1 heteroatom, and the heteroatom is selected from N, O, S or P; m is 0, 1, 2 or 3; C is selected from from 4-7 membered rings; Z ₁ and Z ₂ are each independently selected from N or CR ₄ ; L is selected from single bonds,

,

,

,

,

,

,

,

or

; B is selected from the aryl group of C _6-10 , the heteroaryl group of 5-10 yuan, the aryl group of C _6-10 substituted by 1~3 substituents, the 5-10 substituted by 1~3 substituents Elementary heteroaryl; each of the substituents is independently selected from H, halogen, cyano, amino, ester, ureido, carbamate, amido, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, C _1-6 alkylamino, C _3-12 cycloalkylamino, C _{1- 6} haloalkyl, C _1-6 haloalkoxy, C _3-6 halocycloalkyl, C _3-6 halocycloalkoxy, C _1-6 haloalkylamino, C _3-12 Halogenated cycloalkylamino, C _6-10 aryl, 5-10 membered heteroaryl, or amine, ester, urea, carbamate substituted by 1~3 R , amido, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, C _1-6 alkylamino, C _3-12 cycloalkylamino, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 halocycloalkyl, C _3-6 halocycloalkoxy, C _1-6 haloalkylamino, C _3-12 halocycloalkylamino, C _6-10 aryl, 5-10 membered heteroaryl; each of the Rs is independently selected from halogen, cyano , amino group, hydroxyl group, ester group, urea group, urethane group, amido group, C _1-6 alkyl group, C _1-6 alkoxy group, C _3-6 cycloalkyl group, C _3-6 cycloalkoxy, C _1-12 alkylamino, C _6-10 aryl, 5-10 membered heteroaryl,

,

,

,

,

,

or

; Wherein, Y ₁ , Y ₂ , Y ₃ , Y ₄ , Y ₅ are each independently selected from hydrogen, halogen, C _1-12 alkyl, C _3-12 cycloalkyl, C _1-12 alkylamine One or more carbon atoms selected from C _1-12 alkyl, C _3-12 cycloalkyl, C _1-12 alkyl are replaced by one or more of N, O, _S A group formed by heteroatom replacement, a group formed by replacing one or more carbon atoms in a C _3-12 cycloalkyl group with one or more heteroatoms in N, O, and S; R ₄ , R ₆ , R ₇ , R ₉ and R ₁₀ are each independently selected from H, halogen, cyano, amine, ester, pyl, ureido, carbamate, amido, phosphorus oxy, C _{1- 6} alkyl, C _1-6 deuterated alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, C _6-10 aryl , a 5-10 membered heteroaryl group, a 5-10 membered aliphatic heterocyclic group, or an amine group, ester group, pylori group, urea group, carbamate group, Amino group, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, C _6-10 aryl, 5- 10-membered heteroaryl, 5-10 membered aliphatic heterocyclic group; R ₅ is selected from H, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _{3 -6} cycloalkoxy group, C _6-10 aryl group, 5-10 membered heteroaryl group; wherein, when Z ₁ and Z ₂ are both selected from CH, A is selected from

When B is selected from a _C6-10 aryl group substituted by 1 to 3 substituents, and a 5-10 membered heteroaryl group substituted by 1 to 3 substituents, the 1 to 3 substituents mentioned above on B At least 1 of the

. The compound used as a kinase inhibitor as described in Claim 1, wherein the structural formula is shown in Formula II:

In formula II, Z ₃ and Z ₄ are each independently selected from N and CR ₄ ; R ₁ and R ₂ are each independently selected from H, halogen, cyano, amine, ester, urea, and carbamate group, amido group, C _1-6 alkyl group, C _1-6 alkoxy group, C _3-6 cycloalkyl group, C _3-6 cycloalkoxy group, C _1-6 alkylamino group , C _3-12 cycloalkylamino, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 halocycloalkyl, C _3-6 halocycloalkoxy , C _1-6 haloalkylamino group, C _3-12 halocycloalkylamino group, C _6-10 aryl group, 5-10 membered heteroaryl group, or substituted by 1 to 3 R Amino group, ester group, urea group, urethane group, amido group, C _1-6 alkyl group, C _1-6 alkoxy group, C _3-6 cycloalkyl group, C _{3- 6} cycloalkoxy, C _1-6 alkylamino, C _3-12 cycloalkylamino, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 halo Cycloalkyl, C _3-6 halocycloalkoxy, C _1-6 haloalkylamino, C _3-12 halocycloalkylamino, C _6-10 aryl, 5-10 membered Heteroaryl; _R3 is selected from

,

,

,

,

,or

; Wherein, Y ₁ , Y ₂ , Y ₃ , Y ₄ , and Y ₅ are each independently selected from hydrogen, halogen, C _1-12 alkyl, C _1-12 alkoxy, C _3-12 cycloalkane group, a C _1-12 alkylamino group, and the R-substituted C _1-12 alkylamino group. The compound used as a kinase inhibitor as claimed in claim 2, wherein Z ₁ is CR ₄ , Z ₂ is CH, wherein R ₄ is selected from H, a 5-9 membered heteroaromatic ring containing more than one nitrogen atom, _5-9 membered heteroaryl, cyano,

,

,

,

,

,

,

or

; R ₁₂ and R ₁₃ are each independently selected from H, ester group, acyl group, C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 cycloalkoxy group, C _6-10 aryl group, 5-9 membered heteroaryl group, or ester group, acyl group, C _1-6 alkyl group, C _3-6 cycloalkyl group, C _{3 -6} cycloalkoxy, C _6-10 aryl, 5-9 membered heteroaryl. The compound used as a kinase inhibitor as described in claim 1 or claim 2, wherein the compound used as a kinase inhibitor is a compound represented by formula III:

In formula III, R ₈ is hydrogen, C _3-6 cycloalkyl, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl; R ₄ is selected from H,

,

,

,

,

,

,

,

,

,

,

,

; Wherein, R ₁₄ is C _1-3 alkyl, n is an integer of 1-3, R ₁₂ , R ₁₃ , R ₁₅ are each independently selected from H or C _1-3 alkyl; Z ₃ , Z ₄ are each independently selected from CH or N; R is selected from hydrogen, C _1-3 alkoxy, C _1-3 haloalkoxy, C _{1-3 deuterated} alkoxy, C _3-6 cycloalkane base _; R2 is selected from

, wherein, the D ring is a 4-6-membered cycloalkylamino group; R ₃ is selected from

; Wherein, when R ₄ is selected from

,

,

,

,

,

,

,

, when Z ₃ and Z ₄ select CH at the same time, R ₂ is selected from

; when R ₄ is selected from H, R ₂ is selected from

. The compound used as a kinase inhibitor as described in claim 1 or claim 2, wherein the compound used as a kinase inhibitor is a compound represented by formula III':

In formula III', R ₈ is hydrogen, C _3-6 cycloalkyl, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl; R ₄ is selected from

,

,

,

,

,

,

,

,

,

,

,

; Wherein, R ₁₄ is C _1-3 alkyl, n is an integer of 1-3, R ₁₂ , R ₁₃ , R ₁₅ are each independently selected from H or C _1-3 alkyl; Z ₃ , Z ₄ are each independently selected from CH or N, and at least one is selected from N; R is selected from hydrogen, C _1-3 alkoxy, C _1-3 haloalkoxy, C _{1-3 deuterated} alkoxy , C _3-6 cycloalkyl; R ₂ is selected from

, wherein, the D ring is a 4-6-membered cycloalkylamino group; R ₃ is selected from

. The compound used as a kinase inhibitor as described in claim 1 or claim 2, wherein the compound used as a kinase inhibitor is represented by formula IV, formula V, formula VI, formula VII, formula VIII, and formula IX Compound:

;

;

;

;

;

; In formula IV, formula V, formula VI, formula VII, formula VIII, and formula IX, R is selected from hydrogen, C _1-3 alkoxy, C _{1-3 haloalkoxy, C 1-3 deuterium} Substituted alkoxy, C _3-6 cycloalkyl; R ₂ is selected from

, wherein, the D ring is a 4-6-membered cycloalkylamino group; R ₃ is selected from

_{; R is} selected from H,

,

,

,

,

,

,

,

,

,

,

,

; wherein, R ₁₄ is C _1-3 alkyl, n is an integer of 1-3, R ₁₂ , R ₁₃ , R ₁₅ are each independently selected from H or C _1-3 alkyl; R ₁₆ is selected from H or C _1-3 alkyl. The compound used as a kinase inhibitor as claimed in claim 1, wherein the structural formula of the compound used as a kinase inhibitor is selected from the following structures:

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

. The compound used as a kinase inhibitor as claimed in claim 1, wherein the compound used as a kinase inhibitor is a compound represented by formula X:

; In formula X, R ₈ is selected from H, C _1-4 alkyl, C _1-4 deuterated alkyl, C _1-4 haloalkyl; Y ₁ , Y ₂ , Y ₃ are each independently selected from H, D, halogen, C _1-4 haloalkyl, C _1-4 deuterated alkyl, -CH ₂ NR ₁₁₁ R ₁₁₂ or

, wherein, the D ring is a 4-6 membered cycloalkylamino group or a 4-6 membered heterocycloalkylamino group, and the heterocycloalkylamino group is that 1-3 ring carbon atoms on the cycloalkylamino group are heterocycloalkylamino Atom substitution, heteroatoms are selected from O, S or N; R ₄ is selected from

,

,

,

,

,

,

,

,

,

,

; wherein R ₄₀ is selected from H, C _1-4 alkyl, or C _1-4 deuterated alkyl, or C _1-4 haloalkyl; R ₁₁ is selected from

,

,

,

,

,

,

,

,

,

,

; wherein R ₁₁₀ , R ₁₁₁ , and R ₁₁₂ are each independently selected from H, C _1-4 alkyl, or C _1-4 deuterated alkyl, or C _1-4 haloalkyl; wherein, when R ₁₁ selected from

, Y ₁ , Y ₂ , Y ₃ are all H, R ₈ is methyl, R ₄ is

or

When, R ₄₀ is selected from H, C _2-4 alkyl, C _1-4 deuterated alkyl or C _1-4 haloalkyl. The compound used as a kinase inhibitor as described in Claim 8, wherein the compound used as a kinase inhibitor is a compound shown in formula XI and formula XII:

;

; In formula XI and formula XII, R ₁₁ is selected from

,

,

,

. The compound used as a kinase inhibitor as described in any one of claim 1, claim 8 to claim 9, wherein the compound used as a kinase inhibitor is a compound of the following structural formula:

. The compound used as a kinase inhibitor as claimed in claim 1, wherein the compound used as a kinase inhibitor is a compound represented by formula X':

; In formula X', R ₈ is selected from H, C _1-4 alkyl, C _1-4 deuterated alkyl, C _1-4 haloalkyl; Y ₁ , Y ₂ , Y ₃ are each independently selected from H, D, halogen, C _1-4 haloalkyl, C _1-4 deuterated alkyl, -CH ₂ NR ₁₁₁ R ₁₁₂ or

, wherein, the D ring is a 4-6 membered cycloalkylamino group or a 4-6 membered heterocycloalkylamino group, and the heterocycloalkylamino group is that 1-3 ring carbon atoms on the cycloalkylamino group are heterocycloalkylamino Atom substitution, the heteroatom is selected from O, S or N; R ₁₁ is selected from

,

,

,

,

,

; wherein R ₁₁₀ , R ₁₁₁ , and R ₁₁₂ are each independently selected from H, C _1-4 alkyl, or C _1-4 deuterated alkyl, or C _1-4 haloalkyl. The compound used as a kinase inhibitor as claimed in claim 1 or claim 11, wherein the compound used as a kinase inhibitor is a compound of the following structural formula:

,

,

,

,

,

,

,

. A use of the compound as a kinase inhibitor as described in any one of claim 1 to claim 12 in the preparation of a drug for treating related diseases caused by EGFR mutation and/or Her2 mutation. The use according to claim 13, wherein the EGFR mutation and/or Her2 mutation is exon 20 insertion mutation, EGFR exon 19 deletion, EGFR exon 21 L858R point mutation.