COMPOUND USED AS KINASE INHIBITOR AND USE THEREOF

Abstract

The present invention relates to a compound used as a kinase inhibitor and to the use thereof. The structure of the compound is as shown in formula I. The present compound used as a kinase inhibitor has good inhibitory activity on EGFR and Her2 exon 20 insertion mutations, and has excellent potential to be developed into a drug for treating related diseases.

##STR00001##

Claims

1. A compound used as a kinase inhibitor, wherein the compound is represented by formula I, or an isomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof; ##STR00099## wherein in formula I, X.sub.1 is selected from N or CR.sub.2; X.sub.2 is selected from N or CR.sub.3; X.sub.3 is selected from N or CR.sub.4; L.sub.1 and L.sub.3 are each independently selected from a single bond, ##STR00100## L.sub.2 is selected from a single bond, ##STR00101## A is selected from C.sub.6-10 aryl, and C.sub.5-12 heteroaryl; or A is C.sub.6-10 aryl substituted with 1, 2 or 3 substituents or C.sub.5-12 heteroaryl substituted with 1, 2 or 3 substituents; the substituent is selected from any one of H, halogen, cyano, amino, ester, urea, carbamate, amide, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkoxy, C.sub.6-10 aryl, and C.sub.5-12 heteroaryl; or the substituent is amino group, ester group, urea group, carbamate group, amide group, C.sub.1-6 alkyl group, C.sub.1-6 alkoxy group, C.sub.3-6 cycloalkyl group, C.sub.3-6 cycloalkoxy group, C.sub.6-10 aryl, and C.sub.5-12 heteroaryl, which is substituted with 1, 2 or 3 R; R is selected from halogen, cyano, hydroxyl, amino, ester, urea, carbamate, amide, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, and C.sub.5-12 heteroaryl; B is a nitrogen-containing heterocyclic group or a nitrogen-containing heterocyclic group substituted by R.sub.1, and the number of nitrogen heteroatoms in the nitrogen-containing heterocyclic group is one or more; the R.sub.1 is selected from ##STR00102## and Y.sub.1, Y.sub.2, Y.sub.3, Y.sub.4, and Y.sub.5 are each independently selected from hydrogen, halogen, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, and C.sub.1-12 alkylamino; or Y.sub.1, Y.sub.2, Y.sub.3, Y.sub.4, and Y.sub.5 are each independently C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, or C.sub.1-12 alkylamino, which is substituted by the R; R.sub.Y is selected from C.sub.1-12 alkyl, C.sub.1-12 alkyl substituted by the R, C.sub.3-12 cycloalkyl, and C.sub.3-12 cycloalkyl substituted by the R; or R.sub.Y is C.sub.1-12 alkyl, C.sub.1-12 alkyl substituted by the R, C.sub.3-12 cycloalkyl group, or a group formed by replacing one or more carbon atoms in the C.sub.3-12 cycloalkyl group substituted by the R with one or more heteroatoms in N, O, and S; wherein R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently selected from H, halogen, cyano, amino, ester, urea, carbamate, amide, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkoxy, C.sub.6-10 aryl, and C.sub.5-12 heteroaryl; or R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently amino group, ester group, urea group, carbamate group, amide group, C.sub.1-6 alkyl group, C.sub.1-6 alkoxy group, C.sub.3-6 cycloalkyl group, C.sub.3-6 cycloalkoxy group, C.sub.6-10 aryl, or C.sub.5-12 heteroaryl, which is substituted with the 1, 2 or 3 R; wherein when L.sub.2 is selected from ##STR00103## B is selected from ##STR00104## wherein when L.sub.2 is selected from ##STR00105## and B is selected from ##STR00106## A is selected from ##STR00107## wherein m, n, m′ and n′ are each independently selected from 0, 1, 2, and 3; C is selected from H, halogen, cyano, amino, ester, urea, ether, carbamate, amide, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkoxy, C.sub.6-10 aryl, C.sub.5-12 heteroaryl, and aliphatic heterocycle; or C is amino group, ester group, urea group, ether group, carbamate group, amide group, C.sub.1-6 alkyl group, C.sub.1-6 alkoxy group, C.sub.3-6 cycloalkyl group, C.sub.3-6 cycloalkoxy group, C.sub.6-10 aryl, C.sub.6-10 heteroaryl, or aliphatic heterocycle, which is substituted by the 1, 2 or 3 R.

2. The compound used as the kinase inhibitor according to claim 1, wherein when L.sub.2 is selected from a single bond, ##STR00108## B is selected from: ##STR00109## ##STR00110##

3. The compound used as the kinase inhibitor according to claim 2, wherein R.sub.1 is selected from ##STR00111## X.sub.2 and X.sub.3 are selected from CH; X.sub.1 is selected from N; L.sub.3 is selected from ##STR00112## C is selected from C.sub.1-3 alkyl, ##STR00113## L.sub.1 is selected from ##STR00114## A is selected from ##STR00115## Y.sub.1, Y.sub.2 and Y.sub.3 are selected from hydrogen; R.sub.A1, R.sub.A2 and R.sub.A3 are each independently selected from hydrogen, halogen and C.sub.1-3 alkyl; R.sub.C1 and R.sub.C2 are each independently selected from C.sub.1-3 alkyl.

4. The compound used as the kinase inhibitor according to claim 1, wherein L.sub.2 is selected from ##STR00116## B is selected from: ##STR00117## R.sub.1 is selected from ##STR00118## X.sub.2 and X.sub.3 are selected from CH; X.sub.1 is selected from N; L.sub.3 is selected from ##STR00119## C is selected from C.sub.1-3 alkyl, ##STR00120## L.sub.1 is selected from ##STR00121## A is selected from ##STR00122## Y.sub.1, Y.sub.2 and Y.sub.3 are selected from hydrogen; R.sub.A1, R.sub.A2 and R.sub.A3 are each independently selected from hydrogen, halogen and C.sub.1-3 alkyl; R.sub.C1 and R.sub.C2 are each independently selected from C.sub.1-3 alkyl.

5. The compound used as the kinase inhibitor according to claim 1, wherein the compound has a structure shown in formula II: ##STR00123## wherein L.sub.2 is selected from ##STR00124## B is selected from ##STR00125## L.sub.2 is selected from a single bond; B is selected from ##STR00126## R.sub.B is selected from H, ##STR00127## or L.sub.2 is selected from ##STR00128## B is selected from ##STR00129## wherein C is selected from C.sub.1-3 alkyl, ##STR00130## R.sub.1 is selected from ##STR00131## R.sub.6 and R.sub.7 are each independently selected from hydrogen and halogen; Y.sub.1, Y.sub.2, and Y.sub.3 are selected from hydrogen; R.sub.A1, R.sub.A2, R.sub.A3 are each independently selected from hydrogen, halogen, and C.sub.1-3 alkyl; R.sub.C1 and R.sub.C2 are each independently selected from C.sub.1-3 alkyl.

6. The compound used as the kinase inhibitor according to claim 5, wherein L.sub.2 is selected from CF.sub.2, and B is selected from ##STR00132## and m and n are both 1 or 2.

7. The compound used as the kinase inhibitor according to claim 5, wherein L.sub.2 is selected from ##STR00133## and B is selected from ##STR00134## and m, n, m′, and n′ are all 1.

8. The compound used as the kinase inhibitor according to claim 1, wherein the compound is selected from the following compounds: ##STR00135## ##STR00136## ##STR00137## ##STR00138## ##STR00139## ##STR00140## ##STR00141##

9. Use of the compound used as kinase inhibitor according to claim 1 in the preparation of medicine, wherein the medicine is used for treatment of related diseases caused by EGFR mutation and/or Her2 mutation.

10. The use according to claim 9, wherein the EGFR mutation and Her2 mutation are exon 20 insertion mutations.

11. The compound used as the kinase inhibitor according to claim 2, wherein the compound is selected from the following compounds: ##STR00142## ##STR00143## ##STR00144## ##STR00145## ##STR00146## ##STR00147## ##STR00148##

12. The compound used as the kinase inhibitor according to claim 3, wherein the compound is selected from the following compounds: ##STR00149## ##STR00150## ##STR00151## ##STR00152## ##STR00153## ##STR00154## ##STR00155##

13. The compound used as the kinase inhibitor according to claim 4, wherein the compound is selected from the following compounds: ##STR00156## ##STR00157## ##STR00158## ##STR00159## ##STR00160## ##STR00161## ##STR00162##

14. The compound used as the kinase inhibitor according to claim 5, wherein the compound is selected from the following compounds: ##STR00163## ##STR00164## ##STR00165## ##STR00166## ##STR00167## ##STR00168## ##STR00169##

15. The compound used as the kinase inhibitor according to claim 6, wherein the compound is selected from the following compounds: ##STR00170## ##STR00171## ##STR00172## ##STR00173## ##STR00174## ##STR00175## ##STR00176##

16. The compound used as the kinase inhibitor according to claim 7, wherein the compound is selected from the following compounds: ##STR00177## ##STR00178## ##STR00179## ##STR00180## ##STR00181## ##STR00182## ##STR00183##

17. Use of the compound used as kinase inhibitor according to claim 5 in the preparation of medicine, wherein the medicine is used for treatment of related diseases caused by EGFR mutation and/or Her2 mutation.

18. Use of the compound used as kinase inhibitor according to claim 6 in the preparation of medicine, wherein the medicine is used for treatment of related diseases caused by EGFR mutation and/or Her2 mutation.

19. Use of the compound used as kinase inhibitor according to claim 7 in the preparation of medicine, wherein the medicine is used for treatment of related diseases caused by EGFR mutation and/or Her2 mutation.

20. Use of the compound used as kinase inhibitor according to claim 8 in the preparation of medicine, wherein the medicine is used for treatment of related diseases caused by EGFR mutation and/or Her2 mutation.

Description

EXAMPLE 1

[0084] The compound used as a kinase inhibitor in this example has a structural formula as follows:

##STR00057##

[0085] The synthetic route is as follows:

##STR00058##

[0086] The specific synthesis process of the compound of the present embodiment is as follows:

[0087] (1) Synthesis of compound 8: In a dry 100 mL three-necked flask, the intermediate 1 (208 mg, 0.5 mmol), Pd2(dba)3 (tris(dibenzylideneacetone)dipalladium(0), 137 mg, 30 mol %), XPhos (2-dicyclohexylphosphorus-2′,4′,6′,-triisopropylbiphenyl, 143 mg, 60 mol %), NaOtBu (sodium tert-butoxide, 144 mg, 3.0 equiv), a compound 7 (212 mg, 1 mmol) and molecular sieve-dried dioxane (10 mL) were added thereto in sequence, reaction was carried out under argon at 100° C. for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, a small amount of dichloromethane and an aqueous solution were added, filtered through celite, the mixed solution was separated into layers, and the aqueous phase was extracted with dichloromethane. Subsequently, the organic phase was washed with a saturated saline solution, dried and concentrated. Finally, the pure product was isolated by column chromatography: a yellow solid compound 8 (75 mg) with a yield rate of 27%.

[0088] .sup.1HNMR: (CDCl.sub.3, 400 Hz) δ: 8.61 (s, 1 H), 8.46 (t, J=8.6 Hz ,1 H), 7.38 (s, 1 H), 7.30 (dd, J.sub.1=2.0 Hz, J.sub.2=9.1 Hz, 1 H), 7.21 (s, 1 H), 6.73 (s, 1 H), 3.98 (s, 3 H), 3.64-3.72 (m, 4 H), 3.36-3.38 (m, 4 H), 3.00-3.03 (m, 2 H), 1.46 (s, 9 H).

[0089] (2) Synthesis of Compound of Example 1: A compound 8 (70 mg, 0.13 mmol) was added to a dry 25 mL single-neck flask, and 0.5 mL of methanol was added for dissolving, then HCl/MeOH solution (hydrochloric acid in methanol) was slowly added along the flask wall at room temperature, and stirred at room temperature for 2 hours under nitrogen until TLC showed that the compound 8 disappeared, and the reaction was stopped. The solution was directly spin-dried to obtain the crude product solid compound 9. Proceed to the next step with the yield rate of 90%. To the obtained solid compound 9, 5 mL of dichloromethane was added, and triethylamine (64.3 mg, 5.0 equiv) was added thereto, the temperature was lowered to 0° C., and acryloyl chloride 10 (11.5 mg, 1.0 equiv) diluted with DCM was slowly added dropwise, and the mixture was kept in an ice bath. The reaction was carried out under the bath for 0.5 to 1 hour until TLC showed the disappearance of the raw material. After the reaction was completed, an aqueous solution was added to quench, a small amount of dichloromethane was added, and the mixture was filtered through celite. The mixture was separated into layers and the aqueous phase was extracted with dichloromethane. Subsequently, the organic phase was washed with saturated brine solution, dried and concentrated. Finally, the pure product (10 mg) with a yield rate of 15% was obtained through preparative chromatography and separation.

[0090] .sup.1HNMR: (CD.sub.3OD, 400 Hz) δ: 8.58 (s, 1 H), 7.49-7.55 (m, 2 H), 7.40 (s, 1 H), 7.20 (s, 1 H), 6.63 (dd, J.sub.1=10.3 Hz, J.sub.2=16.8 Hz, 1 H), 6.28 (dd, J.sub.1=1.9 Hz, J.sub.2=16.8 Hz, 1 H), 5.75 (dd, J.sub.1=1.9 Hz, J.sub.2=10.5 Hz, 1 H), 4.08 (s, 3 H), 3.95-4.00 (m, 1 H), 3.77-3.87 (m, 3 H), 3.53-3.67 (m, 4 H), 3.09-3.22 (m, 2 H).

EXAMPLE 2

[0091] The compound used as a kinase inhibitor in this example has the structural formula as follows:

##STR00059##

[0092] The synthetic route is as follows:

##STR00060##

[0093] The specific synthesis process is as follows:

[0094] In a dry 50 mL single-necked flask, intermediate 1 (107.7 mg, 0.25 mmol), Pd.sub.2(dba).sub.3 (68.6 mg, 30 mol %), XPhos (71.5 mg, 60 mol %), NaOtBu (72 mg, 3.0 equiv), a compound 7 (53.3 mg, 0.75 mmol), and molecular sieve-dried dioxane (5 mL) were added thereto in sequence, reaction was carried out under argon at 100° C. for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, a small amount of dichloromethane and an aqueous solution were added, filtered through celite, the mixture was separated into layers, and the aqueous phase was extracted with dichloromethane. Subsequently, the organic phase was washed with a saturated saline solution, dried and concentrated. Finally, the pure product (10 mg) with a yield rate of 10% was obtained through preparative chromatography and separation.

[0095] .sup.1HNMR: (CDCl.sub.3, 400 Hz) δ: 8.53 (s, 1 H), 7.49-7.55 (m, 2 H), 7.29 (d, J=4.1 Hz, 1 H), 7.14 (s, 1 H), 4.06 (s, 3 H), 3.59-3.62 (m, 4 H), 2.00-2.04 (m, 4 H).

EXAMPLE 3

[0096] The compound used as a kinase inhibitor in this example has the structural formula as follows:

##STR00061##

[0097] The synthetic route is as follows:

##STR00062##

[0098] The experiment process is as follows:

[0099] (1) Synthesis of compound H2: In a 100 mL three-necked flask, a compound intermediate 1 (0.828 g, 2 mmol) and anhydrous THF (tetrahydrofuran, 30 mL) were added, then NaH (0.32 g, 6 mmol) was added, and then the temperature was lowered to −78 ° C.; n-butyllithium (0.96 mL, 2.4 mmol) was added under nitrogen protection, and the mixture was stirred at this temperature for 1 hour reaction. Next, a compound A-1 (0.584 g, 2.4 mmol) was dissolved in anhydrous THF (5 mL), and was slowly added to the reaction solution at −78° C.; after the dropwise addition was completed, the mixture was naturally raised to room temperature and stirred and kept overnight. Aqueous ammonium chloride solution (30 mL) was added to the reaction solution, extracted three times with ethyl acetate (30 mL), the organic phases were combined, dried, and purified through column chromatography (PE:EA=1:1) to obtain 0.3 g of the product with a yield rate of 27%.

[0100] .sup.1HNMR: (CDCl.sub.3, 400 Hz) δ8.74 (s, 1 H), 8.48 (s, 1 H), 7.38 (t, J=7.6 Hz, 1 H), 7.36˜7.30(m, 2 H), 4.20˜4.15 (m, 5 H), 4.05 (s, 3 H), 1.44 (s, 9 H).

[0101] (2) Synthesis of compound H3: A compound H2 (0.3 g, 0.57 mmol), DAST (diethylaminosulfur trifluoride, 10 mL), DCM (dichloromethane, 5 mL) were added to a 20 mL single-necked flask, and the temperature was raised to 40° C. under nitrogen protection. The mixture was stirred for reaction for 3 hours. Then the reaction solution was carefully added to the aqueous sodium bicarbonate solution, and then extracted with ethyl acetate three times. The organic phases were combined, and column chromatography (PE:EA=1:1) was performed to obtain 90 mg of the product with a yield rate of 28%.

[0102] (3) Synthesis of compound H4: A compound H3 (70 mg, 0.13 mmol) was dissolved in 4 N HCl/MeOH, stirred at room temperature for 3 hours, and then spin-dried for the next step.

[0103] (4) Synthesis of Compound of Example 3: A compound H4 (65 mg, 0.13 mmol), TEA (triethylamine, 80 mg, 0.78 mmol) and DCM (10 mL) were added to a 20 mL single-necked flask, the temperature was lowered to 0° C. under nitrogen protection, a solution of acryloyl chloride (12 mg, 0.13 mmol) in DCM (2 mL) was added, and the reaction was carried out at this temperature for 0.5 hour. Aqueous sodium bicarbonate solution (20 mL) was added, extracted with DCM for three times, and the organic phases were combined, dried, and spin-dried to prepare and separate to obtain 10 mg of the product with a yield rate of 15%.

[0104] .sup.1HNMR: (CD.sub.3OD, 400 Hz) δ8.82 (s, 1 H) , 8.75 (s, 1 H), 8.57˜8.51 (m, 2 H), 7.36 (s, 1 H), 6.39˜6.24 (m, 2 H), 5.77˜5.74 (m, 1 H), 4.43˜4.40 (m, 2 H), 4.12˜4.09 (m, 5 H), 3.97˜3.90 (m, 1 H).

EXAMPLE 4

[0105] The compound of the present embodiment used as a kinase inhibitor has the structural formula as follows:

##STR00063##

[0106] The synthetic route is as follows:

##STR00064##

[0107] The experiment process is as follows:

[0108] (1) Synthesis of compound H11: A compound H2 (52 mg, 0.1 mmol) was dissolved in 4 N HCl/MeOH, stirred at room temperature for 3 hours, and then spin-dried for the next step.

[0109] (2) Synthesis of Compound of Example 4: A compound H11 (52 mg, 0.1 mmol), TEA (60 mg, 0.6 mmol) and DCM (10 mL) were added to a 20 mL single-necked flask, and the temperature was lowered to 0° C. under nitrogen protection, added with acryloyl chloride (9 mg, 0.1 mmol) in DCM (2 mL), reacted at this temperature for 0.5 hour, added with aqueous sodium bicarbonate (20 mL), and extracted with DCM for three times. The organic phases were combined, dried, spin-dried, and 15 mg of product with a yield rate of 21% was obtained through preparative chromatographic and separation.

[0110] .sup.1HNMR: (CD.sub.3OD, 400 Hz) δ9.02 (s, 1 H), 8.75 (s, 1 H), 8.57˜8.51 (m, 2 H), 7.38 (s, 1 H), 6.39˜6.27 (m, 2 H), 5.77˜5.74 (m, 1 H), 4.54˜4.50 (m, 2 H), 4.35˜4.30 (m, 3 H), 4.18 (s, 3 H).

EXAMPLE 5

[0111] The compound used as a kinase inhibitor in this example has the structural formula as follows:

##STR00065##

[0112] The synthetic route is as follows:

##STR00066##

[0113] The experiment process is as follows:

[0114] (1) Synthesis of compound H5: In a 100 mL three-necked flask, a compound intermediate 1 (1.242 g, 3 mmol) and anhydrous THF (30 mL) were added thereto, then added with NaH (0.48 g, 9 mmol), cooled to −78° C., and added with n-butyllithium (1.44 mL, 3.6 mmol) under nitrogen protection; the mixture was stirred at this temperature for reaction for 1 hour, after which a compound A-2 (0.978 g, 3.6 mmol) was dissolved in anhydrous THF (5 mL), and was slowly added to the reaction solution at −78° C. After the dropwise addition was completed, the mixture was naturally raised to room temperature and stirred and kept overnight. Aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and extracted for three times with ethyl acetate (30 mL). The organic phases were combined, dried, and purified by column chromatography (PE:EA=1:1) to obtain 0.51 g of product with a yield rate of 23%.

[0115] .sup.1HNMR: (CDCl.sub.3, 400 Hz) δ8.75 (s, 1 H), 8.44 (t, J=8.4 Hz, 1 H), 8.11 (s, 1 H), 7.58 (s, 1 H), 7.35˜7.32 (m, 2 H), 4.13˜4.06 (m, 5 H), 3.47˜3.40 (m, 1 H), 2.90˜2.83 (m, 2 H), 1.88˜1.83 (m, 2 H), 1.65˜1.60 (m, 2 H), 1.46 (s, 9 H).

[0116] (2) Synthesis of compound H6: A compound H5 (0.5 g, 0.91 mmol), BAST (5 mL), DCM (5 mL) were added to a 20 mL single-necked flask, and the temperature was raised to 45° C. under nitrogen protection, stirred and reacted for 4.5 hours. The reaction solution was carefully added to aqueous sodium bicarbonate solution, then extracted with ethyl acetate for three times. The organic phases were combined, and 50 mg of the product with a yield rate of 10% was obtained through column chromatography (PE:EA=1:1).

[0117] (3) Synthesis of compound H7: A compound H6 (50 mg, 0.1 mmol) was dissolved in 4 N HCl/MeOH, stirred at room temperature for 3 hours, and then spin-dried to proceed to the next step.

[0118] (4) Synthesis of Compound of Example 5: A compound H7 (45 mg, 0.1 mmol), TEA (60 mg, 0.6 mmol) and DCM (10 mL) were added to a 20 mL single-neck flask, and the temperature was lowered to 0° C. under nitrogen protection, added with acryloyl chloride (9 mg, 0.1 mmol) in DCM (2 mL), and reacted at this temperature for 0.5 hour, added with aqueous sodium bicarbonate (20 mL), and extracted for three times with DCM. The organic phases were combined, dried, and spin-dried, and 8 mg of the product with a yield rate of 12% was obtained through preparative chromatography and separation.

[0119] .sup.1HNMR: (CD.sub.3OD, 400 Hz) δ8.75 (s, 1 H), 8.70 (s, 1 H), 8.53˜8.50 (m, 2 H), 7.36 (s, 1 H), 6.79˜6.73 (m, 1 H), 6.21˜6.16 (m, 1 H), 5.75˜5.72 (m, 1 H), 4.23˜4.18 (m, 1 H), 4.12˜4.09 (m, 1 H), 3.34 (s, 3 H), 3.17˜2.89 (m, 3 H), 1.83˜1.68 (m, 2 H), 1.55˜1.46 (m, 2 H).

EXAMPLE 6

[0120] The compound used as a kinase inhibitor in this example has the structural formula as follows:

##STR00067##

[0121] The synthetic route is as follows:

##STR00068##

[0122] The experiment process is as follows:

[0123] (1) Synthesis of compound H12: A compound H5 (55 mg, 0.1 mmol) was dissolved in 4 N HCl/MeOH, stirred at room temperature for 3 hours, and then spin-dried for the next step.

[0124] (2) Synthesis of Compound of Example 6: A compound H12 (52 mg, 0.1 mmol), TEA (60 mg, 0.6 mmol) and DCM (10 mL) were added to a 20 mL single-neck flask, and the temperature was lowered to 0° C. under nitrogen protection, added with acryloyl chloride (9 mg, 0.1 mmol) in DCM (2 mL), reacted at this temperature for 0.5 hour, added with aqueous sodium bicarbonate (20 mL), and extracted for three times with DCM. The organic phases were combined, dried, spin-dried, and 10 mg of product with a yield rate of 20% was obtained through preparative chromatographic and separation.

[0125] .sup.1HNMR: (CD.sub.3OD, 400 Hz) δ8.77 (s, 1H), 8.68 (s, 1 H), 7.55˜7.50 (m, 2 H), 7.37 (s, 1 H), 6.81˜6.74 (m, 1 H), 6.21˜6.17 (m, 1 H), 6.75˜6.72 (m, 1 H), 4.48˜4.45 (m, 2 H), 4.16˜4.11 (m, 5 H), 3.63˜3.57 (m, 1 H), 3.57˜3.50 (m, 1 H), 3.05˜2.94 (m,1 H), 2.01˜195 (m, 2 H), 1.67˜1.60 (m, 2 H).

EXAMPLE 7

[0126] The compound used as a kinase inhibitor in this example has the structural formula as follows:

##STR00069##

[0127] The synthetic route is as follows:

##STR00070##

[0128] The experiment process is as follows:

[0129] (1) Synthesis of compound EH-006D: A 25 mL single-necked bottle was taken and added with an intermediate 3 (273.9 mg, 0.77 mmol) and an intermediate 2 (236 mg, 0.77 mmol) thereto, and then added with anhydrous potassium carbonate (320.7 mg, 2.32 mmol) and DMF (11 mL). The mixture was placed in an oil bath at 85° C. for heating, stirring and reacting overnight, the solvent was evaporated to dryness under reduced pressure, water (70 mL) and ethyl acetate (50 mL) were added to the residue. The mixture was stirred and separated to collect the organic phase, and the aqueous phase was extracted once with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product was subjected to column chromatography (PE:EA=1:1) to obtain a white solid EH-006D (169 mg) with a yield rate of 38.9%.

[0130] (2) Synthesis of compound EH-006E: A 50mL single-necked bottle was taken and added with EH-006D (169 mg, 0.30 mmol) and methanol (6 mL) thereto, but the mixture could not be completely dissolved, then added with concentrated hydrochloric acid (6mL, 37%) at room temperature, so that the solid was completely dissolved to obtain a yellow solution. The yellow solution was stirred at room temperature for 2 hours and the solvent was evaporated to dryness to obtain a yellow powder EH-006E (160 mg) with a yield rate of 99.3%.

[0131] (3) Synthesis of Compound of Example 7: A 50 mL three-necked flask was taken and added with EH-006E (160 mg, 0.30 mmol), sodium bicarbonate (150.7 mg, 1.79 mmol), THF (4 mL) and pure water (4 mL). The reaction solution was cooled in an ice bath to about 4° C. under nitrogen protection. Under this condition, a solution of acryloyl chloride (40.6 mg, 0.45 mmol) in THF (3 mL) was added to the reaction solution with a syringe, and the ice bath was removed after the addition. The reaction solution was stirred at room temperature, reacted and kept overnight, the pH value of the mixture was adjusted to about 8 with solid sodium bicarbonate, and ethyl acetate (50 mL) and water (50 mL) were added thereto. The organic phase was collected by separation, and the aqueous phase was extracted with ethyl acetate (40 mL). The combined organic phases were dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, and the residue was subjected to column chromatography (ethyl acetate as the mobile phase) to obtain a white solid compound Example 7 (53 mg), which was purified through preparative chromatography to obtain 15.7 mg of Example 7-P1 and Example 7-P2 in total with a yield rate of 10.2%.

[0132] .sup.1HNMR: (CDCl.sub.3, 400 Hz) δ11.23 (s, 1 H), 8.40 (s, 1 H), 1.88 (s, 1 H), 7.35˜7.30 (m, 2 H), 7.25˜7.21 (m, 1 H), 6.43˜6.37 (m, 1 H), 6.31˜6.27 (m, 1 H), 5.68˜5.66 (d, J=8 Hz, 1 H), 5.12 (s, 1 H), 3.98 (s, 3 H), 3.79˜3.70 (m, 2 H), 3.43˜3.41 (m, 2 H), 3.05˜2.94 (m, 2 H), 2.29˜2.21 (m, 2 H), 2.04˜1.98 (m, 2 H).

EXAMPLES 8-22

[0133] The compounds of Examples 8-22 used as kinase inhibitors have the structural formulae as listed in Table 1 below, respectively.

TABLE-US-00001 TABLE 1 Compounds of Examples 8-22 Used as Kinase Inhibitors No. of Characterization Example Structural formulae Preparation process results 8 [00071] With reference to Example 7, the intermediate 3 in the first step was replaced with [M + H].sup.+ 519.1/521.1 [00072] 9 [00073] With reference to Example 6, H5 in the first step was replaced with [M + H].sup.+ 515.1/517.1 [00074] 10 [00075] Referring to Example 1, the raw material 7 in the first step was replaced with [M + H].sup.+ 489.1/491.1 [00076] 11 [00077] With reference to Example 6, H5 in the first step was replaced with [M + H].sup.+ 529.1/531.1 [00078] 12 [00079] With reference to Example 5, A-2 in the first step was replaced with [M + H].sup.+ 511.1/513.1 [00080] 13 [00081] With reference to Example 7, the intermediate 2 in the first step was replaced with [M + H].sup.+ 503.1/505.1 [00082] 14 [00083] With reference to Example 7, the intermediate 3 in the first step was replaced with [M + H].sup.+ 543.1/545.1 [00084] 15 [00085] With reference to Example 7, the intermediate 3 in the first step was replaced with [M + H].sup.+ 587.2/589.2 [00086] 16 [00087] With reference to Example 7, the intermediate 3 in the first step was replaced with [M + H].sup.+ 561.1.1/563.1 [00088] 17 [00089] With reference to Example 7, the intermediate 3 in the first step was replaced with [M + H].sup.+ 630.2/632.2 [00090] 18 [00091] With reference to Example 7, the intermediate 3 in the first step was replaced with [M + H].sup.+ 586.2/588.2 [00092] 19 [00093] With reference to Example 7, the intermediate 3 in the first step was replaced with [M + H].sup.+ 600.2/602.2 [00094] 20 [00095] Referring to Example 1, the raw material 7 in the first step was replaced with [M + H].sup.+ 476.1/478.1 [00096] 21 [00097] Example 20 was obtained through chiral preparative chromatography and separation [M + H].sup.+ 476.1/478.1 22 [00098] Example 20 was obtained through chiral preparative chromatography and separation [M + H].sup.+ 476.1/478.1

[0134] 2. In Application Example, the following biological activity test is used to describe the inhibitory activity of the compounds involved in the present disclosure on EGFR exon 20 insertion mutation.

[0135] The kinase activity assay was utilized to screen the activity of the compounds prepared in the example on the EGFR exon 20 insertion mutant kinase at the concentration of ATP Km, and staurosporine was adopted as a reference substance. Screening of biological activity of compounds will be performed in duplicate at 10 concentrations.

[0136] 1. Test sample

[0137] Each sample was prepared as a solution with a concentration of 10 mM.

[0138] 2. Experimental Method

[0139] 1) Basic buffer solution and quench buffer solution for experimental kinases were prepared.

[0140] 20 mMHepes (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.

[0141] 2) Compounds for experimental kinases were prepared.

[0142] Compounds for test were dissolved to specific concentrations in 100% dimethyl sulfoxide. (Serial) dilutions were performed with Integra Viaflo Assist assisted DMSO.

[0143] 3) Reaction Steps

[0144] The kinase was added to freshly prepared basic reaction buffer, and any desired cofactors were added to the above substrate solution.

[0145] The EGFR exon 20 insertion mutant kinase was added to the substrate solution and mixed gently; the compound in 100% dimethyl sulfoxide was fed into the kinase reaction mixture by using Acoustic technology (Echo550; nanoliter range) and incubated for 20 minutes at room temperature.

[0146] 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 the radioactivity was detected by the filter-binding method.

[0147] Kinase activity data are expressed as a percentage of remaining kinase activity in the test sample compared to the medium (dimethyl sulfoxide) reaction. IC.sub.50 values and curve fitting were obtained by using Prism (GRAPHPAD software).

[0148] The test results of the inhibitory activity (IC.sub.50 (nM) value) of the obtained test samples against EGFR exon 20 and Her2 exon20 insertion mutant kinases are shown in Table 2 and Table 3. In Table 2, A<4.0 nM, 4.0 nM≤B<40 nM, C≥40 nM; ND: not detected.

TABLE-US-00002 TABLE 2 Inhibitory activity of the compounds of the present disclosure on EGFR exon20 and Her2 exon20 insertion mutant kinases EGFR Her2 D770- A775- A763_Y764insFHEA N771insNPG G776insYVMA Compound IC50 (nM) IC50 (nM) IC50 (nM) Staurosporine C C C Poziotinib B A B Example 1 B A ND Example 2 A A ND Example 3 A A A Example 4 B A ND Example 5 A A A Example 6 B B ND Example 7 B A A Example 8 B B ND Example 9 B B B Example 10 A A ND Example 11 B B B Example 13 B A A Example 16 A A A Example 17 B A A

[0149] The specific IC.sub.50 values of some compounds of the present disclosure are shown in Table 3 below.

TABLE-US-00003 TABLE 3 Inhibitory activity of different compounds on EGFR exon 20 and Her2 exon20 insertion mutant kinases EGFR Her2 D770- A775- A763_Y764insFHEA N771insNPG G776insYVMA Compound IC50 (nM) IC50 (nM) IC50 (nM) Staurosporine 160.4 46.9 80.7  Poziotinib 4.27 0.943 4.79 Example 1 6.68 1.61 ND Example 2 3.03 1.65 ND Example 3 1.32 0.513 2.61 Example 4 11.8 3.04 ND Example 5 2.19 1.54 1.02 Example 6 16.2 4.51 ND Example 7 4.04 0.833 1.84 (ND: not detected)

[0150] As can be seen from the above table, through the in vitro biological activity screening and with staurosporine as the control group, the compounds we synthesized have good inhibitory ability on EGFR exon 20 insertion mutant kinase, most of which have the same inhibitory activity as poziotinib. Specifically, the activity of the compound of Example 3 was 2-3 times that of poziotinib. The inhibitory activity of the compound of Example 5 on Her2 insertion mutant kinase was about 4 times that of poziotinib, and therefore the compound is highly expected to be further developed as a drug for modulating the activity of EGFR exon 20 insertion mutant kinase or treating diseases related to EGFR exon 20 insertion mutant kinase. Specifically, in the preparation of medicines, the medicines may be prepared in conventional forms such as capsules or tablets.